WO2000012083A1 - Formamides as therapeutic agents - Google Patents

Formamides as therapeutic agents Download PDF

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Publication number
WO2000012083A1
WO2000012083A1 PCT/US1999/019303 US9919303W WO0012083A1 WO 2000012083 A1 WO2000012083 A1 WO 2000012083A1 US 9919303 W US9919303 W US 9919303W WO 0012083 A1 WO0012083 A1 WO 0012083A1
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WIPO (PCT)
Prior art keywords
propyl
ethyl
phenyl
compound
methyl
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PCT/US1999/019303
Other languages
French (fr)
Inventor
Robert Carl Andrews
Marc Werner Andersen
David John Cowan
David Norman Deaton
Scott Howard Dickerson
David Harold Drewry
Michael David Gaul
Michael Joseph Luzzio
Brian Edward Marron
Michael Howard Rabinowitz
Original Assignee
Glaxo Group Limited
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Priority claimed from GBGB9818613.3A external-priority patent/GB9818613D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU55828/99A priority Critical patent/AU5582899A/en
Priority to EP99942456A priority patent/EP1121118A4/en
Priority to JP2000567200A priority patent/JP2002523454A/en
Publication of WO2000012083A1 publication Critical patent/WO2000012083A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/12—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 or doubly bound nitrogen atoms
    • C07D295/125—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in those disease states alleviated by the inhibition or antagonism of matrix metalloproteases, metalloproteases, and/or tumor necrosis factor-alpha (TNF), which pathologically involve aberrant extracellular matrix degradation, shedding of cell surface protein ectodomains, and/or TNF synthesis, such disease states including arthritis, tumor metastasis and diabetes.
  • TNF tumor necrosis factor-alpha
  • the aforementioned pharmacologic activities are useful in the treatment of mammals.
  • the compounds of the present invention can be used in the treatment of osteoarthritis, rheumatoid arthritis, tumor invasion and metastasis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, corneal ulceration and the complications of diabetes.
  • rheumatology oncology, dentistry, opththalmology, gastroenterology, cardiology, neurology, nephrology, infectious disease and endocrinology therapy for such agents.
  • the matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase- 1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and mat ⁇ lysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix.
  • MMP-1 fibroblast collagenase
  • MMP-8 neutrophil collagenase
  • MMP-13 chondrocyte collagenase
  • MMP's 2 and 9 gelatinases A and B
  • MMP's 2 and 9 members of the stromelysin family such as stromelysin-1 (MMP-3), stromely
  • inhibitors of one or more of the matrix metalloproteases would have utility m a wide range of disease states such as m abrogating the initiation of tumor metastasis and angiogenesis and m halting the pathogenesis of demyelmatmg diseases of the nervous system, multiple sclerosis being one example.
  • MMP inhibitors would also find utility in diseases involving connective tissue degradation m the joint, as occurs in osteoarthritis and rheumatoid arthritis.
  • MMP's-1 and -3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.
  • Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's; biochemical studies on the recombinant protein have demonstrated that it cleaves type II collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes m osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
  • inflammatory/autoimmune diseases which include, but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, pe ⁇ odontal disease, gingivitis, and corneal ulceration; n) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endomet ⁇ um, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, bram and central nervous system, thyroid and other endoc ⁇ ne gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkm's lymphomas,
  • metabolic diseases including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone
  • neurologic diseases including but not limited to multiple sclerosis and other demyehnation ailments
  • renal diseases including but not limited to nephrotic syndromes and glomerulonephritis
  • infectious diseases including but not limited to those mediated by viruses, bacteria, fungi
  • vin respiratory diseases, including but not limited to emphysema and COPD.
  • MMP inhibitors include some structure activity relationships for a series of carboxylalkylamine inhibitors. These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zmc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zmc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.
  • Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I)-
  • W is a zinc-chelating acyl derivative group of the formula -C(0)NHOH (which convention and in this application are referred to as "forward hydroxamates”) or a zinc- chelatmg substituted amme group of the formula -NH(OH)C(0)R (which by convention and in this application are referred to as "reverse hydroxamates”), where R is usually hydrogen or alkyl.
  • forward hydroxamates zinc-chelating acyl derivative group of the formula -C(0)NHOH
  • reverse hydroxamates zinc- chelatmg substituted amme group of the formula -NH(OH)C(0)R
  • MMP activity m conditions characterized by its overproduction w ould be of benefit, and compounds which inhibit MMP's would act m this manner at a specific target and be useful and of benefit.
  • the present invention fills this need by providing compounds that are potent, specific, orally active inhibitors of matrix metalloproteases.
  • Tumor necrosis factor- ⁇ (TNF ⁇ ), hereinafter called "TNF”
  • TNF Tumor necrosis factor- ⁇
  • TNF ⁇ Tumor necrosis factor- ⁇
  • Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alamne-76 - vahne-77 peptide bond.
  • TNF convertase an intracellular or cell-associated specific enzyme or family of enzymes, which by convention is called a "TNF convertase", distinct from the matrix metalloproteases but related in that both contain a zmc cation at the active site.
  • TNF convertase enzymatic activity can be detected m monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease - inhibiting compounds.
  • a metalloprotease is thought to mediate the proteolysis of the cell surface-IgE receptor CD23.
  • Certain of the CD23 - derived peptides possess proinflammatory biological activities mimicking those of cytokmes, including TNF ⁇ .
  • Metalloprotease like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectm, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotem receptor, beta amyloid precursor protein, mterleukm-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm-1 receptor type II, CD30, and tumor necrosis factor receptors type I and II.
  • cell surface protein ectodomains such as L-selectm, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotem receptor, beta amyloid precursor protein, mterleukm-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm-1 receptor type II
  • TNF is known to mediate many biological responses in vivo. Preclimcal and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF receptor constructs, and TNF detection techniques have implicated TNF as a mediator in numerous pathologies.
  • the compounds of the present invention by virtue of their activity m inhibiting TNF production and/or their activity in preventing cell surface protein ectodomam shedding should show utility in the treatment of diverse pathologies such as: l) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases and inflammatory gastrointestinal diseases, and systemic lupus erythematosis, ⁇ ) reperfusion injuries, such as those caused by an initial lschemic event; in) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome, ⁇ v) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity
  • the present invention fills this need by providing potent, orally active inhibitors of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
  • CD23 proteolysis in conditions characterized by an overabundance of CD23 proteolytic fragments would be of benefit, and compounds which inhibit CD23 proteolysis would be useful and of benefit.
  • the present invention fills this need by providing potent inhibitors of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
  • a T* where A, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; where A 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR 7 R 8 , OR 7 , SR 7 , or hydrogen, where R 7 and R 8 are as defined below; R, is
  • Di is alkylene, alkenylene, alkynylene, or a direct bond
  • D 2 is arylene, heteroarylene, or a direct bond
  • D 3 is aryl, heteroaryl, or heterocyclyl
  • Y is alkylene, alkenylene, alkynylene, O, S, S(O), S0 2 , NR 9 , Se, Si, C(O), P(O)OR 9 , P(O)R 9 , C(O)O, C(O)NR 9 , NR 9 C(0), OC(O), OC(0)0, NR 9 C(O)0, OC(0)NR 9 , NR 9 C(O)NR 10 , or
  • R 3 is hydrogen or lower alkyl
  • Ei is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
  • E 2 is hydrogen, NR,,Ri 2 , NR supplementSO 2 R, 2 , OR placed, SR,,, S(O)R, ⁇ , SO 2 R n , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R n and R !2 are as defined below;
  • R 5 is hydrogen or lower alkyl; where Zi is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, or a direct bond;
  • Z 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR ]3 Ri4, OR.3, SR 13 , NR 13 SO 2 R 14 , NR 13 C(O)R 14 , C(O)NR, 3 , C(O)R I3 , C(O)OR, 3 , OC(O)R 13 , S(O)R 13 , SO 2 R ]3 , SO 2 NR ]3 R 14 , (O(CH 2 ) q O) m R ⁇ or hydrogen, where m, q, R, 3 and R 1 are as defined below;
  • the present invention provides a family of compounds having the general structural formula:
  • W is a reverse hydroxamic acid group
  • Ri is a substituent other than hydrogen
  • R 2 is an alkylaryl or alkylheteroaryl substituent
  • R 4 is a hpophilic substituent preferably with ste ⁇ c bulk proximal to the peptide backbone.
  • R 2 , R 3 , R,, R 5 , and R show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and m some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases.
  • the alkylaryl or alkylheteroaryl nature of R 2 in combination with an appropriate choice of R R 3 , R 4 , R 5 , and R 6 as described herein is beneficial m achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3).
  • Such molecules can possess an improved therapeutic profile where inhibition of one or more of the matrix metalloproteases is associated with an adverse biological response or abnormal pathology.
  • the alkylaryl or alley lheteroaryl nature of R 2 m combination with an appropriate choice of R b R 3 , R 4 , R 5 , and R 6 as described herein is also beneficial in achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3) in preference to TNF convertase inhibition and inhibition of TNF release from whole cells.
  • reverse hydroxamate compounds of the present invention include those of the formula (II):
  • alkylene alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond
  • a 2 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR 7 R 8 , OR 7 , SR 7 , or hydrogen, where R 7 and R 8 are as defined below;
  • R 2 ⁇ s
  • D ⁇ s alkylene, alkenylene, alkynylene, or a direct bond, D 2 ⁇ s arylene, heteroarylene, or a direct bond; D 3 ⁇ s aryl, heteroaryl, or heterocyclyl;
  • Y is alkylene, alkenylene, alkynylene, O, S, S(O), S0 2 , NR 9 , Se, Si, C(O), P(O)OR 9 , P(O)R 9 C(O)O, C(O)NR 9 , NR 9 C(0), OC(O), OC(0)0, NR 9 C(0)0, OC(0)NR 9 , NR 9 C(O)NR I0 , or
  • E] is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
  • E 2 is hydrogen, NR,,R 12 , NR,,SO 2 R, 2 , OR, , SR U , S(O)R réelle, SO 2 R,,, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R), and R )2 are as defined below;
  • R 5 is hydrogen or lower alkyl
  • Z 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR I3 R t4 ,
  • Preferred embodiments of the invention include compounds of general formula (II) where:
  • Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 3-aminophenoxymethyl, 2-(3-tetrazolyl)-l -ethyl, 2-(3-pyridyl)-l- ethyl, 2-(3-furyl)-l -ethyl, 2-(2-th ⁇ azolyl)-l -ethyl, 3,3,3-trifluoro-l -propyl, 2-(4- trifluorophenyl)-l -ethyl, thiophene-3-ethynyl, 2-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-phenylsulfanylmethyl, trifluoromethyl, trichloromethyl, or vinyl;
  • R 2 is 5-methylthiophene-2-methyl, 2-furanmethyl, thiophene-2-methyl, benzothiophene-2-methyl, benzofuran-2-methyl, 4-fluorobenzyl, 3-phenyl-l -propyl, 3- phenyl-2-methyl- 1 -propyl, 3-(2-pyridyl)-l-propyl, 3-(thiophene-2-yl)- 1 -propyl, 4-phenyl-l - butyl, 3-phenyl-2-propene-l-yl, 3-(benzofuran-3-yl)-l -propyl, 3-(benzothiophene-3-yl)-l- propyl, 3 -(furan-2-yl)-l -propyl, 3-(2-thiazolyl)-l -propyl, 3-(pyrimidin-2-yl)-l -propyl, 3-phenyl-2-ethyl-l -propyl, 3-
  • R 3 is hydrogen;
  • R 4 is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylam ⁇ no)-l -butyl, 2-(2- (benzyloxycarbonylam.no)- 1 -ethylsulfanyl)-2-propyl, 3-pyr ⁇ dylmethyl, 4-(2- naphthylacetylamino)- 1 -butyl, 3 -(benzyloxycarbonylammo)-l -propyl, 3-carbamoylammo-l- propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-( ⁇ m ⁇ no-(2,3,6-t ⁇ methyl- 4-methoxybenzenesulfonylammo))-methylam ⁇ no-l -propyl, 4- benzyloxycarbonylammobenzyl, isopropyl,
  • R 5 is hydrogen
  • Re is methyl, 2-(l-pyrrol ⁇ d ⁇ no)-l -ethyl, 2-py ⁇ dylmethyl, 3-pyr ⁇ dylmethyl, 4- pyridylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-(4-mo ⁇ holmo)-l -ethyl, 3-(4- mo ⁇ hohno)-l -propyl, 3-(4-methylp ⁇ perazme)-l -propyl, 2-(4-methylp ⁇ peraz ⁇ ne)-l -ethyl, 2-(2- pyridyl)- 1 -ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tr ⁇ fluoroethyl;
  • Other preferred embodiments of the invention include compounds of general formula (
  • R is 1-methylbenzyl, benzyl , 3- phenylcarbonylammo-1 -propyl, 2,2-d ⁇ methyl-l -propyl, 3-phenylcarbamoylam ⁇ no-l -propyl, 4-pyr ⁇ dylmethyl, 4-methoxybenzyl, 3-mdolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R ⁇ ; is hydrogen, 2-(2-pyr ⁇ dyl)-l -ethyl, 2-(3- pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, l-(2-am ⁇ noethyl)-p ⁇ peraz ⁇ ne, 2-(4- ⁇ m ⁇ dazolyl)
  • Particularly preferred embodiments of the invention include compounds of general formula II where: Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 2-(3-tetrazolyl)-l-ethyl, 2-(3 -pyridyl)- 1 -ethyl, 2-(3-furyl)-l -ethyl, 3,3,3-tr ⁇ fluoro-l -propyl, 2-(4-t ⁇ fluorophenyl)-l -ethyl, 2-phenylsulfanylmethyl, t ⁇ fluoromethyl, or t ⁇ chloromethyl;
  • R 2 is 5-methylth ⁇ ophene-2-methyl, 2-furanmethyl, th ⁇ ophene-2-methyl, 4- fluorobenzyl, 3-phenyl-l-propyl, 3-phenyl-2-methyl-l -propyl, 3-(2-pyr ⁇ dyl)-l -propyl, 3- (th ⁇ ophene-2-yl)-l -propyl, 4-phenyl-l -butyl, 3-phenyl-2-propene-l-yl, 3-(furan-2-yl)-l- propyl, 3-(2-th ⁇ azolyl)-l -propyl, 3-(3-pyr ⁇ dyl)-l -propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l- propyl, benzoth ⁇ ophene-3-methyl, benzoxazole-2-methyl, 3-(4-chlorophenyl)-l -propyl, 3-(4- fluorophen
  • R 3 is hydrogen
  • R is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylammo)-l -butyl, 2-(2- (benzyloxycarbonylammo)- 1 -ethylsulfanyl)-2-propyl, 3-pyr ⁇ dylmethyl, 4-(2- naphthylacetylammo)- 1 -butyl, 3 -(benzyloxycarbonylamino)- 1 -propyl, 3 -carbamoylammo- 1 - propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, isopropyl, cyclohexyl, 4- cyclopentylacetylammo- 1 -butyl, 4-(3-methoxybenzoylammo)-l -butyl, 4- efhoxycarbonylammo- 1 -butyl, 2-(2-(
  • R5 is hydrogen
  • Ri is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-pyr ⁇ dylmethyl, 3-py ⁇ dylmethyl, 4- pyridylmethyl, cyclopropyl, cyclopentyl, 2-(4-mo ⁇ hohno)-l -ethyl, 3-(4-mo ⁇ holmo)-l- propyl, 3-(4-methylp ⁇ peraz ⁇ ne)-l -propyl, 2-(4-methylp ⁇ peraz ⁇ ne)-l -ethyl, 2-(2-pyr ⁇ dyl)- 1 - ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tr ⁇ fluoroethyl;
  • Other particularly preferred embodiments of the invention include compounds of general formula (II) where
  • R is 1 -methylbenzyl, benzyl, 2,2-d ⁇ methyl-l -propyl, 4- pyridylmethyl, 4-methoxybenzyl, 3- ⁇ ndolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R ⁇ is hydrogen, 2-(2-pyr ⁇ dyl)- 1 -ethyl, 2-(3- pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)- -ethyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • Ri is methyl, ethyl, n-propyl, isopropyl, or 3,3,3-tr ⁇ fluoro-l-propyl;
  • R 2 is 3-phenyl-l-propyl, 3 -(4-chlorophenyl)-l -propyl, 3-(4-fluorophenyl)-l -propyl, 3- (4-tr ⁇ fluoromethylphenyl)-l -propyl, or 3-(th ⁇ ophene-2-yl)-l -propyl;
  • R 3 is hydrogen;
  • R 4 is tert-butyl or 1-phenyl-l -ethyl; R 5 is hydrogen; and
  • R 6 is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-py ⁇ dylmethyl, 3-py ⁇ dylmethyl, or 4- py ⁇ dylmethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • R 4 is benzyl, 4-fluorobenzyl, 2- butyl, cyclohexyl, or isopropyl
  • R 6 is 2-(4-mo ⁇ holmo)-l -ethyl, 3-(4-mo ⁇ holmo)-l- propyl, tetraethyleneglycolyl methyl ether, 2-(2-py ⁇ dyl)-l -ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, or 2- (4-pyr ⁇ dyl)-l -ethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • the compounds of the present invention are inhibitors of matrix metalloproteases, TNF converting enzyme, and TNF activity from whole cells.
  • the compounds of the present invention may also inhibit shedding of pathologically significant cell surface protein ectodomains.
  • the invention described herein is additionally directed to pharmaceutical compositions and methods of inhibiting matrix metalloprotease and/or TNF activity in a mammal, which methods comprise administering, to a mammal in need of inhibition of matrix metalloprotease and/or TNF activity, a therapeutically defined amount of a compound of formula (I) or (II), defined above, as a single or polymo ⁇ hic crystalline form or forms, an amo ⁇ hous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer, a mixture of diastereoisomers, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug,
  • a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof for use in therapy is provided.
  • the present invention provides a method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit a matrix metalloprotease.
  • a matrix metalloprotease- inhibiting amount can be an amount that reduces or inhibits a matrix metalloprotease activity in the subject.
  • the present invention further provides a method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit cellular release of mature tumor necrosis factor.
  • An amount sufficient to inhibit cellular release of mature tumor necrosis factor can be an amount that reduces or inhibits cellular release of mature tumor necrosis factor in the subject.
  • a method of inhibition of shedding of cell surface protein ectodomains comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit shedding of cell surface protein ectodomains
  • An amount sufficient to inhibit shedding of cell surface protein ectodomains can be an amount that reduces or inhibits shedding of one or more cell surface protein ectodomains, such as L-selectin, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotein receptor, beta amyloid precursor protein, ⁇ nterleuk ⁇ n-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm- 1 receptor type II, CD30
  • Also provided is a method of inhibiting CD23 proteolysis comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit CD23 proteolysis
  • An amount sufficient to inhibit CD23 proteolysis can be an amount that reduces or inhibits CD23 proteolysis in the subject.
  • a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting CD23 proteolysis Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to decrease, or inhibit, a malignant growth.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat arthritis.
  • Such an amount can be an amount that relieves, i.e., reduces or eliminates, one or more physiologic characteristic of arthritis
  • composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diabetes.
  • an amount can be an amount that reduces or eliminates one or more of the complications associated with diabetes.
  • the present invention contemplates treating any of these diseases/conditions m a subject by administering to the subject the recited pharmaceutical composition.
  • the compounds of the present invention can be administered to any mammal in need of inhibition of matrix metalloprotease activity, CD23 proteolysis, shedding of cell surface protein ectodomains and/or TNF activity.
  • mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably humans.
  • Certain examples of the invention also are orally bioavailable in animals and possess oral activity in animal models of disease.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochlo ⁇ de, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsamlate, Hexylresorcmate, Hydrabamine, Hydrobromide, Hydroclo ⁇ de, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamo
  • Phosphate/diphosphate Polygalacturonate, Potassium, Sahcylate, Sodium, Stearate, Subacetate, Succmate, Tannate, Tartrate, Teoclate, Tosylate, T ⁇ ethiodide, T ⁇ me hylammonium and Valerate.
  • the present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more of the three stereocenters are inverted.
  • alkyl refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbam
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy
  • alkenyl refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkenylene refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Examples of “alkenylene” as used herein include, but are not limited to, ethene-l,2-d ⁇ yl, propene-l,3-d ⁇ yl, methylene- 1,1-d ⁇ yl, and the like
  • alkynyl refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkynylene refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkynylene as used herein include, but are not limited to, ethyne-l,2-d ⁇ yl, propyne-l,3-d ⁇ yl, and the like.
  • cycloalkyl refers to a alicychc hydrocarbon group with one or more degrees of unsaturation, having from three to twelve carton atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed "Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
  • cycloalkylene refers to an non-aromatic alicychc divalent hydrocarbon radical having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • cycloalkylene examples include, but are not limited to, cyclopropyl- 1,1-d ⁇ yl, cyclopropyl- 1,2-d ⁇ yl, cyclobutyl- 1,2- diyl, cyclopentyl- 1, 3 -diyl, cyclohexyl- 1,4-d ⁇ yl, cycloheptyl-l ,4-dryl, or cyclooctyl- 1,5-d ⁇ yl, and the like.
  • cycloalkenyl refers to a substituted alicychc hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • cycloalkenylene examples include, but are not limited to, 1- cyclopentene-3-yl, l-cyclohexene-3-yl, l-cycloheptene-4-yl, and the like.
