WO2002062766A2 - Melanocortin-4 receptor binding compounds and methods of use thereof - Google Patents

Melanocortin-4 receptor binding compounds and methods of use thereof Download PDF

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WO2002062766A2
WO2002062766A2 PCT/US2002/003566 US0203566W WO02062766A2 WO 2002062766 A2 WO2002062766 A2 WO 2002062766A2 US 0203566 W US0203566 W US 0203566W WO 02062766 A2 WO02062766 A2 WO 02062766A2
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phenyl
methoxy
bromo
tetrahydro
ethyl
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PCT/US2002/003566
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WO2002062766A3 (en
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Martin P. Maguire
Mingshi Dai
Tricia J. Vos
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Millennium Pharmaceuticals, Inc.
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Priority claimed from US09/778,468 external-priority patent/US6699873B1/en
Application filed by Millennium Pharmaceuticals, Inc. filed Critical Millennium Pharmaceuticals, Inc.
Priority to EP02718920A priority Critical patent/EP1363890A4/en
Publication of WO2002062766A2 publication Critical patent/WO2002062766A2/en
Publication of WO2002062766A3 publication Critical patent/WO2002062766A3/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Melanocortins are known to have a broad array of physiological actions (Nakanishi, et al. Nature (1979) 278:423-427). Aside from their well known effects on adrenal cortical functions and on melanocytes, melanocortins have been shown to affect behavior, learning, memory, control ofthe cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev. Exp. Pathol
  • melanocortins have been identified to have immunomodulatory and neurotrophic properties, and to be involved in events surrounding partition (Cannon, J.G. et al. J. Immunol. (1986) 137:2232-2236; Gispen, W.H. Trends Pharm. Sci. (1992) 11 :221-222; Wilson, J.F. Clin. Endocrinol. (1982) 17:233-242; Clark, D. et al. N ⁇ twre (1978) 273:163-164; Silman, R.E. et al.
  • melanocortins are present in a myriad of normal human tissues including the brain, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, J.B. et al. Endocrinol. (1987) 121 :1900-1907; Mountjoy, K.G. et al. Science (1992) 257:1248- 1251; Chhajlani, V. et al., FEBS Lett. (1992) 309:417-420; Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250; Gantz, L. et al, J.
  • the melanocortin-2 receptor (MC2-R or ACTH receptor) is found in the adrenal glands where it mediates the effects of ACTH (adrenocorticotrophic hormone).
  • the melanocortin-3 receptor (MC3-R) is primarily found in the central nervous system (CNS) (Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250), but its physiological function is still unknown.
  • the melanocortin-4 receptor (MC4-R) has been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L. et al. J. Biol. Chem.
  • MC4-R has recently been related to weight homeostasis. MC4-R "knock out" mice have been shown to develop obesity (Huszar et al. Cell (1997) 88:131-141). The feeding behavior leading to the obesity can be inhibited by injection of MSH peptides (Vergoni et al. Neuropeptides (1986) 7:153- 158; Vergoni et al. Eur. J. Pharmacol. (1990) 179:347-355; Fan et al. N ⁇ twre (1997) 385:165-168).
  • MSH peptides The melanocortin-5 receptor (MC5-R) has a wide peripheral distribution and is believed to participate in the regulation ofthe exocrine gland function (Chen et al. Cell (1997) 91 :789-798).
  • the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal.
  • the method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the MC4-R binding compound is ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
  • the MC4-R binding compound is ofthe formula (II):
  • B-A-E (II) wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
  • the invention pertains to another method for treating an MC4-R associated state in a mammal, by administering to a mammal an effective amount of a MC4-R binding compound of formula (III) :
  • B is an anchor moiety
  • L ⁇ and L 2 are linking moieties
  • A is a cyclic moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • the invention also pertains to treating MC4-R associated states with an MC4-R binding compound of formula III, wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; Li is a covalent bond, C ⁇ -C ⁇ 0 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, amino
  • the invention pertains to a method for treating an MC4- R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the compound is ofthe formula (IV):
  • B is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl;
  • A is aryl, heteroaryl, biaryl, cycloalkyl, heterocyclic, or cycloalkenyl;
  • Li and L 2 are selected from the group consisting of a covalent bond, C ⁇ -C 6 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H;
  • t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H;
  • s is CHR 5 , CR 5 , CR 5 R 6 or absent (e.g., leaving a non- cyclic diamine);
  • R is H, substituted or unsubstituted alkyl,
  • compositions for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound ofthe formula (V):
  • B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro;
  • Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl
  • the invention also pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, wherein the compound is an MC4-R antagonist, and is ofthe formula (VI):
  • p i p 2 ⁇ p 3 an( j p 4 ⁇ g optionally substituted carbon, sulfur, or nitrogen, and wherein one of P 1 , P 2 , P 3 and P 4 may represent a covalent bond;
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are optionally substituted carbon or nitrogen;
  • Li is a covalent bond, Cj-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and
  • J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
  • the MC4-R binding compound is of formula (VII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • the MC4-R binding compound is of formula (VIII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • the invention also pertains to MC4-R binding compound ofthe formula (IX):
  • P 2 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
  • P 3 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • P 4 is CH, CC1, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a sulfur atom
  • G 1 and G 2 are each independently CH 2 , S, or O; r is a covalent bond or CH 2 ; t is CH 2 , CHR 3 , or CR 3 R 4 ; s is CH 2 , CHR 5 or CR 5 R 6 ;
  • R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl;
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring;
  • Z 2 is CH, C-(C ⁇ CH), CC1, CBr, CI, CF, or covalently linked to Z 1 to form a naphthyl ring;
  • Z 5 is CH, C-alkoxy or C-OMe
  • R 3 , R 4 , R 5 , and R 6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
  • the invention also features a pharmaceutical composition for the treatment of a
  • compositions contain a pharmaceutically acceptable carrier and a MC4-R binding compound.
  • the compounds are described herein in the context ofthe description ofthe method but it should be understood that the invention further pertains to pharmaceutical compositions containing the compounds and the compounds per se.
  • pharmaceutical compositions ofthe invention include a pharmaceutically acceptable carrier and an effective amount of at least one MC4-R binding compound ofthe formula (I):
  • B-Z-E (I) wherein B is an anchor moiety, Z is an central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • Figures la and lb are bar graphs showing the effects of MT II (a MC4-R agonist) on food intake in lean mice.
  • Figure 2 is a graph depicting the effects of treating lean mice with Compound N and MT II on food intake over a six hour period.
  • Figure 3 is a graph depicting the effects of treating lean mice with Compound O and MT II on food intake over a six hour period.
  • the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal.
  • the method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the MC4-R binding compound is ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • MC4-R includes receptors for ⁇ -melanocyte stimulating hormone.
  • the MC4-R is usually found in the brain where it is widely distributed (Mountjoy et al. Mol. Endocrinol. (1994) 8:1298-1308).
  • Melanocortins are peptide hormones that play an important role in regulating melanocyte pigmentation as well as memory and thermoregulation. They consist of various peptides, such as ⁇ -melanocyte stimulating hormone, that are cleaved from the polypeptide precursor prooptiomelanocortin (POMC).
  • POMC prooptiomelanocortin
  • the effects of melanocortins are mediated via stimulation of adenylate cyclase via the activation ofthe melanocortin receptors.
  • the melancortin-4 receptor (MC4-R) is a G-protein coupled receptor (GPCR) expressed in brain tissue.
  • GPCR G-protein coupled receptor
  • the specific role ofthe MC4-R protein in vivo was investigated by engineering MC4-R "knock out" mice. The mice were unable to produce functional MC4-R protein, because the endogenous MC4-R gene coding sequence was deleted. The knock-out mice were produced by using human MC4-r gene sequences to isolate and clone the murine MC4-r gene. A murine MC4-r targeting construct was then generated which was designed to delete the majority ofthe murine MC4-r coding sequence upon homologous recombination with the endogenous murine MC4-r gene.
  • Embryonic stem (ES) cells containing the disrupted MC4-r gene were produced, isolated and microinjected into murine blastocysts to yield mice chimeric for cells containing a disrupted MC4-r gene.
  • Offspring ofthe chimeric mice resulting from germline transmission ofthe ES genome were obtained and animals heterozygous for the disrupted MC4-R were identified.
  • the animals heterozygous for the MC4-r disrupted gene were bred together, producing litters containing wild-type mice, mice heterozygous for the MC4-r mutation and mice homozygous for the MC4-R mutation. The weight gain ofthe animals was monitored regularly.
  • mice heterozygous null MC4-R mutants showed an increase in weight compared to mice heterozygous for MC4-R deletion and wild type mice as early as 25 days of age.
  • MC4-R deficient mice exhibited, on average, a 55-70% greater weight relative to wild type mice, and an approximately 50% greater weight compared to mice heterozygous for the MC4-R deletion.
  • MC4-R associated states includes those states, disorders, or diseases characterized by aberrant or undesirable activity or expression of MC4-Rs. It also includes those states, disorders and diseases associated with MC4-R ligands (e.g., ⁇ -melanocyte stimulating hormone). The language also includes prevention of states, disorders and diseases characterized by aberrant or undesirable activity of MC4-Rs or its ligands. Examples of MC4-R associated states include, but are not limited to, disorders involving or associated with pigmentation, bones, and weight homeostasis, e.g., weight loss or obesity.
  • MC4-R associated states include the unhealthy decrease in body weight that can occur during an acute inflammatory response or that occurs in a cancer patient as a result of cachexia, radiotherapy or chemotherapy, or to the undesirable decrease in body mass due to simulated or actual weightlessness, such as occurs during space travel.
  • Other examples of unhealthy decreases in weight occur in some patients during advance stages of illnesses such as AIDS. Physiologically, this may be a result from any one of a number of complex factors, such as loss of appetite and possibly abnormal catabolism.
  • This cachexia may be slowed by MC4-R binding compounds.
  • the weight loss is a result of old age, anorexia nervosa, or cachexia (e.g., cachexia associated with cancer or HIV).
  • the MC4-R associated state is not weight loss.
  • the MC4-R associated disorder is a bone associated disorder.
  • MC4-R knockout mice have been shown to have enhanced bone thickness (Ducy et al. Science, (Sept., 2000) 289:1501-1504). Examples of bone associated disorders which may be treated with MC4-R binding compounds ofthe invention include disorders and states where the formation, repair or remodeling of bone is advantageous.
  • bone associated states include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e.g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism.
  • Bone associated disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the compounds of the invention.
  • MC4-R binding compound includes those compounds which interact with the MC4-R resulting in modulation of the activity ofthe MC4-R. In an embodiment, the MC4-R binding compounds are antagonists ofthe MC4-R.
  • the term "antagonist” includes compounds which interact with the MC4-R and modulate, e.g., inhibit or decrease, the ability of a second compound, e.g., ⁇ -melanocyte stimulating hormone or another MC4-R ligand, to interact with the MC4-R.
  • the MC4-R binding compounds is an agonist ofthe MC4-R.
  • agonists includes compounds which interact with the MCR-4 and modulate, e.g., increase or stimulate, its activity and/or its ability to interact with a second compounds, e.g., ⁇ -melanocyte stimulaturing hormone.
  • MC4-R binding compounds can be identified through both in vitro (e.g., cell and non-cell based) and in vivo methods. These methods are described in detail in Examples 2, 3, 4, and 5.
  • the Scincillation Proximity Assay is a non-cell based in vitro assay, described in Example 2. It can be used to identify compounds that interact with, e.g., bind to MC4-R. Such compounds may act as antagonists or agonists of MC4-R activity and may be used in the treatment of body weight disorders.
  • One example of a qualitative measure of binding affinity of a MC4-R binding compound to MC4-R is its IC 50.
  • the MC4-R binding compound binds to the MC4-R with a binding affinity, for example, of about 50 ⁇ M or less, 20 ⁇ M or less, 10 ⁇ M or less, 5 ⁇ M or less, 2.5 ⁇ M or less, or 1 ⁇ M or less.
  • the IC 50 of a MC4-R binding compounds is about 0.5 ⁇ M or less,, about 0.3 ⁇ M or less, about 0.1 ⁇ M or less, about 0.08 ⁇ M or less, about 0.06 ⁇ M or less, about 0.05 ⁇ M or less, about 0.04 ⁇ M or less, or, preferably, about 0.03 ⁇ M or less.
  • isolated membranes are used to identify compounds that interact with MC4-R.
  • 293 cells may be genetically engineered to express the MC4-R.
  • Membranes are be harvested by standard techniques and used in an in vitro binding assay.
  • I-labeled ligand e.g., I- labeled ⁇ -MSH, ⁇ -MSH, or ACTH
  • I-labeled ligand is bound to the membranes and assayed for specific activity; specific binding is determined by comparison with binding assays performed in the presence of excess unlabelled ligand.
  • membranes are incubated with labeled ligand in the presence or absence of test compound.
  • Compounds that bind to the receptor and compete with labeled ligand for binding to the membranes reduced the signal compared to the vehicle control samples.
  • the screens are designed to identify compounds that antagonize the interaction between MC4-R and MC4-R ligands such as ⁇ -MSH, ⁇ -MSH and ACTH.
  • the MC4-R ligands are labeled and test compounds can be assayed for their ability to antagonize the binding of labeled ligand to MC4-R.
  • Cell based assay systems can also be used to identify MC4-R binding compounds.
  • An example of a cell based assay system is the cAMP assay described in detail in Example 3.
  • Cell based methods may use cells that endogenously express MC4- R for screening compounds which bind to MC4-R.
  • cell lines such as 293 cells, COS cells, CHO cells, fibroblasts, and the like, genetically engineered to express the MC4-R can also be used for screening purposes.
  • host cells genetically engineered to express a functional receptor that responds to activation by melanocortin peptides can be used as an endpoint in the assay; e.g., as measured by a chemical, physiological, biological, or phenotypic change, induction of a host cell gene or a reporter gene, change in cAMP levels, adenylyl cyclase activity, host cell G protein activity, extracellular acidification rate, host cell kinase activity, proliferation, differentiation, etc.
  • the host cells expressing functional MC4-R should give a significant response to MC4-R ligand, preferably greater than 5 -fold induction over background.
  • Host cells should preferably possess a number of characteristics, depending on the readout, to maximize the inductive response by melanocortin peptides, for example, for detecting a strong induction of a CRE reporter gene: (a) a low natural level of cAMP, (b) G proteins capable of interacting with the MC4-R, (c) a high level of adenylyl cyclase, (d) a high level of protein kinase A, (e) a low level of phosphodiesterases, and (f) a high level of c AMP response element binding protein would be advantageous.
  • host cells could be engineered to express a greater amount of favorable factors or a lesser amount of unfavorable factors.
  • alternative pathways for induction ofthe CRE reporter could be eliminated to reduce basal levels.
  • the cells expressing the melanocortin receptor are exposed to a test compound or to vehicle controls (e.g., placebos). After exposure, the cells can be assayed to measure the expression and/or activity of components ofthe signal transduction pathway ofthe melanocortin receptor, or the activity ofthe signal transduction pathway itself can be assayed. For example, after exposure, cell lysates can be assayed for induction of cAMP. The ability of a test compound to increase levels of cAMP, above those levels seen with cells treated with a vehicle control, indicates that the test compound induces signal transduction mediated by the melanocortin receptor expressed by the host cell.
  • vehicle controls e.g., placebos.
  • ligands that activate the MC4-R e.g., ⁇ -MSH, ⁇ -MSH or ACTH, to test for inhibition of signal transduction by the test compound as compared to vehicle controls.
  • the assays described above may be conducted using a panel of host cells, each genetically engineered to express one ofthe melanocortin receptors (MC1-R through MC5-R). Expression ofthe human melanocortin receptors is preferred for drug discovery purposes.
  • host cells can be genetically engineered to express any ofthe amino acid sequences shown for melanocortin receptors 1 through 5.
  • MC1-R and MC2-R Mountjoy., 1992, Science 257: 1248-1251 ; Chhajlani & Wikberg, 1992 FEBS Lett. 309: 417-420
  • MC3-R Roselli-Rehfuss et al., 1993, Proc. Natl. Acad. Sci., USA 90: 8856-8860; Gantz et al., 1993, J. Biol. Chem. 268: 8246-8250
  • MC4-R Gantz et al., 1993, J. Biol. Chem. 268: 15174-15179; Mountjoy et al., 1994, Mol.
  • the activation, or inhibition of MC4- R activation is compared to the effect ofthe test compound on the other melanocortin receptors.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than at least one other MC receptors, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC1-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC3-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective. In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC5-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R receptor than at least one, two or three other MC receptors (such as, for example, MC1-R, MC3-R, or MC5-R).
  • the MC4-R binding compounds are more selective for the MC4-R than MC1-R, MC3-R, and MC5-R.
  • the MC4-R binding compounds as at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective for the MC4-R than the MC 1 -R, MC3-R and the MC5-R.
  • the MC4-R binding compound includes compounds ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety
  • anchor moiety includes moieties which interact with the
  • anchor moieties include substituted or unsubstituted alkyl (e.g., branched, straight chain, or cyclic (e.g., cyclohexane, cyclopentane)), alkenyl, alkynyl, aryl (e.g., substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracenyl, fluorenyl, etc.), heterocyclic (e.g., thienyl, morpholinyl, piprazinyl, piperidinyl, etc.), and multicyclic (e.g., indolyl, benzothioenyl, etc.) moieties.
  • Other examples of anchor moieties include carbonyl moieties, thiol groups, cyano groups, amino groups, and hydrogen atoms.
  • the anchor moiety includes substituted or unsubstituted carbocyclic aryl moieties, e.g., phenyl, naphthyl, etc.
  • substituents include halogens (e.g., fluorine, chlorine, iodine, bromine, etc.), alkoxy (e.g., methoxy, ethoxy, isopropoxy, n-propyloxy, n-butyloxy, pentoxy, cyclopentoxy, arylalkyloxy, etc.) hydroxy, alkylcarbonyl, cyano, nitro, thiol, thioether, thioalkyl, alkenyl, alkynyl (e.g., ethynyl, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkoxycarbonyl, aminocarbony
  • the anchor moiety substituent can be substituted itself with one or more halogen, nitro, alkyl, alkenyl, alkynyl, aryl or alkoxy groups, or combinations thereof.
  • the aryl moiety is fused to another ring which can be substituted or unsubstituted, carbocyclic or heterocyclic, aromatic or non-aromatic.
  • the anchor moiety is substituted with at least one halogen, alkoxy group, or alkyl (e.g., substituted or unsubstituted) group.
  • halogen substituted phenyl anchor moieties include ⁇ -iodophenyl, w-iodophenyl, o- bromophenyl, m-bromophenyl, o-chlorophenyl, m-chlorophenyl, ⁇ -fluorophenyl, m- fluorophenyl, ⁇ -fluorophenyl, w-nitrophenyl, or o-methoxy.
  • the anchor moiety may also comprise more than one substituent, e.g.
  • anchor moieties include 2-methoxy-5- bromophenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-iodophenyl, 2-methoxy-5- fluorophenyl, 2-ethoxy-5-bromophenyl, 2-methoxy-6-bromophenyl, 3-methoxy-6- bromophenyl, 2-isopropyl-5-bromophenyl, 2- «-propyl-5-bromophenyl, and 2- cyclopentyloxy-5-bromophenyl.
  • anchor moieties include, but are not limited to, 2-methoxy-5- cyanophenyl, 2-chloro-5-chlorophenyl, 2-methoxy-6-methoxyphenyl, 2-methoxy-5- nitrophenyl, 2-methoxy-5 -phenyl phenyl, 2-methoxy-5-3'-thiofuranyl phenyl, 2- methoxy-5-methylcarbonyl phenyl, 3,5-dimethyloxy phenyl, 2-methoxyphenyl, 2,5- dimethoxy phenyl, 2-fluoro-6-chlorophenyl, and 3-chloro-4-fluorophenyl.
  • the anchor moiety includes substituted and unsubstituted heterocycles.
  • heterocycles include, but are not limited to, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, deazapurinyl, morpholine, piprazine, piperidine, thiomorpholine, and thioazolidine.
  • substituents include alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonyla
  • the anchor moiety is a substituted or unsubstituted fused aryl or biaryl moiety.
  • Biaryl moieties include moieties with two or more aromatic rings, which may be fused or connected through one or more covalent bonds. Examples include biphenyl, fluorene, anthracenyl, benzoquinazolinyl, and naphthyl.
  • substituents of biaryl moieties include alkyl (e.g., substituted and unsubstituted, branched or straight chain, methyl, ethyl, propyl, butyl, pentyl, etc.), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, cyclopentoxy, etc.), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamin
  • Biaryl moieties also include moieties which comprise one or more heterocycles, such as, benzothiofuranyl, benzothienyl, quinolinyl, benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, and indolyl.
  • heterocycles such as, benzothiofuranyl, benzothienyl, quinolinyl, benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, and indolyl.
  • biaryl anchor moieties include naphthyl, 2-methoxynaphthyl, 2-methoxy-5-phenyl phenyl, 2-ethoxynaphthyl, 2-methoxy-5-thiofuranyl phenyl, 2-methyl naphthyl, 2-n- propyl naphthyl, benxothiofuranyl, 2-phenyl phenyl, 2-methoxy-5-4'methoxy-phenyl phenyl; 2-methoxy-5-(3'-fluoro-4'-phenyl) phenyl phenyl; 2-cyclopentoxynaphthyl; quinolinyl; and 2-methoxy-5-(3'-chloro-4'fluoro)phenyl phenyl.
  • the anchor moiety can be multicyclic and comprise a combination of one or more aromatic, non-aromatic, heterocyclic, and heteroaryl rings, which can be fused, bridged, or linked together through covalent bonds.
  • the multicyclic anchor moiety may also be substituted with substituents such as alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato
  • central moiety includes moieties which covalently attach the anchor moiety to the MC4-R interacting moiety.
  • central moieties include cyclic moieties, optionally substituted amines (e.g., tertiary amino, aminoalkylamino, dialkylaminoalkylamino, aminocarbonylamino, aminocarbonylamino; arylaminocarbonylamino groups; arylaminothiocarbonylamino), optionally substituted alkyl groups (e.g., carbon atoms with substituted or unsubstituted alkyl, aryl (e.g., phenyl, naphthyl), heterocyclic moieties (e.g., morpholinyl, piprazinyl, etc.), and carbonyl groups, etc.
  • cyclic moieties e.g., optionally substituted amines (e.g., tertiary amino, aminoalkylamino, dialkylaminoalky
  • substituents ofthe central moiety include, for example, alkyl (e.g., straight, branched or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromefhoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate
  • central moiety may further comprise one or more linking moieties.
  • the linking moieties may covalently link the cyclic moiety to the anchor moiety and/or the MC4-R interacting moiety.
  • central moiety also includes moieties ofthe formula (XII):
  • ⁇ is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl
  • L 3 is a covalent bond, C ⁇ -C branched, unbranched or cyclic alkyl(wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl moiety;
  • A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and ⁇ is 0, 1 or 2.
  • ⁇ is a carbon or nitrogen atom.
  • ⁇ is alkyl, carbocyclic, heterocyclic (e.g., piprazinyl, morphonlinyl, piperidinyl, etc.).
  • A is heterocyclic (e.g., non-aromatic, e.g., substituted or unsubstituted, bridged, fused, or monocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. or aromatic, e.g., pyridinyl, pyrimidinyl, pyrrolyl, etc.), aryl e.g., phenyl, naphthyl) or amino (e.g., substituted or unsubstituted, e.g., alkylamino, dialkyl amino, etc.).
  • heterocyclic e.g., non-aromatic, e.g., substituted or unsubstituted, bridged, fused, or monocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. or aromatic, e.g., pyridinyl, pyr
  • cyclic moiety includes heterocyclic and carbocyclic groups, such as substituted or unsubstituted phenyl, heteroaryl, or biaryl moieties.
  • cyclic moieties include those without aromaticity (e.g., cyclohexane, cyclopentane, etc.) and those with aromaticity, e.g. moieties that have at least one aromatic ring.
  • Cyclic moieties may include one or more heteroatoms.
  • Examples include phenyl, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthyl, quinolyl, indolyl, and the like.
  • the cyclic moiety can be substituted at one or more ring positions with such substituents such as, for example, alkyl (e.g., substituted or unsubstituted methyl, ethyl, propyl, butyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), aryloxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alky
  • the cyclic moiety ofthe present invention is substituted or unsubstituted phenyl, heteroaryl, or biaryl.
  • the language "cyclic moiety” also includes non-aromatic cyclic moieties, such as, substituted or unsubstituted cyclic alkanes, (e.g., cyclohexane, and cyclopentane), cyclic alkenes (e.g., cyclohexene), and substituted or unsubstituted heterocycles (e.g., thiofuran, pyrimidine, pyrazine, pyrrole, imidazole, quinoxaline, etc.).
  • cyclic moiety comprises not only the heterocyclic or carbocyclic moieties, but also may additionally include moieties which further comprise linking moieties, such as Lj and L 2 which, for example, may link the anchor moiety to the carbocyclic or heterocyclic cyclic portion ofthe cyclic moiety. Furthermore, linking moieties may also link the heterocyclic or carbocyclic cyclic moiety to the MC4-R interacting moiety.
  • cyclic moieties include unsubstituted phenyl, halogenated phenyl (e.g., fluoro, bromo, chloro and iodo phenyl), alkyl substituted phenyl (e.g., methyl, ethyl, propyl, etc.),amino substituted phenyl, heteroaryls (e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.).
  • halogenated phenyl e.g., fluoro, bromo, chloro and iodo phenyl
  • alkyl substituted phenyl e.g., methyl, ethyl, propyl, etc.
  • amino substituted phenyl e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.
  • MC4-R interacting moiety (“E") includes moieties which permit the MC4-R binding compound to perform its intended function, e.g., interact with the MC4-R.
  • MC4-R interacting moieties include substituted or unsubstituted alkyl (e.g., substituted with amino, cyano, nitro, hydroxy, etc.), aryl (e.g., phenyl, heteroaryl), amino (e.g., 3-aminopropylamino, dimethyl amino, diethyl amino), amidino, guanidino, carbocyclic and heterocyclic moieties.
  • the language "MC4-R interacting moiety” is not intended to suggest that this moiety is the active pharmacophore ofthe molecule, responsible for the pharmacological, binding or other properties ofthe MC4-R binding compound.
  • the MC4-R interacting moiety is cyclic, e.g., aryl, alkyl, biaryl, polycyclic, heteroaromatic, or heterocyclic.
  • heterocyclic MC4-R interacting moieties include heterocycles which contain nitrogen atoms, such as, substituted and unsubstituted imidazolyl, imidazolinyl, pyridinyl, pyrrolyl, piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, pyrimidinyl, pyridinyl, morpholinyl, diazapanyl, and piperidinyl moieties.
  • the MC4-R interacting moiety may be bicyclic, polycyclic, bridged or a fused ring system. Examples of fused and bridged heterocycles include:
  • the substituent R includes substituted and unsubstituted alkyl (e.g., methyl, ethyl, etc.), arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, arylalkylcarbonyl, and other groups which allow the MC4-R interacting moiety to perform its intended function.
  • the MC4-R interacting moiety can be substituted with substituents such as, but not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, aminoalkyl, and alkylary
  • the MC4-R interacting moiety is not cyclic, e.g., the MC4-R interacting moiety is alkyl, unsubstituted amino, alkylamino, dialkylamino, amidino, guanidino, etc.
  • alkyl MC4-R interacting moieties include straight and branched chain alkyls such as n-butyl, n-pentyl, and n-hexyl.
  • the MC4-R interacting moiety contains one or more nitrogen atoms, e.g., pyridinyl, pyrrolyl, pyrazinyl, imidazolyl, imidazolinyl, quinoxalinyl, or pyrimidinyl.
  • the MC4-R interacting moiety is ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 . or
  • R 6 to form one or more rings
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each substituted or unsubstituted alkyl, alkenyl, alkynyl, heterocyclic, halogen, thiol, thioether, thioalkyl, hydroxyl, nitro, amino, cyano, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring.
  • R 3 , R 4 , R 5 , or R 6 may be bridged, fused, or spiro.
  • the MC4-R interacting moiety is represented by the formula
  • the MC4-R interacting moiety may be bicyclic, e.g., biheterocyclic, for example, quinoxalinyl.
  • the language "linked to form a ring” refers to moieties covalently connected through a chain of atoms (e.g., carbon atoms and/or heteroatoms).
  • the chain of atoms can comprise any number of atoms, which allow the MC4-R binding moiety to perform its intended function.
  • the chain of atoms is selected such that a ring with three, four, five, six, seven, or eight members are formed.
  • the ring that can be formed may be spiro (e.g., connected through the same carbon atom), fused (connected through adjacent carbon atoms), or bridged (e.g., connected through carbon atoms which are neither identical nor adjacent).
  • R and t are linked, e.g., to for a bicyclic moiety.
  • bicyclic moieties include, but are not limited to, imidazopyridinyl, pyrolloimidazolyl, cyclopentaimidazolyl, pyridopyrimidinyl, etc.
  • R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy.
  • s is CR 5 R 6 and R 5 and R 6 are each methyl.
  • r is a covalent bond, and at least one oft and s are CH 2 .
  • t, r, and s are each CH 2 .
  • r is a covalent bond, and t and s are linked through a 4 carbon chain.
  • at least one R group is OH.
  • r is a covalent bond
  • t is CR 3 R 4
  • s is CR 5 R 6
  • R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • MC4-R interacting moieties include, but are not limited to, the following structures:
  • the invention pertains to a method for treating an MC4- R associated state in a mammal, by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • MC4-R binding compounds include compounds comprising the formula (II):
  • B is a anchor moiety; A is a cyclic moiety; and E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • the MC4-R binding compounds of formula (II), may further comprise linking moieties, Li and L 2 .
  • Such MC4-R binding compounds include compounds ofthe formula (III):
  • B is an anchor moiety (as described above), Li and L 2 are linking moieties, A is a cyclic moiety (as described above), and E is a MC4-R interacting moiety.
  • Pharmaceutically acceptable salts ofthe MC4-R binding compound are also included.
  • linking moiety includes moieties which link, preferably covalently, the MC4-R interacting moiety, the cyclic moiety, and the anchor moiety of the invention.
  • linking moieties include covalent bonds, 1-10 atom chains which may be branched or unbranched, substituted or unsubstituted alkyl, heterocyclic, alkenyl, or alkynyl. The chains may be substituted with 0-3 heteroatoms or other moieties which allow the MC4-R binding compound to perform its intended function. Examples of suitable heteroatoms include sulfur, oxygen, nitrogen, and phosphorous.
  • the invention contemplates MC4-R binding compounds which comprises more than two linking moieties.
  • ⁇ is a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms.
  • Lj is selected from the group consisting of a covalent bond, C ⁇ -C 6 , CrC 5 , C ⁇ -C 4 , C 1 -C 3 , C ⁇ - C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms.
  • Li is a thioether (e.g., -S-CH 2 -, S- CH(CH 3 )-, -CH 2 -S-CH 2 , -S-, or -S-CH-(C 6 H 5 )-.), an ether (e.g., -O-CH 2 or -CH 2 -O- CH 2 -), a sulfoxide, a sulfone, an amine (e.g., -NH-, -NH-CH 2 -, -NMe-CH 2 -, CH 2 -NH- CH 2 -, etc.) or alkyl (e.g., -CH 2 -CH 2 -, -CH 2 -, or -CH 2 -CH 2 -CH 2 - ).
  • a thioether e.g., -S-CH 2 -, S- CH(CH 3 )-, -CH 2 -S-CH 2 , -S-,
  • Li in another embodiment, comprises a sulfonyl group.
  • Li can be substituted or unsubstituted (e.g., a hydrogen can be replaced by another moiety), such that the MC4-R binding compound is capable of performing its intended function, e.g., bind to or interact with the MC4-R.
  • substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino),
  • examples of L 2 include a covalent bond, a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms.
  • ⁇ is selected from the group consisting of a covalent bond, CpC , C)-C 5 , C ⁇ -C 4 , C ⁇ -C 3 , Cj-C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms..
  • L 2 is a covalent bond, -CH 2 - or -NH-.
  • L 2 may also comprise one or more carbonyl groups.
  • L 2 can be substituted with any substituent such that the
  • MC4-R binding compound is capable of performing its intended function.
  • substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino
  • the MC4-R binding compound is of formula (III) (e.g., B-L ! -A-L 2 -E), wherein B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl
  • B is substitute
  • Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or more ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, thienyl, pyridinyl, etc.), bicyclic (e.g., methylenedioxyphenyl, isoindole, indole, and indan )or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, iso
  • Li is selected from the group consisting of a covalent bond, C ⁇ -C 6 , C ⁇ -C 5 , C 1 -C 4 , C 1 -C 3 , Ci- C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, substituted or unsubstituted amino (e.g., -NH-, -NH-CH 2 ), ether, thioether, or alkyl (e.g., C1-C10, -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -, etc.);
  • E is unsubstituted amino, unsubstituted and substituted alkylamino (e.g., 3- aminopropylamino), dialkylamino (e.g., dimethyl amino, diethyl amino), amidino, guanidino, heterocyclic (e.g., substituted and unsubstituted imidazolyl, imidazolinyl, piprazinyl, morpholinyl, piperidinyl, imidoazopyridinyl, pyrolloimidazolyl, pyridinyl, or pyrimidinyl) moieties, aryl (e.g., phenyl, heteroaromatic, e.g., substituted and unsubstituted pyrazinyl, imidazolyl, quinoxalinyl, or pyrimidinyl), wherein said substituents include, but are not limited to, amino (e.g., unsubstituted amino, alkylamin
  • the invention pertains to a method for treating an MC4-
  • the compound is ofthe formula (IV):
  • A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, pyridinyl, etc.), or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n- butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy
  • B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy,
  • Li and L 2 are selected from the group consisting of a covalent bond, C C 4 branched or unbranched, substituted or unsubstituted alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH 2 , CHR 1 , CR ⁇ 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CHR 5 , CR 5 R ⁇ or absent (e.g., leaving a non-cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, Li, or L ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each substituted or unsubstituted alkyl, halogen, thiol, thioether, thioalkyl, alkoxy, and may be optionally linked to each other to form additional ring moieties, e.g., quinoxalinyl.
  • Pharmaceutically acceptable salts of the MC4-R binding compounds are also included.
  • A is substituted or unsubstituted phenyl. Examples of substituents include halogens (e.g., fluorine, chlorine, iodine, bromine), alkoxy, alkyl (e.g., methyl, trifluoromethyl), and amino moieties.
  • A is heteroaromatic, (e.g., thienyl), or biaryl, (e.g., napthyl or quinoxalinyl).
  • biaryl e.g., napthyl or quinoxalinyl.
  • B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, thiol, thioether, thioalkyl, cyano, or nitro;
  • L ⁇ is a covalent bond, C ⁇ -C 10 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl;
  • ⁇ is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl;
  • L 3 is a covalent bond, C ⁇ -C 6 branched, unbranched or cyclic alkyl (wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or an aminothiocarbonyl moiety;
  • A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and ⁇ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
  • MC4-R binding compounds with this structure include, but are not limited to, compounds, wherein ⁇ is a carbon atom, L 3 is aminocarbonyloxy, A is substituted aryl, ⁇ is one, Li and L 2 are each CH 2 , and B and E are each pipridinyl.
  • substituents for A include but are not limited to, alkoxy (e.g., Ci-Cio alkoxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy), cyano, halogens (e.g., fluorine, chlorine, bromine, iodine), alkyl (e.g., straight or branched chain, etc.), aryl, alkenyl, alkynyl, nitro, amino, or any other substituents which enables the MC4-R binding compound to perform its intended function, e.g., treat an MC4-R associated state.
  • alkoxy e.g., Ci-Cio alkoxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy
  • compounds of formula (V) include, but are not limited to, compounds wherein ⁇ , L and L 3 together are a single covalent bond, E is alkyl, and B is substituted or unsubstituted heterocyclic.
  • ⁇ is a nitrogen atom
  • L 2 , Li and L 3 are each alkyl
  • E is substituted amino (e.g., alkyl substituted), or heterocyclic (e.g., piprazinyl, piperidinyl, morpholinyl, etc.)
  • B and A are each aryl (e.g., phenyl, anthracenyl, biaryl, e.g., naphthyl).
  • the invention pertains to yet another method for treating an MC4-R associated state in a mammal by administering to a mammal an effective amount of a
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are optionally substituted carbon or nitrogen;
  • L 1 is a covalent bond, Cj-C branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
  • substituents of P 1 , P , P 3 , P 4 , Z 1 , Z , Z , Z 4 , and Z 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n- propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substitute
  • P 1 , P 2 , P 3 , and P 4 are each substituted or unsubstituted carbon (e.g., CH).
  • P 1 and P 3 may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, CI, C-aryl, C-alkyl (e.g., C-Me, C-ethyl, C-propyl, etc.) C-alkoxy (e.g., C-OMe, C-O-ethyl, C-OCF 3, etc.).
  • P 2 is CH and P 4 is CCl or CF.
  • P 1 is a covalent bond
  • P 2 and P 3 are each optionally substituted carbon
  • P 4 is S (e.g., thienyl).
  • Z 3 and Z 4 are each CH.
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring.
  • Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • Z 2 may be substituted with a chain of atoms which covalently links it to Z 1 to form a naphthyl ring.
  • Z 5 examples include, but are not limited to, CH and C-alkoxy.
  • C- alkoxy includes carbon atoms covalently bound to an alkoxy group, as described below.
  • alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc.
  • L 2 is a covalent bond.
  • J examples include, but are not limited to, substituted or unsubstituted piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl, mo ⁇ holinyl, or piperidinyl. Furthermore, J may be a substituted or unsubstituted fused ring or bridged heterocycle.
  • each of P 1 , P 2 , P 3 , and P 4 are each optionally substituted carbon; Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each also optionally substituted carbon (e.g., alkoxy substituted, halogen substituted or linked to form a ring); wherein Li is either -S-CH -, or CH 2 -CH 2 .
  • L 2 is a covalent bond and J is a moiety of formula XIII, as described above.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, ⁇ , or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, ⁇ or substituted carbon.
  • substituents of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , P 1 , P 2 , P 3 , P 4 , and P 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsub
  • P 1 , P 2 , P 3 , P 4 and P 5 are each substituted or unsubstituted carbon (e.g., CH).
  • P and P may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, or CI.
  • P 1 , P 2 , P 3 , and P 4 can be linked covalently to form a bicyclic ring.
  • Z 3 and Z 4 are each CH.
  • Z is CH, or covalently linked to Z to form a naphthyl ring.
  • Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
  • P 5 is C-L 2 -J, wherein C is a carbon atom, L 2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group.
  • L is a covalent bond and J is a moiety of formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , alkenyl, CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • compounds of formula VII also include compounds
  • J is wherein R is alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) or hydrogen.
  • the compounds include those in which P 1 , P 2 , and P 3 are each CH, and P 4 is CCl.
  • the compounds also include those wherein Z 1 , Z 3 , and Z 4 are each CH, Z 5 is COMe, and Z 2 is CBr, as well as those wherein Z 1 is covalently linked to Z 2 to form a naphthyl ring, and Z 3 , Z 4 and Z 5 are each CH.
  • the MC4-R binding compound is of formula (VIII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; and P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • substituents of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , P 1 , P 2 , P 3 , P 4 , and P 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alky
  • P 1 , P 2 , P 3 , and P 4 are each substituted or unsubstituted carbon (e.g., CH).
  • P and P may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, or CI.
  • P 1 , P 2 , P 3 , and P 4 can be linked covalently to form a bicyclic ring.
  • Z 3 and Z 4 are each CH.
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring. Examples of Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF. 1
  • Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
  • P 5 is C-L 2 -J, wherein C is a carbon atom, L 2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group.
  • L 2 is a covalent bond and J is a moiety of formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , alkenyl, CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 j or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, aryl, hydroxyl, nitro, amino, cyano, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention pertains to MC4-R binding compounds of formulae VII and VIII.
  • Examples of MC4-R binding compound of these formulae include, for example, compounds wherein P 5 is a carbon covalently bonded to a moiety of formula XIII.
  • the moiety of formula XIII is not benzoimidazole.
  • Z 3 is not ethoxy.
  • the invention pertains to both methods of using and MC4-R binding compounds of formula (IX):
  • I P 2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
  • P 3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • P 4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • G 1 and G 2 are each independently CH 2 , S, or O
  • r is a covalent bond or CH 2
  • t is CH 2 , CHR 3 , or CR 3 R 4
  • s is CH 2 , CHR 5 or CR 5 R 6
  • R is hydrogen alkyl, alkoxycarbonyl, or alkylcarbonyl;
  • Z is CH, or covalently linked to Z to form a naphthyl ring
  • Z 2 is CH, C-(C ⁇ CH), CCl, CBr, CI, CF, or covalently linked to Z 1 to form a naphthyl ring;
  • Z 5 is CH, C-alkoxy (e.g., C-OMe);
  • R 3 , R 4 , R 5 , and R 6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, amino, or pharmaceutically acceptable salts thereof.
  • the language "linked to form a naphthyl ring” includes moieties which join Z 1 and Z 2 to form a naphthyl (fused) ring system.
  • Z 1 is CH; Z 2 is CBr; and Z 5 is C-OMe.
  • P 2 is CH.
  • P 4 is CCl or CF.
  • G' and G 2 are each CH 2 .
  • G 1 and G 2 together are -CH 2 -CH 2 -, -CH 2 -O-, -O-CH 2 -, -CH 2 -
  • r is a covalent bond
  • s is CR 5 R 6
  • t is CR 3 R 4
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • R is hydrogen or alkyl (e.g., methyl, ethyl, propyl or butyl, etc.)
  • Z , Z , Z , Z , and Z are CH, ⁇ , or substituted carbon
  • P ⁇ P 2 , P 3 , and P 4 are CH, ⁇ or substituted carbon
  • P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also relates to the invention.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C ⁇ -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent;
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 ; or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also relates to the invention.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and
  • P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR ⁇ 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent;
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also pertains to MC4-R binding compound ofthe formula (XVI):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and P 5 is C-L2-J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl
  • the invention includes compounds wherein P 1 , P 2 , P 3 , and P 4 of any one of formulas VII, VIII, XV, or XVI are each substituted or unsubstituted carbon.
  • P 1 is CH.
  • at least one of P 2 , P 3 and P 4 is a substituted carbon.
  • P 2 , P 3 and P 4 are selected from the group consisting of CH, CF, Cl, CBr, C-alkyl, C-alkoxy, or CI.
  • the compounds of formulae VII, VIII, XV, or XVI include compounds wherein Z 3 and Z 4 are each CH.
  • Z 1 is CH.
  • Z 1 is covalently linked to Z 2 to form a naphthyl ring.
  • Z 2 is CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein L 2 is a covalent bond. Also included are compounds wherein R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy.
  • the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein s is CR 5 R 6 and R 5 and R 6 are each methyl.
  • r is a covalent bond.
  • each of t, r and s may be CH 2 .
  • the MC4-R binding compounds of the invention of formula VII do not include benzoimadazole as the moiety of formula XIII, when P , P , P 3 , P 4 , Z 1 , Z 2 , Z 4 , Z 3 , and Z 5 are each CH.
  • the compounds ofthe invention do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, when P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 4 , and Z 5 are each CH and Z 3 is C-OEt or CH.
  • the MC4-R binding compounds ofthe invention of formula VIII do not include compounds wherein the moiety of formula XIII is benzoimidazolyl. In another further embodiment, the MC4-R binding compounds ofthe
  • the compounds of formula VIII ofthe invention do not include compounds wherein the moiety of formula is 4,5-dihydro-lH-imidazole, when P 1 , P 2 , P 3 , and P 4 are each CH, and wherein one or two of Z 1 , Z 2 , or Z 3 is CCl, and the remaining Z groups are CH.
  • the MC4-R binding compounds of formula VIII ofthe invention do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, and when P 1 , P 2 , P 3 , and P 4 are each CH, and Z 2 is CCl and the remaining Z groups are CH.
  • the compounds of formula VIII ofthe invention do not include compounds wherein when the moiety of formula XIII is tetrahydropyrimidine, and when P 1 , P 2 , P 3 , and P 4 are each CH, and Z 1 and one of Z 4 or Z 5 are CCl and the remaining Z groups are CH.
  • the MC4-R binding compounds ofthe invention do not include compounds of formula XV, wherein the moiety of formula VIII is not benzoimidazole if P 1 , P 2 , P 3 , P 4 are each CH, and wherein Z 2 is CMe and the remaining Z groups are CH.
  • the MC4-R binding compounds ofthe invention do not include compounds of formula XVI, wherein the moiety of formula XVI, wherein L 2 is not NH (e.g., amino), if P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 4 , Z 3 , and Z 5 are each CH.
  • the MC4-R binding compounds of formula XVI ofthe invention do not include compounds wherein P groups are substituted to form a naphthyl ring.
  • the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal.
  • Compounds of formula (X) are also included in the invention. In this embodiment, the compound is ofthe formula (X):
  • Ar and Ar' are aromatic groups
  • R 11 is selected independently for each position capable of substitution from the group hydrogen, cyano, nitro, alkoxy, halogen, alkyl, amino, or aryloxy.
  • R 12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • R 13 is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl (e.g., C J -C I Q alkyl, e.g., methyl, ethyl, etc.) acyl, carbonyl, or SO 2 CH 3 , and may optionally be linked to an R 16 or an R 16' group;
  • R 16 and R 16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R 13 or another R 16 or R 16 group, to form a fused or spiro ring system;
  • X is NR 17 , S, O or a covalent bond
  • R 17 is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic, or carbonyl;
  • R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroaromatic, halogen, nitro, cyano, amino, or aryl, for each occurrence; w is O, 1, 2, 3, or 4; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof.
  • Ar groups examples include:
  • R is acyl, alkyl or hydrogen.
  • Ar is, ,
  • R 1 1 is selected independently for each aromatic position capable of substitution.
  • exemplary R 11 groups include, but are not limited to, hydrogen, halogen (e.g., fluorine, chlorine, or bromine), alkyl, amino, and benzyloxy.
  • halogen e.g., fluorine, chlorine, or bromine
  • alkyl e.g., benzyloxy
  • Ar' groups include:
  • R 19 is hydrogen, alkyl, acyl, aryl, alkenyl, or alkynyl.
  • each R group is selected independently from the group consisting of hydrogen, alkoxy, halogen (e.g., fluorine, bromine, chlorine, or iodine), and cyano.
  • alkoxy groups include C ⁇ -C ⁇ 0 alkoxy, such as, methoxy, ethoxy, n-propoxy, i-propoxy, and cyclopentoxy.
  • Examples of X include covalent bond, S, O and NR .
  • Examples of R include hydrogen, alkyl (e.g., Ci-Cio alkyl, e.g., methyl), or acyl.
  • R 16 and R 16 include alkyl and hydrogen. Each R 16 and R 16 group is selected independently for each occurrence. In a further embodiment, at least one of R 16 or R 16 are at least once hydrogen. In another embodiment, at least one of R 16 or R 16' are at least once C ⁇ -C ⁇ 0 alkyl, e.g., methyl or ethyl.
  • R 14 and R 15 are each independently hydrogen, alkyl (e.g., Ci-Cio, e.g., methyl) or phenyl for each occurrence.
  • R is hydrogen, acyl, alkyl (e.g., Ci-Cio alkyl, e.g., methyl, ethyl, etc.) acyl, carboxy, or SO 2 CH 3 .
  • acyl group include, but are not limited to, optionally substituted C ⁇ -C ⁇ oalkyl acyl (e.g., i- propylcarbonyl and benzylcarbonyl).
  • w is 2 or 3. In yet another further embodiment, e is 0 or 1. In yet another further embodiment, f is 0 or 1.
  • the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal.
  • the compound is ofthe formula (XI): wherein
  • Ar and Ar' are aromatic groups, as described above; R 1 ' is selected independently for each position capable of substitution from the group hydrogen, halogen, alkyl, amino, cyano, or aryloxy.
  • R is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • X is NR 17 , S, O or a covalent bond
  • R 17 is hydrogen, alkyl, acyl, heterocyclic, or carbonyl
  • R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, or aryl, for each occurrence;
  • R 20 and R 21 are each independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, hydrogen, or carbonyl, and may optionally be linked to form a heterocycle (e.g., mo ⁇ honlinyl, piperazinyl, piperidinyl, etc.); v is 0, 1, 2, 3, 4, 5, or 6; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof.
  • Examples of Ar, Ar', R 1 ', R 12 , R 14 , R 15 and X moieties include those described for formula (X).
  • MC4-R binding compounds include compounds ofthe formula (XVII
  • Ar and Ar' are aromatic groups
  • R 1 ' is selected independently for each position capable of substitution from the group hydrogen, cyano, alkoxy, nitro, halogen, alkyl, amino, or aryloxy;
  • R 12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • R is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, acyl, carbonyl, or SO 2 CH 3 , and may optionally be linked to an R or an R group;
  • R 16 and R 16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R 13 or another R 16 or R 16 group, to form a fused or spiro ring system;
  • X is NR 17 , S, O or a covalent bond;
  • R 17 is hydrogen, alkyl, or carbonyl;
  • R 14 and R 15 are each independently hydrogen, halogen, or alkyl; w is 1, 2, 3, or 4; e is 0 or 1 ; f is 0 or 1, wherein both e and fare not both 0 if X is a covalent bond, and pharmaceutically acceptable salts thereof.
  • Ar, Ar', R 11 , R 12 , R 14 , R 15 , R 16 and R 16' and X moieties include those described for formula (X).
  • the invention also pertains to the following compounds:
  • the invention also pertains to methods of using these compounds in methods for treating MC4-R associated states in a mammal by administering an effective amount of the compound to a mammal, such that the MC4-R associated state is treated, as well as pharmaceutical compositions comprising these compounds.
  • MC4-R binding compounds include compounds ofthe formulae:
  • the invention also includes MC4-R binding compounds such as:
  • 1-carboxylic acid tert-butyl ester l-(2- ⁇ 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl ⁇ -4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one; l-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-lH-isoindole; 1 -(2-Methoxy-benzyl)-2-methyl-2,3-dihydro- 1 H-isoindole;
  • the methods ofthe invention do not include methods wherein 2-[2-(2,5-dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]- 1, 4, 5, 6-tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-
  • the compounds claimed as MC4-R binding compounds do not include those listed above.
  • the methods ofthe invention do not include methods wherein 2-naphthalen- 1 -ylmethyl-4,5-dihydro- 1 H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l-methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl-10H- phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro- phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5- dihydro-1 H-imidazole (TOLAZOLINE; Compound AZ) are used as MC4-R binding compounds.
  • the invention pertain to compounds other than those listed above as MC4-R binding compounds.
  • the methods ofthe invention do not include 5-(4- chloro-phenyl)-2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT) as an MC4-R binding compound.
  • MASPINDOL 5-(4- chloro-phenyl)-2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol
  • the compounds ofthe invention include MC4-R binding compounds other than MASPINDOL.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., Ci-Cio for straight chain, C 3 -C 10 for branched chain), and more preferably 6 or fewer.
  • preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromefhyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc.
  • aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, imidazoline, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, isoindole, indan or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamin
  • alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C5 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C5 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • acyl includes compounds and moieties which contain the acyl radical
  • substituted acyl includes acyl groups where one or more ofthe hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cyclic groups such as cyclopentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom such as alkyl aminos, alkenyl aminos, dialkyl aminos, aryl aminos, acyl aminos, etc.
  • alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group and is included in the term "amino.”
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups and is included in the term “amino.”
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively, and are included in the term “amino.”
  • alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group and is included in the term “amino.”
  • amide or "aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carboxy moiety refers to groups such as “alkylcarbonyl” groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl” groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl” groups wherein an alkynyl group is covalently bound to a carbonyl group, “arylcarbonyl” groups wherein an aryl group is covalently attached to the carbonyl group.
  • the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety.
  • the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon ofthe carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom are both bond to the carbon ofthe carbonyl group (e.g., also referred to as a "carbamate").
  • aminocarbonylamino groups e.g., ureas
  • heteroatoms e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms.
  • heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thiocarbonyl moiety includes moieties which are analogous to carbonyl moieties.
  • thiocarbonyl moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • thiol includes groups with an -SH group. In certain embodiments, it may also include thioethers, thioalkyls, thioaryls, thiocarbonyl s, as described above.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • polycyclyl or “polycyclic radical” include moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each ofthe rings ofthe polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • heterocycle or “heterocyclic” includes saturated, unsaturated, aromatic (“heteroaryls” or “heteroaromatic”) and polycyclic rings which contain one or more heteroatoms.
  • heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isooxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tetrazole, thiazole, thiophene, and triazole.
  • heterocycles include mo ⁇ holine, piprazine, piperidine, thiomo ⁇ holine, and thioazolidine.
  • the heterocycles may be substituted or unsubstituted.
  • substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylary
  • the structure of some ofthe compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • the compound is an antagonist ofthe MC4-R. In another embodiment, the compound is an agonist ofthe MC4-R. Compounds which are agonists of MC4-R can be identified using the cAMP assay given in Example 5. The term "administering" includes routes of administration which allow the
  • MC4-R binding compound to perform its intended function, e.g. interacting with MC4- Rs and/or treating a MC4-R associated state.
  • routes of administration which can be used include parental injection (e.g., subcutaneous, intravenous, and intramuscular), intraperitoneal injection, oral, inhalation, and transdermal.
  • the injection can be bolus injections or can be continuous infusion.
  • the MC4-R binding compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the MC4-R binding compound can be administered alone or wfth a pharmaceutically acceptable carrier.
  • the MC4-R binding compound can be administered as a mixture of MC4-R binding compounds, which also can be coadministered with a pharmaceutically acceptable carrier.
  • the MC4-R binding compound can be administered prior to the onset of a MC4-R associated state, or after the onset of a MC4-R associated state.
  • the MC4-R binding compound also can be administered as a prodrug which is converted to another form in vivo.
  • the invention includes methods of treating an MC4-R associated state by administering the MC4-R binding compound ofthe invention in combination with art recognized compounds, e.g., therapeutic agents.
  • a patient suffering from cachexia resulting from HIV may be treated using both the MC4-R binding compounds ofthe invention in combination with art recognized compounds for treating the cachexia or HIV itself.
  • the term "combination with” includes both simultaneous administration as well as administration ofthe MC4-R binding compound before the art recognized compound or after the compound.
  • the period between administrations ofthe MC4-R binding compound and the other agent may be any length of time which allows the compositions to perform their intended function, e.g., the interval may be between few minutes, an hour, more than one hour, etc.
  • the MC4-R binding compounds may also be administered in combination with other MC4-R binding compounds ofthe invention.
  • the invention also features a pharmaceutical composition for the treatment of a MC4-R associated state in a mammal.
  • the pharmaceutical composition includes a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound ofthe formula (I):
  • compositions ofthe invention include MC4-R binding compounds of formulae II, III, IV, V, VI, VII, VIII, IX, X, and/or XI.
  • Pharmaceutical compositions comprising pharmaceutically acceptable salts of at least one MC4-R binding compound are also included.
  • the language "effective amount" ofthe compound is that amount necessary or sufficient to treat or prevent a MC4-R associated state, e.g. prevent the various mo ⁇ hological and somatic symptoms of a MC4-R associated state.
  • the effective amount can vary depending on such factors as the size and weight ofthe subject, the type of illness, or the particular MC4-R binding compound. For example, the choice of the MC4-R binding compound can affect what constitutes an "effective amount".
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount ofthe MC4-R binding compound without undue experimentation.
  • An in vivo assay as described in Example 4 below or an assay similar thereto (e.g., differing in choice of cell line or type of illness) also can be used to determine an "effective amount" of a MC4-R binding compound.
  • the ordinarily skilled artisan would select an appropriate amount of a MC4-R binding compound for use in the aforementioned in vivo assay.
  • the effective amount is effective to treat a disorder associated with pigmentation, bones (e.g., osteoporosis, osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, bone formation, bone remodeling, bone healing, or the depletion of calcium in bone, such as that which is related to primary hype ⁇ arathyroidism) or weight loss, e.g., weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
  • bones e.g., osteoporosis, osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, bone formation, bone remodeling, bone healing, or the depletion of calcium in bone, such as that which is related to primary hype ⁇ arathyroidism
  • weight loss e.g., weight loss is a result of anorexia
  • the regimen of administration can affect what constitutes an effective amount.
  • the MC4-R binding compound can be administered to the subject either prior to or after the onset of a MC4-R associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages ofthe MC4-R binding compound(s) can be proportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.
  • treatment includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • pharmaceutical composition includes preparations suitable for administration to mammals, e.g., humans. When the compounds ofthe present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases "pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds ofthe present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion ofthe body, to another organ, or portion ofthe body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients ofthe formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations ofthe present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount ofthe compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound ofthe present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound ofthe present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound ofthe present invention as an active ingredient.
  • a compound ofthe present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; abso ⁇ tion accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms ofthe pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical -formulating art. They may also be formulated so as to provide slow or controlled release ofthe active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients.
  • Liquid dosage forms for oral administration ofthe compounds ofthe invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and e
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations ofthe pharmaceutical compositions ofthe invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds ofthe invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations ofthe present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound ofthe present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds ofthe invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood ofthe intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged abso ⁇ tion ofthe injectable pharmaceutical form may be brought about by the inclusion of agents which delay abso ⁇ tion such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as
  • the abso ⁇ tion ofthe drug in order to prolong the effect of a drug, it is desirable to slow the abso ⁇ tion ofthe drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material having poor water solubility. The rate of abso ⁇ tion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed abso ⁇ tion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly (anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the preparations ofthe present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • any suitable route of administration including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • Actual dosage levels ofthe active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity ofthe particular compound ofthe present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount ofthe pharmaceutical composition required.
  • the physician or veterinarian could start doses ofthe compounds ofthe invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound ofthe invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses ofthe compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats an MC4-R associated state. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • certain embodiments ofthe present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts is art recognized and includes relatively non-toxic, inorganic and organic acid addition salts of compounds ofthe present invention. These salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the compounds ofthe present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances includes relatively non-toxic, inorganic and organic base addition salts of compounds ofthe present invention. These salts can likewise be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • esters refers to the relatively non-toxic, esterified products ofthe compounds ofthe present invention. These esters can be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
  • Hydroxyls can be converted into esters via treatment with an esterifying agent such as alkanoyl halides.
  • the term also includes lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters.
  • a preferred ester group is an acetomethoxy ester group.
  • the amount ofthe MC4-R binding compound is effective to treat a pigmentation or weight loss disorder, e.g., weight loss associated with anorexia nervosa, old age, cachexia, HIV or cancer.
  • the invention also pertains to packaged MC4-R binding compounds.
  • the packaged MC4-R binding compounds include, an MC4-R binding compound (e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI), a container, and directions for using said MC4-R binding compound to treat an MC4-R associated state, e.g., weight loss, etc.
  • an MC4-R binding compound e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI
  • a container e.g., directions for using said MC4-R binding compound to treat an MC4-R associated state, e.g., weight loss, etc.
  • Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen- 1 -ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
  • the pharmaceutical compositions ofthe invention include compositions wherein the MC4-R binding compound is not 5-(4-chloro-phenyl)- 2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT).
  • compositions ofthe invention include compositions wherein the MC4-R binding compound is not 2-naphthalen-l- ylmethyl-4,5-dihydro-l H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l- methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl- 1 OH-phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro-phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5-dihydro-l H-imidazole (TOLAZOLINE; Compound AZ).