  • cycloalkenylene refers to a substituted alicychc divalent hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto
  • heterocyclic or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, S0 2 , O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Such a ring may be optionally fused to one or more of another "heterocyclic” rmg(s) or cycloalkyl ⁇ ng(s).
  • heterocyclic include, but are not limited to, tetrahydrofuran, pyran, 1,4-d ⁇ oxane, 1,3- dioxane, pipe ⁇ dme, pyrrohdme, mo ⁇ holme, piperazine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • heterocyclylene refers to a three to twelve- membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO 2 , O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Such a ring may be optionally fused to one or more benzene rings or to one or more of another "heterocyclic" rings or cycloalkyl ⁇ ngs.
  • heterocyclylene include, but are not limited to, tetrahydrofuran-2,5-d ⁇ yl, mo ⁇ hohne-2,3-d ⁇ yl, pyran-2,4-d ⁇ yl, l,4-d ⁇ oxane-2,3-d ⁇ yl, l ,3-d ⁇ oxane-2,4-d ⁇ yl, pipe ⁇ dine- 2,4-d ⁇ yl, p ⁇ pe ⁇ d ⁇ ne-l,4-d ⁇ yl, pyrrohd ⁇ ne-l,3-d ⁇ yl, mo ⁇ hol ⁇ ne-2,4-d ⁇ yl, p ⁇ perazme-l,4-dy ⁇ l, and the like.
  • aryl refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower
  • arylene refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene ⁇ ngs, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alky
  • heteroaryl refers to a five - to seven - membered aromatic ring, or to a polycychc heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano
  • one or more of the rings may contain one or more heteroatoms.
  • heteroaryl used herein are furan, thiophene, pyrrole, lmidazole, pyrazole, t ⁇ azole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole.
  • heteroarylene refers to a five - to seven - membered aromatic ring diradical, or to a polycychc heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbony
  • heteroarylene used herein are furan-2,5-d ⁇ yl, th ⁇ ophene-2,4-d ⁇ yl, l,3,4-oxad ⁇ azole-2,5-d ⁇ yl, l,3,4-fh ⁇ ad ⁇ azole-2,5- diyl, l,3-th ⁇ azole-2,4-d ⁇ yl, l,3-th ⁇ azole-2,5-d ⁇ yl, py ⁇ d ⁇ ne-2,4-d ⁇ yl, py ⁇ d ⁇ ne-2,3-d ⁇ yl, py ⁇ d ⁇ ne-2,5-d ⁇ yl, py ⁇ m ⁇ d ⁇ ne-2,4-d ⁇ yl, qumohne-2,3-d ⁇ yl, and the like.
  • direct bond refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond”. Where two or more consecutive variables are specified each as a "direct bond”, those substituents flanking (preceding and succeeding) those two or more consecutive specified "direct bonds" are directly joined.
  • alkoxy refers to the group R a O-, where R a is alkyl.
  • alkenyloxy refers to the group R a O-, where R a is alkenyl.
  • alkynyloxy refers to the group R a O-, where R a is alkynyl.
  • alkylsulfanyl refers to the group R a S-, where R a is alkyl.
  • alkenyl sulfanyl refers to the group R a S-, where R a is alkenyl.
  • alkynylsulfanyl refers to the group R a S-, where R a is alkynyl.
  • alkylsulfenyl refers to the group R a S(0)-, where R a is alkyl.
  • alkenylsulfenyl refers to the group R a S(0)-, where R a is alkenyl.
  • alkynylsulfenyl refers to the group R a S(0)-, where R a is alkynyl.
  • alkylsulfonyl refers to the group R a S0 2 -, where R a is alkyl.
  • alkenylsulfonyl refers to the group R a S0 2 -, where
  • R a is alkenyl
  • alkynylsulfonyl refers to the group R a S0 2 -, where R a is alkynyl.
  • acyl refers to the group R a C(O)- , where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
  • aroyl refers to the group R a C(0)- , where R a is aryl.
  • heteroaroyl refers to the group R a C(O)- , where R a is heteroaryl.
  • alkoxycarbonyl refers to the group R a OC(O)-, where R d is alkyl.
  • acyloxy refers to the group R a C(O)0- , where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
  • aroyloxy refers to the group R a C(O)0- , where R a is aryl.
  • heteroaroyloxy refers to the group R a C(O)O- , where R a is heteroaryl.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • the terms "contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO 2 , N, or N-alkyl, including, for example, -CH 2 -O-CH 2 -, -CH 2 -SO 2 -CH 2 -, -CH 2 -NH-CH 3 and so forth.
  • solvate is a complex of variable stoichiometry formed by a solute (m this invention, a compound of formula (I) or (II)) and a solvent.
  • solvents for the pu ⁇ ose of the invention may not interfere with the biological activity of the solute.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • biohydrolyzable ester is an ester of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • a drug substance in this invention, a compound of general formula (I) or (II)
  • b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) or (II) in plasma.
  • biohydrolyzable amide is an amide of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) or (II) in plasma.
  • prodrug includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I) or (II): for example, the lactam formed by a carboxyhc group in R 2 and an amine in R 4 , and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I) or (II).
  • Examples of these functional groups include, but are not limited to, 1,4-d ⁇ hydropy ⁇ dme, N-alkylcarbonyl-l,4-d ⁇ hydropy ⁇ dme, 1,4- cyclohexadiene, tert-butyl, and the like.
  • affinity reagent is a group attached to the compound of formula (I) or (II) which does not affect its m vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not protemaceous.
  • An example of an affinity reagent according to b) would be biotin either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P m any combination.
  • An example of an affinity reagent according to a) above would be fluorescein, either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination.
  • pharmacologically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician This amount can be a therapeutically effective amount.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be inte ⁇ reted as including those limitations given above for "alkyl” and "aryl”.
  • Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. Ci-io) shall refer independently to
  • alkyl the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term "alkyl" appears as its prefix root.
  • halogen or halo shall include iodine, bromine, chlorine and fluorine.
  • mercapto shall refer to the substituent -SH.
  • cyano shall refer to the substituent -CN.
  • aminosulfonyl shall refer to the substituent -
  • sulfenyl shall refer to the substituent -S(O)-
  • sulfonyl shall refer to the substituent -S(O) 2 -.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled m the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
  • DIEA d ⁇ sopropylethylamme
  • BOP ( 1 -benzot ⁇ azolyloxy)t ⁇ s(d ⁇ methylam ⁇ no)phosphon ⁇ um hexafluorophosphate
  • LAH lithium aluminum hydride
  • TFA t ⁇ fluoroacetic acid
  • EDC 1 -ethyl-3-(3-d ⁇ methylammopropyl)-carbod ⁇ m ⁇ de hydrochlo ⁇ de
  • HOBt 1 -hydroxybenzot ⁇ azole
  • SPA scintillation proximity assay
  • EDTA ethylenediamine tetraacetic acid
  • FBS fetal bovine serum
  • PBS phosphate buffered saline solution
  • ELISA enzyme - linked immunosorbent assay
  • Ri, R 2 , R 3 , R 4 , R 5 , and R(, are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl
  • Rn is chosen from the group consisting of hydroxyl, 0-C 6 F 5 , or halogen.
  • the conversion of (V) to (VII) involves methods known in peptide chemistry; for example, the reaction may be conducted using HOBt in combination with a dehydrating agent such as dicyclohexylcarbod ⁇ mide in a suitable solvent, such as DMF.
  • a suitable solvent such as dichloromethane
  • pentafluorophenyl t ⁇ fluoroacetate m the presence of pyridme, or with EDC and pentafluorophenol in a suitable solvent such as dichloromethane.
  • the displacement reaction to produce (VII) is carried out in the presence of a suitable solvent such as dioxane, THF, dichloromethane, or DMF, at a temperature of 0 °C to 140 °C.
  • a suitable solvent such as dioxane, THF, dichloromethane, or DMF
  • the reaction is effected in the presence of an organic base such as NMM or t ⁇ ethylamine.
  • the removal of the RPGi group where RPGi is benzyl may be achieved by hydrogenation of (VII) with palladium on barium sulfate in a suitable solvent such as methanol or THF, or, where RPG, is 2-tetrahydropyranyl, by hydrolysis with aqueous acetic acid at a temperature of 20 °C to 100 °C.
  • Reaction Scheme 2 depicts the synthesis of a compound of formula (IV).
  • R ]6 O is a nucleofugal group such as methanesulfonate, trifluoromethanesulfonate, or p- toluenesulfonate.
  • RPG is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • the acid of formula (VIII) may be converted to the alcohol of formula (IX) by treatment with HOBt, O-benzylhydroxylamine hydrochlo ⁇ de or 2- tetrahydropyranyloxyamine, NMM, and a carbodnmide reagent such as EDC m a suitable solvent such as DMF.
  • the alcohol of formula (IX) may be converted to (X) by treatment with methanesulfonyl chloride, p-toluenesulfonyl chloride, or t ⁇ fluoromethanesulfonic anhydride and pyridine m a suitable solvent such as dichloromethane.
  • (X) to (XI) may be conducted by treatment with potassium carbonate in a suitable solvent such as acetone or 2-butanone, at temperature of 20 °C to 90 °C.
  • (IX) may be converted directly to (XI) by treatment with t ⁇ phenylphosphme and diethyl azodicarboxylate or another azodicarbonyl diester or diamide in a suitable solvent such as THF at a temperature of -78 °C to 50 °C.
  • the compound of formula (XI) may be converted to (XII) by treatment with an inorganic base such as sodium hydroxide in water or water in combination with a water soluble organic cosolvent such as methanol or dioxane, followed by acidification with an acidic solution such as aqueous citric acid or aqueous sodium bisulfate
  • an inorganic base such as sodium hydroxide in water or water in combination with a water soluble organic cosolvent such as methanol or dioxane
  • an acidic solution such as aqueous citric acid or aqueous sodium bisulfate
  • the compound of formula (XII) may be converted to (IV) by treatment with acetic anhydride and formic acid or by treatment with formic acetic anhydride in pyridine m the presence or absence of a suitable cosolvent such as dichloromethane.
  • Ri and R are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R 17 is chosen from the group consisting of lower alkoxy or oxazohdinon-1-yl, where the 4 and 5 positions of an oxazol ⁇ d ⁇ non-1-yl group may be substituted with a lower alkyl, aryl, or lower alkylaryl group and where such an oxazol ⁇ dmon-1-yl substituent may exist as a single stereoisomer or as a mixture of stereoisomers.
  • a carbonyl compound of formula (XIII), where R ⁇ 7 is an alkoxy group such as methoxy or tert-butoxy, may be treated with a strong base such as LDA in a solvent such as THF at a temperature of from -78 °C to 0 °C, followed by treatment with the aldehyde (XIV) to provide (XV).
  • a strong base such as LDA
  • a solvent such as THF
  • R 17 is an oxazol ⁇ dmon-1-yl substituent
  • treatment of (XIII) with a Lewis acid such as d ⁇ (n-butyl)boron trifluoromethanesulfonate in the presence of N,N- diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature of 0 °C followed by addition of the aldehyde (XIV) provides (XV).
  • Treatment of (XV) with aqueous base in the presence or absence of hydrogen peroxide affords (VIII) upon acidification.
  • the acid (VIII) may be converted directly to (IX) as m reaction Scheme 2, or may be treated with a dehydrating agent such a p-toluenesulfonyl chloride in pyridme or with friphenylphosphme and diethyl azodicarboxylate in a suitable solvent such as THF, to afford the lactone (XVI).
  • a dehydrating agent such as a p-toluenesulfonyl chloride in pyridme or with friphenylphosphme and diethyl azodicarboxylate in a suitable solvent such as THF
  • a suitable solvent such as THF
  • Reaction Scheme 4 depicts the preparation of compounds of general formula (VIII).
  • Ri and R 2 are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • Rig is selected from the group consisting of lower alkyl or benzyl.
  • Ri is selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate.
  • ketoester of general formula (XVII) may be formed by treating 2,2-d ⁇ methyl-l,3- d ⁇ oxane-4,6-d ⁇ one with an appropriate acid chloride Ri COCl in the presence of base, an
  • the ketoester of general formula (XVII) may be reduced with a reducing agent such as sodium borohydride to afford the hydroxyester (XVIII)
  • a reducing agent such as sodium borohydride
  • reduction of (XVII) with a chiral catalyst or chiral hgand in the presence of a reducing agent such as hydrogen or a metal hydride such as borane or lithium aluminum hydride may be employed to afford (XVIII) with chiral induction at the newly formed center
  • the alcohol (XVIII) may be converted to (XIX) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of R 2 -R ⁇ 9 in the presence or absence of a cosolvent such as DMPU Removal of the ester group by hydrolysis with aqueous hydroxide ion or, m the case where R 18 is tert-butyl, by treatment with a strong acid such as TFA, affords (VIII)
  • Ri and R 2 are as defined as for formula (II).
  • R 22 is selected from the group consisting of aryl or heteroaryl.
  • R ⁇ 9 ⁇ s selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate .
  • RPG is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R 20 and R ] may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S0 2 substituents.
  • the lactam of general formula (XX) may be treated with a metal catalyst such as tetrak ⁇ s(t ⁇ phenylphosphme)pallad ⁇ um or palladium chloride and R 2 -Ri 9 m a solvent such as acetonit ⁇ le at a temperature of from 20 °C to 200 °C to afford (XXI) Reduction of the olefinic group in (XXI) with hydrogen and a metal catalyst such as palladium on carbon and conversion of the lactam (XI) to the acid (IV) proceeds as outlined in reaction Scheme 2.
  • a metal catalyst such as tetrak ⁇ s(t ⁇ phenylphosphme)pallad ⁇ um or palladium chloride and R 2 -Ri 9 m a solvent such as acetonit ⁇ le at a temperature of from 20 °C to 200 °C to afford (XXI)
  • olefin in compounds of general formula (XXI) may be left in place and manipulation of the lactam (XXI) carried out as described in reaction Scheme 2 to afford (XXII).
  • Acid (XXII) may be converted to (IV) as described in reaction Scheme 2 with or without reduction of the olefin in (XXII), as appropriate
  • R] is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R] 8 is selected from the group consisting of lower alkyl or benzyl.
  • R] 9 is selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate.
  • R 20 , R 2 ⁇ and R 23 may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S0 2 substituents.
  • R 22 is aryl or heteroaryl.
  • R 24 is a t ⁇ alkylstannyl group.
  • the alcohol (XVIII), prepared from (XVII) as outlined in reaction Scheme 4, may be converted to (XXIV) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXIII), m the presence or absence of a cosolvent such as
  • the alkene (XXIV) may be converted to the acid (VIII) as described in reaction Scheme 2.
  • the alcohol (XVIII) may be converted to (XXVI) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXV), in the presence or absence of a cosolvent such as DMPU.
  • Conversion of (XXVI) to (XXVII) proceeds as described in reaction Scheme 2.
  • the alkyne (XXVII) may be treated with R 24 -H and a radical initiator such as azob ⁇ s( ⁇ sobutyron ⁇ t ⁇ le) a solvent such as toluene to afford (XXVIII).
  • the alkenyltin compound (XXVIII) may be treated with a catalyst such as tetrak ⁇ s(t ⁇ phenylphosph ⁇ ne)pallad ⁇ um and R 22 -R ]9 m a solvent such as DMF at a temperature of from 20 °C to 180 °C to provide (XXIX).
  • a catalyst such as tetrak ⁇ s(t ⁇ phenylphosph ⁇ ne)pallad ⁇ um and R 22 -R ]9 m a solvent such as DMF at a temperature of from 20 °C to 180 °C to provide (XXIX).
  • the alkene (XXIX) may be transformed to the lactam (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation.
  • Compound (XXXI) may be converted if desired to (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation.
  • the preparation of compounds of general formula (VI) is shown in reaction Scheme
  • RPG 2 is selected from the group consisting of tert-butoxycarbonyl, allyloxycarbonyl, or benzyloxycarbonyl
  • R 25 is selected from the group consisting of 1 -benzot ⁇ azolyloxy, or bromine
  • the acid of formula (XXXII) may be converted in situ to (XXXIII), where R 25 is bromine, by treatment with bromo-t ⁇ s(pyrrol ⁇ d ⁇ no)phosphon ⁇ um hexafluorophosphate in a suitable solvent such as DMF in the presence of an organic base such as N,N- d ⁇ sopropylethylamme
  • the acid of formula (XXXII) may be converted in situ to (XXXIII), where R 2 5 is benzot ⁇ azolyloxy, by treatment with BOP in a suitable solvent such as DMF in the presence of an organic base such as NMM Addition of the amme (XXXIV) in the displacement step m the presence of a suitable solvent such as DMF and an organic base such as N,N-dnsopropylethylamine affords the amide (XXXV)
  • the compounds of the present invention can be administered in such oral
  • buccal and sublingual dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • they may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intrape ⁇ toneal, mtraarticular, subcutaneous or intramuscular inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the dosage regimen utilizing the compounds of the present invention is selected accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.1 to 2000 mg/kg of body weight per day, and particularly 1 to 1000 mg/kg of body weight per day. Oral dosage units will generally be administered in the range of from 1 to about 250 mg and more preferably from about 25 to 250 mg. The daily dosage for a 70 kg mammal will generally be in the range of about 10 mg to 5 grams of a compound of formula I or II.
  • While the dosage to be administered is based on the usual conditions such as the physical condition of the patient, age, body weight, past medical history, route of administrations, severity of the conditions and the like, it is generally preferred for oral administration to be used to administer to a human. In some cases, a lower dose is sufficient and, in some cases, a higher dose or more doses may be necessary. Topical application similarly may be once or more than once per day depending upon the usual medical considerations.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered m divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered m lntranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skm patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen
  • the compounds herein described m detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "earner" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavonng, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Ghdants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubihzing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium algmate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used m these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, a gar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and dismtegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aligmate, gelatin, or poly vinyl pyrrohdone, a solution retardant such as paraffin, a reso ⁇ tion accelerator such as a quaternary salt and/or an abso ⁇ tion agent such as bentonite, kaolm or dicalcium phosphate
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stea ⁇ c acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound m a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound m a non-toxic vehicle.
  • Solubihzers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or saccharin, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention can also be administered m the form of hposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
  • the compounds of the present invention can also be administered in the form of hposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrohdone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl residues
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (II) in combination with a pharmaceutically acceptable carrier.
  • Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular, intrathecal, lntraarte ⁇ al or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound m a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution.
  • liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular, intrathecal, lntraarte ⁇ al or intravenous injection.
  • a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed.
  • An accompanying vial or vehicle can be provided for mixing prior to administration.
  • Non-toxic salts and salt solutions can be added to render the injection lsotonic.
  • Stabilizers, preservations and emulsifiers can also be added.
  • Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-meltmg water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters, my ⁇ styl palmitate or mixtures thereof.
  • Topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluor
  • compositions are those in a form suitable for oral administration, such as tablets and liquids and the like and topical formulations.
  • reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate.
  • the combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-[(2E)- 3-phenyl-2-propen-l-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield).
  • reaction mixture is quenched by addition 10 mL of saturated aqueous ammonium chloride solution, is poured into 100 mL of 1 M hydrochloric acid, and is extracted with two 100 mL portions of ethyl acetate.
  • the combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 20% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-(3-tnmethyls ⁇ lyl-2-propyne-l-yl)-3-hydroxybutanoate as a yellow oil (5.6 g, 58% yield).
  • 'H NMR 400 MHz, CDCI3 ⁇ 4.04 (m, IH), 3.72 (s, 3H), 2.62 (m, 3H), 1.23 (t, 3H), 0.09 (s,
  • reaction mixture is poured into ethyl acetate/hexanes (1 : 1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • Example 3a (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-((2E)-3-(th ⁇ ophene-2-yl)-2-propene-l- yl)-4-methylazet ⁇ d ⁇ n-2-one
  • To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tnbutylstannyl-2- propene-l-yl)-4-mefhylazet ⁇ d ⁇ n-2-one (400 mg, 0.78 mmol) in 1 mL of dimethylformamide is added 2-bromoth ⁇ ophene (152 mg, 0.93 mmol) and tnphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol)
  • the resulting solution is heated at 80°C for 2 h, then 0.5 mL ammonium hydroxide is added.
  • reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1 : 1 ethyl acetate/hexane (50 mL).
  • the combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3: 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(th ⁇ ophene-2-yl)-2-propene-l-yl)-4- methylazet ⁇ d ⁇ n-2-one as an oil (130 mg, 54% yield).
  • reaction mixture is poured into ethyl acetate/hexane (1.1, 20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1 : 1 ethyl acetate - hexane) to provide (2R,3S)-3-
  • Example 52a (3R,45)- 1 -(2-Tetrahydropyranyloxy)-3 -((2E)-3 -(4-methylphenyl)-2-propene- 1 - yl)-4-methylazet ⁇ d ⁇ n-2-one
  • Example 52c (2R,3S)-2-(3-(4-methylphenyl)-l-propyl)-3-(2- tetrahydropyranyloxyam ⁇ no)butano ⁇ c Acid
  • the solution is stirred at 23 °C for 20 h, then extracted with hexanes (10 mL).
  • the combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4- methylphenyl)-l-propyl)-3-(2-tetrahydropyranyloxyam ⁇ no)butano ⁇ c acid as an oil (114 mg, 67% yield).
  • ⁇ NMR (400 MHz, CDCI3) ⁇ 7.04 (m, 4H), 4.94 (m, 0.5H). 4.84 (m, 0.5H), 3.95 (m. 0.5H),
  • reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochlo ⁇ c acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,3S)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(3-(4-methylphenyl)- 1 -propyl)butano ⁇ c acid [( 15)-2,2- d ⁇ methyl-(l -methylcarbamoyl)- 1 -propyljamide as a white solid (55 mg, 68% yield).
  • Example 61a (3R,45)-l-(2-Tetrahydropyranyloxy)-3-((2E),(4E,Z)-3-phenyl-2,4-pentad ⁇ ene- 1 -yl)-4-methylazet ⁇ d ⁇ n-2-one
  • reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted wit 1 : 1 ethyl acetate/hexane (50 mL).
  • the combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3 : 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E),(4E/Z)-3-phenyl-2,4-pentad ⁇ ene-l-yl)- 4-methylazet ⁇ d ⁇ n-2-one as an oil (140 mg, 49% yield).
  • ⁇ NMR 400 MHz, CDCI3
  • reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,35)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(5-phenyl-l-pentyl)butano ⁇ c acid [(15)-2,2-d ⁇ methyl-(l- mefhylcarbamoyl)-l -propyljamide as a white solid (44 mg, 63% yield).
  • ESI-MS m/z 526.3 (M+Na) + .
  • MMP-1 Matrix Metalloprotease Inhibition Protocol
  • MMP- 13 20 kD truncated collagenase-3
  • MMP-3 stromelysin- 1
  • MMP-9 50 kD truncated gelatmase B
  • the potency of compounds of the invention as inhibitors of cell - free tumor necrosis factor ⁇ converting enzyme is determined as follows: Membrane preparation from MonoMac 6 cells (subfractionated extract from equivalent of 6x10 6 cells per 60 ⁇ l assay) is incubated for 1 hr with 200 nM radiolabeled substrate (B ⁇ ot ⁇ n-SPLAQAVRSSSRT-( 3 H)P-S-NH 2 , 4.1
  • the potency of compounds of the invention as inhibitors of release of soluble tumor necrosis factor ⁇ from stimulated monocytes m vitro is determined as follows: LPS/PMA solution for assay consisting of a) 4 ⁇ L of 5 mg/mL LPS stock and b) 6 ⁇ L of 10 mg/mL PMA stock are added to 500 ⁇ L of medium (RPMI 1640 (Gibco) + 10% FBS + penicillin/streptomycin + 1-glutam ⁇ ne). This solution is then diluted 1 : 1000 (40 ng/mL and 120 ng/mL) for use later in the assay. Compounds (10 mM) are serially diluted 1 :3 in DMSO.
  • MonoMac 6 cell suspension 130 ⁇ L, 1.5 xlO 6 cells/mL
  • LPS/PMA 50 ⁇ L
  • the plate is incubated at 37 °C for 2 hours then spun at 1 ,500 rpm for 3 minutes to pellet cells.
  • the supernatant 120 ⁇ L/well is removed to a new round bottom 96 well plate and diluted 1 : 10 m PBS. Then, 20 ⁇ L of the supernatant is transferred to a Cistron TNF ⁇ ELISA plate and processed according to the manufacturer's instructions to quantitate levels of TNF ⁇ . Percent inhibition of TNF ⁇ release is calculated at each inhibitor concentration and the data were plotted using standard curve fitting programs. Approximate IC ⁇ o values were determined from these curves.
  • mice with a weight of 21 ⁇ 2g are weighed and used.
  • Control and test animals are injected subcutaneously m the axillary region with a suspension of 2 X 10 6 viable tumor cells in 200 uL in PBS + mat ⁇ gel on day 0. Tumors are allowed to grow for 10 to 14 days prior to drug administration.
  • Doses of test drug are given on a mg/kg basis according to the mean body weight for each cage. For each drug, two doses are used, 30 mg/kg and 90 mg/kg and are administered by p.o. route once a day over a 14 day time span.
  • the criterion for antitumor activity is 25% inhibition of tumor growth after 2 weeks of dosmg (day 14).

Abstract

A familly of compounds having general structural formula (I) where W is a reverse hydroxamic acid group, and R1, R2, R3, R4, R5 and R6 are as described in the specification or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof. Also described are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine.

Description

Formamides as Therapeutic Agents
FIELD OF THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in those disease states alleviated by the inhibition or antagonism of matrix metalloproteases, metalloproteases, and/or tumor necrosis factor-alpha (TNF), which pathologically involve aberrant extracellular matrix degradation, shedding of cell surface protein ectodomains, and/or TNF synthesis, such disease states including arthritis, tumor metastasis and diabetes. The aforementioned pharmacologic activities are useful in the treatment of mammals.
More specifically, the compounds of the present invention can be used in the treatment of osteoarthritis, rheumatoid arthritis, tumor invasion and metastasis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, corneal ulceration and the complications of diabetes. At the present time, there is a need in the areas of rheumatology, oncology, dentistry, opththalmology, gastroenterology, cardiology, neurology, nephrology, infectious disease and endocrinology therapy for such agents.
BACKGROUND OF THE INVENTION
The matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase- 1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and matπlysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix. This is a feature of diverse pathologies; therefore, inhibitors of one or more of the matrix metalloproteases would have utility m a wide range of disease states such as m abrogating the initiation of tumor metastasis and angiogenesis and m halting the pathogenesis of demyelmatmg diseases of the nervous system, multiple sclerosis being one example. MMP inhibitors would also find utility in diseases involving connective tissue degradation m the joint, as occurs in osteoarthritis and rheumatoid arthritis. MMP's-1 and -3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.
Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's; biochemical studies on the recombinant protein have demonstrated that it cleaves type II collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes m osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
Compounds which inhibit the activities of one or more of the matrix metalloproteases are recognized as having therapeutic benefit m one or more pathologies where MMP activity is upregulated, such as;
I) inflammatory/autoimmune diseases, which include, but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, peπodontal disease, gingivitis, and corneal ulceration; n) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometπum, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, bram and central nervous system, thyroid and other endocπne gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkm's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof; in) cardiovascular diseases, including but not limited to atherosclerosis, and restenosis;
IV) metabolic diseases, including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone; v) neurologic diseases, including but not limited to multiple sclerosis and other demyehnation ailments; vi) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis; vn) infectious diseases, including but not limited to those mediated by viruses, bacteria, fungi; vin) respiratory diseases, including but not limited to emphysema and COPD.
Many inhibitors of matrix metalloproteases have been disclosed, including some structure activity relationships for a series of carboxylalkylamine inhibitors. These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zmc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zmc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.
Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I)-
Figure imgf000005_0001
(I) where W is a zinc-chelating acyl derivative group of the formula -C(0)NHOH (which
Figure imgf000006_0001
convention and in this application are referred to as "forward hydroxamates") or a zinc- chelatmg substituted amme group of the formula -NH(OH)C(0)R (which by convention and in this application are referred to as "reverse hydroxamates"), where R is usually hydrogen or alkyl. The other substituents vary according to specifications expressed by the art disclosure. It is understood and demonstrated that variations in these substituents can have dramatic effects on potency and selectivities between the matrix metalloproteases.
Suppression of MMP activity m conditions characterized by its overproduction w ould be of benefit, and compounds which inhibit MMP's would act m this manner at a specific target and be useful and of benefit. The present invention fills this need by providing compounds that are potent, specific, orally active inhibitors of matrix metalloproteases.
Tumor necrosis factor-α (TNFα), hereinafter called "TNF", is a mammalian protein capable of inducing cellular effects by virtue of its interaction with specific cellular receptors. It is initially characterized and so named due to its ability to cause death of cancerous cells. It is produced primarily by activated monocytes and macrophages. Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alamne-76 - vahne-77 peptide bond.
Recently, certain compounds having matrix metalloprotease - inhibiting activity have been found to inhibit the release of mature 17 kD TNF from cells. Further, these inhibitors also protect mice from a lethal dose of endotoxm indicating that the compounds can inhibit TNF secretion in vivo These compounds inhibit the cell-associated proteolytic processing of the 26 kD pro-TNF to the mature 17 kD form. The proteolytic activity is thought to reside in an intracellular or cell-associated specific enzyme or family of enzymes, which by convention is called a "TNF convertase", distinct from the matrix metalloproteases but related in that both contain a zmc cation at the active site. TNF convertase enzymatic activity can be detected m monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease - inhibiting compounds.
A metalloprotease is thought to mediate the proteolysis of the cell surface-IgE receptor CD23. Certain of the CD23 - derived peptides possess proinflammatory biological activities mimicking those of cytokmes, including TNFα.
Metalloprotease like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectm, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotem receptor, beta amyloid precursor protein, mterleukm-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm-1 receptor type II, CD30, and tumor necrosis factor receptors type I and II.
TNF is known to mediate many biological responses in vivo. Preclimcal and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF receptor constructs, and TNF detection techniques have implicated TNF as a mediator in numerous pathologies. The compounds of the present invention by virtue of their activity m inhibiting TNF production and/or their activity in preventing cell surface protein ectodomam shedding should show utility in the treatment of diverse pathologies such as: l) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases and inflammatory gastrointestinal diseases, and systemic lupus erythematosis, π) reperfusion injuries, such as those caused by an initial lschemic event; in) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome, ιv) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity, psoriasis, asthma, eczema, allergic rhinitis, and allergic conjunctivitis; v) cardiovascular diseases, including but not limited to hyperhpidemia, chronic obstructive pulmonary disease, myocardial infarction, atherosclerosis, and restenosis; vi) metabolic diseases, including but not limited to osteoporosis, obesity, and diabetes; vn) neurologic diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, aneurism, and stroke; vin) transplant rejection, including but not limited to organ transplant rejection and graft versus host disease; ix) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skm, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, bram and central nervous system, thyroid and other endocπne gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkm's disease, non-Hodgkm's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof; x) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis; xi) cachexia and related wasting syndromes; xn) infectious diseases, including but not limited to HIV infection and neuropathy, Epstem- Barr viral infection, heφes viral infection, malaria, meningitis, schistosomiasis, leprosy, hepatitis (which includes hepatitis A, hepatitis B, and hepatitis C), infectious arthritis, leishmaniasis, tuberculosis, Lyme disease, and viral encephalitis, xin) effects of disease therapy, including but not limited to cytokine therapy, chemotherapy, radiation therapy and therapies using anti-T-cell antibodies or cytotoxin-antibody conjugates; and xiv) ocular diseases, including but not limited to diabetic retmopathy and macular degeneration Suppression of TNF activity in conditions characterized by its oveφroduction would be of benefit, and compounds which inhibit TNF convertase would act in this manner at a specific target and be useful and of benefit. The present invention fulfills this need by providing potent, specific, orally active inhibitors of TNF-α release from cells acting via inhibition of TNF-α converting enzyme (TNFc).
Suppression of shedding of cell surface protein ectodomains m conditions characterized by an overactivity of such a shedding enzyme or enzymes would be of benefit, and compounds which inhibit this cell surface protein ectodomam shedding would be useful and of benefit. The present invention fills this need by providing potent, orally active inhibitors of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
Furthermore, as described above, suppression of CD23 proteolysis in conditions characterized by an overabundance of CD23 proteolytic fragments would be of benefit, and compounds which inhibit CD23 proteolysis would be useful and of benefit. The present invention fills this need by providing potent inhibitors of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a potent, specific, orally active inhibitor of MMP's. It is another object of the present invention to provide a potent, specific, orally active inhibitor of TNF-alpha release from monocyte cells acting via inhibition of TNF-alpha converting enzyme (TNFc).
Furthermore, it is another object of the present invention to provide a potent, orally active inhibitor of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
Accordingly it is another object of the present invention to provide a potent inhibitor of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
It is an object of the present invention to provide a compound of the formula
Figure imgf000010_0001
(ii) where Rj is
AT* where A, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; where A2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR7R8, OR7, SR7, or hydrogen, where R7 and R8 are as defined below; R, is
Figure imgf000011_0001
where Di is alkylene, alkenylene, alkynylene, or a direct bond; D2 is arylene, heteroarylene, or a direct bond; D3 is aryl, heteroaryl, or heterocyclyl;
Y is alkylene, alkenylene, alkynylene, O, S, S(O), S02, NR9, Se, Si, C(O), P(O)OR9, P(O)R9, C(O)O, C(O)NR9, NR9C(0), OC(O), OC(0)0, NR9C(O)0, OC(0)NR9, NR9C(O)NR10, or
T— τ2
where Tj and T2 are, independently, lower alkylene, lower alkenylene, lower alkynylene, O, S, S(O), SO2, NR9, Se, Si, C(O), P(0)OR9, or P(O)R9, where R9 and R,0 are as defined below; n = 0 or 1 ;
R3 is hydrogen or lower alkyl;
— - vΛA
:/ _1
where Ei is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
E2 is hydrogen, NR,,Ri2, NR„SO2R,2, OR„, SR,,, S(O)R,ι, SO2Rn, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where Rn and R!2 are as defined below; R5 is hydrogen or lower alkyl; where Zi is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, or a direct bond;
Z2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR]3Ri4, OR.3, SR13, NR13SO2R14, NR13C(O)R14, C(O)NR,3, C(O)RI3, C(O)OR,3, OC(O)R13, S(O)R13, SO2R]3, SO2NR]3R14, (O(CH2)qO)mRπ or hydrogen, where m, q, R,3 and R1 are as defined below;
R7, R8, R9, Rio, Rπ, Rι2, RB, and R[4 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl; and where m = 1-10 and q = 1-10, or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
DETAILED DESCRIPTION
The present invention provides a family of compounds having the general structural formula:
Figure imgf000012_0001
(l)
or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof, wherein W is a reverse hydroxamic acid group; Ri is a substituent other than hydrogen; R2 is an alkylaryl or alkylheteroaryl substituent
R4 is a hpophilic substituent preferably with steπc bulk proximal to the peptide backbone.
Such compounds are novel and are unknown m the art and, given the appropriate choice of R], R2, R3, R,, R5, and R,, as described herein, show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and m some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases. The alkylaryl or alkylheteroaryl nature of R2 in combination with an appropriate choice of R R3, R4, R5, and R6 as described herein is beneficial m achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3). Such molecules can possess an improved therapeutic profile where inhibition of one or more of the matrix metalloproteases is associated with an adverse biological response or abnormal pathology. The alkylaryl or alley lheteroaryl nature of R2 m combination with an appropriate choice of Rb R3, R4, R5, and R6 as described herein is also beneficial in achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3) in preference to TNF convertase inhibition and inhibition of TNF release from whole cells.
In particular, reverse hydroxamate compounds of the present invention include those of the formula (II):
Figure imgf000013_0001
(ll) where A
where
alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; A2 ιs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR7R8, OR7, SR7, or hydrogen, where R7 and R8 are as defined below; R2 ιs
Figure imgf000014_0001
where
D, ιs alkylene, alkenylene, alkynylene, or a direct bond, D2 ιs arylene, heteroarylene, or a direct bond; D3 ιs aryl, heteroaryl, or heterocyclyl; Y is alkylene, alkenylene, alkynylene, O, S, S(O), S02, NR9, Se, Si, C(O), P(O)OR9, P(O)R9 C(O)O, C(O)NR9, NR9C(0), OC(O), OC(0)0, NR9C(0)0, OC(0)NR9, NR9C(O)NRI0, or
T— τ2
where T, and T2 are, independently, lower alkylene, lower alkenylene, lower alkynylene, O, S, S(O), S02, NR9, Se, Si, C(O), P(0)OR9, or P(O)R9, where R9 and R10 are as defined below; n = 0 or 1 ; R3 is hydrogen or lower alkyl; R4 is
where
E] is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; E2 is hydrogen, NR,,R12, NR,,SO2R,2, OR, ,, SRU, S(O)R„, SO2R,,, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R), and R)2 are as defined below;
R5 is hydrogen or lower alkyl;
Re is
Figure imgf000015_0001
where
lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, or a direct bond; Z2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NRI3Rt4,
OR,3, SRI3, NR13S02R,4, NR13C(0)R,4, C(0)NRl3, C(0)Rl3, C(0)OR13, OC(0)RI3, S(0)R13, SO2R13, S02NRi3Ri4, (0(CH2)qO)mR13 or hydrogen, where m, q, R]3 and R14 are as defined below;
R7, R8, R9, Rio, R11, R12, Rπ, and Rι4 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl; and where m = 1-10 and q = 1-10, or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
Compounds of the present invention which are currently preferred for their high biological activity are listed below m Tables 1 A and IB; variables below are with reference to the generic structure (I).
Table IA
Figure imgf000017_0001
(l)
Figure imgf000017_0002
Figure imgf000018_0001
Table IB
Figure imgf000019_0001
(l)
Figure imgf000019_0003
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Compounds of the present invention which are currently preferred for their high biological activity are listed by name below in Tables 2A and 2B.