  • NAPHAZOLINE 2-naphthalen-l- ylmethyl-4,5-dihydro-l H-imidazole
  • THORADIAZINE THIODIAZINE
  • CLONIDINE (2,6-dichloro-pheny
  • the pharmaceutical compositions ofthe invention includes compositions wherein the MC4-R binding compound is not 2-[2-(2,5- dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-(2- diethylaminoethyl)-urea (Compound AN); 2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]- 1 , 4, 5, 6-tetrahydropyrimidine (Compound AO); l-(4-hydroxy-l, 3, 5-trimethyl-piperadin- 4-yl)-ethanone (Compound AR); 4,6-di
  • the compounds ofthe present invention can be synthesized using standard methods of chemical synthesis and/or can be synthesized using schemes described herein. Synthesis of specific compounds is discussed in detail in the Example sections below. Examples of syntheses of several classes of compounds ofthe invention are outlined in the schemes below. Scheme 1 depicts a method of synthesizing thiomethylene compound ofthe invention.
  • 2-hydroxy or 2-mercapto benzoic acid is heated with the diamine in refluxing 1 ,2-dichlorobenzene to form the corresponding heterocyclic compound.
  • the desired thioether or ether is formed by treating the thiol or alcohol with a corresponding halogenated compound.
  • Scheme 2 depicts a general preparation of ethanyl-linked compounds ofthe invention.
  • Scheme 2 shows a method of synthesizing ethanyl linked compounds by treating ⁇ -tolunitrile with a lithium base in THF at -78 °C. A halogenated alkylaryl compound is then added to form the ethanyl linkage. To form the heterocycle, hydrogen sulfide gas is bubbled through a solution ofthe nitrile and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
  • Scheme 3 depicts a method of preparing methylenethio linked compounds ofthe invention.
  • the methylenethio compounds ofthe invention can be prepared by adding anhydrous K 2 CO 3 to a thiophenol compound (Ar-SH) in DMF. The solution is then stirred and bromomethyl-benzonitrile is subsequently added. The thioether is then converted to the heterocyclic compound by bubbling hydrogen sulfide through a solution ofthe thioether and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
  • cyclic amidines ofthe invention can be prepared by reacting 2-substituted benzonitrile with hydrogen sulfide to form a thiobenzamide.
  • the resulting thiobenzamide is then treated with iodoethane to give a thiobenzimidic acid ethyl ester.
  • the thiobenzimidic acid ethyl ester is suspended in tetrahydrofuran and treated with hydrogen sulfide.
  • the resulting dithiobenzoic acid ethyl ester is then heated with various diamines, in the presence or absence of an added catalyst such as silver trifluoroacetate, to give cyclic amidines.
  • the reaction was capped and heated to 40 °C for 12 hours.
  • the mixture was subsequently diluted with 5 mL of water and extracted with ethyl acetate (2x1 OmL).
  • the organic extracts were washed with water (3xl0mL), brine (2xl0mL), and dried (Na 2 SO 4 ).
  • the solvent was evaporated and the product was purified on silica gel (eluting with 9:1 of hexane/ethyl acetate) to afford 102 mg ofthe product as a colorless oil.
  • the reaction was heated to 45 °C and stirred overnight in a sealed tube.
  • the reaction mixture was diluted with water and extracted with methylene chloride once.
  • the organic layer was washed with brine, dried (MgSO 4 ), filtered and evaporated to give a crude orange oil.
  • the oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly in the next step.
  • MC4-R cells were stable recombinant K293 cells overexpressing the MC4-R.
  • the cells were routinely cultured and passaged in a growth medium composed of DMEM base medium: 10% fetal bovine serum (FBS), IX Glutamine, and 0.5 mg/ml G418.
  • Terminal cultures i.e., those which will be processed to produce plasma membranes
  • the media contained 0.2 mg/ml G418.
  • harvested cells were pelleted and immediately washed with 25 mL of PBS.
  • the washed cells were resuspended in two volumes of STM buffer (0.25 M sucrose, 5 mM Tris, 1 mM MgCl 2 , pH 7.5), containing Boehringer CompleteTM protease inhibitors.
  • Cell breakage was accomplished using a Dounce homogenizer. After 20-30 strokes, nuclei and unbroken cells were pelleted by centrifugation at 1100 rpm for 5 minutes. The supernatant was saved and the pellet was resuspended in 1 volume of STM/protease inhibitors, and then a further lysis step was carried out by the Dounce homogenizer (10-20 strokes).
  • the membrane suspension obtained from the sucrose interface was collected and diluted with 5 mM Tris and 1 mM MgC - Membranes were collected by a further round of centrifugation at 33,000 rpm for 30 minutes (SW-41 Ti rotor).
  • the pellet of membranes was subsequently resuspended in a small (0.5 mL) volume of STM, using a 2 mL Dounce homogenizer, and immediately frozen.
  • the resulting membranes were stable to both freeze-thaw cycles and temperatures around 4°C for at least 6 hours.
  • SPA scincillation proximity assay
  • the membranes from the MC4-R mammalian cells were bound to wheat germ agglutinin (WGA) coated SPA beads.
  • WGA wheat germ agglutinin
  • the membrane coated SPA beads were added to screening plates, which contained the test compounds pre-dissolved in 30 ⁇ L of 10% DMSO. After pre-equilibration ofthe receptor coated beads with the test compounds (1 hour), 2nM of radioactive ligand ([ rl25 I]NDP- ⁇ -MSH) was added. Since the binding ofthe radioactive ligand to the receptor causes the scincillation ofthe beads, blockage ofthe binding ofthe radioactive ligand by a small molecule causes a reduction in scincillation.
  • the membranes were mixed with the SPA beads to make a 2X stock of membrane and beads.
  • the following assay was performed with automation using a Titertec MultiDrop with plate stacker.
  • Binding was initiated by adding 20 ⁇ L of radioactive ligand (a 20 nM solution of [ 125 I]-NDP- ⁇ -MSH) to each test well. The plates were incubated overnight at room temperature and read the following morning.
  • radioactive ligand a 20 nM solution of [ 125 I]-NDP- ⁇ -MSH
  • Results from the SPA are summarized in Table 4.
  • Table 4 * indicates good inhibition ofthe MC4-R, ** indicates very good inhibition ofthe MC4-R, and *** indicates exemplary inhibition ofthe MC4-R.
  • the present invention pertains to the compounds and methods described herein provided that the compound is not selected from the group consisting of those depicted in Table 5.
  • Method MC4 Receptors are expressed in stably transfected K293 cells.
  • the cells are incubated in DMEM base medium (10% FBS, IX glutamine, and 0.4 mg/ml G418) at 37°C, in an atmosphere of 6.0% CO 2 and 90% relative humidity. Two days before the experiment, the cells are trypsinized and 200 ⁇ l ofthe cell suspension (138,000 cells/ml) is deposited into 96-well Costar cell culture plates.
  • test compounds are then dissolved in DMSO creating a 30mM stock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2 ⁇ M in OPTI-MEM (GIBCO-BRL) media with 50 ⁇ M IBMX (isobutylmethylxanthine, Sigma) minutes before the experiment.
  • OPTI-MEM GENERAL-BRL
  • IBMX isobutylmethylxanthine, Sigma
  • the media is then thoroughly removed from the cell culture plates through a 12-channel straight manifold.
  • 90 ⁇ l of OPTI-MEM media with 50 ⁇ M IBMX is added to each well (McHale et al. FEBS Letters 345 (1994) 147-150).
  • the plate is then placed in an incubator set at 37 °C, 6.0% CO and 90% relative humidity. After 15 minutes of incubation, 90 ⁇ l ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX) are added and the plates are incubated for another 10 minutes. 20 ⁇ l ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates are incubated for an additional hour at 37 °C.
  • the media mixture is removed by 12-channel straight manifold. 60 ⁇ l of 70% ethanol is added to each well. The plates are then placed on a shaker for 30 minutes to extract the cAMP. The amount of cAMP is
  • mice Male lean C57BL/6J mice were individually housed in macrolon cages
  • Figure 2 shows that administration of 15 nmol of Compound N partially reverses the effect ofthe administration ofthe MC4-R agonist, MT II.
  • Figure 3 shows that administration of Compound O did not significantly effect the food intake of mice treated with MT II.
  • the cAMP assay identifies compounds which have agonist activity against MC receptors. It is used to identify the selectivity of agonist which selectively antagonize receptors of interest. The following method is outlined for MC4-R, but corresponding procedures were used for the other MC receptors, MC1-R, MC3-R, and MC5-R.

Abstract

MC4-R binding compounds of the formula: B-Z-E (I) wherein B is an anchor moiety, Z is a central moiety, and E is a MC4-R interacting moiety are discussed. Methods of using the compounds to treat MC4-R associated disorders, such as disorders associated with weight loss, are also discussed.

Description

MELANOCORTIN-4 RECEPTOR BINDING COMPOUNDS AND METHODS
OF USE THEREOF
Related Applications This application claims priority to U.S. Patent Application Serial No.
09/778,468, entitled "Melanocortin-4 Receptor Binding Compounds and Methods of Use Thereof," filed on February 1, 2001, which is a continuation-in-part of U.S. Patent Application Serial No. 09/632,309, entitled "Melanocortin-4 Receptor Binding Compounds and Methods of Use Thereof," filed on August 4, 2000; which claims priority to U.S. Provisional Application Serial No. 60/223,277, entitled "Melanocortin-4 Receptor Binding Compounds and Methods of Use Thereof," filed on August 3, 2000; and U.S. Provisional Application Serial No. 60/147,288, entitled "Melanocortin-4 Receptor Binding Compounds and Methods of Use Thereof," filed on August 4, 1999; the entire contents of all ofthe aforementioned applications are hereby incorporated herein by reference.
Background
Melanocortins are known to have a broad array of physiological actions (Nakanishi, et al. Nature (1979) 278:423-427). Aside from their well known effects on adrenal cortical functions and on melanocytes, melanocortins have been shown to affect behavior, learning, memory, control ofthe cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev. Exp. Pathol
(1991) 15:167-199; De Weid et al. Physiol. Rev. (1982) 62:977-1059; Gruber, K.A. et al. Am. J. Physiol. (1989) 257:R681-R694; Murphy et al. Science (1980) 210:1247-
1249; Murphy et al. Science (1983) 221 :192-193; Ellerkmann, E. et al. Endocrinol
(1992) 130:133-138; Versteeg, D.H.G. et al. Life Sci. (1986) 835-840). Peripherally, melanocortins have been identified to have immunomodulatory and neurotrophic properties, and to be involved in events surrounding partition (Cannon, J.G. et al. J. Immunol. (1986) 137:2232-2236; Gispen, W.H. Trends Pharm. Sci. (1992) 11 :221-222; Wilson, J.F. Clin. Endocrinol. (1982) 17:233-242; Clark, D. et al. Nαtwre (1978) 273:163-164; Silman, R.E. et al. Nature (1976) 260:716-718). Furthermore, melanocortins are present in a myriad of normal human tissues including the brain, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, J.B. et al. Endocrinol. (1987) 121 :1900-1907; Mountjoy, K.G. et al. Science (1992) 257:1248- 1251; Chhajlani, V. et al., FEBS Lett. (1992) 309:417-420; Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250; Gantz, L. et al, J. Biol Chem. (1993) 268:15174-15179). Recent studies have described an unexpected diversity of subtypes of receptors for the melanocortin peptides and determined that they belong to the superfamily of seven transmembrane G-protein linked cell surface receptors (Mountjoy, K.G. et al., Science(l992), supra; Chhajlani, V. et al., FEBS Lett. (1992), supra). Five melanocortin receptor subtypes have been cloned. The melanocortin- 1 (MCI) receptor is found in melanoma cells, where it has a role in mediating pigmentation. The melanocortin-2 receptor (MC2-R or ACTH receptor) is found in the adrenal glands where it mediates the effects of ACTH (adrenocorticotrophic hormone). The melanocortin-3 receptor (MC3-R) is primarily found in the central nervous system (CNS) (Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250), but its physiological function is still unknown. The melanocortin-4 receptor (MC4-R) has been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L. et al. J. Biol. Chem. (1993) 268:15174-15179; Mountjoy, K.G. et al. Mol. Endocrinol. (1994) 8:1298-1308). MC4-R has recently been related to weight homeostasis. MC4-R "knock out" mice have been shown to develop obesity (Huszar et al. Cell (1997) 88:131-141). The feeding behavior leading to the obesity can be inhibited by injection of MSH peptides (Vergoni et al. Neuropeptides (1986) 7:153- 158; Vergoni et al. Eur. J. Pharmacol. (1990) 179:347-355; Fan et al. Nαtwre (1997) 385:165-168). The melanocortin-5 receptor (MC5-R) has a wide peripheral distribution and is believed to participate in the regulation ofthe exocrine gland function (Chen et al. Cell (1997) 91 :789-798).
Summary
In one aspect, the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal. The method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. The MC4-R binding compound is ofthe formula (I):
B-Z-E (I)
wherein B is an anchor moiety, Z is a central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In a further embodiment, the MC4-R binding compound is ofthe formula (II):
B-A-E (II) wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In another embodiment, the invention pertains to another method for treating an MC4-R associated state in a mammal, by administering to a mammal an effective amount of a MC4-R binding compound of formula (III) :
B-L A-L2-E (III)
wherein B is an anchor moiety, L\ and L2 are linking moieties, A is a cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
The invention also pertains to treating MC4-R associated states with an MC4-R binding compound of formula III, wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; Li is a covalent bond, Cι-Cι0 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; and A is a substituted or unsubstituted phenyl, heteroaryl, cycloalkyl, or biaryl, and pharmaceutically acceptable salts thereof.
In another embodiment, the invention pertains to a method for treating an MC4- R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. In this embodiment, the compound is ofthe formula (IV):
B-
Figure imgf000004_0001
wherein B is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; A is aryl, heteroaryl, biaryl, cycloalkyl, heterocyclic, or cycloalkenyl; Li and L2 are selected from the group consisting of a covalent bond, Cι-C6 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CHR5, CR5, CR5R6 or absent (e.g., leaving a non- cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, L,, or L2; R1, R2, R3, R4, R5, and R6are each substituted or unsubstituted alkyl, alkenyl, halogen, thiol, thioether, thioalkyl, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring. Pharmaceutically acceptable salts ofthe MC4-R binding compound are also included. The invention also pertains to methods for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound ofthe formula (V):
λ
B L, π L2 E (V) wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, cycloalkyl, or aryl; L3 is a covalent bond, Cι-C6 branched, unbranched or cyclic alkyl, wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl; and A is heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and λ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
In yet another embodiment, the invention also pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, wherein the compound is an MC4-R antagonist, and is ofthe formula (VI):
Figure imgf000005_0001
wherein pi p2 ^ p3 an(j p4 ^g optionally substituted carbon, sulfur, or nitrogen, and wherein one of P1, P2, P3 and P4 may represent a covalent bond; Z1, Z2, Z3, Z4, and Z5 are optionally substituted carbon or nitrogen; Li is a covalent bond, Cj-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
In another embodiment, the MC4-R binding compound is of formula (VII):
Figure imgf000006_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; and
P1, P2, P3, P4, and P5 are CH, N or substituted carbon.
In another embodiment, the MC4-R binding compound is of formula (VIII):
Figure imgf000006_0002
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; and
P1, P2, P3, P4, and P5 are CH, N or substituted carbon.
The invention also pertains to MC4-R binding compound ofthe formula (IX):
Figure imgf000007_0001
wherein:
P2 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
P3 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI; P4 is CH, CC1, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a sulfur atom;
G1 and G2 are each independently CH2, S, or O; r is a covalent bond or CH2; t is CH2, CHR3, or CR3R4; s is CH2, CHR5 or CR5R6;
R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl; Z1 is CH, or covalently linked to Z2 to form a naphthyl ring; Z2 is CH, C-(C≡CH), CC1, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z5 is CH, C-alkoxy or C-OMe;
R3, R4, R5, and R6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof. The invention also features a pharmaceutical composition for the treatment of a
MC4-R associated state in a mammal. The pharmaceutical compositions contain a pharmaceutically acceptable carrier and a MC4-R binding compound. The compounds are described herein in the context ofthe description ofthe method but it should be understood that the invention further pertains to pharmaceutical compositions containing the compounds and the compounds per se. For example, pharmaceutical compositions ofthe invention include a pharmaceutically acceptable carrier and an effective amount of at least one MC4-R binding compound ofthe formula (I):
B-Z-E (I) wherein B is an anchor moiety, Z is an central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
Brief Description of the Drawings Figures la and lb are bar graphs showing the effects of MT II (a MC4-R agonist) on food intake in lean mice.
Figure 2 is a graph depicting the effects of treating lean mice with Compound N and MT II on food intake over a six hour period.
Figure 3 is a graph depicting the effects of treating lean mice with Compound O and MT II on food intake over a six hour period.
Detailed Description of the Invention In one aspect, the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal. The method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. The MC4-R binding compound is ofthe formula (I):
B-Z-E (I)
wherein B is an anchor moiety, Z is a central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
The term "MC4-R" includes receptors for α-melanocyte stimulating hormone. The MC4-R is usually found in the brain where it is widely distributed (Mountjoy et al. Mol. Endocrinol. (1994) 8:1298-1308). Melanocortins are peptide hormones that play an important role in regulating melanocyte pigmentation as well as memory and thermoregulation. They consist of various peptides, such as α-melanocyte stimulating hormone, that are cleaved from the polypeptide precursor prooptiomelanocortin (POMC). The effects of melanocortins are mediated via stimulation of adenylate cyclase via the activation ofthe melanocortin receptors.
The melancortin-4 receptor (MC4-R) is a G-protein coupled receptor (GPCR) expressed in brain tissue. The specific role ofthe MC4-R protein in vivo was investigated by engineering MC4-R "knock out" mice. The mice were unable to produce functional MC4-R protein, because the endogenous MC4-R gene coding sequence was deleted. The knock-out mice were produced by using human MC4-r gene sequences to isolate and clone the murine MC4-r gene. A murine MC4-r targeting construct was then generated which was designed to delete the majority ofthe murine MC4-r coding sequence upon homologous recombination with the endogenous murine MC4-r gene. Embryonic stem (ES) cells containing the disrupted MC4-r gene were produced, isolated and microinjected into murine blastocysts to yield mice chimeric for cells containing a disrupted MC4-r gene. Offspring ofthe chimeric mice resulting from germline transmission ofthe ES genome were obtained and animals heterozygous for the disrupted MC4-R were identified. To assess the role of MC4-R in vivo, the animals heterozygous for the MC4-r disrupted gene were bred together, producing litters containing wild-type mice, mice heterozygous for the MC4-r mutation and mice homozygous for the MC4-R mutation. The weight gain ofthe animals was monitored regularly. Homozygous null MC4-R mutants showed an increase in weight compared to mice heterozygous for MC4-R deletion and wild type mice as early as 25 days of age. By 54-58 days of age, MC4-R deficient mice exhibited, on average, a 55-70% greater weight relative to wild type mice, and an approximately 50% greater weight compared to mice heterozygous for the MC4-R deletion.
The language "MC4-R associated states" includes those states, disorders, or diseases characterized by aberrant or undesirable activity or expression of MC4-Rs. It also includes those states, disorders and diseases associated with MC4-R ligands (e.g., α-melanocyte stimulating hormone). The language also includes prevention of states, disorders and diseases characterized by aberrant or undesirable activity of MC4-Rs or its ligands. Examples of MC4-R associated states include, but are not limited to, disorders involving or associated with pigmentation, bones, and weight homeostasis, e.g., weight loss or obesity. MC4-R associated states include the unhealthy decrease in body weight that can occur during an acute inflammatory response or that occurs in a cancer patient as a result of cachexia, radiotherapy or chemotherapy, or to the undesirable decrease in body mass due to simulated or actual weightlessness, such as occurs during space travel. Other examples of unhealthy decreases in weight occur in some patients during advance stages of illnesses such as AIDS. Physiologically, this may be a result from any one of a number of complex factors, such as loss of appetite and possibly abnormal catabolism. This cachexia, may be slowed by MC4-R binding compounds. In a preferred embodiment ofthe invention, the weight loss is a result of old age, anorexia nervosa, or cachexia (e.g., cachexia associated with cancer or HIV). In one further embodiment, the MC4-R associated state is not weight loss. In an embodiment, the MC4-R associated disorder is a bone associated disorder. MC4-R knockout mice have been shown to have enhanced bone thickness (Ducy et al. Science, (Sept., 2000) 289:1501-1504). Examples of bone associated disorders which may be treated with MC4-R binding compounds ofthe invention include disorders and states where the formation, repair or remodeling of bone is advantageous. For examples bone associated states include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e.g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism. Bone associated disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the compounds of the invention.
The term "mammal" includes organisms which express the MC4-R. Examples of mammals include mice, rats, cows, sheep, pigs, goats, horses, bears, monkeys, dogs, cats and, preferably, humans. Transgenic organisms which express the MC4-R are also included in this definition. The language "MC4-R binding compound" includes those compounds which interact with the MC4-R resulting in modulation of the activity ofthe MC4-R. In an embodiment, the MC4-R binding compounds are antagonists ofthe MC4-R. The term "antagonist" includes compounds which interact with the MC4-R and modulate, e.g., inhibit or decrease, the ability of a second compound, e.g., α-melanocyte stimulating hormone or another MC4-R ligand, to interact with the MC4-R. In another embodiment, the MC4-R binding compounds is an agonist ofthe MC4-R. The term "agonists" includes compounds which interact with the MCR-4 and modulate, e.g., increase or stimulate, its activity and/or its ability to interact with a second compounds, e.g., α-melanocyte stimulaturing hormone. MC4-R binding compounds can be identified through both in vitro (e.g., cell and non-cell based) and in vivo methods. These methods are described in detail in Examples 2, 3, 4, and 5.
The Scincillation Proximity Assay (SPA) is a non-cell based in vitro assay, described in Example 2. It can be used to identify compounds that interact with, e.g., bind to MC4-R. Such compounds may act as antagonists or agonists of MC4-R activity and may be used in the treatment of body weight disorders. One example of a qualitative measure of binding affinity of a MC4-R binding compound to MC4-R is its IC50. Preferably, the MC4-R binding compound binds to the MC4-R with a binding affinity, for example, of about 50μM or less, 20 μM or less, 10 μM or less, 5 μM or less, 2.5 μM or less, or 1 μM or less. In an advantageous embodiment, the IC50 of a MC4-R binding compounds is about 0.5 μM or less,, about 0.3 μM or less, about 0.1 μM or less, about 0.08 μM or less, about 0.06 μM or less, about 0.05 μM or less, about 0.04 μM or less, or, preferably, about 0.03 μM or less.
In the SPA, isolated membranes are used to identify compounds that interact with MC4-R. For example, in a typical experiment using isolated membranes, 293 cells may be genetically engineered to express the MC4-R. Membranes are be harvested by standard techniques and used in an in vitro binding assay. I-labeled ligand (e.g., I- labeled α-MSH, β-MSH, or ACTH) is bound to the membranes and assayed for specific activity; specific binding is determined by comparison with binding assays performed in the presence of excess unlabelled ligand.
To identify MC4-R binding compounds, membranes are incubated with labeled ligand in the presence or absence of test compound. Compounds that bind to the receptor and compete with labeled ligand for binding to the membranes reduced the signal compared to the vehicle control samples. Preferably, the screens are designed to identify compounds that antagonize the interaction between MC4-R and MC4-R ligands such as α-MSH, β-MSH and ACTH. In such screens, the MC4-R ligands are labeled and test compounds can be assayed for their ability to antagonize the binding of labeled ligand to MC4-R.
Cell based assay systems can also be used to identify MC4-R binding compounds. An example of a cell based assay system is the cAMP assay described in detail in Example 3. Cell based methods may use cells that endogenously express MC4- R for screening compounds which bind to MC4-R. Alternatively, cell lines, such as 293 cells, COS cells, CHO cells, fibroblasts, and the like, genetically engineered to express the MC4-R can also be used for screening purposes. Preferably, host cells genetically engineered to express a functional receptor that responds to activation by melanocortin peptides can be used as an endpoint in the assay; e.g., as measured by a chemical, physiological, biological, or phenotypic change, induction of a host cell gene or a reporter gene, change in cAMP levels, adenylyl cyclase activity, host cell G protein activity, extracellular acidification rate, host cell kinase activity, proliferation, differentiation, etc.
To be useful in screening assays, the host cells expressing functional MC4-R should give a significant response to MC4-R ligand, preferably greater than 5 -fold induction over background. Host cells should preferably possess a number of characteristics, depending on the readout, to maximize the inductive response by melanocortin peptides, for example, for detecting a strong induction of a CRE reporter gene: (a) a low natural level of cAMP, (b) G proteins capable of interacting with the MC4-R, (c) a high level of adenylyl cyclase, (d) a high level of protein kinase A, (e) a low level of phosphodiesterases, and (f) a high level of c AMP response element binding protein would be advantageous. To increase response to melanocortin peptide, host cells could be engineered to express a greater amount of favorable factors or a lesser amount of unfavorable factors. In addition, alternative pathways for induction ofthe CRE reporter could be eliminated to reduce basal levels.
In using such cell systems, the cells expressing the melanocortin receptor are exposed to a test compound or to vehicle controls (e.g., placebos). After exposure, the cells can be assayed to measure the expression and/or activity of components ofthe signal transduction pathway ofthe melanocortin receptor, or the activity ofthe signal transduction pathway itself can be assayed. For example, after exposure, cell lysates can be assayed for induction of cAMP. The ability of a test compound to increase levels of cAMP, above those levels seen with cells treated with a vehicle control, indicates that the test compound induces signal transduction mediated by the melanocortin receptor expressed by the host cell. In screening for compounds that may act as antagonists of MC4-R, it is necessary to include ligands that activate the MC4-R, e.g., α-MSH, β-MSH or ACTH, to test for inhibition of signal transduction by the test compound as compared to vehicle controls.
When it is desired to discriminate between the melanocortin receptors and to identify compounds that selectively agonize or antagonize the MC4-R, the assays described above may be conducted using a panel of host cells, each genetically engineered to express one ofthe melanocortin receptors (MC1-R through MC5-R). Expression ofthe human melanocortin receptors is preferred for drug discovery purposes. To this end, host cells can be genetically engineered to express any ofthe amino acid sequences shown for melanocortin receptors 1 through 5. The cloning and characterization of each receptor has been described: MC1-R and MC2-R (Mountjoy., 1992, Science 257: 1248-1251 ; Chhajlani & Wikberg, 1992 FEBS Lett. 309: 417-420); MC3-R (Roselli-Rehfuss et al., 1993, Proc. Natl. Acad. Sci., USA 90: 8856-8860; Gantz et al., 1993, J. Biol. Chem. 268: 8246-8250); MC4-R (Gantz et al., 1993, J. Biol. Chem. 268: 15174-15179; Mountjoy et al., 1994, Mol. Endo. 8: 1298-1308); and MC5-R (Chhajlani et al., 1993, Biochem. Biophys. Res. Commun. 195: 866-873; Gantz et al., 1994, Biochem. Biophys. Res. Commun. 200; 1234-1220), each of which is incoφorated by reference herein in its entirety. Thus, each ofthe foregoing sequences can be utilized to engineer a cell or cell line that expresses one ofthe melanocortin receptors for use in screening assays described herein. To identify compounds that specifically or selectively regulate MC4-R activity, the activation, or inhibition of MC4- R activation is compared to the effect ofthe test compound on the other melanocortin receptors. In certain embodiments, it may be advantageous to select compounds ofthe invention selective for MC4-R, or, alternatively, it may be useful to select compounds which interact with other receptors as well.
In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than at least one other MC receptors, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC1-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC3-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective. In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC5-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
In yet another further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R receptor than at least one, two or three other MC receptors (such as, for example, MC1-R, MC3-R, or MC5-R). In a further embodiment, the MC4-R binding compounds are more selective for the MC4-R than MC1-R, MC3-R, and MC5-R. In a further embodiment, the MC4-R binding compounds as at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective for the MC4-R than the MC 1 -R, MC3-R and the MC5-R.
As stated above, in an embodiment, the MC4-R binding compound includes compounds ofthe formula (I):
B-Z-E (I)
wherein B is an anchor moiety, Z is a central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof. The language "anchor moiety" ("B") includes moieties which interact with the
MC4-R, which may, advantageously, result in the binding ofthe MC4-R binding compound to the MC4-R. Examples of anchor moieties include substituted or unsubstituted alkyl (e.g., branched, straight chain, or cyclic (e.g., cyclohexane, cyclopentane)), alkenyl, alkynyl, aryl (e.g., substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracenyl, fluorenyl, etc.), heterocyclic (e.g., thienyl, morpholinyl, piprazinyl, piperidinyl, etc.), and multicyclic (e.g., indolyl, benzothioenyl, etc.) moieties. Other examples of anchor moieties include carbonyl moieties, thiol groups, cyano groups, amino groups, and hydrogen atoms.
In a further embodiment, the anchor moiety ("B") includes substituted or unsubstituted carbocyclic aryl moieties, e.g., phenyl, naphthyl, etc. Examples of substituents include halogens (e.g., fluorine, chlorine, iodine, bromine, etc.), alkoxy (e.g., methoxy, ethoxy, isopropoxy, n-propyloxy, n-butyloxy, pentoxy, cyclopentoxy, arylalkyloxy, etc.) hydroxy, alkylcarbonyl, cyano, nitro, thiol, thioether, thioalkyl, alkenyl, alkynyl (e.g., ethynyl, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, trifluoromethyl, azido, heterocyclyl, alkylaryl, heteroaryl, alkyl (e.g., unsubstituted (e.g., methyl, ethyl, propyl, butyl, hexyl, etc.) or substituted, e.g., halogen substituted, e.g., trifluoromethyl, trichloromethyl), aryl (e.g., substituted and unsubstituted phenyl, heteroaryl (e.g., thienyl, pyridinyl, etc.), arylalkyl, arylalkenyl, arylalkynyl, or combinations thereof. In yet another further embodiment, the anchor moiety substituent can be substituted itself with one or more halogen, nitro, alkyl, alkenyl, alkynyl, aryl or alkoxy groups, or combinations thereof. In certain embodiments, the aryl moiety is fused to another ring which can be substituted or unsubstituted, carbocyclic or heterocyclic, aromatic or non-aromatic.
In a further embodiment, the anchor moiety is substituted with at least one halogen, alkoxy group, or alkyl (e.g., substituted or unsubstituted) group. Examples of halogen substituted phenyl anchor moieties include ø-iodophenyl, w-iodophenyl, o- bromophenyl, m-bromophenyl, o-chlorophenyl, m-chlorophenyl, ø-fluorophenyl, m- fluorophenyl, ^-fluorophenyl, w-nitrophenyl, or o-methoxy. The anchor moiety may also comprise more than one substituent, e.g. two halogens, e.g., two fluorines, a fluorine and a chlorine. Other examples of anchor moieties include 2-methoxy-5- bromophenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-iodophenyl, 2-methoxy-5- fluorophenyl, 2-ethoxy-5-bromophenyl, 2-methoxy-6-bromophenyl, 3-methoxy-6- bromophenyl, 2-isopropyl-5-bromophenyl, 2-«-propyl-5-bromophenyl, and 2- cyclopentyloxy-5-bromophenyl. Other examples of anchor moieties include, but are not limited to, 2-methoxy-5- cyanophenyl, 2-chloro-5-chlorophenyl, 2-methoxy-6-methoxyphenyl, 2-methoxy-5- nitrophenyl, 2-methoxy-5 -phenyl phenyl, 2-methoxy-5-3'-thiofuranyl phenyl, 2- methoxy-5-methylcarbonyl phenyl, 3,5-dimethyloxy phenyl, 2-methoxyphenyl, 2,5- dimethoxy phenyl, 2-fluoro-6-chlorophenyl, and 3-chloro-4-fluorophenyl.
In another further embodiment, the anchor moiety includes substituted and unsubstituted heterocycles. Examples of such heterocycles include, but are not limited to, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, deazapurinyl, morpholine, piprazine, piperidine, thiomorpholine, and thioazolidine. Examples of substituents include alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, aryl and heteroaryl groups.
In another further embodiment, the anchor moiety ("B") is a substituted or unsubstituted fused aryl or biaryl moiety. Biaryl moieties include moieties with two or more aromatic rings, which may be fused or connected through one or more covalent bonds. Examples include biphenyl, fluorene, anthracenyl, benzoquinazolinyl, and naphthyl. Examples of substituents of biaryl moieties include alkyl (e.g., substituted and unsubstituted, branched or straight chain, methyl, ethyl, propyl, butyl, pentyl, etc.), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, cyclopentoxy, etc.), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, an aromatic heteroaromatic moiety, halogens (e.g., fluorine,, chlorine, bromine, iodine, etc.), combinations thereof and other groups which allow the MC4-R binding compound to perform its intended function. Biaryl moieties also include moieties which comprise one or more heterocycles, such as, benzothiofuranyl, benzothienyl, quinolinyl, benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, and indolyl. Examples of biaryl anchor moieties include naphthyl, 2-methoxynaphthyl, 2-methoxy-5-phenyl phenyl, 2-ethoxynaphthyl, 2-methoxy-5-thiofuranyl phenyl, 2-methyl naphthyl, 2-n- propyl naphthyl, benxothiofuranyl, 2-phenyl phenyl, 2-methoxy-5-4'methoxy-phenyl phenyl; 2-methoxy-5-(3'-fluoro-4'-phenyl) phenyl phenyl; 2-cyclopentoxynaphthyl; quinolinyl; and 2-methoxy-5-(3'-chloro-4'fluoro)phenyl phenyl.
Furthermore, the anchor moiety can be multicyclic and comprise a combination of one or more aromatic, non-aromatic, heterocyclic, and heteroaryl rings, which can be fused, bridged, or linked together through covalent bonds. The multicyclic anchor moiety may also be substituted with substituents such as alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, aryl and heteroaryl groups.
The term "central moiety" ("Z") includes moieties which covalently attach the anchor moiety to the MC4-R interacting moiety. Examples of central moieties include cyclic moieties, optionally substituted amines (e.g., tertiary amino, aminoalkylamino, dialkylaminoalkylamino, aminocarbonylamino, aminocarbonylamino; arylaminocarbonylamino groups; arylaminothiocarbonylamino), optionally substituted alkyl groups (e.g., carbon atoms with substituted or unsubstituted alkyl, aryl (e.g., phenyl, naphthyl), heterocyclic moieties (e.g., morpholinyl, piprazinyl, etc.), and carbonyl groups, etc. Examples of substituents ofthe central moiety include, for example, alkyl (e.g., straight, branched or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromefhoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, arylalkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl (e.g., morpholinyl, piprazinyl, etc.), arylalkyl, alkylaryl and aryl (e.g., substituted or unsubstituted phenyl (e.g., alkyl, halogen, alkoxy substituted), naphthyl, anthracene, etc.) and heteroaryl moieties. Furthermore, the central moiety may further comprise one or more linking moieties. For example, the linking moieties may covalently link the cyclic moiety to the anchor moiety and/or the MC4-R interacting moiety. The term "central moiety" also includes moieties ofthe formula (XII):
Figure imgf000017_0001
wherein π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl; L3 is a covalent bond, Cι-C branched, unbranched or cyclic alkyl(wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl moiety;
A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and λ is 0, 1 or 2. In a further embodiment, π is a carbon or nitrogen atom. In other embodiments, π is alkyl, carbocyclic, heterocyclic (e.g., piprazinyl, morphonlinyl, piperidinyl, etc.). In another further embodiment, A is heterocyclic (e.g., non-aromatic, e.g., substituted or unsubstituted, bridged, fused, or monocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. or aromatic, e.g., pyridinyl, pyrimidinyl, pyrrolyl, etc.), aryl e.g., phenyl, naphthyl) or amino (e.g., substituted or unsubstituted, e.g., alkylamino, dialkyl amino, etc.).
The language "cyclic moiety" includes heterocyclic and carbocyclic groups, such as substituted or unsubstituted phenyl, heteroaryl, or biaryl moieties. Examples of cyclic moieties include those without aromaticity (e.g., cyclohexane, cyclopentane, etc.) and those with aromaticity, e.g. moieties that have at least one aromatic ring. Cyclic moieties may include one or more heteroatoms. Examples include phenyl, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthyl, quinolyl, indolyl, and the like. The cyclic moiety can be substituted at one or more ring positions with such substituents such as, for example, alkyl (e.g., substituted or unsubstituted methyl, ethyl, propyl, butyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), aryloxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, and aryl (e.g., substituted or unsubstituted phenyl, naphthyl) and heteroaryl moieties. The cyclic moiety can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin, or fluorene).
In an embodiment, the cyclic moiety ofthe present invention is substituted or unsubstituted phenyl, heteroaryl, or biaryl. The language "cyclic moiety" also includes non-aromatic cyclic moieties, such as, substituted or unsubstituted cyclic alkanes, (e.g., cyclohexane, and cyclopentane), cyclic alkenes (e.g., cyclohexene), and substituted or unsubstituted heterocycles (e.g., thiofuran, pyrimidine, pyrazine, pyrrole, imidazole, quinoxaline, etc.). The language "cyclic moiety" comprises not only the heterocyclic or carbocyclic moieties, but also may additionally include moieties which further comprise linking moieties, such as Lj and L2 which, for example, may link the anchor moiety to the carbocyclic or heterocyclic cyclic portion ofthe cyclic moiety. Furthermore, linking moieties may also link the heterocyclic or carbocyclic cyclic moiety to the MC4-R interacting moiety. Examples of cyclic moieties include unsubstituted phenyl, halogenated phenyl (e.g., fluoro, bromo, chloro and iodo phenyl), alkyl substituted phenyl (e.g., methyl, ethyl, propyl, etc.),amino substituted phenyl, heteroaryls (e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.).
The language "MC4-R interacting moiety" ("E") includes moieties which permit the MC4-R binding compound to perform its intended function, e.g., interact with the MC4-R. Examples of MC4-R interacting moieties include substituted or unsubstituted alkyl (e.g., substituted with amino, cyano, nitro, hydroxy, etc.), aryl (e.g., phenyl, heteroaryl), amino (e.g., 3-aminopropylamino, dimethyl amino, diethyl amino), amidino, guanidino, carbocyclic and heterocyclic moieties. The language "MC4-R interacting moiety" is not intended to suggest that this moiety is the active pharmacophore ofthe molecule, responsible for the pharmacological, binding or other properties ofthe MC4-R binding compound.
In one embodiment, the MC4-R interacting moiety is cyclic, e.g., aryl, alkyl, biaryl, polycyclic, heteroaromatic, or heterocyclic. Examples of heterocyclic MC4-R interacting moieties include heterocycles which contain nitrogen atoms, such as, substituted and unsubstituted imidazolyl, imidazolinyl, pyridinyl, pyrrolyl, piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, pyrimidinyl, pyridinyl, morpholinyl, diazapanyl, and piperidinyl moieties. The MC4-R interacting moiety may be bicyclic, polycyclic, bridged or a fused ring system. Examples of fused and bridged heterocycles include:
Figure imgf000019_0001
The substituent R includes substituted and unsubstituted alkyl (e.g., methyl, ethyl, etc.), arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, arylalkylcarbonyl, and other groups which allow the MC4-R interacting moiety to perform its intended function.
The MC4-R interacting moiety can be substituted with substituents such as, but not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, aminoalkyl, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, aryl ,heteroaryl moieties and combinations thereof.
In another embodiment, the MC4-R interacting moiety is not cyclic, e.g., the MC4-R interacting moiety is alkyl, unsubstituted amino, alkylamino, dialkylamino, amidino, guanidino, etc. Examples of alkyl MC4-R interacting moieties include straight and branched chain alkyls such as n-butyl, n-pentyl, and n-hexyl. In another embodiment, the MC4-R interacting moiety contains one or more nitrogen atoms, e.g., pyridinyl, pyrrolyl, pyrazinyl, imidazolyl, imidazolinyl, quinoxalinyl, or pyrimidinyl. In a further embodiment, the MC4-R interacting moiety is ofthe formula (XIII):
Figure imgf000020_0001
wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L2, R1, R2, R3, R4, R5. or
R6 to form one or more rings;
R1, R2, R3, R4, R5, and R6 are each substituted or unsubstituted alkyl, alkenyl, alkynyl, heterocyclic, halogen, thiol, thioether, thioalkyl, hydroxyl, nitro, amino, cyano, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring. The carbocyclic ring that is formed through the linkage of R, R1, R2,
R3, R4, R5, or R6 may be bridged, fused, or spiro.
In one embodiment, the MC4-R interacting moiety is represented by the formula
(XIV) below, when s is absent:
Figure imgf000020_0002
(XIV)
For example, in another further embodiment, the MC4-R interacting moiety may be bicyclic, e.g., biheterocyclic, for example, quinoxalinyl. The language "linked to form a ring" refers to moieties covalently connected through a chain of atoms (e.g., carbon atoms and/or heteroatoms). The chain of atoms can comprise any number of atoms, which allow the MC4-R binding moiety to perform its intended function. In a further embodiment, the chain of atoms is selected such that a ring with three, four, five, six, seven, or eight members are formed. The ring that can be formed may be spiro (e.g., connected through the same carbon atom), fused (connected through adjacent carbon atoms), or bridged (e.g., connected through carbon atoms which are neither identical nor adjacent). In an embodiment, R and t are linked, e.g., to for a bicyclic moiety. Examples of bicyclic moieties include, but are not limited to, imidazopyridinyl, pyrolloimidazolyl, cyclopentaimidazolyl, pyridopyrimidinyl, etc.
In a further embodiment R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy. In another further embodiment, s is CR5R6 and R5 and R6 are each methyl. In another further embodiment, r is a covalent bond, and at least one oft and s are CH2. In another, t, r, and s are each CH2. In another, r is a covalent bond, and t and s are linked through a 4 carbon chain. In another further embodiment, at least one R group is OH. In an embodiment, r is a covalent bond, t is CR3R4, and s is CR5R6, wherein R3, R4, R5 and R6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).
Examples of MC4-R interacting moieties include, but are not limited to, the following structures:
Figure imgf000021_0001
In another embodiment, the invention pertains to a method for treating an MC4- R associated state in a mammal, by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. Examples of MC4-R binding compounds include compounds comprising the formula (II):
B-A-E (II) wherein:
B is a anchor moiety; A is a cyclic moiety; and E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
The MC4-R binding compounds of formula (II), may further comprise linking moieties, Li and L2. Such MC4-R binding compounds include compounds ofthe formula (III):
B-Lι-A-L2-E (III)
wherein B is an anchor moiety (as described above), Li and L2 are linking moieties, A is a cyclic moiety (as described above), and E is a MC4-R interacting moiety. Pharmaceutically acceptable salts ofthe MC4-R binding compound are also included.
The language "linking moiety" includes moieties which link, preferably covalently, the MC4-R interacting moiety, the cyclic moiety, and the anchor moiety of the invention. Examples of linking moieties include covalent bonds, 1-10 atom chains which may be branched or unbranched, substituted or unsubstituted alkyl, heterocyclic, alkenyl, or alkynyl. The chains may be substituted with 0-3 heteroatoms or other moieties which allow the MC4-R binding compound to perform its intended function. Examples of suitable heteroatoms include sulfur, oxygen, nitrogen, and phosphorous. The invention contemplates MC4-R binding compounds which comprises more than two linking moieties.
In an embodiment, \ is a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms. In an embodiment, Lj is selected from the group consisting of a covalent bond, Cι-C6, CrC5, Cι-C4, C1-C3, C\- C2, branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms. In a further embodiment, Li is a thioether (e.g., -S-CH2-, S- CH(CH3)-, -CH2-S-CH2, -S-, or -S-CH-(C6H5)-.), an ether (e.g., -O-CH2 or -CH2-O- CH2-), a sulfoxide, a sulfone, an amine (e.g., -NH-, -NH-CH2-, -NMe-CH2-, CH2-NH- CH2-, etc.) or alkyl (e.g., -CH2-CH2-, -CH2-, or -CH2-CH2-CH2- ). In another embodiment,
Figure imgf000023_0001
comprises a sulfonyl group. Furthermore, Li can be substituted or unsubstituted (e.g., a hydrogen can be replaced by another moiety), such that the MC4-R binding compound is capable of performing its intended function, e.g., bind to or interact with the MC4-R. Examples of substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, aryl heteroaryl moieties, or combinations thereof.
In an embodiment, examples of L2 include a covalent bond, a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms. In an embodiment, \ is selected from the group consisting of a covalent bond, CpC , C)-C5, Cι-C4, Cι-C3, Cj-C2, branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms.. In a further embodiment, L2 is a covalent bond, -CH2- or -NH-. Furthermore, L2 may also comprise one or more carbonyl groups. For example, L linkers include substituted urea groups (NH-C=O- NH), oxycarbonylamino groups (-O-C=O-NH), thiocarboynl groups, etc. Furthermore, like Lj, L2 can be substituted with any substituent such that the
MC4-R binding compound is capable of performing its intended function. Examples of substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl, aryl and heteroaryl moieties. In a further embodiment, the MC4-R binding compound is of formula (III) (e.g., B-L!-A-L2-E), wherein B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, thiol, thioether, thioalkyl, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido;
Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or more ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, thienyl, pyridinyl, etc.), bicyclic (e.g., methylenedioxyphenyl, isoindole, indole, and indan )or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido; L2 is a covalent bond, a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms. In an embodiment, Li is selected from the group consisting of a covalent bond, Cι-C6, Cι-C5, C1-C4, C1-C3, Ci- C2, branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, substituted or unsubstituted amino (e.g., -NH-, -NH-CH2), ether, thioether, or alkyl (e.g., C1-C10, -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-, etc.);
E is unsubstituted amino, unsubstituted and substituted alkylamino (e.g., 3- aminopropylamino), dialkylamino (e.g., dimethyl amino, diethyl amino), amidino, guanidino, heterocyclic (e.g., substituted and unsubstituted imidazolyl, imidazolinyl, piprazinyl, morpholinyl, piperidinyl, imidoazopyridinyl, pyrolloimidazolyl, pyridinyl, or pyrimidinyl) moieties, aryl (e.g., phenyl, heteroaromatic, e.g., substituted and unsubstituted pyrazinyl, imidazolyl, quinoxalinyl, or pyrimidinyl), wherein said substituents include, but are not limited to, amino (e.g., unsubstituted amino, alkylamino, dialkyl amino), aminoalkyl (e.g., methylamino, ethylamino, propylamino, etc.), alkyl (e.g., branched and straight chain, substituted and unsubstituted (e.g., carboxy, hydroxy, halogen, amino, cyano, nitro, etc. substituted), methyl, ethyl, propyl, butyl, etc.), aryl (e.g., phenyl, heteroaromatic), alkenyl (e.g., branched or straight chain, substituted or unsubstituted), alkynyl, etc, and pharmaceutically acceptable salts thereof. In another embodiment, the invention pertains to a method for treating an MC4-
R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. In an embodiment, the compound is ofthe formula (IV):
Figure imgf000025_0001
(IV) wherein
A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, pyridinyl, etc.), or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n- butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido;
B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, thiol, thioether, thioalkyl, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido;
Li and L2 are selected from the group consisting of a covalent bond, C C4 branched or unbranched, substituted or unsubstituted alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH2, CHR1, CR^2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CHR5, CR5Rό or absent (e.g., leaving a non-cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, Li, or L ;
R1, R2, R3, R4, R5, and R6 are each substituted or unsubstituted alkyl, halogen, thiol, thioether, thioalkyl, alkoxy, and may be optionally linked to each other to form additional ring moieties, e.g., quinoxalinyl. Pharmaceutically acceptable salts of the MC4-R binding compounds are also included. In one further embodiment, A is substituted or unsubstituted phenyl. Examples of substituents include halogens (e.g., fluorine, chlorine, iodine, bromine), alkoxy, alkyl (e.g., methyl, trifluoromethyl), and amino moieties. In other embodiments, A is heteroaromatic, (e.g., thienyl), or biaryl, (e.g., napthyl or quinoxalinyl). The invention also pertains to methods for treating an MC4-R associated state in a mammal comprising by administering an effective amount of a MC4-R binding compound ofthe formula (V):
λ
B L, π L2 E (V) B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, thiol, thioether, thioalkyl, cyano, or nitro; L\ is a covalent bond, Cι-C10 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl;
L3 is a covalent bond, Cι-C6 branched, unbranched or cyclic alkyl (wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or an aminothiocarbonyl moiety; and
A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and λ is 0, 1 or 2, and pharmaceutically acceptable salts thereof. Examples of MC4-R binding compounds with this structure include, but are not limited to, compounds, wherein π is a carbon atom, L3 is aminocarbonyloxy, A is substituted aryl, λ is one, Li and L2 are each CH2, and B and E are each pipridinyl. Examples of substituents for A include but are not limited to, alkoxy (e.g., Ci-Cio alkoxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy), cyano, halogens (e.g., fluorine, chlorine, bromine, iodine), alkyl (e.g., straight or branched chain, etc.), aryl, alkenyl, alkynyl, nitro, amino, or any other substituents which enables the MC4-R binding compound to perform its intended function, e.g., treat an MC4-R associated state.
Other examples of compounds of formula (V) include, but are not limited to, compounds wherein π, L and L3 together are a single covalent bond, E is alkyl, and B is substituted or unsubstituted heterocyclic. In other compounds of formula (V), ϋ is a nitrogen atom, L2, Li and L3 are each alkyl, E is substituted amino (e.g., alkyl substituted), or heterocyclic (e.g., piprazinyl, piperidinyl, morpholinyl, etc.) and B and A are each aryl (e.g., phenyl, anthracenyl, biaryl, e.g., naphthyl).
In another further embodiment, the invention pertains to yet another method for treating an MC4-R associated state in a mammal by administering to a mammal an effective amount of a
Figure imgf000028_0001
wherein pi p2 ^ p3 ^ an(j p4 are 0ptionaUy substituted carbon, sulfur, or nitrogen, and wherein one of P1, P2, P3, and P4 may represent a covalent bond;
Z1, Z2, Z3, Z4, and Z5 are optionally substituted carbon or nitrogen; L1 is a covalent bond, Cj-C branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof. Examples of substituents of P1, P , P3, P4, Z1, Z , Z , Z4, and Z5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n- propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido groups.
In a further embodiment, P1, P2, P3, and P4 are each substituted or unsubstituted carbon (e.g., CH). For example, P1 and P3 may be CH. In another further embodiment, P2 and P4 are each CH, CF, CCl, CBr, CI, C-aryl, C-alkyl (e.g., C-Me, C-ethyl, C-propyl, etc.) C-alkoxy (e.g., C-OMe, C-O-ethyl, C-OCF3, etc.). In a further embodiment, P2 is CH and P4 is CCl or CF. In an embodiment, P1 is a covalent bond, P2 and P3 are each optionally substituted carbon, and P4 is S (e.g., thienyl).
In a third further embodiment, Z3 and Z4 are each CH. In a fourth further embodiment, Z1 is CH, or covalently linked to Z2 to form a naphthyl ring. Examples of Z2 include CH, C-(C≡CH), CCl, CBr, CI, and CF. Furthermore, Z2 may be substituted with a chain of atoms which covalently links it to Z1 to form a naphthyl ring.
Examples of Z5 include, but are not limited to, CH and C-alkoxy. The term "C- alkoxy" includes carbon atoms covalently bound to an alkoxy group, as described below. Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc.
In yet another further embodiment, L2 is a covalent bond.
Examples of J include, but are not limited to, substituted or unsubstituted piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl, moφholinyl, or piperidinyl. Furthermore, J may be a substituted or unsubstituted fused ring or bridged heterocycle.
In a further embodiment, each of P1, P2, P3, and P4 are each optionally substituted carbon; Z1, Z2, Z3, Z4, and Z5 are each also optionally substituted carbon (e.g., alkoxy substituted, halogen substituted or linked to form a ring); wherein Li is either -S-CH -, or CH2-CH2. In a further embodiment, L2 is a covalent bond and J is a moiety of formula XIII, as described above.
In another embodime
Figure imgf000029_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, Ν, or substituted carbon; and
P1, P2, P3, P4, and P5 are CH, Ν or substituted carbon. Examples of substituents of Z1, Z2, Z3, Z4, Z5, P1, P2, P3, P4, and P5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido groups.
In a further embodiment, P1, P2, P3, P4 and P5 are each substituted or unsubstituted carbon (e.g., CH). For example, P and P may be CH. In another further embodiment, P2 and P4 are each CH, CF, CCl, CBr, or CI. Furthermore, P1, P2, P3, and P4 can be linked covalently to form a bicyclic ring.
In a third further embodiment, Z3 and Z4 are each CH.
In a fourth further embodiment, Z is CH, or covalently linked to Z to form a naphthyl ring. Examples of Z2 include CH, C-(C≡CH), CCl, CBr, CI, and CF.
Furthermore, Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
In a further embodiment, P5 is C-L2-J, wherein C is a carbon atom, L2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group. In yet a further embodiment, L is a covalent bond and J is a moiety of formula (XIII):
Figure imgf000030_0001
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, alkenyl, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L2, R1, R2, R3, R4, R5 , or R6 to form one or more rings; and
R1, R2, R3, R4, R5 , and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
In a further embodiment, compounds of formula VII also include compounds
wherein J is
Figure imgf000031_0001
wherein R is alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) or hydrogen. In another embodiment, the compounds include those in which P1, P2, and P3 are each CH, and P4 is CCl. Furthermore, the compounds also include those wherein Z1, Z3, and Z4 are each CH, Z5 is COMe, and Z2 is CBr, as well as those wherein Z1 is covalently linked to Z2 to form a naphthyl ring, and Z3, Z4 and Z5 are each CH.
In another embodiment, the MC4-R binding compound is of formula (VIII):
Figure imgf000031_0002
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; and P1 , P2, P3, P4, and P5 are CH, N or substituted carbon.
Examples of substituents of Z1, Z2, Z3, Z4, Z5, P1, P2, P3, P4, and P5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido groups. In a further embodiment, P1, P2, P3, and P4 are each substituted or unsubstituted carbon (e.g., CH). For example, P and P may be CH. In another further embodiment, P2 and P4 are each CH, CF, CCl, CBr, or CI. Furthermore, P1, P2, P3, and P4 can be linked covalently to form a bicyclic ring.
In a third further embodiment, Z3 and Z4 are each CH. In a fourth further embodiment, Z1 is CH, or covalently linked to Z2 to form a naphthyl ring. Examples of Z2 include CH, C-(C≡CH), CCl, CBr, CI, and CF. 1
Furthermore, Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
In a further embodiment, P5 is C-L2-J, wherein C is a carbon atom, L2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group. In yet a further embodiment, L2 is a covalent bond and J is a moiety of formula (XIII):
Figure imgf000032_0001
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, alkenyl, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L2, R1, R2, R3, R4, R5 j or R6 to form one or more rings; and
R1, R2, R3, R4, R5, and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, aryl, hydroxyl, nitro, amino, cyano, optionally linked to form a ring with R, R1, R2, R3, R4, R5 , or R6. In another embodiment, the invention pertains to MC4-R binding compounds of formulae VII and VIII. Examples of MC4-R binding compound of these formulae include, for example, compounds wherein P5 is a carbon covalently bonded to a moiety of formula XIII. In a further embodiment, the moiety of formula XIII is not benzoimidazole. In another further embodiment, Z3 is not ethoxy. In another embodiment, the invention pertains to both methods of using and MC4-R binding compounds of formula (IX):
Figure imgf000033_0001
wherein I P2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
P3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI; P4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI; G1 and G2 are each independently CH2, S, or O; r is a covalent bond or CH2; t is CH2, CHR3, or CR3R4; s is CH2, CHR5 or CR5R6; R is hydrogen alkyl, alkoxycarbonyl, or alkylcarbonyl;
1 9 Z is CH, or covalently linked to Z to form a naphthyl ring;
Z2 is CH, C-(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z5 is CH, C-alkoxy (e.g., C-OMe);
R3, R4, R5, and R6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, amino, or pharmaceutically acceptable salts thereof.
The language "linked to form a naphthyl ring" includes moieties which join Z1 and Z2 to form a naphthyl (fused) ring system. Examples of such Z1 and Z2 groups include, but are not limited to, -CH=CH-CH=CH-.
In a further embodiment, Z1 is CH; Z2 is CBr; and Z5 is C-OMe. In another further embodiment, P2 is CH. In another, P4 is CCl or CF. G' and G2 are each CH2. In another, G1 and G2 together are -CH2-CH2-, -CH2-O-, -O-CH2-, -CH2-
1 9
S- or -S-CH2-. In another, Z and Z are linked to form a naphthyl ring.
In an embodiment, r is a covalent bond, s is CR5R6, and t is CR3R4, wherein R3, R4, R5, and R6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl). In another embodiment, R is hydrogen or alkyl (e.g., methyl, ethyl, propyl or butyl, etc.) The
Figure imgf000034_0001
wherein
Z , Z , Z , Z , and Z are CH, Ν, or substituted carbon; P\ P2, P3, and P4 are CH, Ν or substituted carbon; and P5 is C-L2-J, wherein L2 is a covalent bond, alkyl (e.g., C1-C3), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
Figure imgf000034_0002
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5, or R6 to form one or more rings; and
R1, R2, R3, R4, R5 , and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
The invention also
Figure imgf000034_0003
wherein Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and P5 is C-L2-J, wherein L2 is a covalent bond, alkyl (e.g., Cι-C3), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
Figure imgf000035_0001
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 ; or R6to form one or more rings; and
R1, R2, R3, R4, R5, and R6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
The invention also
Figure imgf000035_0002
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and
P5 is C-L2-J, wherein L2 is a covalent bond, alkyl (e.g., C1-C3), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
Figure imgf000035_0003
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR^2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5, or R6to form one or more rings; and
R1, R2, R3, R4, R5, and R6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
The invention also pertains to MC4-R binding compound ofthe formula (XVI):
Figure imgf000036_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and P5 is C-L2-J, wherein L2 is a covalent bond, alkyl (e.g., C1-C3), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
Figure imgf000036_0002
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 , or R6to form one or more rings; and R1, R2, R3, R4, R5, and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
In a further embodiment, the invention includes compounds wherein P1, P2, P3, and P4 of any one of formulas VII, VIII, XV, or XVI are each substituted or unsubstituted carbon. For example, in one embodiment, P1 is CH. In another example, at least one of P2, P3 and P4 is a substituted carbon. In a further embodiment, P2, P3 and P4 are selected from the group consisting of CH, CF, Cl, CBr, C-alkyl, C-alkoxy, or CI. In another embodiment, the compounds of formulae VII, VIII, XV, or XVI, include compounds wherein Z3 and Z4 are each CH. In another further embodiment of the formulae, Z1 is CH. For example, in another further embodiment, Z1 is covalently linked to Z2 to form a naphthyl ring. Z2 is CH, C-(C≡CH), CCl, CBr, CI, and CF.
In another further embodiment, the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein L2 is a covalent bond. Also included are compounds wherein R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy.
In another further embodiment, the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein s is CR5R6 and R5 and R6 are each methyl. In another example r is a covalent bond. Alternatively, each of t, r and s may be CH2.
In one further embodiment, the MC4-R binding compounds of the invention of formula VII do not include benzoimadazole as the moiety of formula XIII, when P , P , P3, P4, Z1, Z2, Z4, Z3, and Z5 are each CH. Furthermore, in another further embodiment, the compounds ofthe invention do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, when P1, P2, P3, P4, Z1, Z2, Z4, and Z5 are each CH and Z3 is C-OEt or CH.