Table 2A
Figure imgf000028_0001
Table 2B
Example Chemical Name
(2R,3S)-3-(Formylhydroxyammo)-2-(3-(4-chlorophenyl)-l-propyl)-4-
15 methylpentanoic Acid [(lS)-2.2-Dιmethyl-(l-(2,2-dιmethyl-l-
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Preferred embodiments of the invention include compounds of general formula (II) where:
Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 3-aminophenoxymethyl, 2-(3-tetrazolyl)-l -ethyl, 2-(3-pyridyl)-l- ethyl, 2-(3-furyl)-l -ethyl, 2-(2-thιazolyl)-l -ethyl, 3,3,3-trifluoro-l -propyl, 2-(4- trifluorophenyl)-l -ethyl, thiophene-3-ethynyl, 2-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-phenylsulfanylmethyl, trifluoromethyl, trichloromethyl, or vinyl;
R2 is 5-methylthiophene-2-methyl, 2-furanmethyl, thiophene-2-methyl, benzothiophene-2-methyl, benzofuran-2-methyl, 4-fluorobenzyl, 3-phenyl-l -propyl, 3- phenyl-2-methyl- 1 -propyl, 3-(2-pyridyl)-l-propyl, 3-(thiophene-2-yl)- 1 -propyl, 4-phenyl-l - butyl, 3-phenyl-2-propene-l-yl, 3-(benzofuran-3-yl)-l -propyl, 3-(benzothiophene-3-yl)-l- propyl, 3 -(furan-2-yl)-l -propyl, 3-(2-thiazolyl)-l -propyl, 3-(pyrimidin-2-yl)-l -propyl, 3- phenyl-2-ethyl-l -propyl, 3-(3-pyridyl)-l-propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l-propyl, 3- phenyl-1 -butyl, 3-phenyl-2-methyl-2-propene-l-yl, 4-phenyl-3-methyl-2-butyl, 4-(3- thiophenyl)-2-butyl, benzothiophene-3-methyl, benzoxazole-2-methyl, 4-(3-furyl)-2-butyl, 3- (4-chlorophenyl)- 1 -propyl, 3-(4- fluorophenyl)- 1 -propyl, 3-(4-trifluoromethylphenyl)- 1 - propyl, benzyl, 5-phenyl-l-pentyl, 5-(4-chlorophenyl)-l-pentyl, 3-(4-methoxyphenyl)-l- propyl, 3-(4-methylphenyl)-l -propyl, 3-(4-biphenyl)-l -propyl, 3-(4'-fluoro-4-biphenyl)-l- propyl, 3-(4'-chloro-4-biphenyl)-l-propyl, 3-(4-phenoxyphenyl)-l -propyl, 3-(4'-chloro-4- phenoxyphenyl)-l -propyl, 3-(4'-fluoro-4-phenoxyphenyl)-l-propyl, 3-(4- thiophenoxyphenyl)- 1 -propyl, 3 -(4 '-chloro-4-thiophenoxyphenyl)- 1 -propyl, 3 -(4 ' -fluoro-4- thiophenoxyphenyl)- 1 -propyl, 4-(4-trifluoromethylphenyl)- 1 -butyl, 4-(4-chlorophenyl)- 1 - butyl, 4-(4-fluorophenyl)-l -butyl, 3-(4-(4-moφholino)phenyl)-l -propyl, or 3-(4-(4- methylpiperazine)phenyl)- 1 -propyl;
R3 is hydrogen; R4 is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylamιno)-l -butyl, 2-(2- (benzyloxycarbonylam.no)- 1 -ethylsulfanyl)-2-propyl, 3-pyrιdylmethyl, 4-(2- naphthylacetylamino)- 1 -butyl, 3 -(benzyloxycarbonylammo)-l -propyl, 3-carbamoylammo-l- propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-(ιmιno-(2,3,6-tπmethyl- 4-methoxybenzenesulfonylammo))-methylamιno-l -propyl, 4- benzyloxycarbonylammobenzyl, isopropyl, cyclohexyl, 4-cyclopentylacetylammo-l -butyl, 4- (3-methoxybenzoylamιno)-l -butyl, 4-ethoxycarbonylamιno- 1 -butyl, 2-(2- (ethoxycarbonylammo)-l-ethylsulfanyl)-2-propyl, 2-butyl, 1-methoxy-l -ethyl, 1-hydroxy-l- ethyl, isopropyl, 2-(methoxymethylammocarbonyl)-l -ethyl, 2-(4-ethoxycarbonyl-l- pιperazmecarbonyl)-l -ethyl, 2-guamdιnesulfonyl-l -ethyl, 2-methyl-4-(2- pyrιdylcarbonylammo)-2 -butyl, 2-(methyl benzylammocarbonyl)-l -ethyl, 2-(4- moφhohnecarbonyl)-l -ethyl, 2-pyrιdylcarbonylammomethyl, acetylaminomethyl, 1- ιsobutoxy-1 -ethyl, carbamoylaminomethyl, dimethylammocarbonylmethyl, 2- dιmethylammosulfonyl-1 -ethyl, 2-methanesulfanyl-2-propyl, 2-hydroxy-2 -propyl, 4-(2- pyrιdylcarbonylammo-1 -butyl, 2-(dιmethylammocarbonyl)- 1 -ethyl, 2-methanesulfonyl-l - ethyl, l-(2-pyrιdylmethoxy)-l -ethyl, 1-benzyloxy-l -ethyl, phenyl, 2-methyl-l -propyl, 3- (ιmmo-(2,2,5,7,8-pentamethylchroman-6-sulfonylammo)methylamιno)-l -propyl, 2-phenyl-l- ethyl, l-(3-pyπdylmethoxy)-l -ethyl, 4-pyrιdylmethyl, 4-methoxybenzyl, 3-mdolemethyl, 2- mdolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2-phenyl-2 -propyl;
R5 is hydrogen; and
Re is methyl, 2-(l-pyrrolιdιno)-l -ethyl, 2-pyπdylmethyl, 3-pyrιdylmethyl, 4- pyridylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-(4-moφholmo)-l -ethyl, 3-(4- moφhohno)-l -propyl, 3-(4-methylpιperazme)-l -propyl, 2-(4-methylpιperazιne)-l -ethyl, 2-(2- pyridyl)- 1 -ethyl, 2-(3-pyrιdyl)-l -ethyl, 2-(4-pyrιdyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-trιfluoroethyl; Other preferred embodiments of the invention include compounds of general formula (II) where Rj, R3,and R5 are as defined above; R2 is 3-(thιophene-3-yl)-l -propyl, 3-(4-pyπdyl)-
1 -propyl, or 3-(4-t-butylphenyl)-l -propyl; R is 1-methylbenzyl, benzyl , 3- phenylcarbonylammo-1 -propyl, 2,2-dιmethyl-l -propyl, 3-phenylcarbamoylamιno-l -propyl, 4-pyrιdylmethyl, 4-methoxybenzyl, 3-mdolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R<; is hydrogen, 2-(2-pyrιdyl)-l -ethyl, 2-(3- pyrιdyl)-l -ethyl, 2-(4-pyrιdyl)-l -ethyl, l-(2-amιnoethyl)-pιperazιne, 2-(4-ιmιdazolyl)-l- ethylamme, 4-fluorobenzyl, 4-methoxybenzyl, 2,2-dιmethyl-l -propyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
Particularly preferred embodiments of the invention include compounds of general formula II where: Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 2-(3-tetrazolyl)-l-ethyl, 2-(3 -pyridyl)- 1 -ethyl, 2-(3-furyl)-l -ethyl, 3,3,3-trιfluoro-l -propyl, 2-(4-tπfluorophenyl)-l -ethyl, 2-phenylsulfanylmethyl, tπfluoromethyl, or tπchloromethyl;
R2 is 5-methylthιophene-2-methyl, 2-furanmethyl, thιophene-2-methyl, 4- fluorobenzyl, 3-phenyl-l-propyl, 3-phenyl-2-methyl-l -propyl, 3-(2-pyrιdyl)-l -propyl, 3- (thιophene-2-yl)-l -propyl, 4-phenyl-l -butyl, 3-phenyl-2-propene-l-yl, 3-(furan-2-yl)-l- propyl, 3-(2-thιazolyl)-l -propyl, 3-(3-pyrιdyl)-l -propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l- propyl, benzothιophene-3-methyl, benzoxazole-2-methyl, 3-(4-chlorophenyl)-l -propyl, 3-(4- fluorophenyl)-l -propyl, 3-(4-trιfluoromethylphenyl)-l-propyl, benzyl, 5-phenyl-l-pentyl, 5- (4-chlorophenyl)-l-pentyl, 3-(4-methoxyphenyl)-l-propyl, 3-(4-methylphenyl)-l -propyl, 3-
(4-bιphenyl)-l -propyl, 3-(4'-fluoro-4-bιphenyl)- 1 -propyl, 3-(4'-chloro-4-bιphenyl)- 1 -propyl,
3-(4-phenoxyphenyl)-l -propyl, 3-(4'-chloro-4-phenoxyphenyl)-l -propyl, 3-(4'-fluoro-4- phenoxyphenyl)- 1 -propyl, 3-(4-thιophenoxyphenyl)- 1 -propyl, 4-(4-tπfluoromethylphenyl)- 1 - butyl, 4-(4-chlorophenyl)-l -butyl, 4-(4-fluorophenyl)-l -butyl, 3-(4-(4-moφholmo)phenyl)-l- propyl, or 3-(4-(4-methylpιperazιne)phenyl)-l -propyl,
R3 is hydrogen;
R, is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylammo)-l -butyl, 2-(2- (benzyloxycarbonylammo)- 1 -ethylsulfanyl)-2-propyl, 3-pyrιdylmethyl, 4-(2- naphthylacetylammo)- 1 -butyl, 3 -(benzyloxycarbonylamino)- 1 -propyl, 3 -carbamoylammo- 1 - propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, isopropyl, cyclohexyl, 4- cyclopentylacetylammo- 1 -butyl, 4-(3-methoxybenzoylammo)-l -butyl, 4- efhoxycarbonylammo- 1 -butyl, 2-(2-(ethoxycarbonylammo)- 1 -ethylsulfanyl)-2-propyl, 2- butyl, 1-methoxy-l -ethyl, 1-hydroxy-l -ethyl, isopropyl, 2-(4-ethoxycarbonyl-l- pιperazιnecarbonyl)-l -ethyl, 2-(methyl benzylaminocarbonyl)- 1 -ethyl, 2- pyridylcarbonylammomethyl, acetylammomethyl, 1 -isobutoxy- 1 -ethyl. carbamoylammomethyl, dimethylammocarbonylmethyl, 2-dιmethylammosulfonyl-l -ethyl, 2- mefhanesulfanyl-2-propyl, 2-hydroxy-2 -propyl, 4-(2-pyπdylcarbonylammo- 1 -butyl, 2- (dimethylaminocarbonyl)- 1 -ethyl, 2-methanesulfonyl- 1 -ethyl, 1 -(2-pyrιdylmethoxy)- 1 -ethyl, 1-benzyloxy-l -ethyl, 2-phenyl-l -ethyl, l-(3-pyπdylmethoxy)-l -ethyl, 4-pyrιdylmethyl, 4- methoxybenzyl, 3-mdolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2- phenyl-2-propyl;
R5 is hydrogen; and
Ri is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-pyrιdylmethyl, 3-pyπdylmethyl, 4- pyridylmethyl, cyclopropyl, cyclopentyl, 2-(4-moφhohno)-l -ethyl, 3-(4-moφholmo)-l- propyl, 3-(4-methylpιperazιne)-l -propyl, 2-(4-methylpιperazιne)-l -ethyl, 2-(2-pyrιdyl)- 1 - ethyl, 2-(3-pyrιdyl)-l -ethyl, 2-(4-pyrιdyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-trιfluoroethyl; Other particularly preferred embodiments of the invention include compounds of general formula (II) where Ri , R3, and R5 are as defined above; R2 is benzyl, 5-phenyl-l-pentyl or 5-
(4-chlorophenyl)-l-pentyl; R, is 1 -methylbenzyl, benzyl, 2,2-dιmethyl-l -propyl, 4- pyridylmethyl, 4-methoxybenzyl, 3-ιndolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R^ is hydrogen, 2-(2-pyrιdyl)- 1 -ethyl, 2-(3- pyrιdyl)-l -ethyl, 2-(4-pyrιdyl)- -ethyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
More particularly preferred embodiments of the invention include compounds of general formula II where:
Ri is methyl, ethyl, n-propyl, isopropyl, or 3,3,3-trιfluoro-l-propyl; R2 is 3-phenyl-l-propyl, 3 -(4-chlorophenyl)-l -propyl, 3-(4-fluorophenyl)-l -propyl, 3- (4-trιfluoromethylphenyl)-l -propyl, or 3-(thιophene-2-yl)-l -propyl; R3 is hydrogen;
R4 is tert-butyl or 1-phenyl-l -ethyl; R5 is hydrogen; and
R6 is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-pyπdylmethyl, 3-pyπdylmethyl, or 4- pyπdylmethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
Other more particularly preferred embodiments of the invention include compounds of general formula (II) where Ri , R3, and R5 are as defined above ; R2 is 3-(4-mefhylphenyl)-l-
propyl, 3-(4-phenoxyphenyl)-l-propyl, or 5-phenyl-l-pentyl, R4 is benzyl, 4-fluorobenzyl, 2- butyl, cyclohexyl, or isopropyl; and R6 is 2-(4-moφholmo)-l -ethyl, 3-(4-moφholmo)-l- propyl, tetraethyleneglycolyl methyl ether, 2-(2-pyπdyl)-l -ethyl, 2-(3-pyrιdyl)-l -ethyl, or 2- (4-pyrιdyl)-l -ethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
The compounds of the present invention are inhibitors of matrix metalloproteases, TNF converting enzyme, and TNF activity from whole cells. The compounds of the present invention may also inhibit shedding of pathologically significant cell surface protein ectodomains. The invention described herein is additionally directed to pharmaceutical compositions and methods of inhibiting matrix metalloprotease and/or TNF activity in a mammal, which methods comprise administering, to a mammal in need of inhibition of matrix metalloprotease and/or TNF activity, a therapeutically defined amount of a compound of formula (I) or (II), defined above, as a single or polymoφhic crystalline form or forms, an amoφhous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer, a mixture of diastereoisomers, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug, a biohydrolyzable ester, or a biohydrolyzable amide thereof.
According to a further aspect of the present invention there is provided a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof for use in therapy.
Thus, the present invention provides a method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit a matrix metalloprotease. A matrix metalloprotease- inhibiting amount can be an amount that reduces or inhibits a matrix metalloprotease activity in the subject.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting a matrix metalloprotease.
The present invention further provides a method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit cellular release of mature tumor necrosis factor. An amount sufficient to inhibit cellular release of mature tumor necrosis factor can be an amount that reduces or inhibits cellular release of mature tumor necrosis factor in the subject.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the intracellular release of tumor necrosis factor alpha.
Also provided is a method of inhibition of shedding of cell surface protein ectodomains, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit shedding of cell surface protein ectodomains An amount sufficient to inhibit shedding of cell surface protein ectodomains can be an amount that reduces or inhibits shedding of one or more cell surface protein ectodomains, such as L-selectin, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotein receptor, beta amyloid precursor protein, ιnterleukιn-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm- 1 receptor type II, CD30, and tumor necrosis factor receptors type I and II, in the subject.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the shedding of cell surface protein ectodomains.
Also provided is a method of inhibiting CD23 proteolysis, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit CD23 proteolysis An amount sufficient to inhibit CD23 proteolysis can be an amount that reduces or inhibits CD23 proteolysis in the subject.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting CD23 proteolysis Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to decrease, or inhibit, a malignant growth.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the growth of tumor metastases.
Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat arthritis. Such an amount can be an amount that relieves, i.e., reduces or eliminates, one or more physiologic characteristic of arthritis
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for treating arthritis.
Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diabetes. Such an amount can be an amount that reduces or eliminates one or more of the complications associated with diabetes.
According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for treating diabetes.
Additionally, the present invention contemplates treating any of these diseases/conditions m a subject by administering to the subject the recited pharmaceutical composition.
The compounds of the present invention can be administered to any mammal in need of inhibition of matrix metalloprotease activity, CD23 proteolysis, shedding of cell surface protein ectodomains and/or TNF activity. Such mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably humans.
Certain examples of the invention also are orally bioavailable in animals and possess oral activity in animal models of disease.
Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloπde, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsamlate, Hexylresorcmate, Hydrabamine, Hydrobromide, Hydrocloπde, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,
Phosphate/diphosphate, Polygalacturonate, Potassium, Sahcylate, Sodium, Stearate, Subacetate, Succmate, Tannate, Tartrate, Teoclate, Tosylate, Tπethiodide, Tπme hylammonium and Valerate.
Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) or (II) and these form a further aspect of the invention.
Also included within the scope of the invention are the individual enantiomers of the compounds represented by formula (I) or (II) above as well as any wholly or partially racemic mixtures thereof. The present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more of the three stereocenters are inverted.
As used herein, the term "lower" refers to a group having between one and six carbons.
As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkyl" as used herein include, but are not limited to, methyl, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, and the like.
As used herein, the term "alkenyl" refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkenylene" as used herein include, but are not limited to, ethene-l,2-dιyl, propene-l,3-dιyl, methylene- 1,1-dιyl, and the like.
As used herein, the term "alkynyl" refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
As used herein, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkynylene" as used herein include, but are not limited to, ethyne-l,2-dιyl, propyne-l,3-dιyl, and the like.
As used herein, "cycloalkyl" refers to a alicychc hydrocarbon group with one or more degrees of unsaturation, having from three to twelve carton atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed "Cycloalkyl" includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
As used herein, the term "cycloalkylene" refers to an non-aromatic alicychc divalent hydrocarbon radical having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "cycloalkylene" as used herein include, but are not limited to, cyclopropyl- 1,1-dιyl, cyclopropyl- 1,2-dιyl, cyclobutyl- 1,2- diyl, cyclopentyl- 1, 3 -diyl, cyclohexyl- 1,4-dιyl, cycloheptyl-l ,4-dryl, or cyclooctyl- 1,5-dιyl, and the like.
As used herein, the term "cycloalkenyl" refers to a substituted alicychc hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "cycloalkenylene" as used herein include, but are not limited to, 1- cyclopentene-3-yl, l-cyclohexene-3-yl, l-cycloheptene-4-yl, and the like.
As used herein, the term "cycloalkenylene" refers to a substituted alicychc divalent hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed Examples of "cycloalkenylene" as used herein include, but are not limited to, 4,5-cyclopentene-l,3-dιyl, 3,4-cyclohexene-l,l-dιyl, and the like.
As used herein, the term "heterocyclic" or the term "heterocyclyl" refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, S02, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another "heterocyclic" rmg(s) or cycloalkyl πng(s). Examples of "heterocyclic" include, but are not limited to, tetrahydrofuran, pyran, 1,4-dιoxane, 1,3- dioxane, pipeπdme, pyrrohdme, moφholme, piperazine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
As used herein, the term "heterocyclylene" refers to a three to twelve- membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another "heterocyclic" rings or cycloalkyl πngs. Examples of "heterocyclylene" include, but are not limited to, tetrahydrofuran-2,5-dιyl, moφhohne-2,3-dιyl, pyran-2,4-dιyl, l,4-dιoxane-2,3-dιyl, l ,3-dιoxane-2,4-dιyl, pipeπdine- 2,4-dιyl, pιpeπdιne-l,4-dιyl, pyrrohdιne-l,3-dιyl, moφholιne-2,4-dιyl, pιperazme-l,4-dyιl, and the like.
As used herein, the term "aryl" refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.
As used herein, the term "arylene" refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene πngs, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "arylene" include, but are not limited to, benzene- 1,4-dιyl, naphthalene- 1,8-dιyl, anthracene- 1,4-dιyl, and the like.
As used herein, the term "heteroaryl" refers to a five - to seven - membered aromatic ring, or to a polycychc heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycychc aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl" used herein are furan, thiophene, pyrrole, lmidazole, pyrazole, tπazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole. pyridme, pyridazine, pyrazme, pyrimidine, quinolme, lsoqumolme, benzofuran, benzothiophene, mdole, and mdazole, and the like
As used herein, the term "heteroarylene" refers to a five - to seven - membered aromatic ring diradical, or to a polycychc heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed For polycychc aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of "heteroarylene" used herein are furan-2,5-dιyl, thιophene-2,4-dιyl, l,3,4-oxadιazole-2,5-dιyl, l,3,4-fhιadιazole-2,5- diyl, l,3-thιazole-2,4-dιyl, l,3-thιazole-2,5-dιyl, pyπdιne-2,4-dιyl, pyπdιne-2,3-dιyl, pyπdιne-2,5-dιyl, pyπmιdιne-2,4-dιyl, qumohne-2,3-dιyl, and the like. As used herein, the term "direct bond", where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond". Where two or more consecutive variables are specified each as a "direct bond", those substituents flanking (preceding and succeeding) those two or more consecutive specified "direct bonds" are directly joined.
As used herein, the term "alkoxy" refers to the group RaO-, where Ra is alkyl.
As used herein, the term "alkenyloxy" refers to the group RaO-, where Ra is alkenyl.
As used herein, the term "alkynyloxy" refers to the group RaO-, where Ra is alkynyl.
As used herein, the term "alkylsulfanyl" refers to the group RaS-, where Ra is alkyl.
As used herein, the term "alkenyl sulfanyl" refers to the group RaS-, where Ra is alkenyl.
As used herein, the term "alkynylsulfanyl" refers to the group RaS-, where Ra is alkynyl.
As used herein, the term "alkylsulfenyl" refers to the group RaS(0)-, where Ra is alkyl. As used herein, the term "alkenylsulfenyl" refers to the group RaS(0)-, where Ra is alkenyl.
As used herein, the term "alkynylsulfenyl" refers to the group RaS(0)-, where Ra is alkynyl.
As used herein, the term "alkylsulfonyl" refers to the group RaS02-, where Ra is alkyl.
As used herein, the term "alkenylsulfonyl" refers to the group RaS02-, where
Ra is alkenyl.
As used herein, the term "alkynylsulfonyl" refers to the group RaS02-, where Ra is alkynyl.
As used herein, the term "acyl" refers to the group RaC(O)- , where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
As used herein, the term "aroyl" refers to the group RaC(0)- , where Ra is aryl.
As used herein, the term "heteroaroyl" refers to the group RaC(O)- , where Ra is heteroaryl.
As used herein, the term "alkoxycarbonyl" refers to the group RaOC(O)-, where Rd is alkyl. As used herein, the term "acyloxy" refers to the group RaC(O)0- , where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
As used herein, the term "aroyloxy" refers to the group RaC(O)0- , where Ra is aryl.
As used herein, the term "heteroaroyloxy" refers to the group RaC(O)O- , where Ra is heteroaryl.
As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
As used herein, the terms "contain" or "containing" can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example, -CH2-O-CH2-, -CH2-SO2-CH2-, -CH2-NH-CH3 and so forth.
As used herein, the term "solvate" is a complex of variable stoichiometry formed by a solute (m this invention, a compound of formula (I) or (II)) and a solvent. Such solvents for the puφose of the invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid. As used herein, the term "biohydrolyzable ester" is an ester of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) or (II) in plasma. Many examples of such are known m the art and include by way of example lower alkyl esters, lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylammo alkyl esters, and cholme esters. An example of such a biohydrolyzable ester applied to the general formula (II) is illustrated below in general formula (III).
Figure imgf000052_0001
(III)
As used herein, the term "biohydrolyzable amide" is an amide of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) or (II) in plasma. Many examples of such are known m the art and include by way of example lower alkyl amides, α-ammo acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. As used herein, the term "prodrug" includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I) or (II): for example, the lactam formed by a carboxyhc group in R2 and an amine in R4, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I) or (II). Examples of these functional groups include, but are not limited to, 1,4-dιhydropyπdme, N-alkylcarbonyl-l,4-dιhydropyπdme, 1,4- cyclohexadiene, tert-butyl, and the like.
As used herein, the term "affinity reagent" is a group attached to the compound of formula (I) or (II) which does not affect its m vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not protemaceous. An example of an affinity reagent according to b) would be biotin either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P m any combination. An example of an affinity reagent according to a) above would be fluorescein, either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination.
The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician This amount can be a therapeutically effective amount. Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be inteφreted as including those limitations given above for "alkyl" and "aryl". Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. Ci-io) shall refer independently to
the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term "alkyl" appears as its prefix root.
As used herein, the term "oxo" shall refer to the substituent =O.
As used herein, the term "halogen" or "halo" shall include iodine, bromine, chlorine and fluorine.
As used herein, the term "mercapto" shall refer to the substituent -SH.
As used herein, the term "carboxy" shall refer to the substituent -COOH.
As used herein, the term "cyano" shall refer to the substituent -CN.
As used herein, the term "aminosulfonyl" shall refer to the substituent -
SO2NH2.
As used herein, the term "carbamoyl" shall refer to the substituent -C(O)NH2
As used herein, the term "sulfanyl" shall refer to the substituent -S-.
As used herein, the term "sulfenyl" shall refer to the substituent -S(O)- As used herein, the term "sulfonyl" shall refer to the substituent -S(O)2-.
The compounds of formula (I) and (II) can be prepared readily according to the following reaction Schemes (m which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled m the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
Abbreviations used in the Examples are as follows: g = grams mg = milligrams
L = liters mL = millihters psi = pounds per square inch
M = molar
N = normal mM = milhmolar l.V. = intravenous p.o. = per oral s.c. = subcutaneous
Hz = hertz mol = moles mmol = milhmoles mbar = millibar rt = room temperature min = minutes h = hours mp = melting point
TLC = thin layer chromatography
Rf = relative TLC mobility
MS = mass spectrometry NMR = nuclear magnetic resonance specfroscopy
APCI = atmospheric pressure chemical lonization
ESI = electrospray lonization m/z = mass to charge ratio tr = retention time ether = diethyl ether
MeOH = methanol
EtOAc = ethyl acetate
TEA = tπethylamine
DIEA = dπsopropylethylamme BOP = ( 1 -benzotπazolyloxy)tπs(dιmethylamιno)phosphonιum hexafluorophosphate
THF = tetrahydrofuran DMF = N, N-dimethylformamide
DMSO = dimethylsulfoxide
LAH = lithium aluminum hydride
TFA = tπfluoroacetic acid EDC =1 -ethyl-3-(3-dιmethylammopropyl)-carbodπmιde hydrochloπde
HOBt = 1 -hydroxybenzotπazole
LDA = lithium dnsopropylamide
THP = tetrahydropyranyl
NMM = N-methylmoφholine, 4-methylmoφholme HMPA = hexamethylphosphoπc tπamide
DMPU = 1,3-dιmethypropylene urea hr = hours d = days mm = minutes ppm = parts per million kD = kiloDalton
LPS = hpopolysacchaπde
PMA = phorbol myπstate acetate
SPA = scintillation proximity assay EDTA = ethylenediamine tetraacetic acid
FBS = fetal bovine serum
PBS = phosphate buffered saline solution
ELISA = enzyme - linked immunosorbent assay
Several of the following examples represent pairs of stereoisomers which were separated as diastereoisomers but were not identified therein. Determination and/or preparation of the R and 5 isomers could advantageously be approached by stereoselective chemical methods (see, e.g., "Advanced Organic Chemistry", Carey and Sundberg, 3rd edition, Plenum Press, 1990, 596), by analytical methods such as X-ray crystallography, or by determination of biological activity and subsequent correlation to biologically active compounds of known stereochemistry.
GENERAL REACTION SCHEMES
Compounds of the invention may be prepared by methods known in the art, where such a method is shown in reaction Scheme 1.
Reaction Scherre 1
Figure imgf000058_0001
IV V
Figure imgf000058_0002
VII
Ri, R2, R3, R4, R5, and R(, are as defined as for formula (II). RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl Rn is chosen from the group consisting of hydroxyl, 0-C6F5, or halogen.
When R,5 is hydroxyl, the conversion of (V) to (VII) involves methods known in peptide chemistry; for example, the reaction may be conducted using HOBt in combination with a dehydrating agent such as dicyclohexylcarbodπmide in a suitable solvent, such as DMF. When R!5 is 0-C6F5, the conversion of (IV) to (V) is conducted by treating (IV) m a suitable solvent such as dichloromethane with pentafluorophenyl tπfluoroacetate m the presence of pyridme, or with EDC and pentafluorophenol in a suitable solvent such as dichloromethane. The displacement reaction to produce (VII) is carried out in the presence of a suitable solvent such as dioxane, THF, dichloromethane, or DMF, at a temperature of 0 °C to 140 °C. The reaction is effected in the presence of an organic base such as NMM or tπethylamine. The removal of the RPGi group where RPGi is benzyl may be achieved by hydrogenation of (VII) with palladium on barium sulfate in a suitable solvent such as methanol or THF, or, where RPG, is 2-tetrahydropyranyl, by hydrolysis with aqueous acetic acid at a temperature of 20 °C to 100 °C.
Reaction Scheme 2 depicts the synthesis of a compound of formula (IV).
Reaction Scheme 2
Figure imgf000059_0001
Figure imgf000059_0002
X XI
Figure imgf000059_0003
XII IV Ri and R2 are as defined for formula (II)
R]6O is a nucleofugal group such as methanesulfonate, trifluoromethanesulfonate, or p- toluenesulfonate.
RPG] is selected from the group consisting of benzyl or 2-tetrahydropyranyl. The acid of formula (VIII) may be converted to the alcohol of formula (IX) by treatment with HOBt, O-benzylhydroxylamine hydrochloπde or 2- tetrahydropyranyloxyamine, NMM, and a carbodnmide reagent such as EDC m a suitable solvent such as DMF. The alcohol of formula (IX) may be converted to (X) by treatment with methanesulfonyl chloride, p-toluenesulfonyl chloride, or tπfluoromethanesulfonic anhydride and pyridine m a suitable solvent such as dichloromethane. The conversion of (X) to (XI) may be conducted by treatment with potassium carbonate in a suitable solvent such as acetone or 2-butanone, at temperature of 20 °C to 90 °C. Alternatively, (IX) may be converted directly to (XI) by treatment with tπphenylphosphme and diethyl azodicarboxylate or another azodicarbonyl diester or diamide in a suitable solvent such as THF at a temperature of -78 °C to 50 °C. The compound of formula (XI) may be converted to (XII) by treatment with an inorganic base such as sodium hydroxide in water or water in combination with a water soluble organic cosolvent such as methanol or dioxane, followed by acidification with an acidic solution such as aqueous citric acid or aqueous sodium bisulfate The compound of formula (XII) may be converted to (IV) by treatment with acetic anhydride and formic acid or by treatment with formic acetic anhydride in pyridine m the presence or absence of a suitable cosolvent such as dichloromethane.
An alternative route of preparation of compounds of formula (IX) is depicted in reaction Scheme 3. Reaction Scherre 3
Figure imgf000061_0001
VIII
Figure imgf000061_0002
IX
Ri and R are as defined as for formula (II).
RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl. R17 is chosen from the group consisting of lower alkoxy or oxazohdinon-1-yl, where the 4 and 5 positions of an oxazolιdιnon-1-yl group may be substituted with a lower alkyl, aryl, or lower alkylaryl group and where such an oxazolιdmon-1-yl substituent may exist as a single stereoisomer or as a mixture of stereoisomers.
A carbonyl compound of formula (XIII), where Rι7 is an alkoxy group such as methoxy or tert-butoxy, may be treated with a strong base such as LDA in a solvent such as THF at a temperature of from -78 °C to 0 °C, followed by treatment with the aldehyde (XIV) to provide (XV). Where R17 is an oxazolιdmon-1-yl substituent, treatment of (XIII) with a Lewis acid such as dι(n-butyl)boron trifluoromethanesulfonate in the presence of N,N- diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature of 0 °C, followed by addition of the aldehyde (XIV) provides (XV). Treatment of (XV) with aqueous base in the presence or absence of hydrogen peroxide affords (VIII) upon acidification. The acid (VIII) may be converted directly to (IX) as m reaction Scheme 2, or may be treated with a dehydrating agent such a p-toluenesulfonyl chloride in pyridme or with friphenylphosphme and diethyl azodicarboxylate in a suitable solvent such as THF, to afford the lactone (XVI). Treatment of the lactone (XVI) with H2NO-RPG, in the presence of a Lewis acid such as trimethylalummum m a suitable solvent such as toluene affords the alcohol (IX).
Reaction Scheme 4 depicts the preparation of compounds of general formula (VIII).
Reacticfi Scherre 4
Figure imgf000062_0001
XVII XVIII
Figure imgf000062_0002
XIX
VIII
Ri and R2 are as defined as for formula (II).
RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
Rig is selected from the group consisting of lower alkyl or benzyl.
Ri is selected from the group consisting of chloride, bromide, iodide, or tπfluoromethanesulfonate.
The ketoester of general formula (XVII) may be formed by treating 2,2-dιmethyl-l,3- dιoxane-4,6-dιone with an appropriate acid chloride Ri COCl in the presence of base, an
alcohol solvent, and heat. The ketoester of general formula (XVII) may be reduced with a reducing agent such as sodium borohydride to afford the hydroxyester (XVIII) Alternately, reduction of (XVII) with a chiral catalyst or chiral hgand in the presence of a reducing agent such as hydrogen or a metal hydride such as borane or lithium aluminum hydride may be employed to afford (XVIII) with chiral induction at the newly formed center The alcohol (XVIII) may be converted to (XIX) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of R2-Rι9 in the presence or absence of a cosolvent such as DMPU Removal of the ester group by hydrolysis with aqueous hydroxide ion or, m the case where R18 is tert-butyl, by treatment with a strong acid such as TFA, affords (VIII) An alternate preparation of compounds of general formula (XI) and a preparation of compounds of general formulae (XXII) and (IV) is depicted in reaction Scheme 5
Reaction Scheme 5
Figure imgf000064_0001
IV
Ri and R2 are as defined as for formula (II).
R22 is selected from the group consisting of aryl or heteroaryl.
Rι9 ιs selected from the group consisting of chloride, bromide, iodide, or tπfluoromethanesulfonate .
RPG, is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
R20 and R ] may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S02 substituents. The lactam of general formula (XX) may be treated with a metal catalyst such as tetrakιs(tπphenylphosphme)palladιum or palladium chloride and R2 -Ri9 m a solvent such as acetonitπle at a temperature of from 20 °C to 200 °C to afford (XXI) Reduction of the olefinic group in (XXI) with hydrogen and a metal catalyst such as palladium on carbon and conversion of the lactam (XI) to the acid (IV) proceeds as outlined in reaction Scheme 2. Alternately, the olefin in compounds of general formula (XXI) may be left in place and manipulation of the lactam (XXI) carried out as described in reaction Scheme 2 to afford (XXII). Acid (XXII) may be converted to (IV) as described in reaction Scheme 2 with or without reduction of the olefin in (XXII), as appropriate
The preparation of compounds of general formula (VIII) and (XI) is shown in reaction Scheme 6.
Reaction Scherre 6
O O XVII
Figure imgf000066_0001
Figure imgf000066_0002
VIII
XXIV
Figure imgf000066_0003
XXVI
RPG,
Figure imgf000066_0004
ll
RPG,
Figure imgf000066_0005
XXIX Reaction Scherre 6, oont.
Figure imgf000067_0001
XXXI
RPG,
Figure imgf000067_0002
R], R2, and D, are as defined as for formula (II). RPG] is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
R]8 is selected from the group consisting of lower alkyl or benzyl.
R]9 is selected from the group consisting of chloride, bromide, iodide, or tπfluoromethanesulfonate.
R20 , R2ι and R23 may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S02 substituents.
R22 is aryl or heteroaryl.
R24 is a tπalkylstannyl group.
The alcohol (XVIII), prepared from (XVII) as outlined in reaction Scheme 4, may be converted to (XXIV) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXIII), m the presence or absence of a cosolvent such as
DMPU. The alkene (XXIV) may be converted to the acid (VIII) as described in reaction Scheme 2. The alcohol (XVIII) may be converted to (XXVI) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXV), in the presence or absence of a cosolvent such as DMPU. Conversion of (XXVI) to (XXVII) proceeds as described in reaction Scheme 2. The alkyne (XXVII) may be treated with R24-H and a radical initiator such as azobιs(ιsobutyronιtπle) a solvent such as toluene to afford (XXVIII). The alkenyltin compound (XXVIII) may be treated with a catalyst such as tetrakιs(tπphenylphosphιne)palladιum and R22-R]9 m a solvent such as DMF at a temperature of from 20 °C to 180 °C to provide (XXIX). The alkene (XXIX) may be transformed to the lactam (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation. The alkyne (XXX) (where R23 = H) may be treated with R22-R19 in the presence of tetrakιs(tπphenylphosphιne)palladιum and cuprous chloride in a solvent such as DMF or acetonitπle at a temperature of 60 °C to 120 °C to afford (XXXI). Compound (XXXI) may be converted if desired to (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation. The preparation of compounds of general formula (VI) is shown in reaction Scheme
7.
Reaction Scheme 7
Figure imgf000068_0001
R4 XXXII R xxxiii
Figure imgf000068_0002
XXXV VI R3, R4, R5, and R,, are as defined for general formula (II)
RPG2 is selected from the group consisting of tert-butoxycarbonyl, allyloxycarbonyl, or benzyloxycarbonyl
R25 is selected from the group consisting of 1 -benzotπazolyloxy, or bromine The acid of formula (XXXII) may be converted in situ to (XXXIII), where R25 is bromine, by treatment with bromo-tπs(pyrrolιdιno)phosphonιum hexafluorophosphate in a suitable solvent such as DMF in the presence of an organic base such as N,N- dπsopropylethylamme The acid of formula (XXXII) may be converted in situ to (XXXIII), where R25 is benzotπazolyloxy, by treatment with BOP in a suitable solvent such as DMF in the presence of an organic base such as NMM Addition of the amme (XXXIV) in the displacement step m the presence of a suitable solvent such as DMF and an organic base such as N,N-dnsopropylethylamine affords the amide (XXXV) Alternatively, the intermediate of formula (XXXII) may be treated with carbonyldnmidazole in a solvent such as dichloromethane, followed by treatment with the amme (XXXIV) to afford (XXXV) Alternatively, the intermediate of formula (XXXII) may be treated with HOBt, the amme (XXXIV), an organic base such as NMM, and a carbodnmide reagent such as EDC m a suitable solvent such as DMF, at a temperature of 0 °C to 80 °C to provide (XXXV) The compound of formula (XXXV) may be converted to (VI) by deprotection, conditions being particular to the nature of RPG2 For example, where RPG2 is tert-butoxycarbonyl, conversion of (XXXV) to (VI) may be accomplished by treatment of (XXXV) with TFA in the presence or absence of a suitable solvent such as dichloromethane, at a temperature of 0 °C to 50 °C
PHARMACEUTICAL FORMULATION AND DOSES
The compounds of the present invention can be administered in such oral
(including buccal and sublingual) dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intrapeπtoneal, mtraarticular, subcutaneous or intramuscular inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
The dosage regimen utilizing the compounds of the present invention is selected accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.1 to 2000 mg/kg of body weight per day, and particularly 1 to 1000 mg/kg of body weight per day. Oral dosage units will generally be administered in the range of from 1 to about 250 mg and more preferably from about 25 to 250 mg. The daily dosage for a 70 kg mammal will generally be in the range of about 10 mg to 5 grams of a compound of formula I or II.
While the dosage to be administered is based on the usual conditions such as the physical condition of the patient, age, body weight, past medical history, route of administrations, severity of the conditions and the like, it is generally preferred for oral administration to be used to administer to a human. In some cases, a lower dose is sufficient and, in some cases, a higher dose or more doses may be necessary. Topical application similarly may be once or more than once per day depending upon the usual medical considerations. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered m divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered m lntranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skm patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen
In the methods of the present invention, the compounds herein described m detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "earner" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavonng, preservative, dispersing and coloring agent can also be present.
Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Ghdants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubihzing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be mcoφorated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium algmate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used m these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, a gar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and dismtegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aligmate, gelatin, or poly vinyl pyrrohdone, a solution retardant such as paraffin, a resoφtion accelerator such as a quaternary salt and/or an absoφtion agent such as bentonite, kaolm or dicalcium phosphate The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of steaπc acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets The compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound m a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound m a non-toxic vehicle. Solubihzers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or saccharin, and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the present invention can also be administered m the form of hposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
The compounds of the present invention can also be administered in the form of hposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrohdone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl residues Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (II) in combination with a pharmaceutically acceptable carrier.
Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular, intrathecal, lntraarteπal or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound m a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution.
Alternatively, a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Non-toxic salts and salt solutions can be added to render the injection lsotonic. Stabilizers, preservations and emulsifiers can also be added.
Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-meltmg water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters, myπstyl palmitate or mixtures thereof. Topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, tπchlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The preferred pharmaceutical compositions are those in a form suitable for oral administration, such as tablets and liquids and the like and topical formulations.
EXAMPLES
The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way Reagents are commercially available or are prepared according to procedures in the literature Example 1 ; (2R,35)-3-(Formylhydroxyamino)-2-(3-phenyl-l-propyl)butanoic Acid \(lS)-2,2- Dimethyl- 1 -(methylcarbamoyl)- 1 -propyljamide
Figure imgf000076_0001
Example la; Methyl (2R,3R)-2-[(2E)-3-Phenyl-2-propen-l-yl]-3-hydroxybutanoate
To a solution of diisopropylamme (47.1 g, 466.1 mmol) in THF (500 mL) cooled to -
50 °C is added n-butylhthium (466.1 mmol, 2.5M in hexanes) and the resulting solution is stirred at -50 °C for 0.5 h. The reaction mixture is cooled to -78 °C followed by slow addition of methyl (3R)-3-hydroxybutanoate (25 g, 21 1.9 mmol). After 0.5 h a solution of cmnamyl bromide (45.9 g, 233.0 mmol) m HMPA (10 mL) is added and the reaction mixture is allowed to warm to 0 °C and stirred for 16 h. The reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-[(2E)- 3-phenyl-2-propen-l-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield).
'H NMR (400 MHz, CDCI3) δ 7.32-7.18 (m, 5H), 6 44 (d, IH), 6.13 (m, IH), 3.98 (m, IH),
3.69 (s, 3H), 2.56 (m, 4H), 1.25 (t, 3H) ppm ESI-MS m z 257.2 (M+Na)\
Example lb; Methyl (2R,3R)-2-(3-Phenyl-l-propyl)-3-hydroxybutanoate
A solution of methyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-l-yl]-3-hydroxybutanoate
(42.0 g, 179.5 mmol) m 400 mL of methanol is treated with 400 mg of 10% palladium on carbon. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 16 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide methyl (2R,3R)-2-(3-phenyl-l- propyl)-3-hydroxybutanoate as an oil (42.2 g, 100% yield).
Η NMR (400 MHz, CDCI3) δ 7.25 (m, 2H), 7.17 (m, 3H), 3.88 (m, IH), 3.69 (s, 3H), 2.61
(m, 2H), 2.42 (m, 2H), 1.72 (m, IH), 1.62 (m, 3H), 1.19 (d, 3H) ppm. ESI-MS m/z 259.2 (M+Na)+.
Example lc; (2R,3R)-2-(3-Phenyl-l-propyl)-3-hydroxybutanoιc Acid
To a solution of methyl (2R,3R)-2-(3-phenyl-l-propyl)-3-hydroxybutanoate (42.2 g, 179.5 mmol) in THF - methanol (3: 1, 535 mL) is added 2 M aqueous sodium hydroxide solution (135 mL, 269.3 mmol). The solution is stirred at 23 °C for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-l-propyl)-3-hydroxybutanoιc acid as an oil (33.0 g, 83% yield). Η NMR (400 MHz, CDCI3) δ 7.28 (m, 2H), 7.16 (m, 3H), 3.93(m, IH), 2.63 (m, 2H), 2.43
(m, IH), 1.69 (m, 4H), 1.26 (d, 3H) ppm. ESI-MS m z 221.3 (M-H)".
Example Id; (2R,3R)-2-(3-Phenyl-l-propyl)-3-hydroxybutanoιc Acid 2- Tetrahydropyranyloxyamide
To a solution of (2R,3R)-2-(3-phenyl-l-propyl)-3-hydroxybutanoιc acid (33.0 g, 148.7 mmol) m dichloromethane (300 mL) is added 2-tetrahydropyranyloxyamme (18.3 g, 156.1 mmol) and EDC (31.2 g, 163.5 mmol). The resulting solution is stirred at 23 °C for 16 h, then diluted with dichloromethane (500 mL) and washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The reaction mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-l-propyl)-3- hydroxybutanoic acid 2-tetrahydropyranyloxyamιde as a foam (47.8 g, 100% yield). Η NMR (400 MHz, CDCI3) δ 8.66 (bs, IH), 7.25 (m, 2H), 7.17 (m, 3H), 4.94 (m, IH), 3.89
(m, 2H), 3.61 (m, IH), 2.62 (t, 2H), 1.93 (m, IH), 1.78 (m, 4H), 1.66 (m, 6H), 1.23 (d, 3H) ppm. ESI-MS m/z 320.4 (M-H)".
Example le; (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-(3-phenyl-l-propyl)-4-methylazetιdm-2- one
To a solution of (2R,3R)-2-(3-phenyl-l-propyl)-3-hydroxybutanoιc acid 2- tetrahydropyranyloxyamide (47.8 g, 148.7 mmol) m 150 mL of dichloromethane at 0 °C is added pyridme (64 mL) and methanesulfonyl chloride (20.4 g, 178.4 mmol). The resulting solution is allowed to warm to 23 °C and is stirred at 23 °C for 14 h, concentrated in vacuo, and diluted with dichloromethane (500 mL). The organic layer is washed with 1 M hydrochloric acid, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to provide the desired methanesulfonate intermediate.
A suspension of potassium carbonate (61.5 g) in acetone (500 mL) is heated to reflux for 1 h. A solution of the above methanesulfonate in acetone (1000 mL) is added and the resulting suspension is heated at reflux for 28 h. The mixture is allowed to cool to 25 °C and is filtered, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3: 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-(3- phenyl- 1 -propyl)-4-methylazetιdm-2-one as an oil (34.0 g, 75% yield). Η NMR (400 MHz, CDCI3) δ 7.25 (m, 2H), 7.17 (m, 3H), 5.13 (m, 0.5H), 4.99 (m, 0.5H),
4.15-3.98 (m, 2H), 3.64 (m, IH), 2.93 (m, IH), 2.67 (m, 2H), 1.89-1.51 (m, 10H), 1.28 (d, 1.5H), 1.26 (d, 1.5H) ppm. ESI-MS m/z 326.4 (M+Na)+.