In another further embodiment, the MC4-R binding compounds ofthe invention of formula VIII, do not include compounds wherein the moiety of formula XIII is benzoimidazolyl. In another further embodiment, the MC4-R binding compounds ofthe
9 1 ~ invention of formula VIII, do not include compounds wherein P is not Cl, if P , P , or P4 are CH. In another further embodiment, the MC4-R binding compounds ofthe invention of formula VIII, do not include compounds wherein P1, P2, P3, P4, Z1, Z2, Z4, Z3, and Z5 are each CH, when the moiety of formula XIII is tetrahydropyrimidine. In another further embodiment, the compounds of formula VIII ofthe invention do not include compounds wherein the moiety of formula is 4,5-dihydro-lH-imidazole, when P1, P2, P3, and P4 are each CH, and wherein one or two of Z1, Z2, or Z3 is CCl, and the remaining Z groups are CH. In another further embodiments, the MC4-R binding compounds of formula VIII ofthe invention, do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, and when P1, P2, P3, and P4 are each CH, and Z2 is CCl and the remaining Z groups are CH. In another further embodiments, the compounds of formula VIII ofthe invention, do not include compounds wherein when the moiety of formula XIII is tetrahydropyrimidine, and when P1, P2, P3, and P4 are each CH, and Z1 and one of Z4 or Z5 are CCl and the remaining Z groups are CH.
In another further embodiment, the MC4-R binding compounds ofthe invention do not include compounds of formula XV, wherein the moiety of formula VIII is not benzoimidazole if P1, P2, P3, P4 are each CH, and wherein Z2 is CMe and the remaining Z groups are CH. In another further embodiment, the MC4-R binding compounds ofthe invention do not include compounds of formula XVI, wherein the moiety of formula XVI, wherein L2 is not NH (e.g., amino), if P1, P2, P3, P4, Z1, Z2, Z4, Z3, and Z5 are each CH. In another embodiment, the MC4-R binding compounds of formula XVI ofthe invention do not include compounds wherein P groups are substituted to form a naphthyl ring. In another embodiment, the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal. Compounds of formula (X) are also included in the invention. In this embodiment, the compound is ofthe formula (X):
Figure imgf000038_0001
wherein
Ar and Ar' are aromatic groups;
R11 is selected independently for each position capable of substitution from the group hydrogen, cyano, nitro, alkoxy, halogen, alkyl, amino, or aryloxy.
R12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
R13 is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl (e.g., CJ-CIQ alkyl, e.g., methyl, ethyl, etc.) acyl, carbonyl, or SO2CH3, and may optionally be linked to an R16 or an R16' group; R16 and R16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R13 or another R16 or R16 group, to form a fused or spiro ring system;
X is NR17, S, O or a covalent bond;
R17 is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic, or carbonyl;
R14 and R15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroaromatic, halogen, nitro, cyano, amino, or aryl, for each occurrence; w is O, 1, 2, 3, or 4; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof.
Examples of Ar groups include:
Figure imgf000039_0001
wherein R is acyl, alkyl or hydrogen.
In a further embodiment, Ar is, ,
Figure imgf000039_0002
R1 1 is selected independently for each aromatic position capable of substitution. Exemplary R11 groups include, but are not limited to, hydrogen, halogen (e.g., fluorine, chlorine, or bromine), alkyl, amino, and benzyloxy. Examples of Ar' groups include:
Figure imgf000040_0001
wherein R19 is hydrogen, alkyl, acyl, aryl, alkenyl, or alkynyl.
1
In a further embodiment, each R group is selected independently from the group consisting of hydrogen, alkoxy, halogen (e.g., fluorine, bromine, chlorine, or iodine), and cyano. Examples of alkoxy groups include Cι-Cι0 alkoxy, such as, methoxy, ethoxy, n-propoxy, i-propoxy, and cyclopentoxy.
Examples of X include covalent bond, S, O and NR . Examples of R include hydrogen, alkyl (e.g., Ci-Cio alkyl, e.g., methyl), or acyl.
Examples of R16 and R16 include alkyl and hydrogen. Each R16 and R16 group is selected independently for each occurrence. In a further embodiment, at least one of R16 or R16 are at least once hydrogen. In another embodiment, at least one of R16 or R 16' are at least once Cι-Cι0 alkyl, e.g., methyl or ethyl.
In yet another further embodiment, R14 and R15 are each independently hydrogen, alkyl (e.g., Ci-Cio, e.g., methyl) or phenyl for each occurrence. In yet another further embodiment, R is hydrogen, acyl, alkyl (e.g., Ci-Cio alkyl, e.g., methyl, ethyl, etc.) acyl, carboxy, or SO2CH3. Examples of acyl group include, but are not limited to, optionally substituted Cι-Cιoalkyl acyl (e.g., i- propylcarbonyl and benzylcarbonyl).
In yet another further embodiment, w is 2 or 3. In yet another further embodiment, e is 0 or 1. In yet another further embodiment, f is 0 or 1.
In another embodiment, the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal. In this embodiment, the compound is ofthe formula (XI):
Figure imgf000041_0001
wherein
Ar and Ar' are aromatic groups, as described above; R1 ' is selected independently for each position capable of substitution from the group hydrogen, halogen, alkyl, amino, cyano, or aryloxy.
19
R is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
X is NR17, S, O or a covalent bond; R17 is hydrogen, alkyl, acyl, heterocyclic, or carbonyl;
R14 and R15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, or aryl, for each occurrence;
R20 and R21 are each independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, hydrogen, or carbonyl, and may optionally be linked to form a heterocycle (e.g., moφhonlinyl, piperazinyl, piperidinyl, etc.); v is 0, 1, 2, 3, 4, 5, or 6; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof. Examples of Ar, Ar', R1 ', R12, R14, R15 and X moieties include those described for formula (X).
Other examples of MC4-R binding compounds include compounds ofthe formula (XVII
(XVIII)
Figure imgf000041_0002
wherein
Ar and Ar' are aromatic groups;
R1 ' is selected independently for each position capable of substitution from the group hydrogen, cyano, alkoxy, nitro, halogen, alkyl, amino, or aryloxy; R12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
1 '
R is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, acyl, carbonyl, or SO2CH3, and may optionally be linked to an R or an R group; R16 and R16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R13 or another R16 or R16 group, to form a fused or spiro ring system; X is NR17, S, O or a covalent bond; R17 is hydrogen, alkyl, or carbonyl;
R14 and R15 are each independently hydrogen, halogen, or alkyl; w is 1, 2, 3, or 4; e is 0 or 1 ; f is 0 or 1, wherein both e and fare not both 0 if X is a covalent bond, and pharmaceutically acceptable salts thereof.
Examples of Ar, Ar', R11, R12, R14, R15, R16 and R16' and X moieties include those described for formula (X).
The invention also pertains to the following compounds:
Figure imgf000042_0001
The invention also pertains to methods of using these compounds in methods for treating MC4-R associated states in a mammal by administering an effective amount of the compound to a mammal, such that the MC4-R associated state is treated, as well as pharmaceutical compositions comprising these compounds.
Other examples of MC4-R binding compounds include compounds ofthe formulae:
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000047_0004
and pharmaceutically acceptable salts thereof.
The invention also includes MC4-R binding compounds such as:
2-[2-(4-benzyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-iodo-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3-bromo-benzylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-[2-(2-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3-iodo-benzylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole;
2-{2-[2-(2-methoxy-naphthalen-l-yl)-ethyl]-phenyl}-l,4,5,6-tetrahydropyrimidine;
2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6,-tetrahydropyrimidine; 2-{2-[2-(2-methyl-naphthalen- 1 -yl)-ethyl]-phenyl} -1 ,4,5,6-tetrahydropyrimidine; 2-{2-[2-(2,3-dihydro-benzo[l,4]dioxin-5-yl) -ethyl]-phenyl}-l,4,5,6- tetrahydropyrimidine;
2-[2-(2-methoxy-napthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-(2-Benzylsulfanyl-phenyl)- 1 ,4,5,6-tetrahydro-pyrimidine; 2-(2-Pentadecylsulfanyl-phenyl)- 1 ,4,5,6-tetrahydro-pyrimidine;
2-(2-Cyclohexylmethylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro- 1 H-imidazole;
2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(Naphthalen- 1 -ylmethoxy)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-{2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}- ethanone;
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole;
2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH-benzoimidazole;
2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-[2-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline;
2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)-pyridin-3-yl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,3-Dihydro-benzo[l,4]dioxin-5-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(6-Methoxy-2,3-dihydro-benzo[l,4]dioxin-5-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; l-Methyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; 2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-yloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole;
2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; 2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-l ,4,5,6-tetrahydropyrimidine;
2- [2-(Biphenyl-3 -ylmethylsulfanyl)-phenyl] - 1 ,4,5 ,6-tetrahydro-pyrimidine;
2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(4,4'-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3'-Chloro-4'-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]- 1 ,4,5,6- tetrahydro-pyrimidine;
2-[2-(l-Naphthalen-l-yl-ethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-lH-imidazole;
2-(2-Benzhydrylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2'-Fluoro-4"-methoxy-[l,l';4,,l"]teφhenyl-3"-ylmethylsulfanyl)-phenyl]-l,4,5,6- tetrahydro-pyrimidine;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;
2-[4-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-propoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-moφholin-2-yl}- methylamine;
2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;
2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Ethoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Propoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]- benzonitrile; l-{4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl}- ethanone;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;
C- {4-[2-(2-Methoxy-naphthalen- 1 -ylmethylsulfanyl)-benzyl]-moφholin-2-yl } - methylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l, 5,6,7,8, 8a-hexahydro- imidazo[l ,5-a]pyridine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro-lH- pyrrolo[l,2-c]imidazole;
2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(Naphthalen- 1 -ylmethylsulfanyl)-3-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
1 - { 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl] -5 ,6-dihydro-4H-pyrimidin- 1 -yl } -
3 -methy 1-butan- 1 -one ; l-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}-
2-phenyl-ethanone;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine; 2-[2-(2-Isopropoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Cyclopentyloxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
(5-Bromo-2-methoxy-benzyl)-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-l,4,5,6-tetrahydro-pyrimidine; 2-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(6-Bromo-2-methoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2- [3 -Chloro-2-(2-methoxy-naphthalen- 1 -ylsulfanylmethy l)-phenyl]- 1 ,4,5 ,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[l -(2-Naphthalen- 1 -yl-ethyl)- 1 H-pyrrol-2-yl]- 1 ,4,5,6-tetrahydro-pyrimidine; (5-Bromo-2-methoxy-benzyl)-methyl-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]- amine;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;
2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-(2-o-Tolylsulfanylmethyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; 4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-moφholine;
3'-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-l-yl-6,7-dihydro-quinoxaline; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine; C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-moφholin-3-yl}- methylamine;
1 - [3 -Fluoro-2-(2-naphthalen- 1 -y 1-ethy l)-benzy 1] -piperazine ; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine; 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol;
[2-(Naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 1 -aza-bicyclo[2.2.2]oct-3-yl ester;
[2-(2-Methyl-naphthalen-l -ylmethylsulfanyl)-phenyl]-carbamic acid 1 -aza- bicyclo[2.2.2]oct-3-yl ester; [2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- ethyl ester;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}- methanol;
4-tert-Butyl-N-naphthalen- 1 -ylmethyl-N-(2-piperidin- 1 -yl-ethyl)-benzamide; N,N-Dimethyl-N'-naphthalen-2-ylmethyl-N'-naphthalen- 1 -ylmethyl-propane- 1,3- diamine;
N-(5-Bromo-2-methoxy-benzyl)-N',N'-dimethyl-N-naphthalen- 1 -ylmethyl-propane- 1,3- diamine;
1 -Naphthalen- 1 -ylmethyl-3 -phenethyl- 1 -(2-piperidin- 1 -y l-ethyl)-thiourea; 3-(4-Dimethylamino-phenyl)-l-(3-dimethylamino-propyl)-l-naphthalen-l-ylmethyl- thiourea;
4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-l- carboxylic acid ethyl ester;
2-[2-(2-Naphthalen-l-yl-ethyl)-phenyl]-ethylamine; Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen-l-ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
(2-Hexyloxy-phenyl)-carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmethyl-ethyl ester;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-pyrrolidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-piperidine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-propan-l-ol;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-l-ol; 1 - [2-(5 -Bromo-2-methoxy-benzy lsulfanyl)-benzy 1] -pyrrolidin-3 -ol ;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}-methanol;
{l-[2-(Naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-pyrrolidin-l-yl]-ethyl-N-pyrrolidine; N-pyrrolyl-[ 1 -(2-naphthalen- 1 -yl-ethyl)-pyrrolidin-2-ylmethyl]-amine; l-(2-Naphthalen-l-yl-ethyl)-piperidine-2-carboxylic acid methyl ester;
(3 -Bromo-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -y lmethyl-amine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;
(5-Bromo-2-methoxy-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -ylmethyl- amine;
( 1 -Ethyl -pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
(3 -Bromo-benzyl)-(3 -imidazol- 1 -yl-propyl)-naphthalen- 1 -ylmethyl-amine;
(3-Imidazol- 1 -yl-propyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine; [2-(Naphthalenl -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin-l -yl-1 -piperidin-
1-ylmethyl-ethyl ester;
[2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid 2-dimethylamino-ethyl ester; l-[2-(Naphthalen-l-ylsulfanylmethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(naphthalen-l-ylsulfanylmethyl)-benzyl]- amine; l-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-benzyl]-piperazine;
N,N-Dimethyl-N'-(2-naphthalen- 1 -yl-ethyl)-N'-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol; 1 -[2-(2-Naphthalen- 1 -yl-ethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine;
1 -[3-Fluoro-2-(2-naphthalen- 1 -yl-ethyl)-benzyl]-piperazine;
{ 1 - [3 -Chloro-2-(naphthalen- 1 -ylsulfanylmethyl)-benzyl] -piperidin-2-yl } -methanol;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol; {l-[2-(2-Naphthalen-l-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine;
1 -[2-(2-Naphthalen- 1 -yl-ethyl)-benzyl]-pyrrolidin-3-ylamine; l-Phenyl-3-piperazin-l-yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(2-Naphthalen- 1 -yl-ethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[3-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(4-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5-dihydro- lH-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl-l, 4,5,6- tetrahydro-pyrimidine; 2-[3-(Naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-fluoro-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-4,5-dihydro- 1 H-imidazole;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Bromo-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[4-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}-l, 4,5,6- tetrahydro-pyrimidine ;
2-[2-(2-Naphthalen-l-yl-ethyl)-3-trifluoromethyl-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(6-Fluoro-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; { 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl} -methanol;
2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-l-yl)- propyl]-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine; \ -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine;
5,5-Dimethyl-2-[2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-l H-imidazole;
2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5- dihydro- 1 H-imidazole; 3-(2-Naphthalen-l -yl-ethyl)-2-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;
Amino-[2-(2-naphthalen- 1 -yl-ethyl)-phenyl]-acetonitrile;
1 -[2-(2-Naphthalen-l -yl-ethyl)-phenyl]-ethane-l ,2-diamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-l-methyl-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4- dimethyl-4,5-dihydro-l H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5- dimethyl-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Methoxy-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[2-(l-Methyl-2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine;
2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -methyl-phenyl } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[3-Methoxy-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-Chloro-6-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol; 2-[3 -Methoxy-2-(naphthalen- 1 -ylsulfanylmethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidin-
5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5-dihydro-
1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5- dihydro-1 H-imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]- 1,4,5,6- tetrahydro-pyrimidine;
4,4-Dimethyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2- [5 -(5 -Bromo-2-methoxy-benzyl)-2-methy l-thiophen-3 -y 1] - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}-l, 4,5,6- tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- benzonitrile;
2-{3-Benzyloxy-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2- { 5 - [2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -2 ,3 -dihy dro-benzo [1,4] dioxin-6-y 1 } -
1 ,4,5,6-tetrahydro-pyrimidine;
2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[l,4]dioxin-6- yl}-l ,4,5,6-tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2- {2- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -3 -butoxy-pheny 1 } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-l, 4,5,6- tetrahydro-pyrimidine ;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-l, 4,5,6- tetrahydro-pyrimidine ;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[3-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-4,5-dihydro- 1 H-imidazole;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1-carboxylic acid l-acetoxy-2-mefhyl-propyl ester;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1-carboxylic acid 1-acetoxy-ethyl ester; 3-(5-Bromo-2-methoxy-phenyl)-5-chloro-3,4-dihydro-isoquinolin- 1 -ylamine;
2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-l,4,5,6- tetrahydro-pyrimidin-5 -ol ; 2-[(5-Bromo-2-methoxy-phenyl)-(3-piperidin- 1 -yl-propylamino)-methyl]-3-chloro-6- methyl-phenol; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl} -diethyl-amine;
3-(5-Bromo-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole;
(l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)- methanol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine; l-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-lH-isoindole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1-carboxylic acid 1-acetoxy-ethyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{ 2- [2-(5-Bromo-2 -methoxy -pheny l)-ethy 1] -3 -fluoro-benzy 1 } -diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -fluoro-benzyl } -piperidin-2-yl)- methanol;
4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl- 1 ,2,3 ,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine; {2- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-benzyl } -diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole;
( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -chloro-benzyl } -piperidin-2-yl)- methanol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l ,4,5,6-tetrahydropyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;
1 -(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro- 1 H-isoindole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1-carboxylic acid 1-acetoxy-ethyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine; 4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-4,5-dihydro-lH- imidazole; { 2-[3 -(5 -Bromo-2-methoxy-phenyl)-3 ,4-dihydro- 1 H-isoquinolin-2-yl]-ethyl } -diethyl- amine; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-ethanone; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1-carboxylic acid ethyl ester;
2- { 2- [2-(5 -Bromo-2-methoxy-pheny l)-ethyl] -3 -chloro-pheny 1 } -4, 5 -dihydro-imidazole-
1-carboxylic acid isobutyl ester; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1-carboxylic acid tert-butyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one; l-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-lH-isoindole; 1 -(2-Methoxy-benzyl)-2-methyl-2,3-dihydro- 1 H-isoindole;
2-Methyl- 1 -naphthalen- 1 -ylmethyl-2,3-dihydro- 1 H-isoindole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}-2,2- dimethyl-propan- 1 -one;
{ 2- [ 1 -(5 -Bromo-2-methoxy-benzy 1)- 1 ,3 -dihydro-isoindol-2-yl]-ethyl } -diethyl-amine; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-methyl-l,4,5,6-tetrahydro- pyrimidine;
2- [3 -Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl] -5,6-dihydro-4H-pyrimidine- 1 - carboxylic acid tert-butyl ester;
2- [3 -Chloro-2-(2 -naphthalen- 1 -yl-ethyl)-phenyl] -4,5 -dihydro- 1 H-imidazole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}- ethanone;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid isobutyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid tert-butyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid ethyl ester;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl- benzamide; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-ethyl-4,5-dihydro-lH-imidazole; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-2,2-dimethy 1-propan- 1 -one;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-lH-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine- 1 -carboxylic acid isobutyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isocyanomethyl-4,5- dihydro- 1 H-imidazole; 2- {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl} - 1 -methyl-4,5-dihydro- 1 H- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-ethyl-4,5-dihydro-lH- imidazole; 3-(5-Bromo-2-methoxy-benzyl)-2-methyl-2,3-dihydro-isoindol-l-one;
4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-propyl-4,5-dihydro-
1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a- hexahydro- 1 H-benzoimidazole;
5,5-Dimethyl-2-[2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro-
1 H-imidazole; N-(5-Bromo-2-methoxy-benzyl)-N'-methyl-N-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-l,4,5,6- tetrahydro-py rimidine ;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N'-trimethyl-benzamidine; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-methyl-4,5-dihydro-lH-imidazole; l-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-
1 H-imidazole;
({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-l-yl- methy lene)-methy 1-amine ; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isopropyl-4,5-dihydro-
1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-(2,2,2-trifluoro-ethyl)-
4, 5 -dihy dro- 1 H-imidazole ;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine, and pharmaceutically acceptable salts thereof.
Other compounds ofthe invention are shown in Table 4.
In one further embodiment, the methods ofthe invention do not include methods wherein 2-[2-(2,5-dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]- 1, 4, 5, 6-tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-
(2-diethylaminoethyl)-urea (Compound AN); 2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]-
1, 4, 5, 6-tetrahydropyrimidine (Compound AO); l-(4-hydroxy-l, 3, 5-trimethyl- piperadin-4-yl)-ethanone (Compound AR); 4,6-dimethyl-2-piperazin-l-yl-pyrimidine (Compound FP); 2-piperazin-l-yl-pyrimidine (Compound FR); l-pyridin-2-yl- piperazine (Compound FS); 2-piperazin-l-yl-4-trifluoromethyl pyrimidine (Compound FT); 6-piperazin-l-yl-7-trifluoromethyl-thieno [3 ,2-b]pyridine-3 -carboxylic acid methyl ester (Compound FU); 5-bromo-2-piperazin-l-yl)-pyrimidine (Compound FV); l-(3- trifluoromethyl-pyridin-2-yl)-piperazine (Compound FW); l-(5-trifluoromethyl-pyridin- 2-yl)-piperazine (Compound FX); piperazine (Compound KY); or (2-Hexyloxy-phenyl)- carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmethyl-ethyl ester (Compound OQ) are used as MC4-R binding compounds. In another further embodiment, the compounds claimed as MC4-R binding compounds do not include those listed above. In another embodiment, the methods ofthe invention do not include methods wherein 2-naphthalen- 1 -ylmethyl-4,5-dihydro- 1 H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l-methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl-10H- phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro- phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5- dihydro-1 H-imidazole (TOLAZOLINE; Compound AZ) are used as MC4-R binding compounds. In another further embodiment, the invention pertain to compounds other than those listed above as MC4-R binding compounds.
In another further embodiment, the methods ofthe invention do not include 5-(4- chloro-phenyl)-2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT) as an MC4-R binding compound. In one embodiment, the compounds ofthe invention include MC4-R binding compounds other than MASPINDOL.
The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In an embodiment, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., Ci-Cio for straight chain, C3-C10 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromefhyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc.
The term "aryl" includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, imidazoline, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, isoindole, indan or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin). The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C5 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C2-C includes alkenyl groups containing 2 to 6 carbon atoms.
Moreover, the term alkenyl includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C5 for branched chain). The term C2-C6 includes alkynyl groups containing 2 to 6 carbon atoms.
Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. The term "acyl" includes compounds and moieties which contain the acyl radical
(CH3CO-) or a carbonyl group. The term "substituted acyl" includes acyl groups where one or more ofthe hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. The term "aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms. The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cyclic groups such as cyclopentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom such as alkyl aminos, alkenyl aminos, dialkyl aminos, aryl aminos, acyl aminos, etc. The term "alkyl amino" includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group and is included in the term "amino." The term "dialkyl amino" includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups and is included in the term "amino." The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively, and are included in the term "amino." The term "alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group and is included in the term "amino."
The term "amide" or "aminocarboxy" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarboxy" groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "carboxy moiety" or "carbonyl moiety" refers to groups such as "alkylcarbonyl" groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl" groups wherein an alkynyl group is covalently bound to a carbonyl group, "arylcarbonyl" groups wherein an aryl group is covalently attached to the carbonyl group. Furthermore, the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon ofthe carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom are both bond to the carbon ofthe carbonyl group (e.g., also referred to as a "carbamate"). Furthermore, aminocarbonylamino groups (e.g., ureas) are also include as well as other combinations of carbonyl groups bound to heteroatoms (e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms). Furthermore, the heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties. The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. The term "thiocarbonyl moiety" includes moieties which are analogous to carbonyl moieties. For example, "thiocarbonyl" moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc.
The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above.
The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
The term "thiol" includes groups with an -SH group. In certain embodiments, it may also include thioethers, thioalkyls, thioaryls, thiocarbonyl s, as described above. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O". The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
The terms "polycyclyl" or "polycyclic radical" include moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each ofthe rings ofthe polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. The term "heterocycle" or "heterocyclic" includes saturated, unsaturated, aromatic ("heteroaryls" or "heteroaromatic") and polycyclic rings which contain one or more heteroatoms. Examples of heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isooxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tetrazole, thiazole, thiophene, and triazole. Other heterocycles include moφholine, piprazine, piperidine, thiomoφholine, and thioazolidine. The heterocycles may be substituted or unsubstituted. Examples of substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be noted that the structure of some ofthe compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
In a further embodiment, the compound is an antagonist ofthe MC4-R. In another embodiment, the compound is an agonist ofthe MC4-R. Compounds which are agonists of MC4-R can be identified using the cAMP assay given in Example 5. The term "administering" includes routes of administration which allow the
MC4-R binding compound to perform its intended function, e.g. interacting with MC4- Rs and/or treating a MC4-R associated state. Examples of routes of administration which can be used include parental injection (e.g., subcutaneous, intravenous, and intramuscular), intraperitoneal injection, oral, inhalation, and transdermal. The injection can be bolus injections or can be continuous infusion. Depending on the route of administration, the MC4-R binding compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function. The MC4-R binding compound can be administered alone or wfth a pharmaceutically acceptable carrier. Further, the MC4-R binding compound can be administered as a mixture of MC4-R binding compounds, which also can be coadministered with a pharmaceutically acceptable carrier. The MC4-R binding compound can be administered prior to the onset of a MC4-R associated state, or after the onset of a MC4-R associated state. The MC4-R binding compound also can be administered as a prodrug which is converted to another form in vivo.
In one embodiment ofthe invention, the invention includes methods of treating an MC4-R associated state by administering the MC4-R binding compound ofthe invention in combination with art recognized compounds, e.g., therapeutic agents. For example, a patient suffering from cachexia resulting from HIV, may be treated using both the MC4-R binding compounds ofthe invention in combination with art recognized compounds for treating the cachexia or HIV itself. The term "combination with" includes both simultaneous administration as well as administration ofthe MC4-R binding compound before the art recognized compound or after the compound. The period between administrations ofthe MC4-R binding compound and the other agent may be any length of time which allows the compositions to perform their intended function, e.g., the interval may be between few minutes, an hour, more than one hour, etc. In addition, the MC4-R binding compounds may also be administered in combination with other MC4-R binding compounds ofthe invention.
The invention also features a pharmaceutical composition for the treatment of a MC4-R associated state in a mammal. The pharmaceutical composition includes a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound ofthe formula (I):
B-Z-E (I)
wherein B is an anchor moiety, Z is a central moiety, and E is a MC4-R interacting moiety. In other embodiments, the pharmaceutical compositions ofthe invention include MC4-R binding compounds of formulae II, III, IV, V, VI, VII, VIII, IX, X, and/or XI. Pharmaceutical compositions comprising pharmaceutically acceptable salts of at least one MC4-R binding compound are also included.
The language "effective amount" ofthe compound is that amount necessary or sufficient to treat or prevent a MC4-R associated state, e.g. prevent the various moφhological and somatic symptoms of a MC4-R associated state. The effective amount can vary depending on such factors as the size and weight ofthe subject, the type of illness, or the particular MC4-R binding compound. For example, the choice of the MC4-R binding compound can affect what constitutes an "effective amount". One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount ofthe MC4-R binding compound without undue experimentation. An in vivo assay as described in Example 4 below or an assay similar thereto (e.g., differing in choice of cell line or type of illness) also can be used to determine an "effective amount" of a MC4-R binding compound. The ordinarily skilled artisan would select an appropriate amount of a MC4-R binding compound for use in the aforementioned in vivo assay. Advantageously, the effective amount is effective to treat a disorder associated with pigmentation, bones (e.g., osteoporosis, osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, bone formation, bone remodeling, bone healing, or the depletion of calcium in bone, such as that which is related to primary hypeφarathyroidism) or weight loss, e.g., weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
The regimen of administration can affect what constitutes an effective amount. The MC4-R binding compound can be administered to the subject either prior to or after the onset of a MC4-R associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages ofthe MC4-R binding compound(s) can be proportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.
The term "treated," "treating" or "treatment" includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder. The language "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds ofthe present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The phrase "pharmaceutically acceptable carrier" is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds ofthe present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion ofthe body, to another organ, or portion ofthe body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients ofthe formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations ofthe present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount ofthe compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound ofthe present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound ofthe present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound ofthe present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms ofthe invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absoφtion accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms ofthe pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical -formulating art. They may also be formulated so as to provide slow or controlled release ofthe active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incoφorating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients. Liquid dosage forms for oral administration ofthe compounds ofthe invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert dilutents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
Formulations ofthe pharmaceutical compositions ofthe invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds ofthe invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations ofthe present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound ofthe present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absoφtion enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds ofthe invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood ofthe intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions ofthe invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absoφtion ofthe injectable pharmaceutical form may be brought about by the inclusion of agents which delay absoφtion such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absoφtion ofthe drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amoφhous material having poor water solubility. The rate of absoφtion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absoφtion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such as polylactide-polyglycolide.
Depending on the ratio of drug to polymer, and the nature ofthe particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
The preparations ofthe present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless ofthe route of administration selected, the compounds ofthe present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions ofthe present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels ofthe active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity ofthe particular compound ofthe present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician or veterinarian could start doses ofthe compounds ofthe invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound ofthe invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses ofthe compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats an MC4-R associated state. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
While it is possible for a compound ofthe present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition. As set out above, certain embodiments ofthe present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" is art recognized and includes relatively non-toxic, inorganic and organic acid addition salts of compounds ofthe present invention. These salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). In other cases, the compounds ofthe present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances includes relatively non-toxic, inorganic and organic base addition salts of compounds ofthe present invention. These salts can likewise be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The term "pharmaceutically acceptable esters" refers to the relatively non-toxic, esterified products ofthe compounds ofthe present invention. These esters can be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst. Hydroxyls can be converted into esters via treatment with an esterifying agent such as alkanoyl halides. The term also includes lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters. (See, for example, Berge et al., supra.) A preferred ester group is an acetomethoxy ester group. Preferably, the amount ofthe MC4-R binding compound is effective to treat a pigmentation or weight loss disorder, e.g., weight loss associated with anorexia nervosa, old age, cachexia, HIV or cancer. The invention also pertains to packaged MC4-R binding compounds. The packaged MC4-R binding compounds include, an MC4-R binding compound (e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI), a container, and directions for using said MC4-R binding compound to treat an MC4-R associated state, e.g., weight loss, etc.
Examples of MC4-R binding compounds for inclusion in pharmaceutical compositions include, for example,
2-[2-(4-benzyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-[2-(2-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole;
2-{2-[2-(2-methoxy-naphthalen-l-yl)-ethyl]-phenyl}-l,4,5,6-tetrahydropyrimidine;
2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6,-tetrahydropyrimidine;
2- {2-[2-(2-methyl-naphthalen- 1 -yl)-ethyl]-phenyl} - 1 ,4,5,6-tetrahydropyrimidine; 2-{2-[2-(2,3-dihydro-benzo[l,4]dioxin-5-yl) -ethyl]-phenyl}-l,4,5,6- tetrahydropyrimidine ;
2-[2-(2-methoxy-napthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-(2-Benzylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-(2-Pentadecylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine; 2-(2-Cyclohexylmethylsulfanyl-phenyl)- 1 ,4,5 ,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro-l H-imidazole; 2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-ylmethoxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
1 - { 2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-5 ,6-dihydro-4H-pyrimidin- 1 -yl } - ethanone; 2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzo imidazole;
2- [2-(2-Iodo-benzylsulfanyl)-phenyl] -3 a,4,5 ,6,7,7a-hexahydro- 1 H-benzoimidazole;
2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-[2-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline; 2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)-pyridin-3-yl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,3-Dihydro-benzo[l ,4]dioxin-5-ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine; 2-[2-(6-Methoxy-2,3-dihydro-benzo[l,4]dioxin-5-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
1 -Methyl-2-[2-(naphthalen-l -ylmethylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; 2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2-(Naphthalen- 1 -yloxymethyl)-phenyl] - 1 ,4,5 ,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole;
2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(4,4'-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(3'-Chloro-4'-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-py rimidine ;
2-[2-(l-Naphthalen-l-yl-ethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-lH-imidazole; 2-(2-Benzhydrylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2'-Fluoro-4"-methoxy-[l, l';4',l "]teφhenyl-3"-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-py rimidine ;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;
2-[4-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzy 1] - 1 ,4,5 ,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2- [2-(5 -Bromo-2-propoxy-benzylsulfanyl)-phenyl]- 1 ,4,5 ,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-moφholin-2-yl}- methylamine; 2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;
2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Ethoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Propoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]- benzonitrile; l-{4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl}- ethanone;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
1 - [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzyl] -piperidine;
C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l, 5,6,7,8, 8a-hexahydro- imidazo[l ,5-a]pyridine; 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro- 1 H- pyrrolo[l ,2-c]imidazole;
2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(Naphthalen-l-ylmethylsulfanyl)-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-pheny 1]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}-
3-methyl-butan-l-one; l-{2-[2-(5 -Bromo-2-methoxy-benzylsulfany l)-phenyl] -5 ,6-dihydro-4H-pyrimidin- 1 -yl } -
2-phenyl-ethanone;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine;
2-[2-(2-Isopropoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Cyclopentyloxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
(5-Bromo-2-methoxy-benzyl)-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-l,4,5,6-tetrahydro-pyrimidine; 2-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(6-Bromo-2-methoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Chloro-2-(2-methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2- [ 1 -(2 -Naphthalen- 1 -yl-ethyl)- 1 H-pyrrol-2-yl] - 1 ,4,5 ,6-tetrahydro-pyrimidine;
(5-Bromo-2-methoxy-benzyl)-methyl-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]- amine;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;
2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-(2-o-Tolylsulfanylmethyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;
2- [2-(5 -Bromo-2-methoxy-benzy lsulfanyl)-benzyl] - 1 ,4,5 ,6-tetrahydro-pyrimidine; [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;
4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-moφholine;
3'-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-l-yl-6,7-dihydro-quinoxaline; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine; C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-moφholin-3-yl}- methylamine;
1 -[3 -Fluoro-2-(2 -naphthalen- 1 -yl-ethyl)-benzyl]-piperazine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol; [2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid l-aza-bicyclo[2.2.2]oct-3-yl ester;
[2-(2-Methyl-naphthalen-l -ylmethylsulfanyl)-phenyl]-carbamic acid 1 -aza- bicyclo[2.2.2]oct-3-yl ester; [2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- ethyl ester;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}- methanol; 4-tert-Butyl-N-naphthalen- 1 -ylmethyl-N-(2-piperidin- 1 -yl-ethyl)-benzamide;
N,N-Dimethyl-N'-naphthalen-2-ylmethyl-N' -naphthalen- 1 -ylmethyl-propane- 1 ,3- diamine;
N-(5-Bromo-2-methoxy-benzyl)-N',N'-dimethyl-N-naphthalen- 1 -ylmethyl-propane- 1 ,3- diamine; 1 -Naphthalen- 1 -ylmethy 1-3 -phenethyl- 1 -(2-piperidin- 1 -yl-ethyl)-thiourea;
3-(4-Dimethylamino-phenyl)- 1 -(3 -dimethylamino-propyl)- 1 -naphthalen- 1 -ylmethyl- thiourea;
4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-l- carboxylic acid ethyl ester; 2-[2-(2-Naphthalen-l-yl-ethyl)-phenyl]-ethylamine;
Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen- 1 -ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
(2-Hexyloxy-phenyl)-carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmefhyl-efhyl ester; 3 - [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzy loxy] -pyrrolidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-piperidine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyi)-benzylamino]-propan-l-ol;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-l-ol; 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ol;
{ 1 - [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzy 1] -pyrrolidin-2-yl } -methanol;
{ l-[2-(Naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-pyrrolidin- 1 -yl]-ethyl-N-pyrrolidine;
N-pyrrolyl-[l-(2-naphthalen-l-yl-ethyl)-pyrrolidin-2-ylmethyl]-amine; 1 -(2 -Naphthalen- 1 -yl-ethyl)-piperidine-2-carboxylic acid methyl ester;
(3-Bromo-benzyl)-(l-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-l-ylmethyl-amine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;
(5-Bromo-2-methoxy-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -ylmethyl- amine; (1 -Ethyl-pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
(3-Bromo-benzyl)-(3-imidazol- 1 -yl-propyl)-naphthalen- 1 -ylmethyl-amine;
(3 -Imidazol- 1 -yl-propyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine; [2-(Naphthalenl -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- 1 -piperidin-
1-ylmethyl-ethyl ester;
[2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid 2-dimethylamino-ethyl ester;
1 -[2-(Naphthalen- 1 -ylsulfanylmethyl)-berizyl]-piperazine; [3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(naphthalen-l-ylsulfanylmethyl)-benzyl]- amine;
1 - [3 -Chloro-2-(naphthalen- 1 -ylsulfanylmethyl)-benzy 1] -piperazine;
N,N-Dimethyl-N'-(2 -naphthalen- 1 -yl-ethyl)-N'-naphthalen- 1 -y lmethyl-ethane- 1 ,2- diamine; { 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl} -methanol; l-[2-(2-Naphthalen-l-yl-ethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine; l-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-benzyl]-piperazine;
{ l-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol; { 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3 -chloro-benzy l]-piperidin-2-yl} -methanol;
{ l-[2-(2-Naphthalen-l-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;
[3-(2-Methyl-piperidin- 1 -yl)-propyl]-[2-(2-naphthalen-l -yl-ethyl)-benzyl] -amine;
1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-benzyl]-pyrrolidin-3-ylamine; l-Phenyl-3-piperazin-l-yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenylJ-6-ethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(2-Naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5-dihydro-
1 H-imidazole;
2- [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-3 -fluoro-phenyl]-5 ,5-dimethyl- 1 ,4,5 ,6- tetrahydro-pyrimidine ;
2-[3-(Naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro-pyrimidine; 2- {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl } - 1 ,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2- [2-(5 -Bromo-2-methoxy-phenylsulfanylmethy l)-3 -fluoro-phenyl]- 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[3-Bromo-2-(naphthalen-l -ylsulfanylmethyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l,4,5,6-tetrahydro- py rimidine;
2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[4-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}-l, 4,5,6- tetrahydro-pyrimidine;
2- [2-(2 -Naphthalen- 1 -yl-ethyl)-3-trifluoromethyl-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine; 2-[2-(6-Fluoro-naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl}-methanol;
2- [3-Fluoro-2-(2 -naphthalen- 1 -yl-ethyl)-phenyl] - 1 ,4,5 ,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-l-yl)- propyl] -amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine;
5,5-Dimethyl-2-[2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-l H-imidazole;
2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5- dihydro- 1 H-imidazole;
3-(2-Naphthalen-l-yl-ethyl)-2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine; Amino-[2-(2-naphthalen- 1 -yl-ethyl)-phenyl]-acetonitrile;
1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-phenyl]-ethane- 1 ,2-diamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2- [3 -Fluoro-2-(naphthalen- 1 -y lsulfany lmethyl)-pheny 1] -5 ,5 -dimethyl-4, 5 -dihydro- 1 H- imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-l-methyl-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4- dimethyl-4,5-dihydro- 1 H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5- dimethyl- 1, 4,5, 6-tetrahydro-pyrimidine;
2-[3-Methoxy-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2- (5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]- 1 ,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[2-(l-Methyl-2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[3-Methoxy-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2- { 2- [2-Chloro-6-( 1 ,4,5,6-tetrahydro-pyrimidin-2-yl)-pheny l]-ethyl } -phenol ;
2- [3 -Methoxy-2-(naphthalen- 1 -ylsulfanylmethyl)-phenyl]- 1 ,4,5 ,6-tetrahydro-pyrimidin- 5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5-dihydro-
1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5- dihydro- 1 H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-l,4,5,6- tetrahydro-pyrimidine;
4,4-Dimethyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[5-(5-Bromo-2-methoxy-benzyl)-2-methyl-thiophen-3 -yl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-ρhenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2- {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}- 1 ,4,5,6- tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-l,4,5,6-tetrahydro- py rimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- benzonitrile;
2-{3-Benzyloxy-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-2,3-dihydro-benzo[l,4]dioxin-6-yl}-
1 ,4,5,6-tetrahydro-pyrimidine; 2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[l,4]dioxin-6- yl}-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -propyl-phenyl } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -isobutoxy-phenyl } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-l, 4,5,6- tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-l,4,5,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4.5-dihydro-lH- imidazole;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[3-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-4,5-dihydro-
1 H-imidazole;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide; N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide;
2- [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-3 -fluoro-phenyl]-5 ,6-dihydro-4H- pyrimidine-1 -carboxylic acid l-acetoxy-2-methyl-propyl ester;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; 3 -(5 -Bromo-2-methoxy-phenyl)-5 -chloro-3 ,4-dihydro-isoquinolin- 1 -ylamine;
2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine ;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-l, 4,5,6- tetrahydro-pyrimidin-5-ol; 2- [(5 -Bromo-2-methoxy-pheny l)-(3 -piperidin- 1 -yl-propylamino)-methyl]-3 -chloro-6- methyl-phenol; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine;
1 - { 2- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -6-methyl-benzyl } -4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-diethyl-amine;
3-(5-Bromo-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole; ( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -chloro-benzyl } -piperidin-2-yl)- methanol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;
1 -(5 -Bromo-2 -methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro- 1 H-isoindole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone;
1 - {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl} -4-methyl-piperazine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine; l-(2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -fluoro-benzyl } -piperidin-2-yl)- methanol;
4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole; (l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)- methanol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine; l-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-lH-isoindole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester;
1 -(2- {2- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-phenyl } -5 ,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{ 2-[2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -3 -fluoro-benzyl } -diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide; 3-(5-Bromo-2-methoxy-phenyl)-2 -methyl- 1 ,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-4,5-dihydro-lH- imidazole;
{ 2-[3-(5 -Bromo-2-methoxy-phenyl)-3 ,4-dihydro- 1 H-isoquinolin-2-yl] -ethyl } -diethyl- amine; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-ethanone;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid ethyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole- 1 -carboxylic acid isobutyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid tert-butyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one; 1 -(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-l H-isoindole; l-(2-Methoxy-benzyl)-2-methyl-2,3-dihydro-l H-isoindole;
2-Methyl-l-naphthalen-l-ylmethyl-2,3-dihydro-lH-isoindole; 1 - {2-[3-Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl]-4,5-dihydro-imidazol- 1 -yl} -2,2- dimethyl-propan- 1 -one;
{2-[l -(5-Bromo-2-methoxy-benzyl)-l ,3-dihydro-isoindol-2-yl]-ethyl} -diethyl-amine;
2-[3-Chloro-2-(2-naphthalen-l -yl-ethyl)-phenyl]-l -methyl-1 ,4,5,6-tetrahydro- pyrimidine;
2- [3 -Chloro-2-(2 -naphthalen- 1 -yl-ethyl)-phenyl] -5 ,6-dihydro-4H-pyrimidine- 1 - carboxylic acid tert-butyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-lH-imidazole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}- ethanone;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid isobutyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid tert-butyl ester; 2-[3-Chloro-2-(2 -naphthalen- 1 -yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid ethyl ester;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl- benzamide;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l -ethyl-4,5-dihydro-lH-imidazole; 1 -(2- { 2- [2-(5 -Bromo-2-methoxy-phenyl)-ethylJ-3 -chloro-phenyl } -5 ,6-dihydro-4H- pyrimidin- 1 -yl)-2,2-dimethyl-propan- 1 -one;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-lH-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid isobutyl ester; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isocyanomethyl-4,5- dihydro- 1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-ethyl-4,5-dihydro-lH- imidazole;
3-(5-Bromo-2-methoxy-benzyl)-2-methyl-2,3-dihydro-isoindol-l-one;
4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy -benzyl)- 1, 2,3, 4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-propyl-4,5-dihydro- 1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a- hexahydro- 1 H-benzoimidazole;
5,5-Dimethyl-2-[2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-lH-imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro- 1 H-imidazole;
N-(5-Bromo-2-methoxy-benzyl)-N'-methyl-N-naphthalen-l-ylmethyl-ethane-l,2- diamine; 2- { 2- [2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -3 -chloro-phenyl } - 1 -ethyl- 1 ,4, 5 ,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N'-trimethyl-benzamidine; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-methyl-4,5-dihydro-lH-imidazole; l-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- 1 H-imidazole;
({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-l-yl- methylene)-methyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isopropyl-4,5-dihydro- 1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-(2,2,2-trifluoro-ethyl)- 4,5-dihydro-l H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine, and pharmaceutically acceptable salts thereof. Also included are compositions containing the compounds listed in Table 4. In a further embodiment, the pharmaceutical compositions ofthe invention include compositions wherein the MC4-R binding compound is not 5-(4-chloro-phenyl)- 2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT).
In another embodiment, the pharmaceutical compositions ofthe invention include compositions wherein the MC4-R binding compound is not 2-naphthalen-l- ylmethyl-4,5-dihydro-l H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l- methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl- 1 OH-phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro-phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5-dihydro-l H-imidazole (TOLAZOLINE; Compound AZ). In another further embodiment, the pharmaceutical compositions ofthe invention includes compositions wherein the MC4-R binding compound is not 2-[2-(2,5- dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-(2- diethylaminoethyl)-urea (Compound AN); 2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]- 1 , 4, 5, 6-tetrahydropyrimidine (Compound AO); l-(4-hydroxy-l, 3, 5-trimethyl-piperadin- 4-yl)-ethanone (Compound AR); 4,6-dimethyl-2-piperazin-l-yl-pyrimidine (Compound FP); 2-piperazin-l-yl-pyrimidine (Compound FR); l-pyridin-2-yl-piperazine (Compound FS); 2-piperazin-l-yl-4-trifluoromethyl pyrimidine (Compound FT); 6- piperazin-l-yl-7-trifluoromethyl-thieno [3 ,2-b]pyridine-3 -carboxylic acid methyl ester (Compound FU); 5-bromo-2-piperazin-l-yl)-pyrimidine (Compound FV); l-(3- trifluoromethyl-pyridin-2-yl)-piperazine (Compound FW); l-(5-trifluoromethyl-pyridin- 2-yl)-piperazine (Compound FX); piperazine (Compound KY); or (2-Hexyloxy-phenyl)- carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmethyl-ethyl ester (Compound OQ).
The compounds ofthe present invention can be synthesized using standard methods of chemical synthesis and/or can be synthesized using schemes described herein. Synthesis of specific compounds is discussed in detail in the Example sections below. Examples of syntheses of several classes of compounds ofthe invention are outlined in the schemes below. Scheme 1 depicts a method of synthesizing thiomethylene compound ofthe invention.
Figure imgf000094_0001
Y = O or S; q = bond, CH2, fused-cyclchexane R = various alkyl, cycloalkyl, aryl or heteroaryl X = I, Br or CI
Scheme 1
2-hydroxy or 2-mercapto benzoic acid is heated with the diamine in refluxing 1 ,2-dichlorobenzene to form the corresponding heterocyclic compound. The desired thioether or ether is formed by treating the thiol or alcohol with a corresponding halogenated compound.
Scheme 2 depicts a general preparation of ethanyl-linked compounds ofthe invention.
Figure imgf000094_0002
1,3-diaminopropane, H S
Figure imgf000094_0003
Scheme 2
Scheme 2 shows a method of synthesizing ethanyl linked compounds by treating α-tolunitrile with a lithium base in THF at -78 °C. A halogenated alkylaryl compound is then added to form the ethanyl linkage. To form the heterocycle, hydrogen sulfide gas is bubbled through a solution ofthe nitrile and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
Scheme 3 depicts a method of preparing methylenethio linked compounds ofthe invention.
Figure imgf000095_0001
1,3-diaminopropane, H2S
Figure imgf000095_0002
Scheme 3
As depicted in Scheme 3, the methylenethio compounds ofthe invention can be prepared by adding anhydrous K2CO3 to a thiophenol compound (Ar-SH) in DMF. The solution is then stirred and bromomethyl-benzonitrile is subsequently added. The thioether is then converted to the heterocyclic compound by bubbling hydrogen sulfide through a solution ofthe thioether and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
Figure imgf000095_0003
Scheme 4
As depicted in Scheme 4, cyclic amidines ofthe invention can be prepared by reacting 2-substituted benzonitrile with hydrogen sulfide to form a thiobenzamide. The resulting thiobenzamide is then treated with iodoethane to give a thiobenzimidic acid ethyl ester. In the presence of hydrochloric acid, the thiobenzimidic acid ethyl ester is suspended in tetrahydrofuran and treated with hydrogen sulfide. The resulting dithiobenzoic acid ethyl ester is then heated with various diamines, in the presence or absence of an added catalyst such as silver trifluoroacetate, to give cyclic amidines.
The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all references, pending patent applications and published patent applications, cited throughout this application are hereby incoφorated by reference. It should be understood that the animal models used throughout the examples are accepted animal models and that the demonstration of efficacy in these animal models is predictive of efficacy in humans.
EXEMPLIFICATION OF THE INVENTION:
EXAMPLE 1: Synthesis of Compounds B, HO, and IZ
Synthesis of Compound B
2-(4,5-Dihydro-lH-imidazol-2-yl)-benzenethiol. To a suspension of 20.0 g (0.1 12 mol) of thiosalicylic acid in 200 mL of 1 ,2-dichlorobenzene was added 21.6 mL (0.323 mol) of ethylenediamine. The mixture was refluxed under nitrogen for 4 h then cooled to ca. 60 °C and 50 mL of methanol was added. The solution was allowed to stand at 22 °C over night and the resulting yellow crystalline solid collected and washed with ether to give 10.6 g of pure product.
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl1-l,4,5,6-tetrahydro-pyrimidine; hydrochloride (Compound B). To a solution of 750 mg (3.90 mmol) of 2-(l,4,5,6- Tetrahydro-pyrimidin-2-yl)-benzenethiol was added 1.04 g (5.81 mmol) of 1 -Chloro-2- chloromethyl-3-fluoro-benzene. The solution was stirred overnight at 22 °C and 2-3 mL of ether was added to induce crystallization. The crystals were collected and washed with ether to give 1.34 g of product.
NMR Data for Compound B
Η NMR (300 MHz, CD3OD) δ 2.01-2.09 (2H, m), 3.49 (4H, br t, J = 5.8 Hz), 4.28 (2H, s), 7.01-7.07 (IH, m), 7.22-7.33 (2H, m), 7.48 (2H, m), 7.56-7.64 (IH, m), 7.75 (IH, d, J = 7.8 Hz) Synthesis of Compound HO:
Figure imgf000097_0001
Compound HO
Figure imgf000097_0002
Scheme 5
2-(2-Naphthalen- 1 -yl-ethyl)-benzonitrile. A solution of 1.26 mL (911 mg, 9.00 mmol) of diisopropylamine in 50 mL of THF (tetrahydrofuran) was cooled to -78 °C under nitrogen and 5.6 mL (9.0 mmol) of «-butyllithium, 1.6 M in hexanes, was added via syringe. The mixture was stirred at -78 °C for 1 hour and a solution of 353 mg (3.00 mmol) of α-tolunitrile in 10 mL of THF was added. The solution was stirred at -78 °C for one additional hour and a solution of 1.57 mL (9.00 mmol) of HMPA and 583 mg (3.30 mmol) of 1-chloromethylnaphthalene in 10 mL of THF was added dropwise. After stirring for one additional hour at -78°C, the reaction was quenched with water and extracted with Et2O (diethyl ether) (2x30 mL). The organic layer was washed with aqueous 1 N HCI (30mL), water (3x30mL), brine (30mL) and dried (Na2SO4). The solvent was evaporated to give 735 mg of crude product which was used directly in the next step.
Figure imgf000097_0003
Scheme 6
2-[2-(2-Naphthalen-l-yl-ethyl)-phenyll-l,4,5,6-tetrahydro-pyrimidine (Compound IQ). Hydrogen sulfide gas was bubbled through a solution of 735 mg of crude 2-(2- Naphthalen-l-yl-ethyl)-benzonitrile in 5 mL of 1,3 -diaminopropane for 5 minutes, as depicted in Scheme 6. The reaction was capped and heated to 80 °C for 72 hours. The reaction mixture was then diluted with 5 mL of water and extracted with ethyl acetate (2x1 OmL). The organic extracts were washed with water (3x1 OmL), brine (2x1 OmL), dried (Na2SO4) and the solvent was evaporated. The residue was purified on silica gel (eluting with 90:10:1:1 of dichloromethane/methanol/water/formic acid) to afford 310 mg ofthe formate salt ofthe product as a colorless oil.
NMR Data for Compound HO: 'H NMR (300 MHz, CDC13) δ 1.35-1.50 (2H, m), 2.80-2.95 (4H, m), 3.03 (2H, t, J = 6.8), 3.30 (2H, t, J = 6.8), 6.77 (IH, d, J = 6.9), 7.03-7.30 (3H, m), 7.30-7.57 (4H, m), 7.67 (IH, d, J = 8.1), 7.80-7.90 (IH, m), 7.94-8.03 (IH, m), 8.06 (2H, brs, formate salt).
Synthesis of Compound IZ:
Figure imgf000098_0001
Compound IZ
Figure imgf000098_0002
Scheme 7
2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-benzonitrile. As depicted in Scheme 7 above, to a solution of 104 mg (0.470 mmol) of 2-methoxy-5-bromo-thiophenol in 5 mL of DMF was added 162 mg (1.18 mmol) of anhydrous to a solution of 104 mg (0.470 mmol) of 2-methoxy-5-bromo-thiophenol in 5 mL of DMF was added 162 mg (1.18 mmol) of anhydrous K2CO3. The solution was stirred for 15 minutes at 22 °C and 103 mg (0.520 mmol) of 2-bromomethyl-benzonitrile was added. The reaction was capped and heated to 40 °C for 12 hours. The mixture was subsequently diluted with 5 mL of water and extracted with ethyl acetate (2x1 OmL). The organic extracts were washed with water (3xl0mL), brine (2xl0mL), and dried (Na2SO4). The solvent was evaporated and the product was purified on silica gel (eluting with 9:1 of hexane/ethyl acetate) to afford 102 mg ofthe product as a colorless oil.
Figure imgf000099_0001
Scheme 8
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl1-l,4,5,6-tetrahydro- pyrimidine. (Compound DV) Compound DV was obtained from 2-(5-Bromo-2- methoxy-phenylsulfanylmethyl)-benzonitrile, 1,3-propanediamine and hydrogen sulfide in 73% yield by a procedure analogous to that used for the preparation of 2-[2-(2- Naphthalen-1 -yl-ethyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine described above. Following chromatography, the material was converted to the hydrochloride salt and recrystallized from methanol/ether.
NMR Data for Compound IZ
'H NMR (300 MHz, DMSO-d6) δ 1.95-2.10 (2H, m), 3.45-3.55 (4H, m), 3.86 (3H, s),
4.40 (2H, s), 6.97-7.04 (IH, m), 7.36-7.65 (6H, m), 10.03 (2H, s, hydrochloride salt).
Synthesis of Compound UZ:
Figure imgf000099_0002
Compound UZ
Figure imgf000099_0003
Scheme 9
9, 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzamide. As shown in Scheme 9, hydrogen sulfide gas was bubbled into a solution of 2.75 g (7.8 mmol) of 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzonitrile in 20 mL of ethanol and triethylamine (5:4 v/v) for 10 minutes. The solution was then heated to 80 °C in a sealed pressure tube for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate twice. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to give 3.0 g of crude product which was used directly in the next step.
Figure imgf000100_0001
Scheme 10 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl1-3-chloro-thiobenzimidic acid ethyl ester.
To a solution of 3.0 g (7.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro- thiobenzamide in 50 mL of acetone was added 6 mL (75 mmol) of iodoethane (Scheme
10). The reaction was heated to 80 °C for 2 hours and then stirred at room temperature overnight. A white solid precipitated out ofthe solution and was filtered to give 3.23 g ofthe iodide salt. The salt was neutralized by partitioning between CH2CI2 and 1 N aqueous sodium hydroxide. After drying (MgSO4) and evaporation ofthe organic layer,
2.8 g of crude powder was obtained which was used directly in the next step.
Figure imgf000100_0002
Scheme 11
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-dithiobenzoic acid ethyl ester. As shown in Scheme 11 , hydrogen sulfide gas (~2 mL) was condensed into a cooled (- 78 °C) solution of 2.8 grams (6.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3- chloro-thiobenzimidic acid ethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL of tetrahydrofuran. The reaction was heated to 45 °C and stirred overnight in a sealed tube. The reaction mixture was diluted with water and extracted with methylene chloride once. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to give a crude orange oil. The oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly in the next step.
Figure imgf000101_0001
Scheme 12
2-{2[2-(5-Bromo-2-methoxy-phenyl)-ethyπ-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro- lH-benzoimidazole (Compound UZ). As shown in Scheme 12, a solution of 187 mg (0.43 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-dithiobenzoic acid ethyl ester in 2.5 mL of trans-l, 2 diaminocyclohexane was heated to 110 °C in a sealed pressure tube for 12 hours. The reaction mixture was diluted with water and extracted with methylene chloride twice. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (eluting with 95:5 CH2Cl2/methanol) to give a yellow oil. The oil was treated with methanolic HCI and evaporated to yield 34 mg of product as a pure hydrochloride salt.
NMR Data for Compound UZ
Η NMR (300 MHz, CD3OD) δ 1.41-1.58 (2 H, br m), 1.64-1.80 (2 H, br m), 1.98 (2 H, br m), 2.30 (2 H, br m), 2.78-2.97 (2 H, m), 3.08 (1 H, m), 3.22-3.36 (1 H, m), 3.61 (2 H, m), 3.59 (3 H, s), 6.81 (1 H, d, J= 8.7 Hz), 7.21 (1 H, m), 7.34 (1 H, dd, J= 2.5, 8.6 Hz), 7.42 (2 H, m), 7.75 (1 H, dd, J= 2.3, 7.0 Hz).
The compounds given in Table 1 , were made using procedures similar to that used for Compound B. The ES-LRMS values each had a relative intensity of 100.
Table 1: Physical Data of Selected MC4-R Binding Compounds
Figure imgf000102_0001
Example 2: Scincillation Proximity Assay (SPA)
High-Throughput Receptor Binding Screening for MC4-R Binding Compounds A. Preparation of Membranes from MC4-R Cells A crude preparation of plasma membranes, of sufficient purity for use in the scincillation proximity assay (SPA), was prepared using the following protocol (Maeda et al. (1983) Biochem. Biophys. Acta 731 :115-120).
MC4-R cells were stable recombinant K293 cells overexpressing the MC4-R. The cells were routinely cultured and passaged in a growth medium composed of DMEM base medium: 10% fetal bovine serum (FBS), IX Glutamine, and 0.5 mg/ml G418. Terminal cultures (i.e., those which will be processed to produce plasma membranes) were grown in identical media, with the exception that the media contained 0.2 mg/ml G418.
At 4°C, harvested cells were pelleted and immediately washed with 25 mL of PBS. The washed cells were resuspended in two volumes of STM buffer (0.25 M sucrose, 5 mM Tris, 1 mM MgCl2, pH 7.5), containing Boehringer Complete™ protease inhibitors. Cell breakage was accomplished using a Dounce homogenizer. After 20-30 strokes, nuclei and unbroken cells were pelleted by centrifugation at 1100 rpm for 5 minutes. The supernatant was saved and the pellet was resuspended in 1 volume of STM/protease inhibitors, and then a further lysis step was carried out by the Dounce homogenizer (10-20 strokes). This material was then combined with the first supernatant. 11.25 mL ofthe homogenate was gently layered on top of 27.25 mL f 42% (w/w) sucrose (5 mM Tris, 1 mM MgCl2, pH 7.5). After spinning at 28,000 rpm (ultracentrifuge, SW-28 rotor) for 90 minutes, membranes were collected at the interface with a transfer pipette.
The membrane suspension obtained from the sucrose interface was collected and diluted with 5 mM Tris and 1 mM MgC - Membranes were collected by a further round of centrifugation at 33,000 rpm for 30 minutes (SW-41 Ti rotor). The pellet of membranes was subsequently resuspended in a small (0.5 mL) volume of STM, using a 2 mL Dounce homogenizer, and immediately frozen. The resulting membranes were stable to both freeze-thaw cycles and temperatures around 4°C for at least 6 hours.