Example If; (2R,35)-2-(3-Phenyl-l-propyl)-3-(2-tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-(3-phenyl-l-propyl)-4- methylazetιdm-2-one (20.5 g, 67.6 mmol) in dioxane (220 mL) is added 1 M aqueous sodium hydroxide (102 mL). The solution is stirred at 23 °C for 20 h, then extracted with hexanes (200 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 300 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,35)-2-(3-phenyl-l-propyl)-3-(2- tetrahydropyranyloxyammo)butanoιc acid as an oil (21.5 g, 99% yield) 'H NMR (400 MHz, CDCI3) δ 7.28 (m, 2H), 7.18 (m, 3H), 4.84 ( , 0.5H), 4.70 (m, 0.5H),
3.96 (m, 0.5H), 3.89 (m, 0.5H), 3.56 (m, IH), 3.34 (m, 0.5H), 3.24 (m, 0.5H), 2.97 (m, 0.5H), 2.81 (m, 0.5H), 2.65 (m, 2H), 1.96-1.45 (m, 10H), 1.31 (m, IH), 1.06 (d, 1.5 H), 0.99 (d, 1.5
H) ppm.
ESI-MS m/z 344.3 (M+H)+.
Example lg; (2R,35)-2-(3-Phenyl-l-propyl)-3-(formyl-2- tetrahydropyranyloxyammo)butanoιc Acid
To a solution of (2R,35)-2-(3-phenyl-l-propyl)-3-(2- tetrahydropyranyloxyamιno)butanoιc acid (21.4 g, 66.7 mmol) in pyridme (100 mL) at 0 °C is added formic acetic anhydride ( 30 mL). The resulting solution is allowed to warm to 25 °C, stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (300 mL) and washed sequentially with 1 M hydrochloπc acid (200 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,35)-2- (3-Phenyl-l-propyl)-3-(formyl-2-tetrahydropyranyloxyammo)butanoιc acid as an oil (18.9 g, 81% yield).
ESI-MS m/z 372.3 (M+Na)+. ESI-MS m/z 348.4 (M-H) .
Example lh; (25)-2-tert-butoxycarbonylammo-3,3-dιmethylbutanoιc Acid Methylamide
To a solution of (25)-2-tert-butoxycarbonylamιno-3,3-dιmethylbutanoιc acid (120 g, 519 mmol) in dichloromethane (800 mL) is added 1,1-carbonyldnmidazole (88.4 g, 545 mmol). The resulting solution is stirred at 25 °C for 1 h and methylamine hydrochloπde (52.5 g, 779 mmol) and triethylamme (157.3 g, 1557 mmol) are added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (600 mL) and washed with 1
M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (25)-2-tert- butoxycarbonylammo-3,3-dιmethylbutanoιc acid methylamide as a white solid (126 g, 100% yield).
Η NMR (400 MHz, CDCI3) δ 5.81 (bs, IH), 5.30 (m, IH), 3.80 (d, IH), 2.81 (d, 3H), 1.43
(s, 9H), 0.99 (s, 9H) ppm. ESI-MS m z 245.4 (M+H)+.
Example li; (25)-2- Ammo-3, 3 -dirnethylbutanoic Acid Methylamide
To a solution of (25)-2-tert-butoxycarbonylammo-3, 3 -dirnethylbutanoic acid methylamide (126 g, 519 mmol) in dichloromethane (320 mL) cooled at 0 °C is added tπfluoroacetic acid (320 mL). The resulting solution is allowed to warm to 25 °C and is stirred for 18 h. The reaction mixture is concentrated, brought to pH=10 with 2 M sodium hydroxide, and extracted with 4:1 dichloromethane/isopropanol (1000 mL). The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (25)-2-Amιno-3,3- dimethylbutanoic acid methylamide (40.5 g, 79% yield) as a white solid. 'H NMR (400 MHz, CDCI3) δ 6.69 (bs, IH), 3.10 (s, IH), 2.82 (d, 3H), 1.50 (bs, 2H), 0.99
(s, 9H) ppm. ESI-MS m/z 145.2 (M+H)+.
Example lj; (2R,35)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-phenyl-l- propyl)butanoιc Acid [(15)-2,2-Dιmethyl-l -(methylcarbamoyl)- 1 -propyljamide
To a solution of (2R,35)-2-(3-phenyl- 1 -propyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc acid (5.5 g, 15 76 mmol) m DMF (20 mL) is added BOP reagent (7.66 g. 17 34 mmol), HOBt ( 2.34 g, 17.34 mmol), and NMM (4.78 g, 47.28 mmol). After 30 mm, addition of (25)-2-Ammo-3,3-dιmethylbutanoιc acid methylamide (3.4 g, 23.64) occurs and the resulting solution is stirred at 25 °C for 20 h. The reaction mixture is poured into ethyl acetate/hexanes (1.1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and punfied by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,35)-3- (Formyl-2-tetrahydropyranyloxyamιno)-2-(3-phenyl-l -propyl)butanoιc acid [(15)-2,2- dιmethyl-1 -(methylcarbamoyl)- 1 -propyljamide as a white solid (2.7 g, 36% yield). Η NMR (400 MHz, CDCI3) δ 8.40 and 8.02 (s, IH), 7.22 (m, 2H), 7.08 (m, 3H), 6.38 (m,
IH), 5.88 (m, IH), 4.82 (m, IH), 4.38 and 3.56 (m, IH), 4.22 (m, IH), 3.94 (m, IH), 2.74 (m, 3H), 2.56 (m, 3H), 1.82 (m, 2H), 1.74-1.42 (m, 10H), 1.28 and 1.22 (d, 3H), 0.96 (s, 9H) ppm.
ESI-MS m/z 498.4 (M+Na)+.
Example 1; (2R,35)-3-(Formylhydroxyammo)-2-(3-phenyl-l-propyl)butanoιc Acid [(15)-2,2- Dime hyl- 1 -(methylcarbamoyl)- 1 -propyljamide
A solution of (2/?,35)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-phenyl-l- propyl)butanoιc acid [(15)-2,2-dιmethyl-l-(methylcarbamoyl)-l-propyl]amιde (3.0 g, 6.32 mmol) in acetic acid - water (4: 1, 10 mL) is heated to 50 °C for 16 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane - diethyl ether to provide (2R,35)-3-(Formylhydroxyamιno)-2-(3-phenyl-l-propyl)butanoιc acid [(15)- 2,2-dιmethyl-l -(methylcarbamoyl)- 1 -propyljamide as a white solid (2.3 g, 93% yield). Η NMR (400 MHz, CD3OD) δ 8.25 and 7.99 (s, IH), 7.22 (m, 2H), 7.10 (m, 3H), 4.48 and
3.82 (dq, IH), 4.24 (s, IH), 2.84 and 2.78 (m, IH), 2.61 (s, 3H), 2.58 (m, IH), 2.44 (m, 2H),
1.52 (m, 4H), 1.24 and 1.18 (d, 3H), 0.99 (s, 9H) ppm.
ESI-MS m z 414.5 (M+Na)+.
Anal. Calcd. for C21H33N304: C, 64.42; H, 8.50; N, 10.73. Found. C, 64.44; H, 8.50; N,
10.70.
Example 2; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4-chlorophenyl)-l-propyl)butanoιc Acid [( 1 )-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyl] amide
Figure imgf000083_0001
Example 2a; Methyl (2R,3R)-2-(3-tπmethylsιlyl-2-propyne-l-yl)-3-hydroxybutanoate
To a solution of diisopropylamine (9.42 g, 93.22 mmol) in THF (100 mL) cooled to -
50 °C is added n-butylhthium (93.22 mmol, 2.5M in hexanes) and the resulting solution is stirred at -50 °C for 0.5 h. The reaction mixture is cooled to -78 °C followed by slow addition of methyl (3R)-3-hydroxybutanoate (5 g, 42.37 mmol). After 0.5 h a solution of 3- tπme hylsilyl propargyl bromide (9.76 g, 50.85 mmol) in HMPA (1 mL) is added and the reaction mixture is allowed to warm to 0 °C and stirred for 16 h. The reaction mixture is quenched by addition 10 mL of saturated aqueous ammonium chloride solution, is poured into 100 mL of 1 M hydrochloric acid, and is extracted with two 100 mL portions of ethyl acetate. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 20% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-(3-tnmethylsιlyl-2-propyne-l-yl)-3-hydroxybutanoate as a yellow oil (5.6 g, 58% yield). 'H NMR (400 MHz, CDCI3) δ 4.04 (m, IH), 3.72 (s, 3H), 2.62 (m, 3H), 1.23 (t, 3H), 0.09 (s,
9H) ppm.
ESI-MS m/z 251.2 (M+Na)+.
Example 2b; (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc Acid
To a solution of methyl (2R,3R)-2-(3-tπmethylsιlyl-2-propyne-l-yl)-3- hydroxybutanoate (5.6 g, 24.56 mmol) in THF - methanol (3:1, 160 mL) is added 2 M aqueous sodium hydroxide solution (40 mL, 36.8 mmol). The solution is stirred at 23 °C for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH=3 with 1 M HCl and is extracted with two 100 mL portions of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc acid as an oil (3.0 g, 86% yield). Η NMR (400 MHz, CDCI3) δ 7.28 (m, 2H), 7.16 (m, 3H), 3.93(m, IH), 2.63 (m, 2H), 2.43
(m, IH), 1.69 (m, 4H), 1.26 (d, 3H) ppm. ESI-MS m/z 221.3 (M-H)".
Example 2c; (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc Acid 2- Tetrahydropyranyloxyamide To a solution of (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc acid (3.0 g, 21.13 mmol) in dichloromethane (50 mL) is added 2-tetrahydropyranyloxyamιne (3.0 g, 25.35 mmol) and EDC (4.5 g, 23.24 mmol). The resulting solution is stirred at 23 °C for 4 h, then diluted with dichloromethane ( 100 mL) and washed with 1 M hydrochloric acid. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc acid 2- tetrahydropyranyloxyamide as a foam (1.9 g, 37% yield). Η NMR (400 MHz, CDCI3) δ
8.82 (bs, IH), 4.96 (m, IH), 3.94 (m, 2H), 3.62 (m, IH), 2.64 (m, IH), 2.56 (m, IH), 2.23 (m, IH), 2.04 (m, IH), 1.82 (m, 2H), 1.61 (m, 4H), 1.23 (d, 3H) ppm. ESI-MS m/z 240.3 (M-H)".
Example 2d; (3R,45)- 1 -(2-Tetrahydropyranyloxy)-3-(2-propyne- 1 -yl)-4-methylazetιdιn-2-one
To a solution of (2R,3R)-2-(2-propyne-l-yl)-3-hydroxybutanoιc acid 2- tefrahydropyranyloxyamide (1.9 g, 7.88 mmol) in 20 mL of dichloromethane at 0 °C is added pyridine (5 mL) and methanesulfonyl chloride (0.99 g, 8.67 mmol). The resulting solution is allowed to warm to 23 °C and is stirred at 23 °C for 16 h, concentrated in vacuo, and diluted with dichloromethane (100 mL). The organic layer is washed with 1 M hydrochloric acid, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to provide the desired methanesulfonate intermediate.
A suspension of potassium carbonate (3.26 g) m acetone (10 mL) is heated to reflux for 1 h. A solution of the above methanesulfonate in acetone (100 mL) is added and the resulting suspension is heated at reflux for 6 h. The mixture is allowed to cool to 25 °C and is filtered, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 4: 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-(2- propyne-l-yl)-4-methylazetιdιn-2-one as an oil (1.3 g, 74% yield). Η NMR (400 MHz, CDCI3) δ 5.15 (m, 0.5H), 4 99 (m, 0.5H), 4.20-4 01 (m, 2H), 3 62 (m,
IH), 3.18 (m, IH), 2.63 (m, IH), 2.40 (m, IH), 1.99 (m, IH), 1 89-1.51 (m, 6H), 1.42 (d, 1.5H), 1.38 (d, 1.5H) ppm. ESI-MS m/z 246.3 (M+Na)+.
Example 2e; (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-((2E -3-tπbutylstannyl-2-propene-l-yl)- 4-methylazetιdιn-2-one
To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-(2-propyne-l-yl)-4- methylazetιdm-2-one (1.32 g, 5.83 mmol) in 20 mL of toluene is added tributyltm hydride
(1.70 g, 5.83 mmol) and AIBN (30 mg). The resulting solution is heated at reflux for 4 h then concentrated in vacuo. The reaction mixture is purified by silica gel chromatography (elution with 8: 1 hexanes - ethyl acetate) to provide (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3- tπbutylstannyl-2-propene-l-yl)-4-methylazetιdιn-2-one as an oil (2.6 g, 87% yield). Η NMR (400 MHz, CDCI3) δ 5.94 (m, 2H), 5.16 (m, 0.5H), 4.99 (m, 0.5H), 4.20-4.01 (m,
2H), 3.62 (m, IH), 3.12 (m, IH), 2.61 (m, IH), 2.36 (m, IH), 1.76 (m, 2H), 1.58 (m, 4H), 1.44 (m, 6H), 1.26 (m, 9H), 0.86 (m, 15H) ppm. ESI-MS m/z 538.2 (M+Na)+.
Example 2f; (3R,AS)- 1 -(2-Tetrahydropyranyloxy)-3-((2E)-3-(4-chlorophenyl)-2-propene- 1 - yl)-4-methylazetιdιn-2-one
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tnbutylstannyl-2- propene-l-yl)-4-methylazetιdιn-2-one (0.92 g, 1.79 mmol) in 3 mL of dimethylformamide is added 4-chloroιodobenzene (470 mg, 1.97 mmol) and tπphenyphosphine palladium (II) dichloride (63 mg, 0.09 mmol). The resulting solution is heated at 80°C for 16 h, then 0.5 mL ammonium hydroxide is added The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1 : 1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3.1 hexanes - ethyl acetate) to provide (3R,45)- 1 -(2-tetrahydropyranyloxy)-3-((2E)-3-(4-chlorophenyl)-2-propene- 1 -yl)-4- methylazetιdm-2-one as an oil (370 mg, 61% yield). Η NMR (400 MHz, CDCI3) δ 7.30 (d, 2H), 7.16 (d, 2H), 6.38 (m, IH), 6.18 (m, IH), 5.16
(m, 0.5H), 4.99 (m, 0.5H), 4.20-4.01 (m, 2H), 3.62 (m, IH), 3.12 (m, IH), 2.62 (m, IH), 2.42 (m, IH), 1.76 (m, 2H), 1.58 (m, 4H), 1.36 (m, 3H) ppm. ESI-MS m/z 358.2 (M+Na)+.
Example 2g; (3R,45)-l-(2-Tetrahydropyranyloxy)-3-( 3-(4-chlorophenyl)-l-propyl)-4- methylazetιdm-2-one
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-chlorophenyl)-2- propene-l-yl)-4-methylazetιdιn-2-one (0.37 g, 1.10 mmol) in 5 mL of methanol is treated with 30 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred undei 1 atmosphere pressure of hydrogen gas for 30 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-l-propyl)-4- methylazetιdm-2-one as an oil (360 mg, 97% yield). Η NMR (400 MHz, CDCI3) δ 7.22 (d, 2H), 7.08 (d, 2H), 5.16 (m, 0.5H), 4.96 (m, 0.5H),
4.16-3.96 (m, 2H), 3.62 (m, IH), 2.88 (m, IH), 2.62 (m, 2H), 1.82-1 44 (m, 10H), 1.22 (m, 3H) ppm. ESI-MS m z 360.3 (M+Na)+. Example 2h; (2R,35)-2-(3-(4-chlorophenyl)-l-propyl)-3-(2- tetrahydropyranyloxyammo)butanoιc Acid
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-l- propyl)-4-methylazetιdιn-2-one (360 mg, 1.07 mmol) in dioxane (3.2 mL) is added 1 M aqueous sodium hydroxide (1.6 mL). The solution is stirred at 23 °C for 72 h, then extracted with hexanes (20 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 30 mL portions of ethyl acetate The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,35)-2-(3-(4- chlorophenyl)-l-propyl)-3-(2-tetrahydropyranyloxyammo)butanoιc acid as an oil (380 mg, 99% yield) Η NMR (400 MHz, CDCI3) δ 7.22 (d, 2H), 7.06 (d, 2H), 4 92 (m, 0.5H), 4.78 (m, 0.5H),
3.95 (m. 0.5H), 3.86 (m, 0.5H), 3.57 (m, IH), 3.36 (m, 0.5H), 3.24 (m, 0.5H), 2.94 (m, 0.5H), 2.81 (m, 0.5H), 2.62 (m, 2H), 1.94-1.66 (m, 4H), 1.62-1.44 (m, 6H), 1.24 (m, IH), 1.08 (d, 1.5H), 1.02 (d, 1.5H) ppm. ESI-MS m/z 354.2 (M-H)
Example 2ι; (2R,35)-2-(3-(4-chlorophenyl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (2R,35)-2-(3-(4-chlorophenyl)-l-propyl)-3-(2- tetrahydropyranyloxyamιno)butanoιc acid (380 mg, 1.07 mmol) in pyridine (4 mL) at 0 °C is added formic acetic anhydride ( 0 9 mL) The resulting solution is allowed to warm to 25 °C, stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution The organic layei is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,35)-2- (3-(4-chlorophenyl)-l-propyl)-3-(formyl-2-tetrahydropyranyloxyammo)butanoιc acid as an oil (385 mg, 94% yield). ESI-MS m/z 406.2 (M+Na)+. ESI-MS m/z 382.3 (M-H) .
Example 2j; (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4-chlorophenyl)-l- propyl)butanoιc Acid [(15)-2,2-Dιmethyl-(l -methylcarbamoyl)- 1 -propyljamide
To a solution of (2R,35)-2-(3-(4-chlorophenyl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyammo)butanoιc acid (230 mg, 0.60 mmol) m DMF (2 mL) is added BOP reagent (292 mg, 0.66 mmol), HOBt ( 89 mg, 0.66 mmol), and NMM (182 mg, 1.80 mmol). After 30 mm, addition of (25)-2-Amιno-3, 3 -dirnethylbutanoic acid methylamide (104 mg, 0.72 mmol) occurs and the resulting solution is stirred at 25 °C for 18 h. The reaction mixture is poured into ethyl acetate/hexanes (1 : 1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1 : 1 ethyl acetate - hexane) to provide (2R,35)-3- (Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4-chlorophenyl)-l-propyl)butanoιc acid [(15)- 2,2-dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide as a white solid (215 mg, 70% yield). ESI-MS m/z 532.0 (M+Na)+.
Example 2; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4-chlorophenyl)-l-propyl)butanoιc Acid [( 15)-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide
A solution of (2R,35)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4- chlorophenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -methylcarbamoyl)- 1 - propyljamide (215 mg, 0.422 mmol) in acetic acid - water (4- 1, 1 mL) is heated to 50 °C for 18 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane - diethyl ether to provide (2R,35)-3-(Formylhydroxyammo)-2-(3- (4-chlorophenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -methylcarbamoyl)- 1 - propyljamide as a white solid (135 mg, 75% yield). Η NMR (400 MHz, CD3OD) δ 8.25 and 7.98 (s, IH), 8.16 and 8.05 (m, IH), 7.22 (d, 2H),
7.09 (d, 2H), 4.48 and 3.82 (m, IH), 4 23 (m, IH), 2.84 and 2.78 (m, IH), 2.61 (s, 3H), 2.58
(m, IH), 2.44 (m, IH), 1.48 (m, 4H), 1.24 and 1 18 (d, 3H), 0.98 (s, 9H) ppm
ESI-MS m/z 448.2 (M+Na)+.
Anal. Calcd. for C21H32N304C1,: C, 59.22; H, 7.57; N, 9.87. Found: C, 59.23; H, 7.63; N,
9.82.
Example 3; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(thιophene-2-yl)-l-propyl)butanoιc Acid [( 15)-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide
Figure imgf000090_0001
Example 3a; (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-((2E)-3-(thιophene-2-yl)-2-propene-l- yl)-4-methylazetιdιn-2-one To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tnbutylstannyl-2- propene-l-yl)-4-mefhylazetιdιn-2-one (400 mg, 0.78 mmol) in 1 mL of dimethylformamide is added 2-bromothιophene (152 mg, 0.93 mmol) and tnphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol) The resulting solution is heated at 80°C for 2 h, then 0.5 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1 : 1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3: 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(thιophene-2-yl)-2-propene-l-yl)-4- methylazetιdιn-2-one as an oil (130 mg, 54% yield).
Η NMR (400 MHz, CDCI3) δ 7.08 (m, IH), 6.92 (m, IH), 6.85 (m, IH), 6.56 (m, IH), 6.01
(m, IH), 5.15 (m, 0.5H), 5.00 (m, 0.5H), 4.17-4.08 (m, 2H), 3.62 (m, IH), 3.10 (m, IH), 2.62 (m, IH), 2.40 (m, IH), 1.78 (m, 2H), 1.64 (m, 4H), 1.36 (m, 3H) ppm. ESI-MS m/z 330.2 (M+Na)+.
Example 3b; (3R,45)-l-(2-Tetrahydropyranyloxy)-3-( 3-(thιophene-2-yl)-l-propyl)-4- methylazetιdm-2-one
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(thιophene-2-yl)-2- propene-l-y])-4-methylazetιdιn-2-one (130 mg, 0.423 mmol) in 3 mL of methanol is treated with 20 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 72 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,45)-1 -(2-tetrahydropyranyloxy)-3-(3-(thιophene-2-yl)-l-propyl)-4- methylazetιdιn-2-one as an oil (130 mg, 100% yield) Η NMR (400 MHz, CDCI3) δ 7.04 (m, IH), 6.86 (m, IH), 6.77 (m, IH), 5.16 (m, 0.5H),
4.96 (m, 0.5H), 4.16-3.96 (m, 2H), 3.61 (m, IH), 2.88 (m, 3H), 1.90-1 44 (m, 10H), 1.24 (m,
3H) ppm.
ESI-MS m/z 332.2 (M+Na)+
Example 3c; (2R,35)-2-(3-(thιophene-2-yl)-l-propyl)-3-(2- tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-(3-(thιophene-2-yl)-l-propyl)-
4-methylazetιdιn-2-one (91 mg, 0.295 mmol) in dioxane (1 mL) is added 1 M aqueous sodium hydroxide (0.44 mL). The solution is stirred at 23 °C for 18 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,35)-2-(3- (thιophene-2-yl)-l -propyl)-3-(2-tetrahydropyranyloxyamιno)butanoιc acid as an oil (91 mg, 94% yield). Η NMR (400 MHz, CDCI3) δ 7.04 (m, IH), 6.85 (m, IH), 6.75 (m, IH), 4.84 (m, 0.5H),
4.68 (m, 0.5H), 3.98 (m. 0.5H), 3.86 (m, 0.5H), 3.57 (m, IH), 3.36 ( , 0.5H), 3.25 (m, 0.5H), 2.96 (m, 0.5H), 2.2.82 (m, 2.5 H), 1.94-1.66 (m, 4H), 1.62-1.44 (m, 6H), 1.37 (m, IH), 1.06 (d, 1.5H), 1.00 (d, 1.5H) ppm. ESI-MS m/z 338.3 (M-H) .
Example 3d; (2R,35)-2-(3-(thιophene-2-yl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyammo)butanoιc Acid To a solution of (2R,35)-2-(3-(thιophene-2-yl)-l-propyl)-3-(2- tetrahydropyranyloxyammo)butanoιc acid (91 mg, 0.278 mmol) m pyridine (1 mL) at 0 °C is added formic acetic anhydride ( 0.3 mL). The resulting solution is allowed to warm to 25 °C, stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2- (3-(thιophene-2-yl)-l-propyl)-3-(formyl-2-tefrahydropyranyloxyamιno)butanoιc acid as an oil (90 mg, 91% yield).
ESI-MS m/z 378.1 (M+Na)+. ESI-MS m/z 354.3 (M-H)".
Example 3e; (2R,35)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-(thιophene-2-yl)-l - propyl)butanoιc Acid [(lS)-2,2-Dιmethyl-(l-methylcarbamoyl)-l-propylJamιde
To a solution of (2R,3S)-2-(3-(thιophene-2-yl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc acid (70 mg, 0.197 mmol) m DMF (1 mL) is added BOP reagent (96 mg, 0.217 mmol), HOBt ( 29 mg, 0.217 mmol), and NMM (100 mg, 0.986 mmol). After 30 mm, addition of (25)-2-Amιno-3,3-dιmethylbutanoιc acid methylamide (34 mg, 0.237 mmol) occurs and the resulting solution is stirred at 25 °C for 20 h. The reaction mixture is poured into ethyl acetate/hexane (1.1, 20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1 : 1 ethyl acetate - hexane) to provide (2R,3S)-3-
(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-(thιophene-2-yl)-l-propyl)butanoιc acid [(15)- 2,2-dιmethyl-(l -methylcarbamoyl)-! -propyljamide as a white solid (13 mg, 14% yield) ESI-MS m z 504.0 (M+Na)+.
Example 3; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(thιophene-2-yl)-l-propyl)butanoιc Acid
[( lS)-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide
A solution of (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-(thιophene-2- yl)- 1 -proρyl)butanoιc acid [(lS)-2,2-dιmethyl-(l -methylcarbamoyl)- 1 -propyljamide (13 mg,
0.027 mmol) in acetic acid - water (4: 1, 1 mL) is heated to 50 °C for 18 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane - diethyl ether to provide (2R,3S)-3-(Formylhydroxyamιno)-2-(3-(thιophene-
2-yl)-l-propyl)butanoιc acid [(lS)-2,2-dιmethyl-(l-methylcarbamoyl)-l-propyl]amιde as a white solid (9 mg, 85% yield).
Η NMR (400 MHz, CD3OD) δ 8.25 and 7.98 (s, IH), 8.15 and 8.00 (m, IH), 7.04 (m, IH),
6.83 (m, IH), 6.72 (m, IH), 4.48 and 3.82 (m, IH), 4.23 (d, IH), 2.84-2.65 (m, 3H), 2.61 (m,
3H), 1.43 (m, 4H), 1.24 and 1.16 (d, 3H), 0.98 (s, 9H) ppm.
ESI-MS m/z 420.1 (M+Na)+.
Example 20; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4-chlorophenyl)-l-propyl)butanoιc Acid [(15)-2,2-Dιmethyl-(l-(2-pyndylmethyl)carbamoyl)-l -propyljamide
Figure imgf000094_0001
Example 20a, (25)-2-tert-butoxycarbonylammo-3, 3 -dirnethylbutanoic Acid 2- pyπdylmethylamide
To a solution of (2S)-2-tert-butoxycarbonylammo-3,3-dιmethylbutanoιc acid (1 1.6 g,
50 mmol) in dichloromethane (100 mL) is added EDC (14.4 g, 75 mmol), HOBT (7.65 g, 50 mmol), and 2-pyπdylmethylamme (6 48g, 60mmol). The resulting solution is stirred at 25 °C for 18 h, then diluted with dichloromethane (200 mL) and washed with 2 M hydrochloric acid and 2 M sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylammo-3,3-dιmethylbutanoιc acid 2-pyπdylmefhylamιde as a white solid (16 g, 100%> yield).
Η NMR (400 MHz, d6DMSO) 8.46 (d, IH), 7.68 (t, IH), 7.27 (d, IH), 7.22 (dd, IH), 6.50 (d, IH). 4.32 (d, 2H), 3.86 (d, IH), 1.37 (s, 9H), 0.88 (s, 9H) ppm.
Example 20b; (25)-2-Ammo-3, 3 -dirnethylbutanoic Acid 2-pyπdylmethylamιde
To a solution of (25)-2-tert-butoxycarbonylammo-3,3-dιmethylbutanoιc acid 2- pyπdylmefhylamide (16 g, 50 mmol) in dichloromethane (25 mL) cooled at 0 QC is added tπfluoroacetic acid (150 mL). The resulting solution is allowed to warm to 25 °C and is stirred for 18 h. The reaction mixture is diluted with toluene, concentrated, brought to pH=10 with 2 M sodium hydroxide, and extracted with 3: 1 dichloromethane/isopropanol (200 mL). The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (25)-2-Amιno-3,3- dimethylbutanoic acid 2-pyπdylmethylamιde (1 1 g, 100% yield) as a white solid. Η NMR (400 MHz, d6-DMSO) δ 8.43 (d, IH), 8.35 (m, IH), 7.72 (t, IH), 7.27 (d, IH), 7.21 (dd, IH), 4.34 (d, 2H), 2.85 (s, IH), 1.68 (bs, 2H), 0.92 (s, 9H) ppm. Example 20c, (2R,35)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-(4-chlorophenyl)-l- propyl)butanoιc Acid [( 15)-2,2-Dιmethyl-( 1 -(2-pyπdylmethyl)carbamoyl)- 1 -propyljamide
To a solution of (2R,35)-2-(3-(4-chlorophenyl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc acid (2 g, 5.21 mmol) in DMF (15 mL) is added BOP reagent (2.53 g, 5.72 mmol), HOBt ( 0.77 g, 5 72 mmol), and NMM (2.1 g, 20 86 mmol). After 30 mm, addition of (25)-2-Ammo-3, 3 -dirnethylbutanoic acid 2-pyπdylmethylamιde (1.26 g, 5.72 mmol) occurs and the resulting solution is stirred at 25 °C for 72 h. The reaction mixture is poured into ethyl acetate (100 mL) and washed sequentially with 1 M aqueous sodium carbonate and saturated aqueous sodium chloride The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with ethyl acetate) to provide (2R,35)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4- chlorophenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -(2-pyπdylmethyl)carbamoyl)- 1 - propyljamide as a white solid (2.4 g, 79% yield). ESI-MS m/z 586.9 (M+H)+.
Example 20, (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4-chlorophenyl)-l-propyl)butanoιc Acid [(15)-2,2-Dιmethyl-(l-(2-pyπdylmethyl)carbamoyl)-l -propyljamide
A solution of (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4- chlorophenyl)- 1 -propyl)butanoιc acid [( 1 S)-2,2-dιmethyl-( 1 -(2-pyπdylmethyl)carbamoyl)- 1 - propyljamide (2.4 g, 4 09 mmol) in acetic acid - water (4.1, 10 mL) is heated to 50 °C for 36 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is recrystallized from dichloromethane/methanol - diethyl ether to provide (2R,35)-3-(Formylhydroxyammo)-2-(3-
(4-chlorophenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -(2-pyπdylmethyl)carbamoyl)-
1 -propyljamide as a white solid (1.59 g, 77% yield) Η NMR (400 MHz, CD3OD) δ 8.63 (m, IH), 8.40 (m, IH), 8.25 and 7.99 (s, IH), 8.22 and
8.16 (d, IH), 7.61 (t, IH), 7.29 (d, IH), 7.21 (m, IH), 7.08 (d, 2H), 7.00 (d, 2H), 4.57 (m, IH), 4.52 and 3.82 (m, IH), 4.36-4.30 (m, 2H), 2.91 and 2.82 (m, IH), 2.56 (m, IH), 2.41 (m, IH), 1.44 (m, 4H), 1.26 and 1.18 (d, 3H), 1.01 (s, 9H) ppm. ESI-MS m/z 503.1 (M+H)+.
Example 52; (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4-methylphenyl)- 1 -propyl)butanoιc Acid [(15)-2,2-Dιmethyl-(l -methylcarbamoyl)-! -propyljamide
Figure imgf000097_0001
Example 52a; (3R,45)- 1 -(2-Tetrahydropyranyloxy)-3 -((2E)-3 -(4-methylphenyl)-2-propene- 1 - yl)-4-methylazetιdιn-2-one
To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tπbutylstannyl-2- propene-l-yl)-4-methylazetιdm-2-one (400 mg, 0.78 mmol) m 1 mL of dimethylformamide is added 4-bromotoluene (180 mg, 0.93 mmol) and tπphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol). The resulting solution is heated at 80°C for 18 h, then 1 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted wit 1 : 1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3 : 1 hexanes - ethyl acetate) to provide (3R,AS)- 1 -(2-tetrahydropyranyloxy)-3-((2E)-3-(4-methylphenyl)-2-propene- 1 -yl)-4- mefhylazetιdιn-2-one as an oil (165 mg, 67% yield) Η NMR (400 MHz. CDCI3) δ 7.30 (m, 2H), 7.16 (m, 2H), 6.43 (m, IH), 6.18 (m, IH), 5.22
(m, 0.5H), 5.04 (m, 0.5H), 4.24-4.08 (m, 2H), 3.64 (m, IH), 3.16 (m, IH), 2.68 (m, IH), 2.46 (m, IH), 2.37 (m, 3H), 1.78 (m, 2H), 1.64 (m, 4H), 1.36 (m, 3H) ppm
Example 52b; (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-( 3-(4-methylphenyl)-l-propyl)-4- methylazetιdιn-2-one
To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-methylphenyl)-2- propene-l-yl)-4-methylazetιdm-2-one (165 mg, 0.524 mmol) in 4 mL of methanol is treated with 20 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 72 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,4S)-l-(2-tetrahydropyranyloxy)-3-(3-(4-methylphenyl)-l-propyl)-4- methylazetιdm-2-one as an oil (160 mg, 96% yield). Η NMR (400 MHz, CDCI3) δ 7.04 (m, 4H), 5.16 (m, 0.5H), 4.96 (m, 0.5H), 4.16-3.96 (m,
2H), 3.58 (m, IH), 2.88 (m, IH), 2.62 (m, 2H), 2.28 (s, 3H), 1.82-1.44 (m, 10H), 1.22 (m, 3H) ppm.
Example 52c; (2R,3S)-2-(3-(4-methylphenyl)-l-propyl)-3-(2- tetrahydropyranyloxyamιno)butanoιc Acid To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-(3-(4-methylphenyl)-l- propyl)-4-methylazetιdιn-2-one (160 mg, 0.51 mmol) in dioxane (1.5 mL) is added 1 M aqueous sodium hydroxide (0.75 mL). The solution is stirred at 23 °C for 20 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4- methylphenyl)-l-propyl)-3-(2-tetrahydropyranyloxyamιno)butanoιc acid as an oil (114 mg, 67% yield). Η NMR (400 MHz, CDCI3) δ 7.04 (m, 4H), 4.94 (m, 0.5H). 4.84 (m, 0.5H), 3.95 (m. 0.5H),
3.86 (m, 0.5H), 3.57 (m, IH), 3.41 (m, 0.5H), 3.30 (m, 0.5H), 2.94 (m, 0.5H), 2.81 (m, 0.5H), 2.58 (m, 2H), 2.28 (s, 3H), 1.94-1.66 (m, 4H), 1.62-1.44 (m, 6H), 1.32 (m, IH), 1.10 (d, 1.5H), 1.04 (d, 1.5H) ppm. ESI-MS m/z 334.4 (M-H)".
Example 52d; (2R,35)-2-(3-(4-methylphenyl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (2R,35)-2-(3-(4-methylphenyl)-l-propyl)-3-(2- tetrahydropyranyloxyammo)butanoιc acid (114 mg, 0.34 mmol) in pyridme (2 mL) at 0 °C is added formic acetic anhydride ( 0.3 mL). The resulting solution is allowed to warm to 25 °C, stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-
(3-(4-methylphenyl)-l-propyl)-3-(formyl-2-tetrahydropyranyloxyamιno)butanoιc acid as an oil (120 mg, 97% yield). ESI-MS m z 386.3 (M+Na)\ ESI-MS m/z 362.4 (M-H)".
Example 52e; (2R.35)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(3-(4-methylphenyl)-l- propyl)butanoιc Acid [(15)-2,2-Dιmethyl-(l-methylcarbamoyl)-l-propyl]amιde
To a solution of (2R,35)-2-(3-(4-methylphenyl)-l-propyl)-3-(formyl-2- tetrahydropyranyloxyammo)butanoιc acid (60 mg, 0.165 mmol) in DMF (1 mL) is added BOP reagent (80 mg, 0.182 mmol), HOBt ( 25 mg, 0 182 mmol), and NMM (67 mg, 0.66 mmol). After 30 mm, addition of (2S)-2-Ammo-3,3-dιmethylbutanoιc acid methylamide (35 mg, 0.25 mmol) occurs and the resulting solution is stirred at 25 °C for 48 h. The reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochloπc acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,3S)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(3-(4-methylphenyl)- 1 -propyl)butanoιc acid [( 15)-2,2- dιmethyl-(l -methylcarbamoyl)- 1 -propyljamide as a white solid (55 mg, 68% yield). ESI-MS m z 512.3 (M -Na)+.
Example 52; (2R,35)-3-(Formylhydroxyammo)-2-(3-(4-methylphenyl)-l-propyl)butanoιc Acid [( 15)-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide
A solution of (2R,35)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(3-(4- methylphenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -methylcarbamoyl)- 1 - propyljamide (55 mg, 0.112 mmol) in acetic acid - water (4.1, 1 mL) is heated to 50 °C for 18 h. The reaction mixture is concentrated, then dissolved m toluene and concentrated in vacuo.
The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane - diethyl ether to provide (2R,35)-3-(Formylhydroxyamιno)-2-(3-(4- methylphenyl)- 1 -propyl)butanoιc acid [( 15)-2,2-dιmethyl-( 1 -methylcarbamoyl)- 1 - propyljamide as a white solid (31 mg, 68% yield). Η NMR (400 MHz, CD3OD) δ 8.25 and 7.98 (s, IH), 8.12 and 8.00 (m, IH), 6.98 (m, 4H),
4.48 and 3.82 (m, IH), 4.23 (d, IH), 2.84 and 2.76 (m, IH), 2.61 (m, 3H), 2.56 (m, IH), 2.42
(m, 2H), 2.23 (s, 3H), 1.43 (m, 4H), 1.24 and 1.18 (d, 3H), 0.98 (s, 9H) ppm.
ESI-MS m/z 428.2 (M+Na)+.
Anal. Calcd. for C22H35N304: C, 65.16; H, 8.70; N, 10.36. Found: C, 64.99; H, 8.60; N,
10.37.
Example 61; (2R,35)-3-(Formylhydroxyammo)-2-(5-phenyl-l-pentyl)butanoιc Acid [(15)- 2,2-Dιmefhyl-( 1 -methylcarbamoyl)- 1 -propyljamide
Figure imgf000101_0001
Example 61a; (3R,45)-l-(2-Tetrahydropyranyloxy)-3-((2E),(4E,Z)-3-phenyl-2,4-pentadιene- 1 -yl)-4-methylazetιdιn-2-one
To a solution of (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tπbutylstannyl-2- propene-l-yl)-4-methylazetιdιn-2-one (450 mg, 0.875 mmol) in 2 mL of dimethylformamide is added β-bromostyrene (212 mg, 1.05 mmol) and tπphenyphosphme palladium (II) dichloride (31 mg, 0.044 mmol). The resulting solution is heated at 80°C for 18 h, then 0.5 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted wit 1 : 1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3 : 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E),(4E/Z)-3-phenyl-2,4-pentadιene-l-yl)- 4-methylazetιdιn-2-one as an oil (140 mg, 49% yield).
Η NMR (400 MHz, CDCI3) δ 7.41-7.18 (m, 5H), 6.78-6.36 (m, 2H), 6.43 (m, IH), 6.22 (m,
IH), 5.83 (m, IH), 5.16 (m, 0.5H), 5.00 (m, 0.5H), 4.18-4.02 (m, 2H), 3.64 (m, IH), 3.04 (m, IH), 2.58 (m, IH), 2.36 (m, IH), 1.78 (m, 2H), 1.64 (m, 4H). 1.32 (m, 3H) ppm. ESI-MS m/z 350.3 (M+Na)+.
Example 61b; (3R,45)-l-(2-Tetrahydropyranyloxy)-3-(5-phenyl-l-pentyl)-4-methylazetιdιn- 2-one
To a solution of (3 ?,45)-l-(2-tetrahydropyranyloxy)-3-((2E),(4E/Z)-3-phenyl-2,4- pentadιene-l-yl)-4-methylazetιdιn-2-one (140 mg, 0.428 mmol) in 2 mL of methanol is treated with 14 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 18 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,AS)- 1 -(2-tetrahydropyranyloxy)-3 -(5 -phenyl- 1 -pentyl)-4-methylazetιdm-2-one as an oil (140 mg, 99% yield). Η NMR (400 MHz, CDCI3) δ 7.28 (m, 2H), 7.09 (m, 3H), 5.16 (m, 0.5H), 5.02 (m, 0.5H),
4.21-3.96 (m, 2H), 3.64 (m, IH), 2.94 (m, IH), 2.62 (m, 2H), 1.82-1.44 (m, 14H), 1.35 (m, 3H) ppm. ESI-MS m/z 354.3 (M+Na)+.
Example 61c; (2R,35)-2-(5-phenyl-l-pentyl)-3-(2-tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-(5-phenyl-l-pentyl)-4- methylazetιdιn-2-one (140 mg, 0.428 mmol) in dioxane (1.2 mL) is added 1 M aqueous sodium hydroxide (0.64 mL). The solution is stirred at 23 °C for 24 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(5-phenyl- l-pentyl)-3-(2-tetrahydropyranyloxyamιno)butanoιc acid as an oil (105 mg, 71% yield). Η NMR (400 MHz, CDCI3) δ 7.28 (m, 2H), 7.14 (m, 3H), 4.94 (m, 0.5H), 4.84 (m, 0.5H),
3.95 (m. 0.5H), 3.86 (m, 0.5H), 3.57 (m, IH), 3.41 (m, 0.5H), 3.30 (m, 0.5H), 2.90 ( , 0.5H), 2.78 (m, 0.5H), 2.58 (m, 2H), 1.94-1.66 (m, 4H), 1.62-1.44 (m, 6H), 1.32 (m, 5H), 1.10 (d, 1.5H), 1.04 (d, 1.5H) ppm. ESI-MS m/z 348.4 (M-H) .
Example 61d; (2R,35)-2-(5-phenyl-l-pentyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc Acid
To a solution of (2R,3S)-2-(5-phenyl-l-pentyl)-3-(2- tetrahydropyranyloxyamιno)butanoιc acid (105 mg, 0 30 mmol) in pyridme (1.5 mL) at 0 °C is added formic acetic anhydride ( 0.3 mL). The resulting solution is allowed to warm to 25
°C, stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved m ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloπc acid (20 mL) and saturated aqueous sodium chloride solution The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2- (5-phenyl-l-pentyl)-l-propyl)-3-(formyl-2-tetrahydropyranyloxyamιno)butanoιc acid as an oil (105 mg, 92% yield). ESI-MS m/z 400.3 (M+Na)+. ESI-MS m/z 376 4 (M-H)".
Example 61 e; (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyammo)-2-(5-phenyl-l- pentyl)butanoιc Acid [( 15)-2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide
To a solution of (2R,35)-2-(5-phenyl-l-pentyl)-3-(formyl-2- tetrahydropyranyloxyamιno)butanoιc acid (52 mg, 0.139 mmol) m DMF (1 mL) is added BOP reagent (67 mg, 0.153 mmol), HOBt ( 21 mg, 0.153 mmol), and NMM (42 mg, 0.42 mmol). After 30 mm, addition of (25)-2-Amιno-3,3-dιmethylbutanoιc acid methylamide (30 mg, 0.21 mmol) occurs and the resulting solution is stirred at 25 °C for 72 h. The reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,35)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(5-phenyl-l-pentyl)butanoιc acid [(15)-2,2-dιmethyl-(l- mefhylcarbamoyl)-l -propyljamide as a white solid (44 mg, 63% yield). ESI-MS m/z 526.3 (M+Na)+.