B. High-throughput screen
A scincillation proximity assay (SPA) format ligand binding assay was used. The membranes from the MC4-R mammalian cells (K293 expressing MC4-R) were bound to wheat germ agglutinin (WGA) coated SPA beads. The membrane coated SPA beads were added to screening plates, which contained the test compounds pre-dissolved in 30μL of 10% DMSO. After pre-equilibration ofthe receptor coated beads with the test compounds (1 hour), 2nM of radioactive ligand ([ rl25 I]NDP-α-MSH) was added. Since the binding ofthe radioactive ligand to the receptor causes the scincillation ofthe beads, blockage ofthe binding ofthe radioactive ligand by a small molecule causes a reduction in scincillation.
1. Pre-Binding ofthe MC4R Membranes to the WGA-SPA beads
The membranes were mixed with the SPA beads to make a 2X stock of membrane and beads.
For a twenty plate batch of screening plates, the components were mixed in proportions given in Table 2. The membranes and beads were stirred with a magnetic stir bar at room temperature for 1-2 hours to allow binding.
Table 2
Figure imgf000104_0001
the exact amount of membranes used varies with the quality of the membrane preparation and must be checked for each new batch
2. Binding Assay
The following assay was performed with automation using a Titertec MultiDrop with plate stacker.
30 μL of 10% DMSO was added per well to the dried compound film in an OptiPlate. Then, 5μL of cold NDP-α-MSH was added to the control wells. Subsequently, 50μl per well of 2X membranes and beads were added and pre- equilibrated with the compounds for 1 hour.
Binding was initiated by adding 20μL of radioactive ligand (a 20 nM solution of [125I]-NDP-α-MSH) to each test well. The plates were incubated overnight at room temperature and read the following morning.
The reagents and amounts are summarized below in Table 3. Table 3
Figure imgf000105_0001
Test compound stock diluted in BuOH 1 : 10, 25 μL dried in assay plate in hood prior to addition of assay buffer. Well contained 0.5 nmol of each test compound (20/well) in 2.5 μL 100% DMSO.
Potency of inhibitors was quantified with respect to positive (100% inhibition) and negative (no inhibitor; 0% inhibition) controls. The following formula was used:
% Inhibition = {l-[cpm-(positive control)]/[(negative control)-(positive control)]}* 100%
Results from the SPA, are summarized in Table 4. In Table 4, * indicates good inhibition ofthe MC4-R, ** indicates very good inhibition ofthe MC4-R, and *** indicates exemplary inhibition ofthe MC4-R.
Compounds which were found to be not active as MC4-R binding compounds, using the SPA assay described herein, are depicted in Table 5.
In an embodiment, the present invention pertains to the compounds and methods described herein provided that the compound is not selected from the group consisting of those depicted in Table 5.
Table 4
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
ill
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
TABLE 5
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Example 3: cAMP Assay for MC4-R Antagonist Activity
Method MC4 Receptors are expressed in stably transfected K293 cells. The cells are incubated in DMEM base medium (10% FBS, IX glutamine, and 0.4 mg/ml G418) at 37°C, in an atmosphere of 6.0% CO2 and 90% relative humidity. Two days before the experiment, the cells are trypsinized and 200 μl ofthe cell suspension (138,000 cells/ml) is deposited into 96-well Costar cell culture plates. The test compounds are then dissolved in DMSO creating a 30mM stock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2 μM in OPTI-MEM (GIBCO-BRL) media with 50 μM IBMX (isobutylmethylxanthine, Sigma) minutes before the experiment.
The media is then thoroughly removed from the cell culture plates through a 12-channel straight manifold. 90 μl of OPTI-MEM media with 50 μM IBMX is added to each well (McHale et al. FEBS Letters 345 (1994) 147-150). The plate is then placed in an incubator set at 37 °C, 6.0% CO and 90% relative humidity. After 15 minutes of incubation, 90 μl ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX) are added and the plates are incubated for another 10 minutes. 20 μl ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates are incubated for an additional hour at 37 °C.
After the incubation, the media mixture is removed by 12-channel straight manifold. 60 μl of 70% ethanol is added to each well. The plates are then placed on a shaker for 30 minutes to extract the cAMP. The amount of cAMP is
1 S detected by the cyclic AMP [ I] Biotrak SPA screening assay system (Amersham). The system involves adding 50 μl of IX assay buffer into each well of an OptiPlate-96 (Packard). 50 μl ofthe tracer solution (cAMP-125I) is added into each well. 5 μl ofthe cAMP extract is added into the mixture, followed by the addition of cAMP antiserum and 50 μl of SPA PVT-antibody binding beads. The plates are then covered with TopSeal-A (Parkard) and incubated at room temperature for up to fifteen hours before being analyzed using a TOPCOUNT machine.
Compounds O, N, AG, AL, and AM were found to be at least 100 fold more selective for MC4-R than MC1-R, MC3-R and MC5-R. Example 4: In Vivo Assay for MC4-R Antagonist Activity
The following in vivo assay was used to test the effects of MC4-R antagonists on mice. Male lean C57BL/6J mice were individually housed in macrolon cages
(22 ± 2C°; 12: 12 h light/dark cycle with lights off at 6 pm). Tap water and mouse chow diet were given ad libitum. Mice were stereotaxically implanted with a chronic guide cannula aimed to the third ventricle (intracerabro ventricular) one week prior to testing. It had been previously determined that food deprived lean mice which had been injected with 0.1 nmol of MT II (a MC4-R agonist) prior to refeeding showed decreased feeding response within 1 hour of injection (Figure 1). In previous experiments using peptidic MC4-R antagonists, it has been shown that the decreased feeding response of MT II treated food-deprived mice can be reversed by the intracerabroventricular injection of MC4-R antagonists. In this experiment, food deprived lean mice were injected intracerabroventricularly with either Compound N or Compound O, at a dose of 15 nmol prior to injection of MT II at the dose of 0.05 nmol.
The results ofthe experiment are shown in Figures 2 and 3. Figure 2 shows that administration of 15 nmol of Compound N partially reverses the effect ofthe administration ofthe MC4-R agonist, MT II. Figure 3 shows that administration of Compound O did not significantly effect the food intake of mice treated with MT II.
Example 5: cAMP Assay for MC Receptor Agonist Activity (cAMP Assay)
The cAMP assay identifies compounds which have agonist activity against MC receptors. It is used to identify the selectivity of agonist which selectively antagonize receptors of interest. The following method is outlined for MC4-R, but corresponding procedures were used for the other MC receptors, MC1-R, MC3-R, and MC5-R.
Method
MC4 Receptors are expressed in stably transfected HEK293 cells. The cells are incubated in DMEM base medium (10% FBS, IX glutamine, and 0.4 mg/ml G418) at 37°C, in an atmosphere of 6.0% CO2 and 90% relative humidity. Two days before the experiment, the cells are trypsinized and 200 μl ofthe cell suspension (138,000 cells/ml) is deposited into 96-well Costar cell culture plates. The test compounds are then dissolved in DMSO creating a 30mM stock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2 μM in OPTI-MEM (GIBCO-BRL) media with 50 μM IBMX (isobutylmethylxanthine, Sigma) minutes before the experiment. The media is then thoroughly removed from the cell culture plates through a 12-channel straight manifold. 90 μl of OPTI-MEM media with 50 μM IBMX is added to each well (McHale et al. FEBS Letters 345 (1994) 147-150). The plate is then placed in an incubator set at 37 °C, 6.0% CO2 and 90% relative humidity. After 15 minutes of incubation, 90 μl ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX) are added and the plates are incubated for another 10 minutes. 20 μl ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates are incubated for an additional hour at 37 °C.
After the incubation, the media mixture is removed by 12-channel straight manifold. 60 μl of 70% ethanol is added to each well. The plates are then placed on a shaker for 30 minutes to extract the cAMP. The amount of c AMP is detected by the cyclic AMP [125I] Biotrak SPA screening assay system (Amersham). The system involves adding 50 μl of IX assay buffer into each well of an OptiPlate-96 (Packard). 50 μl ofthe tracer solution (cAMP-125I) is added into each well. 5 μl ofthe cAMP extract is added into the mixture, followed by the addition of cAMP antiserum and 50 μl of SPA PVT-antibody binding beads. The plates are then covered with
TopSeal-A (Packard) and incubated at room temperature for up to fifteen hours before being analyzed using a TOPCOUNT machine.
INCORPORATION BY REFERENCE The entire contents of all references and patents cited herein are hereby incorporated by reference. The entire contents of U.S. Patent 5,908,609 and all its references also expressly incoφorated herein.
EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope ofthe following claims.

Claims

1. A method for treating a MC4-R associated state in a mammal comprising administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated, wherein said compound is ofthe formula (I):
B-Z-E (I) wherein
B is an anchor moiety; Z is a central moiety; and
E is a MC4-R interacting moiety.
2. The method of claim 1, wherein said compound binds to the MC4-R with an IC50 of about 5 μM or less.
3. The method of claim 2, wherein said compound binds to the MC4-R with an IC50 of about 1 μM or less.
4. The method of claim 3, wherein said compound binds to the MC4-R with an IC 0 of about 0.5 μM or less.
5. The method of claim 4, wherein said compound binds to the MC4-R with an IC50 of about 0.1 μM or less.
6. The method of claim 5, wherein said compound binds to the MC4-R with an IC50 of about 0.05 μM or less.
7. The method of claim 6, wherein said compound binds to the MC4-R with an IC50 of about 0.03 μM or less.
8. The method of claim 1, wherein said compound is an antagonist ofthe MC4-R.
9. The method of claim 1, wherein said compound is an agonist ofthe MC4-R.
10. The method of claim 1 , wherein said effective amount is effective to treat a disorder associated with pigmentation, bones or weight loss.
11. The method of claim 10, wherein said effective amount is effective to treat a disorder associated with weight loss.
12. The method of claim 11, wherein said weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
13. The method of claim 1, wherein said mammal is a human.
14. A method for treating an MC4-R associated state in a mammal comprising administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated, wherein said compound is ofthe formula (III):
B-L!-A-L2-E (III)
wherein:
B is an anchor moiety; L) and L2 are linking moieties; A is a cyclic moiety; and E is a MC4-R interacting moiety,
15. The method of claim 14, wherein B is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heterocyclic.
16. The method of claim 15, wherein B is aryl.
17. The method of claim 16, wherein B is carbocyclic.
18. The method of claim 17, wherein B is phenyl.
19. The method of claim 18, wherein B is substituted with at least one substituent, wherein each substituent is independently selected from the group consisting of halogens, alkoxy, hydroxy, alkylcarbonyl, cyano, nitro, thioether, thioalkyl, thiol, alkyl, alkenyl, alkynyl, aryl, arylalkynyl, and arylalkyl.
20. The method of claim 19, wherein B is substituted with at least one halogen.
21. The method of claim 19, wherein B is substituted with at least one alkoxy group.
22. The method of claim 20, wherein B is 2-alkoxy-5-bromo phenyl.
23. The method of claim 22, wherein B is 2-methoxy-5-bromo phenyl.
24. The method of claim 19, wherein B is substituted with at least one alkyl group.
25. The method of claim 16, wherein B comprises more than one aromatic ring.
26. The method of claim 25, wherein B is substituted or unsubstituted naphthyl, fluorene, anthracene, or biphenyl.
27. The method of claim 26, wherein B is substituted or unsubstituted naphthyl.
28. The method of claim 26, wherein B is substituted with one or more substituents selected from the group consisting of halogens, alkoxy, hydroxy, alkylcarbonyl, cyano, nitro, thiol, thioether, thioalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkynyl, and arylalkyl.
29. The method of claim 15, wherein B comprises a heterocycle.
30. The method of claim 29, where B comprises a substituted heterocycle.
31. The method of claim 29, wherein B is substituted or unsubstituted furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, piperidinyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, or deazapurinyl.
32. The method of claim 14, wherein Lj is a covalent bond or a substituted or unsubstituted chain of one to six atoms.
33. The method of claim 32, wherein said chain comprises a carbon atom and at least one other atom selected from the group consisting of carbon, sulfur, oxygen, or nitrogen.
34. The method of claim 33, wherein said chain comprises a sulfur atom.
35. The method of claim 33, wherein said chain comprises an oxygen atom.
36. The method of claim 33, wherein said chain comprises two carbon atoms.
37. The method of claim 14, wherein A is substituted or unsubstituted phenyl, heteroaryl, or bicyclic.
38. The method of claim 37, wherein A is unsubstituted phenyl.
39. The method of claim 37, wherein A is substituted phenyl.
40. The method of claim 39, wherein A is substituted with one or more substituents selected from the group consisting hydroxy, chlorine, fluorine, bromine, iodine, amino, cyano, alkoxy, aryl, and alkyl.
41. The method of claim 40, wherein A is substituted with chlorine.
42. The method of claim 40, wherein A is substituted with fluorine.
43. The method of claim 40, wherein said alkyl group is methyl, trifluoromethyl, ethyl, propyl, or butyl.
44. The method of claim 40, wherein said alkoxy group is methoxy, ethoxy, propoxy, or butoxy.
45. The method of claim 37, wherein A is heteroaryl and selected from the group consisting of pyrimidyl, pyrazinyl, thienyl, pyrrolyl, imidazolyl, and quinoxalinyl.
46. The method of claim 37, wherein A is bicyclic and selected from the group consisting of methylenedioxyphenyl, isoindole, indole, and indan.
47. The method of claim 14, wherein L2 is selected from the group consisting of a covalent bond, a carbonyl moiety, a thiocarbonyl moiety or Cι-C6 branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur and nitrogen atoms.
48. The method of claim 47, wherein L2 is a covalent bond.
49. The method of claim 14, wherein said MC4-R interacting moiety is a substituted or unsubstituted amino group, alkyl, cyano, guanidino, amidino, or a heterocyclic moiety.
50. The method of claim 49, wherein E is dialkylamino.
51. The method of claim 49, wherein E is heterocyclic.
52. The method of claim 51 , wherein E contains a nitrogen atom.
53. The method of claim 52, wherein E is substituted or unsubstituted piprazinyl, imidazolyl, imidazolinyl, imidoazopyridinyl, pyroUoimidazolyl, pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl, moφholinyl, or piperidinyl.
54. The method of claim 51 , wherein E is multicyclic.
55. The method of claim 54, wherein E is a bridged or fused ring.
56. The method of claim 52, wherein E is ofthe formula (XIII):
Figure imgf000172_0001
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, alkenyl, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L2, R1, R2, R3, R4, R5 ; or
R to form a ring; and R1, R2, R3, R4, R5, and R6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, aryl, hydroxyl, nitro, amino, cyano, optionally linked to form a ring with R, R1, R2, R3, R4, R5 , or R6.
57. The method of claim 56, wherein each of r, s and t are CH2.
58. The method of claim 56, wherein R is H, alkyl, arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, or arylalkylcarbonyl.
59. The method of claim 58, wherein R is selected from the group consisting of methyl, ethyl, and propyl.
60. The method of claim 56, wherein r is a covalent bond.
61. The method of claim 14, wherein said compound is an MC4-R antagonist.
62. The method of claim 14, wherein said effective amount is effective to treat a disorder associated with weight loss or bones.
63. The method of claim 62, wherein said weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
64. The method of claim 14, wherein said mammal is a human.
65. A method for treating an MC4-R associated state in a mammal comprising administering an effective amount of a MC4-R binding compound to said mammal, such that the MC4-R associated state is treated, wherein said compound is an MC4-R antagonist, and is ofthe formula (III):
B-Lι-A-L2-E (III) wherein
B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro;
Li is a covalent bond, CpCβ branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; and
A is a substituted or unsubstituted phenyl, heteroaryl, cycloalkyl, or biaryl, and pharmaceutically acceptable salts thereof.
66. The method of claim 65, wherein B is substituted or unsubstituted phenyl or naphthyl.
67. The method of claim 65, wherein B is phenyl substituted with at least one halogen or alkoxy substituent.
68. The method of claim 65, wherein Li is a thioether or an ether.
69. The method of claim 65, wherein L2 is a covalent bond.
70. The method of claim 65, wherein A is phenyl.
71. The method of claim 65, wherein A is heteroaryl.
72. The method of claim 65, wherein E is heterocyclic.
73. A method for treating an MC4-R associated state in a mammal comprising administering an effective amount of a MC4-R binding compound to said mammal, such that the MC4-R associated state is treated, wherein said compound is an MC4-R antagonist, and is ofthe formula (V):
La λ
B L, π L2 E (V) B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro;
Li is a covalent bond, Ct-C6 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, cycloalkyl, or aryl;
L3 is a covalent bond, Cι-C6 branched, unbranched or cyclic alkyl, wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl; and Λ is heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and λ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
74. A method for treating an MC4-R associated state in a mammal comprising administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated, wherein said compound is an MC4-R antagonist, and is of
Figure imgf000175_0001
wherein P1, P2, P3, and P4 are optionally substituted carbon, sulfur, or nitrogen, and wherein one of P1, P2, P3, and P4 may represent a covalent bond;
Z1, Z2, Z3, Z4, and Z5 are optionally substituted carbon or nitrogen; L1 is a covalent bond, Cι-C6 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and
J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
75. The method of claim 74, wherein P1, P , P , and P4 are each substituted or unsubstituted carbon.
76. The method of claim 74, wherein P4 is sulfur, P1 is a covalent bond, and P2 and P3 are substituted or unsubstituted carbon.
1 ^
77. The method of claim 75, wherein P and P are CH.
78. The method of claim 75, wherein P2 and P4 are each independently CH, CF, CCl, CBr, CI, C-alkyl, C-alkoxy, or C-aryl.
79. The method of claim 78, wherein P2 is CH.
80. The method of claim 78, wherein P4 is CCl or CF.
81. The method of claim 74, wherein Z3 and Z4 are each CH.
82. The method of claim 74, wherein Z is CH, or covalently linked to Z to form a naphthyl ring.
83. The method of claim 74, wherein Z2 is CH, C-(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring.
2
84. The method of claim 83, wherein Z is CBr.
85. The method of claim 74, wherein Z5 is CH, C-alkoxy, or COH.
86. The method of claim 85, wherein Z5 is C-OMe.
87. The method of claim 74, wherein L is a covalent bond.
88. The method of claim 74, wherein J is substituted or unsubstituted imidazolyl, imidazolinyl, piprazinyl, imidoazopyridinyl, pyroUoimidazolyl, pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl, moφholinyl, or piperidinyl.
89. The method of claim 74, wherein J is a substituted or unsubstituted fused ring or bridged heterocycle.
90. The method of claim 74, wherein said MC4-R binding compound is ofthe formula (IX):
Figure imgf000176_0001
wherein:
P2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond; P3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI;
P4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a sulfur atom;
G1 and G2 are each independently CH , S, or O; r is a covalent bond or CH2; t is CH2, CHR3, or CR3R4; s is CH2, CHR5 or CR5R6;
R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl; Z1 is CH, or covalently linked to Z2 to form a naphthyl ring; Z2 is CH, C-(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z5 is CH, or C-alkoxy;
R3, R4, R5, and R6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
91. The method of claim 90, wherein Z1 is CH, Z2 is CBr and Z5 is C-OMe.
92. The method of claim 90, wherein P2 is CH.
93. The method of claim 90, wherein P4 is CCl or CF.
94. The method of claim 90, wherein G and G are each CH2.
95. The method of claim 90, wherein G1 and G2 together are -CH2-S- or -S-CH2-.
96. The method of claim 90, wherein Z and Z are linked to form a naphthyl ring.
97. The method of claim 90, wherein r is a covalent bond; s is CR5R6; and t is CR3R4, wherein R3, R4, R5, and R6 are each independently hydrogen or alkyl.
98. The method of claim 90, wherein R is hydrogen.
99. The method of claim 90, wherein R is alkyl.
100. The method of claim 99, wherein R is methyl, ethyl, propyl or butyl.
101. The method of claim 74, wherein said compound is selected from the group consisting of:
Figure imgf000178_0001
Figure imgf000179_0002
Figure imgf000179_0003
Figure imgf000179_0001
Figure imgf000179_0004
Figure imgf000180_0001
Figure imgf000180_0002
Figure imgf000180_0003
Figure imgf000180_0005
Figure imgf000180_0004
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000182_0002
Figure imgf000182_0003
Figure imgf000182_0004
102. The method of claim 65, wherein said compound is selected from the group consisting of: 2-[2-(4-benzyloxy-benzylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro- 1 H-imidazole;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-[2-(2-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole;
2- { 2- [2-(2-methoxy-naphthalen- 1 -y l)-ethy 1] -phenyl } - 1 ,4, 5 ,6-tetrahy dropy rimidine ;
2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6,-tetrahydropyrimidine;
2-{2-[2-(2-methyl-naphthalen-l-yl)-ethyl]-phenyl}-l,4,5,6-tetrahydropyrimidine; 2-{2-[2-(2,3-dihydro-benzo[l,4]dioxin-5-yl) -ethyl]-phenyl}-l, 4,5,6- tetrahydropyrimidine; 2-[2-(2-methoxy-napthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-(2-Benzylsulfanyl-phenyl)- 1 ,4,5,6-tetrahydro-pyrimidine;
2-(2-Pentadecylsulfanyl-phenyl)- 1 ,4,5,6-tetrahydro-pyrimidine;
2-(2-Cyclohexylmethylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Methyl-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-l H-imidazole;
2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro- 1 H-imidazole;
2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-ylmethoxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 1 - { 2- [2-(2-Chloro-6-fluoro-benzylsulfany l)-phenyl]-5 ,6-dihydro-4H-pyrimidin- 1 -yl } - ethanone;
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole;
2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH-benzoimidazole; 2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-[2-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline;
2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)-pyridin-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2,3-Dihydro-benzo[l,4]dioxin-5-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(6-Methoxy-2,3-dihydro-benzo[l,4]dioxin-5-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; 1 -Methyl-2-[2-(naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-yloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(Biphenyl-3-ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(4,4'-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3'-Chloro-4'-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine; 2- [2-(l -Naphthalen- 1 -yl-ethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-lH-imidazole;
2-(2-Benzhydrylsulfanyl-phenyl)- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2'-Fluoro-4,,-methoxy-[l,l,;4,,l"]teφhenyl-3"-ylmethylsulfanyl)-phenyl]-l,4,5,6- tetrahydro-pyrimidine; 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;
2-[4-(Naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-propoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-moφholin-2-yl}- methylamine;
2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;
2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Ethoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Propoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 4-Methoxy-3-[2-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]- benzonitrile; l-{4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl}- ethanone;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;
C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine;
1 - [2-(5 -Bromo-2-methoxy-benzy lsulfanyl)-benzyl] -pyrrolidin-3 -ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; 3-[2-(5-Bromo-2 -methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l, 5,6,7,8, 8a-hexahydro- imidazo[l ,5-a]pyridine;
3 - [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-3 -fluoro-phenyl]-5 ,6,7,7a-tetrahydro- 1 H- pyrrolo[l ,2-c]imidazole;
2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[3-Fluoro-2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(Naphthalen- 1 -ylmethylsulfanyl)-3-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}-
3 -methyl-butan- 1 -one; l-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}-
2-phenyl-ethanone; 2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine;
2-[2-(2-Isopropoxy-naphthalen- 1 -ylmethylsulfanyl)-pheriyl]- 1 ,4,5,6-tetrahydropyrimidine; 2-[2-(2-Cyclopentyloxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
(5-Bromo-2-methoxy-benzyl)-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(2-Methoxy-naphthalen- 1 -ylsulfanylmethyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(6-Bromo-2-methoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Chloro-2-(2-methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[l -(2 -Naphthalen-1 -yl-ethyl)- 1 H-pyrrol-2-yl]- 1 ,4,5,6-tetrahydro-pyrimidine;
(5-Bromo-2-methoxy-benzyl)-methyl-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]- amine; 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;
2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(2-o-Tolylsulfanylmethyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;
4- [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzyl] -moφholine;
3'-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl; 2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-l-yl-6,7-dihydro-quinoxaline; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;
C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-moφholin-3-yl}- methylamine;
1 - [3 -Fluoro-2-(2-naphthalen- 1 -yl-ethyl)-benzyl]-piperazine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol;
[2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid l-aza-bicyclo[2.2.2]oct-3-yl ester;
[2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 1 -aza- bicyclo[2.2.2]oct-3-yl ester;
[2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- ethyl ester; { l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}- methanol;
4-tert-Butyl-N-naphthalen- 1 -ylmethyl-N-(2-piperidin- 1 -yl-ethyl)-benzamide;
N,N-Dimethyl-N'-naphthalen-2-ylmethyl-N'-naphthalen-l -ylmethyl-propane- 1,3- diamine; N-(5-Bromo-2-methoxy-benzyl)-N',N'-dimethyl-N-naphthalen-l -ylmethyl-propane- 1 ,3- diamine;
1 -Naphthalen- 1 -ylmethyl-3 -phenethyl- 1 -(2-piperidin- 1 -y l-ethyl)-thiourea;
3 -(4-Dimethylamino-phenyl)- 1 -(3 -dimethylamino-propy 1)- 1 -naphthalen- 1 -ylmethyl- thiourea; 4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-l- carboxylic acid ethyl ester;
2-[2-(2-Naphthalen-l-yl-ethyl)-phenyl]-ethylamine;
Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen- 1 -ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
(2-Hexyloxy-phenyl)-carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmethyl-ethyl ester;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-pyrrolidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-piperidine; 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-propan-l-ol;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-l-ol; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ol;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}-methanol; { 1 - [2-(Naphthalen- 1 -y lsulfany lmethy l)-benzy 1] -piperidin-2-y 1 } -methanol ;
2-[2-(Naphthalen- 1 -y lsulfany lmethy l)-pyrrolidin-l -yl]-ethyl-N-pyrrolidine;
N-pyrrolyl-[ 1 -(2 -naphthalen- 1 -yl-ethyl)-pyrrolidin-2-ylmethyl]-amine;
1 -(2 -Naphthalen- l-yl-ethyl)-piperidine-2-carboxylic acid methyl ester; (3 -Bromo-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -ylmethyl-amine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;
(5-Bromo-2-methoxy-benzyl)-( 1 -ethyl-pyrrolidin-2-y lmethy l)-naphthalen- 1 -ylmethyl- amine;
( 1 -Ethyl-pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
(3 -Bromo-benzy l)-(3 -imidazol- 1 -yl-propyl)-naphthalen- 1 -ylmethyl-amine;
(3-Imidazol-l-yl-propyl)-naphthalen-2-ylmethyl-naphthalen-l-ylmethyl-amine;
[2 -(Naphthalen 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- 1 -piperidin-
1 -ylmethyl-ethyl ester; [2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid 2-dimethylamino-ethyl ester;
1 -[2-(Naphthalen- 1 -ylsulfanylmethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(naphthalen-l-ylsulfanylmethyl)-benzyl]- amine; l-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-benzyl]-piperazine; N,N-Dimethyl-N'-(2-naphthalen- 1 -yl-ethyl)-N'-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;
1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine; 1 -[3-Fluoro-2-(2 -naphthalen- 1 -yl-ethyl)-benzyl]-piperazine;
{ l-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;
{ l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;
{ l-[2-(2-Naphthalen-l-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine; 1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-benzyl]-pyrrolidin-3-ylamine;
1 -Phenyl-3-piperazin- 1 -yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2- [2-(2 -Naphthalen- 1 -yl-ethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine; 2-[3-(2-Methoxy-naphthalen- 1 -ylsulfanylmethyl)-thiophen-2-yl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5-dihydro-
1 H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl-l, 4,5,6- tetrahydro-pyrimidine;
2-[3-(Naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-l ,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-4,5-dihydro- 1 H-imidazole;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Bromo-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[4-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2-(Naphthalen- 1 -ylsulfanylmethyl)-thiophen-3 -yl]- 1 ,4,5 ,6-tetrahydro-pyrimidine; 2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -trifluoromethyl-phenyl } - 1 ,4,5,6- tetrahydro-pyrimidine ;
2-[2-(2 -Naphthalen- 1 -yl-ethyl)-3-trifluoromethyl-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(6-Fluoro-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl}-methanol; 2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-l-yl)- propylj-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine; 5,5-Dimethyl-2-[2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5- dihydro- 1 H-imidazole; 3-(2-Naphthalen-l-yl-ethyl)-2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;
Amino-[2-(2 -naphthalen- 1 -yl-ethyl)-phenyl]-acetonitrile;
1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-phenyl]-ethane- 1 ,2-diamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-l-methyl-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4- dimethyl-4,5-dihydro-l H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5- dimethyl-l,4,5,6-tetrahydro-pyrimidine;
2- [3 -Methoxy-2-(2 -naphthalen- 1 -yl-ethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[2-( 1 -Methyl-2 -naphthalen- 1 -yl-ethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[3-Methoxy-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-Chloro-6-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol; 2-[3-Methoxy-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidin-
5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5-dihydro-
1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2- [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-3 ,4-difluoro-phenyl]- 1 ,4,5 ,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5- dihydro- 1 H-imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-l,4,5,6- tetrahydro-pyrimidine;
4,4-Dimethyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[5-(5-Bromo-2-methoxy-benzyl)-2-methyl-thiophen-3-yl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}-l, 4,5,6- tetrahydro-py rimidine ; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- benzonitrile;
2- { 3 -Benzy loxy-2-[2-(5 -bromo-2-methoxy-phenyl)-ethyl]-phenyl } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-2,3-dihydro-benzo[l,4]dioxin-6-yl}-
1 ,4,5,6-tetrahydro-pyrimidine;
2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[l,4]dioxin-6- yl }- 1 ,4,5 ,6-tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-l, 4,5,6- tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-l, 4,5,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[3-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-4,5-dihydro- 1 H-imidazole;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1 -acetoxy-2-methyl-propyl ester;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; 3-(5-Bromo-2-methoxy-phenyl)-5-chloro-3,4-dihydro-isoquinolin-l-ylamine;
2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-l,4,5,6- tetrahydro-pyrimidin-5-ol; 2-[(5-Bromo-2-methoxy-phenyl)-(3-piperidin-l-yl-propylamino)-methyl]-3-chloro-6- methyl-phenol; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-diethyl-amine;
3-(5-Bromo-2-methoxy-phenyl)- 1 ,2,3,4-tetrahydro-isoquinoline;
1 - { 2- [2-(5 -Bromo-2 -methoxy -phenyl)-ethyl]-3 -chloro-benzyl } -piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine; {2- [2-(5 -Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-benzyl } -diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole;
(l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)- methanol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;
1 -(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro- 1 H-isoindole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; 1 -(2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-phenyl } -5 ,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{ 2- [2-(5 -Bromo-2-methoxy-pheny l)-ethyl] -3-fluoro-benzy 1 } -diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3 -fluoro-benzyl } -piperidin-2-yl)- methanol;
4-Fluoro-N- { 2-[4-(2-methoxy-phenyl)-piperazin- 1 -yl] -ethyl } -N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2 -methoxy -phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -3 -chloro-benzyl } -4-methy 1-piperazine ; l-{2-[2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -3 -chloro-benzyl } -piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole;
( 1 - { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-benzyl } -piperidin-2-yl)- methanol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l ,4,5,6-tetrahydropyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;
1 -(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro- 1 H-isoindole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; 1 -(2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-phenyl } -5 ,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine; 4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-4,5-dihydro-lH- imidazole; {2- [3 -(5 -Bromo-2-methoxy-phenyl)-3 ,4-dihydro- 1 H-isoquinolin-2-yl]-ethyl } -diethyl- amine; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-ethanone; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid ethyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid isobutyl ester; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid tert-butyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one;
1 -(5 -Bromo-2-methoxy-benzy l)-2 ,3 -dihydro- 1 H-isoindole ; 1 -(2-Methoxy-benzyl)-2-methyl-2,3-dihydro- 1 H-isoindole;
2-Methyl- 1 -naphthalen- 1 -ylmethyl-2,3 -dihydro- 1 H-isoindole;
1 - {2-[3-Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl]-4,5-dihydro-imidazol- 1 -yl } -2,2- dimethy 1-propan- 1 -one;
{ 2-[ 1 -(5 -Bromo-2-methoxy-benzyl)- 1 ,3 -dihydro-isoindol-2-yl]-ethyl } -diethyl-amine; 2-[3-Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl]- 1 -methyl- 1 ,4,5,6-tetrahydropyrimidine;
2- [3 -Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl]-5 ,6-dihydro-4H-pyrimidine- 1 - carboxylic acid tert-butyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-lH-imidazole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}- ethanone;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid isobutyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid tert-butyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid ethyl ester;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl- benzamide; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-ethyl-4,5-dihydro-l H-imidazole; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-2,2-dimethyl-propan- 1 -one;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-lH-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine- 1 -carboxylic acid isobutyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isocyanomethyl-4,5- dihydro- 1 H-imidazole; 2- {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl} - 1 -methyl-4,5-dihydro- 1 H- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-ethyl-4,5-dihydro-lH- imidazole; 3 -(5 -Bromo-2-methoxy-benzyl)-2-rnethyl-2,3 -dihydro-isoindol- 1 -one;
4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)- 1 ,2,3 ,4-tetrahydro-isoquinoline;
4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-propyl-4,5-dihydro-
1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a- hexahydro- 1 H-benzoimidazole;
5,5-Dimethyl-2-[2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-lH-inιidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro-
1 H-imidazole; N-(5-Bromo-2-methoxy-benzyl)-N'-methyl-N-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-l,4,5,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N'-trimethyl-benzamidine; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-methyl-4,5-dihydro-lH-imidazole; l-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-
1 H-imidazole;
({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-l-yl- methylene)-methyl-amine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isopropyl-4,5-dihydro-
1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-(2,2,2-trifluoro-ethyl)-
4,5-dihydro-l H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine, and pharmaceutically acceptable salts thereof.
103. An MC4-R binding compound of the formula (IX):
Figure imgf000197_0001
wherein:
P2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
P3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI; P4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI or a sulfur atom;
G and G are each independently CH2, S, or O; r is a covalent bond or CH ; t is CH2, CHR3, or CR3R4; s is CH2, CHR5 or CR5R6;
R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl; Z1 is CH, or covalently linked to Z2 to form a naphthyl ring; Z2 is CH, C-(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z5 is CH, or C-alkoxy;
R3, R4, R5, and R are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
104. The compound of claim 103, wherein Z1 is CH, Z2 is CBr and Z5 is C-OMe.
105. The compound of claim 103, wherein P is CH.
106. The compound of claim 103, wherein P4 is CCl or CF.
107. The compound of claim 103, wherein G and G are each CH2.
108. The compound of claim 103, wherein G and G together are -CH2-S- or -S- CH2-.
109. The compound of claim 103, wherein Z and Z are linked to form a naphthyl ring.
110. The compound of claim 103, wherein r is a covalent bond, s is R5R6, and t is R3R4, wherein each of R3, R4, R5 and R6 are each independently alkyl, hydroxy, or hydrogen.
111. An MC4-R binding compound or pharmaceutically acceptable salts thereof, wherein said compound is selected from the group consisting of:
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000200_0002
Figure imgf000200_0003
Figure imgf000200_0004
Figure imgf000200_0006
Figure imgf000200_0005
Figure imgf000201_0001
112. A pharmaceutical composition for the treatment of a MC4-R associated state in a mammal comprising a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound ofthe formula (I):
B-Z-E (I)
wherein
B is an anchor moiety;
Z is a central moiety;
E is a MC4-R interacting moiety; and pharmaceutically acceptable salts thereof.
113. The pharmaceutical composition of claim 112, wherein said MC4-R binding compound is an MC4-R antagonist.
114. The pharmaceutical composition of claim 112, wherein said MC4-R associated state is associated with pigmentation.
115. The pharmaceutical composition of claim 112, wherein said MC4-R associated state is associated with weight loss.
116. The pharmaceutical composition of claim 115, wherein said weight loss is a result of old age, anorexia nervosa, HIV cachexia or cancer cachexia.
117. The pharmaceutical composition of claim 112, wherein said mammal is a human.
118. The pharmaceutical composition of claim 112, wherein said MC4-R binding compound is ofthe formula (IX):
Figure imgf000203_0001
wherein:
P2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond; P3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI;
P4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a sulfur atom;
G1 and G2 are each independently CH2, S, or O; r is a covalent bond or CH2; t is CH2, CHR3, or CR3R4; s is CH2, CHR5 or CR5R6; R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl;
1
Z is CH, or covalently linked to Z to form a naphthyl ring; Z2 is CH, C-(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z5 is CH, or alkoxy; R3, R4, R5, and R6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
119. The pharmaceutical composition of claim 112, wherein said MC4-R binding compound is selected from the group consisting of: 2-[2-(4-benzyloxy-benzylsulfanyl)- phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2-(naphthalen- 1 -ylmethylsulfanyl)-phenyl] - 1 ,4,5,6-tetrahydro-pyrimidine; 2-[2-(3-chloro-benzylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro-l H-imidazole;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; 2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(2-bromo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-iodo-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole; 2-{2-[2-(2-methoxy-naphthalen-l-yl)-ethyl]-phenyl}-l,4,5,6-tetrahydropyrimidine;
2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6,-tetrahydropyrimidine;
2-{2-[2-(2-methyl-naphthalen-l-yl)-ethyl]-phenyl}-l,4,5,6-tetrahydropyrimidine;
2-{2-[2-(2,3-dihydro-benzo[l,4]dioxin-5-yl) -ethyl]-phenyl}-l, 4,5,6- tetrahydropyrimidine; 2-[2-(2-methoxy-napthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydropyrimidine;
2-(2-Benzylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-(2-Pentadecylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-(2-Cyclohexylmethylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2- [2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-l H-imidazole;
2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro- 1 H-imidazole;
2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2- [2-(Naphthalen- 1 -ylmethoxy)-phenyl]- 1 ,4,5 ,6-tetrahydro-pyrimidine; 2-[2-(2-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-{2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-l-yl}- ethanone;
2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH- benzoimidazole; 2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-lH-benzoimidazole;
2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
4-[2-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline;
2- [2-(2 -Methoxy-5 -nitro-benzy lsulfany l)-pyridin-3 -y 1] - 1 ,4, 5 ,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2- [2-(2,3 -Dihydro-benzo [ 1 ,4]dioxin-5 -ylmethylsulfanyl)-phenyl]- 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-[2-(6-Methoxy-2,3-dihydro-benzo[l, 4]dioxin-5-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahy dro-pyrimidine ; 2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole; l-Methyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-yloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole;
2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(Biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(4,4'-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(3'-Chloro-4'-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-[2-( 1 -Naphthalen- 1 -yl-ethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-lH-imidazole;
2-(2-Benzhydrylsulfanyl-phenyl)-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,-Fluoro-4M-methoxy-[l,l';4',l"]teφhenyl-3"-ylmethylsulfanyl)-phenyl]-l,4,5,6- tetrahydro-pyrimidine;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;
2-[4-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-propoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-moφholin-2-yl}- methylamine;
2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;
2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Ethoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Propoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 4-Methoxy-3-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]- benzonitrile;
1 - {4-Methoxy-3 - [2-( 1 ,4,5 ,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl } - ethanone; 2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;
C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; 1 -[2-(2-Methoxy-naphthalen- 1 -ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,5,6,7,8,8a-hexahydro- imidazo[l ,5-a]pyridine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro-lH- pyrrolo [ 1 ,2-c] imidazole ; 2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-l ,4,5,6-tetrahydro-pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(Naphthalen-l-ylmethylsulfanyl)-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
1 - { 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl] -5 ,6-dihydro-4H-pyrimidin- 1 -yl } -
3-methyl-butan- 1 -one;
1 - { 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl] -5 ,6-dihydro-4H-pyrimidin- 1 -yl } -
2-phenyl-ethanone; 2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine;
2-[2-(2-Isopropoxy-naphthalen- 1 -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(2-Cyclopentyloxy-naphthalen-l -ylmethylsulfanyl)-phenyl]- 1 ,4,5,6-tetrahydro- pyrimidine;
(5-Bromo-2-methoxy-benzyl)-[2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(6-Bromo-2-methoxy-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Chloro-2-(2-methoxy-naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[l-(2-Naphthalen-l-yl-ethyl)-lH-pyrrol-2-yl]-l,4,5,6-tetrahydro-pyrimidine; (5-Bromo-2-methoxy-benzyl)-methyl-[2-(l ,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]- amine;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;
2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-(2-o-Tolylsulfanylmethyl-phenyl)-l ,4,5,6-tetrahydro-pyrimidine;
2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-l,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine; 4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-moφholine;
3'-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl;
2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-l-yl-6,7-dihydro-quinoxaline; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;
C-{4-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-moφholin-2-yl}- methylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine; l-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine; l-[2-(2-Methoxy-naphthalen-l-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;
C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-moφholin-3-yl}- methylamine; l-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-benzyl]-piperazine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol;
[2-(Naphthalen-l-ylmethylsulfanyl)-phenyl]-carbamic acid l-aza-bicyclo[2.2.2]oct-3-yl ester;
[2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 1 -aza- bicyclo[2.2.2]oct-3-yl ester; [2-(2-Methyl-naphthalen- 1 -ylmethylsulfanyl)-pheny l]-carbamic acid 2-piperidin- 1 -yl- ethyl ester;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}- methanol; 4-tert-Butyl-N-naphthalen- 1 -ylmethyl-N-(2-piperidin- 1 -yl-ethyl)-benzamide;
N,N-Dimethyl-N'-naphthalen-2-ylmethyl-N'-naphthalen- 1 -ylmethyl-propane- 1 ,3 - diamine;
N-(5-Bromo-2-methoxy-benzyl)-N',N'-dimethyl-N-naphthalen- 1 -ylmethyl-propane- 1,3- diamine; 1 -Naphthalen- 1 -ylmethyl-3 -phenethyl- 1 -(2-piperidin- 1 -yl-ethyl)-thiourea;
3-(4-Dimethylamino-phenyl)-l-(3-dimethylamino-propyl)-l-naphthalen-l-ylmethyl- thiourea;
4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-l- carboxylic acid ethyl ester; 2-[2-(2 -Naphthalen- 1 -yl-ethyl)-phenyl]-ethylamine;
Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen- 1 -ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
(2-Hexyloxy-phenyl)-carbamic acid 2-piperidin- 1-yl-l-piperidin-l-ylmethyl-ethyl ester; 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-pyrrolidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-phenyl]-piperidine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-propan-l-ol;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-l-ol; 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ol;
{l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}-methanol;
{ l-[2-(Naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;
2-[2-(Naphthalen- 1 -ylsulfanylmethyl)-pyrrolidin- 1 -yl]-ethyl-N-pyrrolidine;
N-pyrrolyl-[l-(2-naphthalen-l-yl-ethyl)-pyrrolidin-2-ylmethyl]-amine; l-(2-Naphthalen-l-yl-ethyl)-piperidine-2-carboxylic acid methyl ester;
(3-Bromo-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -ylmethyl-amine;
3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;
(5-Bromo-2-methoxy-benzyl)-( 1 -ethyl-pyrrolidin-2-ylmethyl)-naphthalen- 1 -ylmethyl- amine; (1 -Ethyl-pyrrolidin-2-y lmethyl)-naphthalen-2-y Imethyl-naphthalen- 1 -ylmethyl-amine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;
(3-Bromo-benzyl)-(3-imidazol- 1 -yl-propyl)-naphthalen- 1 -ylmethyl-amine;
(3-Imidazol- 1 -yl-propyl)-naphthalen-2-ylmethyl-naphthalen- 1 -ylmethyl-amine; [2-(Naphthalen 1 -ylmethylsulfanyl)-phenyl]-carbamic acid 2-piperidin- 1 -yl- 1 -piperidin-
1-ylmethyl-ethyl ester;
[2-(Naphthalen-l-y lmethy lsulfany l)-phenyl]-carbamic acid 2-dimethylamino-ethyl ester;
1 -[2-(Naphthalen- 1 -ylsulfanylmethyl)-benzyl]-piperazine; [3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(naphthalen-l-ylsulfanylmethyl)-benzyl]- amine;
1 -[3-Chloro-2-(naphthalen- 1 -ylsulfanylmethyl)-benzyl]-piperazine;
N,N-Dimethyl-N'-(2 -naphthalen- 1 -yl-ethyl)-N'-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine; {l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;
1 -[2-(2 -Naphthalen- 1 -yl-ethyl)-benzyl]-piperazine;
[3-(2-Methyl-piperidin-l-yl)-propyl]-[2-(2-naphthalen-l-yl-ethyl)-benzyl]-amine; l-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-benzyl]-piperazine;
{l-[3-Chloro-2-(naphthalen-l-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol; { 1 -[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl} -methanol;
{l-[2-(2-Naphthalen-l-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;
[3 -(2-Methy 1-piperidin- 1 -yl)-propyl]- [2-(2 -naphthalen- 1 -yl-ethyl)-benzyl] -amine;
1 -[2-(2-Naphthalen-l -yl-ethyl)-benzyl]-pyrrolidin-3-ylamine; l-Phenyl-3-piperazin-l-yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl- 1 ,4,5,6-tetrahydropyrimidine;
2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(2-Naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[3-(2-Methoxy-naphthalen-l-ylsulfanylmethyl)-thiophen-2-yl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(4-Methyl-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(5 -Bromo-2-methoxy-benzy lsulfany l)-3 -fluoro-pheny 1] -4,4-dimethy 1-4, 5 -dihy dro-
1 H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl-l, 4,5,6- tetrahydro-pyrimidine;
2-[3-(Naphthalen- 1 -ylsulfanylmethyl)-thiophen-2-yl]- 1 ,4,5,6-tetrahydro-pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-l,4,5,6-tetrahydro-pyrimidine;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[3-Bromo-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine; 2-[4-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(Naphthalen-l-ylsulfanylmethyl)-thiophen-3-yl]-l,4,5,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}-l,4,5,6- tetrahydro-py rimidine ;
2-[2-(2-Naphthalen-l-yl-ethyl)-3-trifluoromethyl-phenyl]-l,4,5,6-tetrahydro-pyrimidine; 2-[2-(6-Fluoro-naphthalen-l-ylmethylsulfanyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
{ 1 - [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl] -piperidin-2-yl } -methanol ;
2-[3-Fluoro-2-(2-naphthalen-l -yl-ethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidine;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-l-yl)- propyl]-amine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine;
5,5-Dimethyl-2-[2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-lH-imidazole;
2-[3-Fluoro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5- dihydro- 1 H-imidazole;
3-(2-Naphthalen-l-yl-ethyl)-2-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine; Amino- [2-(2-naphthalen- 1 -y 1-ethy l)-pheny 1] -acetonitrile ;
1 -[2 -(2 -Naphthalen- 1 -yl-ethyl)-phenyl] -ethane- 1 ,2-diamine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-lH- imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[3-Fluoro-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-lH- imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-l-methyl-ethyl]-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4- dimethyl-4,5-dihydro- 1 H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5- dimethyl- 1 ,4,5,6-tetrahydro-pyrimidine;
2-[3-Methoxy-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[2-(l-Methyl-2-naphthalen-l-yl-ethyl)-phenyl]-l,4,5,6-tetrahydro-pyrimidine;
3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; l-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]- propan-2-ol;
2-[3-Methoxy-2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-Chloro-6-(l,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol;
2-[3-Methoxy-2-(naphthalen- 1 -ylsulfanylmethyl)-phenyl]- 1 ,4,5,6-tetrahydro-pyrimidin- 5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5-dihydro-
1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5- dihydro- 1 H-imidazole ;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
4,4-Dimethyl-2-[2-(naphthalen-l-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-l,4,5,6-tetrahydro- pyrimidine;
2-[5-(5-Bromo-2-methoxy-benzyl)-2-methyl-thiophen-3-yl]-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl} - 1 ,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl} - 1 ,4,5,6-tetrahydropyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}-l, 4,5,6- tetrahydro-pyrimidine ;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol; 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(l,4,5,6-tetrahydro-pyrimidin-2-yl)- benzonitrile;
2- { 3 -Benzyloxy-2- [2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl } - 1 ,4,5 ,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2- { 5 - [2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -2,3 -dihy dro-benzo [ 1 ,4] dioxin-6-y 1 } -
1 ,4,5,6-tetrahydro-pyrimidine; 2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[l,4]dioxin-6- yl } - 1 ,4,5 ,6-tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propyl-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidin-5-ol;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-l,4,5,6- tetrahydro-pyrimidine ; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-l,4,5,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]- 1 -methyl-4,5-dihydro- 1 H- imidazole;
[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[3-(l,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-methyl-4,5-dihydro-
1 H-imidazole;
N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide; N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid l-acetoxy-2-methyl-propyl ester;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; 3-(5-Bromo-2-methoxy-phenyl)-5-chloro-3,4-dihydro-isoquinolin-l-ylamine;
2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-l, 4,5,6- tetrahydro-pyrimidine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-l, 4,5,6- tetrahydro-pyrimidin-5-ol; 2-[(5-Bromo-2-methoxy-phenyl)-(3-piperidin-l-yl-propylamino)-methyl]-3-chloro-6- methyl-phenol; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-diethyl-amine;
3-(5-Bromo-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;
{ 2- [2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -3 -chloro-benzy 1 } -diethyl-amine ;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole; (l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)- methanol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine;
1 - [2-(5 -Bromo-2-methoxy-benzylsulfanyl)-benzyl] -4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine; l-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-l H-isoindole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
(l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidin-2-yl)- methanol;
4-Fluoro-N- { 2- [4-(2-methoxy-phenyl)-piperazin- 1 -yl]-ethyl } -N-pyridin-2-yl- benzamide;
3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine; {2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-lH- imidazole; (l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)- methanol;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-l,4,5,6-tetrahydro- pyrimidine; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine; l-{2-[2-(5 -Bromo-2-methoxy-pheny l)-ethy 1] -6-chloro-benzy 1 } -piperidine ;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine; l-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-lH-isoindole;
2-{2-[2-(5 -Bromo-2-methoxy-phenyl)-ethy 1] -3 -chloro-phenyl } - 5 ,6-dihydro-4H- pyrimidine-1 -carboxylic acid 1-acetoxy-ethyl ester;
1 -(2- {2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-phenyl } -5 ,6-dihydro-4H- pyrimidin- 1 -yl)-ethanone; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;
{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine; l-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;
4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-l-yl]-ethyl}-N-pyridin-2-yl- benzamide; 3-(5-Bromo-2-methoxy-phenyl)-2-methyl-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-4,5-dihydro-lH- imidazole;
{2-[3-(5-Bromo-2-methoxy-phenyl)-3,4-dihydro-lH-isoquinolin-2-yl]-ethyl}-diethyl- amine; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-ethanone;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid ethyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole- 1 -carboxylic acid isobutyl ester;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-
1 -carboxylic acid tert-butyl ester; l-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one; l-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-lH-isoindole; l-(2-Methoxy-benzyl)-2-methyl-2,3-dihydro-l H-isoindole;
2-Methyl- 1 -naphthalen- 1 -y lmethyl-2,3-dihydro- 1 H-isoindole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}-2,2- dimethy 1-propan- 1 -one ;
{2-[l-(5-Bromo-2-methoxy-benzyl)-l,3-dihydro-isoindol-2-yl]-ethyl}-diethyl-amine;
2-[3-Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl]- 1 -methyl- 1 ,4,5,6-tetrahydro- pyrimidine;
2-[3 -Chloro-2-(2-naphthalen- 1 -yl-ethyl)-phenyl] -5 ,6-dihydro-4H-pyrimidine- 1 - carboxylic acid tert-butyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-lH-imidazole; l-{2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-l-yl}- ethanone;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid isobutyl ester;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l -carboxylic acid tert-butyl ester; 2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-l-carboxylic acid ethyl ester;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl- benzamide;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-ethyl-4,5-dihydro-lH-imidazole; 1 -(2- { 2- [2-(5-Bromo-2-methoxy-phenyl)-ethyl] -3 -chloro-phenyl } -5,6-dihydro-4H- pyrimidin- 1 -yl)-2,2-dimethyl-propan- 1 -one;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-lH-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidine-1 -carboxylic acid isobutyl ester; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isocyanomethyl-4,5- dihydro- 1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-methyl-4,5-dihydro-lH- imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-l-ethyl-4,5-dihydro-lH- imidazole;
3-(5-Bromo-2-methoxy-benzyl)-2-methyl-2,3-dihydro-isoindol-l-one;
4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-propyl-4,5-dihydro- 1 H-imidazole;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a- hexahydro- 1 H-benzoimidazole;
5,5-Dimethyl-2-[2-(naphthalen-l-ylsulfanylmethyl)-phenyl]-4,5-dihydro-l H-imidazole; 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro-
1 H-imidazole;
N-(5-Bromo-2-methoxy-benzyl)-N'-methyl-N-naphthalen- 1 -ylmethyl-ethane- 1 ,2- diamine; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-ethyl-l,4,5,6- tetrahydro-pyrimidine;
2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N'-trimethyl-benzamidine;
2-[3-Chloro-2-(2-naphthalen-l-yl-ethyl)-phenyl]-l-methyl-4,5-dihydro-lH-imidazole; l-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- 1 H-imidazole;
({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-l-yl- methylene)-methyl-amine;
2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-isopropyl-4,5-dihydro-
1 H-imidazole; 2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-l-(2,2,2-trifluoro-ethyl)-
4,5-dihydro-l H-imidazole;
2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-l,4,5,6-tetrahydro- pyrimidine, and pharmaceutically acceptable salts thereof.
120. The pharmaceutical composition of claim 112, wherein said pharmaceutical composition is suitable for oral administration.
121. The MC4-R binding compound of the formula ( VII) :
Figure imgf000218_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, Ν, or substituted carbon; P1, P2, P3, and P4 are CH, Ν or substituted carbon; and P5 is C-J, wherein J is a moiety ofthe formula (XIII):
Figure imgf000219_0001
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 , or R6to form one or more rings; and
R1, R2, R3, R4, R5 , and R6 are each independently halogen, thiol, thioalkyl, thioester, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
122. The MC4-R binding compound ofthe formula (VIII):
Figure imgf000219_0002
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and P5 is C-J, wherein J is a moiety ofthe formula (XIII):
Figure imgf000219_0003
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR'R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 , or R6to form one or more rings; and R1, R2, R3, R4, R5 , and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
123. The MC4-R binding compound of the formula (XV):
Figure imgf000220_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and P5 is C-J, wherein J is a moiety ofthe formula (XIII):
Figure imgf000220_0002
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR!R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 , or R6to form one or more rings; and
R1, R2, R3, R4, R5 , and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5 ; or R6.
124. The MC4-R binding compound ofthe formula (XVI):
Figure imgf000221_0001
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; P1, P2, P3, and P4 are CH, N or substituted carbon; and P5 is C-J, wherein J is a moiety ofthe formula (XIII):
Figure imgf000221_0002
(XIII) wherein r is a covalent bond, CH, CH2, CHR1, CR*R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CH, CH2, CHR5, CR5R6, or absent;
R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R1, R2, R3, R4, R5 ; or R6to form one or more rings; and
R1, R2, R3, R4, R5 , and R6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R1, R2, R3, R4, R5, or R6.
125. The compound of any one of claims 121-124, wherein P1, P2, P3, and P4 are each substituted or unsubstituted carbon.
126. The compound of claim 125, wherein P is CH.
127. The compound of claims 121-124, wherein at least one of P2, P3 and P4 is substituted carbon.
128. The compound of any one of claims 121-124, wherein P2, P3 and P4 are each independently selected from the group consisting of CH, CF, Cl, CBr, C-alkyl, C- alkoxy, C-aryl, and CI.
129. The compound of any one of claims 121 - 124, wherein Z3 and Z4 are each CH.
130. The compound of any one of claims 121-124, wherein Z1 is CH.
131. The compound of any one of claims 121-124, wherein Z1 is covalently linked to Z to form a naphthyl ring.
132. The compound of any one of claims 121-124, wherein Z is CH, C-(C≡CH), CCl, CBr, CI, or CF.
133. The compound of any one of claims 121 - 124, wherein L is a covalent bond.
134. The compound of any one of claims 121-124, wherein R is H, alkyl, arylcarboxy, alkylcarboxy, or arylalkylcarboxy.
135. The compound of any one of claims 121 - 124, wherein s is CR5R6 and R5 and R6 are each methyl.
136. The compound of any one of claims 121 - 124, wherein r is a covalent bond.
137. The compound of any one of claims 121 - 124, wherein t, r and s are CH2.
138. The compound of claim 121, wherein J is
Figure imgf000222_0001
wherein R is alkyl or hydrogen.
139. The compound of claim 138, wherein R is methyl, ethyl, or propyl.
140. The compound of any one of claims 121, 138 or 139, wherein P , P , and P are each CH, and P4 is CCl.
141. The compound of claim 121, wherein Z 1 , Z 73 , and Z are each CH, Z is COMe and Z2 is CBr.
142. The compound of claim 121, wherein Z is covalently linked to Z to form a naphthyl ring, and Z3, Z4 and Z5 are each CH.
143. An MC4-R binding compound ofthe formula (XVIII):
Figure imgf000223_0001
(XVIII) wherein
Ar and Ar' are aromatic groups;
R1 ' is selected independently for each position capable of substitution from the group hydrogen, cyano, alkoxy, nitro, halogen, alkyl, amino, or aryloxy; R12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
R13 is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, acyl, carbonyl, or SO2CH3, and may optionally be linked to an R16 or an R16 group; R16 and R16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R13 or another R16 or R1 group, to form a fused or spiro ring system; X is NR17, S, O or a covalent bond; R17 is hydrogen, alkyl, or carbonyl;
R14 and R15 are each independently hydrogen, halogen, or alkyl; w is 1, 2, 3, or 4; e is 0 or 1; f is 0 or 1, wherein both e and f are not both 0 if X is a covalent bond, and pharmaceutically acceptable salts thereof.
144. The compound ofthe formula:
Figure imgf000224_0001
or a pharmaceutically acceptable salt thereof.
145. The compound ofthe formula:
Figure imgf000224_0002
or a pharmaceutically acceptable salt thereof.
146. The compound ofthe formula:
Figure imgf000224_0003
or a pharmaceutically acceptable salt thereof.
147. The compound of the formula:
Figure imgf000224_0004
or a pharmaceutically acceptable salt thereof.
148. The compound ofthe formula:
Figure imgf000224_0005
or a pharmaceutically acceptable salt thereof.
149. The compound ofthe formula:
Figure imgf000225_0001
or a pharmaceutically acceptable salt thereof.
150. The compound of the formula:
Figure imgf000225_0002
or a pharmaceutically acceptable salt thereof.
151. A method for treating a MC4-R associated state in a mammal comprising administering an effective amount of a compound to a mammal, such that the MC4-R associated state is treated, wherein said compound is any one ofthe compounds of claims 144-150.
152. A method for treating a disorder associated with pigmentation or weight loss, comprising administering an effective amount of a compound of any one of claims 144- 150.
153. The method of claim 152, wherein said effective amount is effective to treat a disorder associated with pigmentation, weight loss, or bones.
154. The method of claim 153, wherein said weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
155. The method of claim 153, wherein said bone associated disorder is selected from the group consisting of osteogenesis imperfecta, hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, osteoporosis, myeloma bone disease, the depletion of calcium in bone, and bone fracture.
156. A pharmaceutical composition for the treatment of a MC4-R associated state in a mammal comprising a pharmaceutically acceptable carrier and an effective amount of an compound of any one of claims 144-150.
157. The method of any one of claims 1, 14, 65, 73, 74, 90, 101, or 102 wherein said MC4-R associated state is a bone associated state.
158. The method of claim 157, wherein said bone associated state is osteogenesis imperfecta, hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, the depletion of calcium in bone, bone remodelling associated state or bone fracture.
159. The method of claim 157, wherein said bone associated state is osteoporosis.
160. A pharmaceutical composition of claim 112, wherein said effective amount is effective to treat a bone associated disorder.
161. The pharmaceutical composition of claim 160, wherein said bone associated disorder is osteogenesis imperfecta, osteoporosis, hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, the depletion of calcium in bone, or bone fracture.
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