Example 61 ; (2R,35)-3-(Formylhydroxyammo)-2-(5-phenyl-l-pentyl)butanoιc Acid [(15)- 2,2-Dιmethyl-( 1 -methylcarbamoyl)- 1 -propyljamide A solution of (2R,35)-3-(Formyl-2-tetrahydropyranyloxyamιno)-2-(5-phenyl-l- pentyl)butanoιc acid [(15)-2,2-dιmethyl-(l-methylcarbamoyl)-l-propyl]amιde (44 mg, 0.087 mmol) in acetic acid - water (4: 1, 1 mL) is heated to 50 °C for 18 h. The reaction mixture is concenfrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is recrystalhzed from hot dichloromethane/methanol - diethyl ether to provide (2R,35)-3-(Formylhydroxyamιno)-2-(5- phenyl- 1 -pentyl)butanoιc acid [(15)-2,2-dιmethyl-(l -methylcarbamoyl)- 1 -propyljamide as a white solid (27 mg, 74% yield). 'H NMR (400 MHz, CD3OD) δ 8.25 and 7.98 (s, IH), 8.06 and 8.00 (m, IH), 7.21 (m, 2H),
7.08 (m, 3H), 4.48 and 3.82 (m, IH), 4.23 (d, IH), 2.80 and 2.72 (m, IH), 2.63 (m, 3H), 2.56 (m, 2H), 1.55 (m, 2H), 1.41 (m, 2H), 1.30-1.18 (m, 7H), 0.98 (s, 9H) ppm. ESI-MS m/z 442.4 (M+Na)+. Anal. Calcd. for C23H37N304: C, 65.98; H, 8.89; N, 10.02. Found: C, 65.84; H, 8.95; N, 9.95.
PHARMACOLOGY
The efficacy of compounds of the present invention as inhibitors of matrix metalloproteases, TNFα converting enzyme and TNFα cellular release can be evaluated and measured using pharmacological methods known in the art or as described m detail below based on similarly established methodologies.
Pharmacological Example 1
A. Matrix Metalloprotease Inhibition Protocol The potency of compounds of the invention as inhibitors of 19 kD truncated collagenase- 1 (MMP-1), 20 kD truncated collagenase-3 (MMP- 13), stromelysin- 1 (MMP-3), and 50 kD truncated gelatmase B (MMP-9) is determined according to the general procedure of Bickett et. al. (Anal Biochem. 1993. 272, 58-64) using the fluorogemc substrate, DNP-Pro- Cha-Gly-Cys(Me)-Hιs-Ala-Lys(NMA)-NH2 (DNP = 2,4-dιnιtrophenyl, NMA = N-
methylanthranihc acid). Assays are conducted in a total volume of 0.180 mL assay buffer (200 mM NaCl, 50 mM Tπs, 5 mM CaCl2, 10 μM ZnS04, 0.005% Bπj 35, pH=7.6) m each
well of a black 96 well microtiter plate. 19 kD collagenase- 1, 20 kD collagenase-3, stromelysin- 1 , and 50 kD gelatmase B concentrations are adjusted to 500 pM, 30 pM, 5 nM, and 100 pM, respectively. A dose response is generated using an eleven - point, 3 - fold serial dilution with initial starting test compound concentrations of 100, 10, or 1 μM. Inhibitor and enzyme reactions are incubated for 30 minutes at ambient temperature and then initiated with 10 μM fluorogemc substrate (above). The product formation is measured at Excιtatιon343/Emιssιon45o nm after 45-180 minutes using a Fluostar SLT fluorescence
analyzer. Percent inhibition is calculated at each inhibitor concentration and the data were plotted using standard curve fitting programs. Approximate IC50 values were determined from these curves. Assays were run at low substrate concentration ([S]«Km) such that the calculated IC50 values are equivalent to K, within experimental error.
B. TNFα Converting Enzyme Inhibition Protocol
The potency of compounds of the invention as inhibitors of cell - free tumor necrosis factor α converting enzyme is determined as follows: Membrane preparation from MonoMac 6 cells (subfractionated extract from equivalent of 6x106 cells per 60 μl assay) is incubated for 1 hr with 200 nM radiolabeled substrate (Bιotιn-SPLAQAVRSSSRT-(3H)P-S-NH2 , 4.1
Ci/mmol, ref # 0935 from Zeneca) m 10 mM hepes buffer, 250 mM sucrose, pH=7.5 The reaction is quenched by addition of streptavidin SPA beads (Amersham RPNQ0006), with excess binding capacity relative to substrate, suspended m 250 mM EDTA, pH=8.0. Binding is complete within 15 minutes and plates are counted m a Wallac 1450 Microbeta liquid scintillation counter Percent inhibition is calculated at each inhibitor concentration and the data were plotted using standard curve fitting programs. Approximate IC50 values were determined from these curves. Assays were run at low substrate concentration ([S]«Km) such that the calculated IC50 values are equivalent to K, within experimental error.
C. Cell - Based TNFα Release Inhibition Protocol
The potency of compounds of the invention as inhibitors of release of soluble tumor necrosis factor α from stimulated monocytes m vitro is determined as follows: LPS/PMA solution for assay consisting of a) 4 μL of 5 mg/mL LPS stock and b) 6 μL of 10 mg/mL PMA stock are added to 500 μL of medium (RPMI 1640 (Gibco) + 10% FBS + penicillin/streptomycin + 1-glutamιne). This solution is then diluted 1 : 1000 (40 ng/mL and 120 ng/mL) for use later in the assay. Compounds (10 mM) are serially diluted 1 :3 in DMSO. Compound dilutions (20 μL) are added to a sterile round bottom 96 well plate (20 μL:200 μL total volume = 1 : 10 for final concentrations of 50 μM for test compounds). MonoMac 6 cell suspension (130 μL, 1.5 xlO6 cells/mL) is then added to each well resulting in 2 x 105 cells/well. LPS/PMA (50 μL) solution is then added to each well to begin stimulation (final concentrations of 10 ng/mL and 30 ng/mL respectively). The plate is incubated at 37 °C for 2 hours then spun at 1 ,500 rpm for 3 minutes to pellet cells. The supernatant ( 120 μL/well) is removed to a new round bottom 96 well plate and diluted 1 : 10 m PBS. Then, 20 μL of the supernatant is transferred to a Cistron TNFα ELISA plate and processed according to the manufacturer's instructions to quantitate levels of TNFα. Percent inhibition of TNFα release is calculated at each inhibitor concentration and the data were plotted using standard curve fitting programs. Approximate IC^o values were determined from these curves.
Results are listed in Table 3.
Table 3
Example TNFα Collagenase- Collagenase- Gelatmase Stromelysm- TNFα Conver1 K, 3 K, B K, 1 K, Release ting Inhibition Enzyme IC50 K,
Example ++ ++++ +
1
Example nd
2
Example ++ +++ ++++ nd 3
Example ++ ++ +++++ +++ nd 9
Example + ++ ++++ ++ nd 20
Example ++ ++ +++++ ++++ +++ nd 24
Example ++ ++ ++++ ++++ +++ nd
52
Example + ++ ++++ +++ nd 61
+++++ 0.001 nM - 0.5 nM
Key; ++++ 0.5 nM - 5 nM
+++ 5 nM - 50 nM
++ 50 nM - 500 nM
+ > 500 nM nd not done
D. Evaluation in Xenograft in vivo Assays
Female NU/NU mice with a weight of 21 ± 2g are weighed and used. Control and test animals are injected subcutaneously m the axillary region with a suspension of 2 X 106 viable tumor cells in 200 uL in PBS + matπgel on day 0. Tumors are allowed to grow for 10 to 14 days prior to drug administration. Doses of test drug are given on a mg/kg basis according to the mean body weight for each cage. For each drug, two doses are used, 30 mg/kg and 90 mg/kg and are administered by p.o. route once a day over a 14 day time span. Tumor weight is calculated from two peφendicular cahper measurements of the tumor using the formula, tumor weight = length x wιdth2 ÷ 2 in millimeters. For each animal, tumor weight is monitored over the course of the experiment, and expressed as the percent of the tumor's weight. For each group, the mean increase in tumor weight over the course of the experiment is calculated (tumor weightday 50 - tumor weightday 14 = ≡ tumor weight) and the results expressed as percent inhibition of tumor growth with respect to the control group [1 - (≡ tumor weight treated group / (≡ tumor weight control group)] x 100. Results are presented in
Table 4. The criterion for antitumor activity is 25% inhibition of tumor growth after 2 weeks of dosmg (day 14).
Inhibition was scored as follows:
= 0-25% Inhibition + = 26-50% Inhibition ++ = 51 -75% Inhibition +-H- = 76-100 % Inhibition -I I M = >100%> Inhibition (Tumor Regression)
Table 4
Figure imgf000110_0001
While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled m the art will appreciate that vanous changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth herein above may be applicable as a consequence of variations m the responsiveness of the mammal being treated for inflammatory conditions, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical earners, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be inteφreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000112_0001
(i i) where R, is
A
where A, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
A2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR7R8, OR7, SR7, or hydrogen, where R7 and Rg are as defined below;
R2 is
Figure imgf000112_0002
where D, is alkylene, alkenylene, alkynylene, or a direct bond;
D2 is arylene, heteroarylene, or a direct bond;
D3 is aryl, heteroaryl, or heterocyclyl;
Y is alkylene, alkenylene, alkynylene, O, S, S(O), S02, NR9, Se, Si, C(O), P(0)OR9, P(0)R9, C(0)0, C(0)NR9, NR9C(0), OC(O), OC(0)0, NR9C(0)0, OC(0)NR9, NR9C(O)NR,0, or τ—τ2 where Ti and T2 are, independently, lower alkylene, lower alkenylene, lower alkynylene, O, S, S(O), S02, NR9, Se, Si, C(O), P(0)OR9, or P(0)R9, where R9 and R10 are as defined below; n = 0 or l;
R3 is hydrogen or lower alkyl;
^ is
where E, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
E2 is hydrogen, NR„R12, NRπS02R12, OR,,, SR„, S(0)Rπ, S02R„, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R,, and R,2 are as defined below;
R5 is hydrogen or lower alkyl;
Re is
zΓêæ
Figure imgf000114_0001
where
lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, or a direct bond;
Z2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR,3R,4, OR.3, SR,3. NR,3S02R14, NR,3C(0)R,4, C(0)NR,3, C(0)R,3, C(0)OR,3, OC(0)R,3, S(0)R,3, S02R13, S02NR,3R,4, (0(CH2)qO)mR,3 or hydrogen, where m, q, R,3 and R,4 are as defined below; R7, R8, R9, Rio, R11, R12, R13, and R,4 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl; and where m = 1-10 and q = 1-10 and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof
2. A compound of the formula:
Figure imgf000115_0001
(ll) where
R, is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 3-ammophenoxymethyl, 2-(3-tetrazolyl)-l-ethyl, 2-(3-pyndyl)-l- ethyl, 2-(3-furyl)-l -ethyl, 2-(2-thιazolyl)-l -ethyl, 3,3,3-tπfluoro-l-propyl, 2-(4- tπfluorophenyl)-l -ethyl, thιophene-3-ethynyl, 2-mtrophenoxymethyl, 3-mtrophenoxymethyl, 2-phenylsulfanylmethyl, tπfluoromethyl, tπchloromethyl, or vinyl,
R2 is 5 -methylthιophene-2 -methyl, 2-furanmethyl, thιophene-2-methyl, benzothιophene-2-methyl, benzofuran-2-methyl, 4-fluorobenzyl, 3-phenyl-l-propyl, 3- phenyl-2-methyl-l -propyl, 3 -(2-ρyπdyl)- 1 -propyl, 3-(thιophene-2-yl)-l -propyl, 4-phenyl-l- butyl, 3-phenyl-2-propene-l-yl, 3-(benzoflιran-3-yl)-l -propyl, 3-(benzothιophene-3-yl)-l- propyl, 3-(furan-2-yl)-l -propyl, 3-(2-thιazolyl)-l -propyl, 3-(pyπmιdιn-2-yl)-l -propyl, 3- phenyl-2-ethyl-l -propyl, 3-(3-pyπdyl)-l -propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l-propyl, 3- phenyl-1 -butyl, 3-phenyl-2-methyl-2-propene-l-yl, 4-phenyl-3-methyl-2-butyl, 4-(3- thιophenyl)-2-butyl, benzothιophene-3-methyl, benzoxazole-2-methyl, 4-(3-furyl)-2-butyl, 3- (4-chlorophenyl)-l -propyl, 3-(4-fluorophenyl)-l -propyl, 3-(4-tπfluoromethylphenyl)-l- propyl, benzyl, 5-phenyl-l-pentyl, 5-(4-chlorophenyl)-l-pentyl, 3-(4-methoxyphenyl)-l- propyl, 3 -(4-methylphenyl)- 1 -propyl, 3-(4-bιphenyl)-l -propyl, 3-(4'-fluoro-4-bιphenyl)-l- propyl, 3-(4'-chloro-4-bιphenyl)-l-propyl, 3-(4-phenoxyphenyl)-l -propyl, 3-(4'-chloro-4- phenoxyphenyl)-l -propyl, 3-(4'-fluoro-4-phenoxyphenyl)-l -propyl, 3-(4- thιophenoxyphenyl)-l -propyl, 3-(4'-chloro-4-thιophenoxyphenyl)-l -propyl, 3-(4'-fluoro-4- thiophenoxyphenyl)- 1 -propyl, 4-(4-tπfluoromethylphenyl)- 1 -butyl, 4-(4-chlorophenyl)- 1 - butyl, 4-(4-fluorophenyl)-l -butyl, 3-(4-(4-moφhohno)phenyl)-l -propyl, or 3-(4-(4- methylpιperazme)phenyl)- 1 -propyl,
R3 is hydrogen,
R» is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylammo)-l -butyl, 2-(2- (benzyloxycarbonylammo)-l-ethylsulfanyl)-2-propyl, 3-pyndylmethyl, , 4-(2- naphthylacetylammo)- 1 -butyl, 3-(benzyloxycarbonylammo)-l -propyl, 3-carbamoylammo-l- propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-(ιmmo-(2,3,6-tπmefhyl- 4-methoxybenzenesulfonylammo))-methylammo- 1 -propyl, 4- benzyloxycarbonylammobenzyl, isopropyl, cyclohexyl, 4-cyclopentylacetylammo-l -butyl, 4- (3-methoxybenzoylammo)- 1 -butyl, 4-ethoxycarbonylamιno- 1 -butyl, 2-(2- (ethoxycarbonylamιno)-l-ethylsulfanyl)-2-propyl, 2-butyl, 1 -methoxy- 1 -ethyl, 1 -hydroxy- 1- ethyl, isopropyl, 2-(methoxymethylamιnocarbonyl)-l -ethyl, 2-(4-ethoxycarbonyl-l- pιperazιnecarbonyl)-l -ethyl, 2-guamdinesulfonyl-l -ethyl, 2-methyl-4-(2- pyπdylcarbonylamιno)-2-butyl, 2-(methyl benzylaminocarbonyl)- 1 -ethyl, 2-(4- moφholmecarbonyl)- 1 -ethyl, 2-pyπdylcarbonylamιnomethyl, acetylaminomethyl, 1- ιsobutoxy-1 -ethyl, carbamoylammomethyl, dimethylammocarbonylmethyl, 2- dιmethylamιnosulfonyl-1 -ethyl, 2-methanesulfanyl-2-propyl, 2-hydroxy-2-propyl, 4-(2- pyπdylcarbonylammo- 1 -butyl, 2-(dιmethylamιnocarbonyl)- 1 -ethyl, 2-methanesulfonyl- 1 - ethyl, l-(2-pyπdylmethoxy)-l -ethyl, 1 -benzyloxy- 1 -ethyl, phenyl, 2-methyl-l -propyl, 3- (ιmιno-(2,2,5,7,8-pentamethylchroman-6-sulfonylamιno)methylamιno)-l-propyl, 2-phenyl-l - ethyl, l-(3-pyπdylmethoxy)-l -ethyl, 4-pyπdylmethyl, 4-methoxybenzyl, 3-ιndolemethyl, 2- mdolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2-phenyl-2-propyl;
R5 is hydrogen; and
R6 is methyl, 2-(l-pyrrolιdmo)-l -ethyl, 2-pyπdylmethyl, 3-pyπdylmethyl, 4- pyπdylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-(4-moφhohno)-l -ethyl, 3-(4- moφholmo)- 1 -propyl, 3-(4-methylpιperazme)- 1 -propyl, 2-(4-methylpιperazιne)- 1 -ethyl, 2-(2- pyπdyl)-l -ethyl, 2-(3-pyπdyl)-l -ethyl, 2-(4-pyπdyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tnfluoroethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
3. A compound of the formula:
Figure imgf000117_0001
(II) where Ri , R3,and R5 are as defined above in claim 2 and where R is 3-(th╬╣ophene-3-yl)-l-
propyl, 3-(4-pyπdyl)- 1 -propyl, or 3-(4-t-butylphenyl)- 1 -propyl, R4 is 1-methylbenzyl, benzyl , 3-phenylcarbonylamιno-l -propyl, 2,2-dιmethyl-l -propyl, 3-phenylcarbamoylammo-l -propyl, 4-pyπdylmethyl, 4- methoxybenzyl, 3-ιndolemethyl, 2-ιndolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2- phenyl-2-propyl; and Re is hydrogen, 2-(2-pyndyl)-l -ethyl, 2-(3-pyπdyl)-l -ethyl, 2-(4-pyπdyl)-l -ethyl, l-(2- amιnoethyl)-pιperazιne, 2-(4-ιmιdazolyl)-l-ethylamιne, 4-fluorobenzyl, 4-methoxybenzyl, 2,2-dιmethyl-l -propyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
A compound of the formula:
Figure imgf000118_0001
(ID where
R, is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 2-(3-tetrazolyl)-l-ethyl, 2-(3-pyπdyl)-l -ethyl, 2-(3-furyl)-l -ethyl, 3,3,3-tnfluoro-l-propyl, 2-(4-tπfluorophenyl)-l -ethyl, 2-phenylsulfanylmethyl, tπfluoromethyl, or tπchloromethyl;
R2 is 5-methylthιophene-2-methyl, 2-furanmethyl, thιophene-2-methyl, 4- fluorobenzyl, 3-phenyl-l-propyl, 3-phenyl-2-methyl-l -propyl, 3 -(2-pyndyl)- 1 -propyl, 3- (thιophene-2-yl)- 1 -propyl, 4-phenyl- 1 -butyl, 3-phenyl-2-propene- 1 -yl, 3-(furan-2-yl)- 1 - propyl, 3-(2-thιazolyl)-l -propyl, 3-(3-pyndyl)-l -propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l- propyl, benzothιophene-3-methyl, benzoxazole-2-methyl, 3-(4-chlorophenyl)-l -propyl, 3-(4- fluorophenyl)-l -propyl, 3-(4-tπfluoromethylphenyl)-l -propyl, benzyl, 5-phenyl-l-pentyl, 5- (4-chlorophenyl)-l-pentyl, 3-(4-methoxyphenyl)-l -propyl, 3 -(4-methylphenyl)- 1 -propyl, 3- (4-bιphenyl)- 1 -propyl, 3-(4'-fluoro-4-bιphenyl)- 1 -propyl, 3-(4'-chloro-4-bιphenyl)- 1 -propyl, 3-(4-phenoxyphenyl)-l -propyl, 3-(4'-chloro-4-phenoxyphenyl)-l -propyl, 3-(4'-fluoro-4- phenoxyphenyl)- 1 -propyl, 3-(4-thιophenoxyphenyl)- 1 -propyl, 4-(4-tπfluoromethylphenyl)- 1 - butyl, 4-(4-chlorophenyl)-l -butyl, 4-(4-fluorophenyl)-l -butyl, 3-(4-(4-moφholmo)phenyl)-l- propyl, or 3-(4-(4-methylpιperazιne)phenyl)-l-propyl;
R3 is hydrogen;
R4 is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylamιno)-l -butyl, 2-(2- (benzyloxycarbonylamιno)-l-ethylsulfanyl)-2-propyl, 3-pyndylmethyl, 4-(2- naphthylacetylammo)- 1 -butyl, 3-(benzyloxycarbonylamιno)- 1 -propyl, 3 -carbamoylammo- 1 - propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, isopropyl, cyclohexyl, 4- cyclopentylacetylamino- 1 -butyl, 4-(3-methoxybenzoylamιno)-l -butyl, 4- ethoxycarbonylam o- 1 -butyl, 2-(2-(ethoxycarbonylamιno)- 1 -ethylsulfanyl)-2-propyl, 2- butyl, 1 -methoxy- 1 -ethyl, 1 -hydroxy- 1 -ethyl, isopropyl, 2-(4-ethoxycarbonyl- 1- pιperazmecarbonyl)-l -ethyl, 2-(methyl benzylammocarbonyl)-l -ethyl, 2- pyridylcarbonylammomethyl, acetylammomethyl, 1 -isobutoxy- 1 -ethyl, carbamoylammomethyl, dimethylammocarbonylmethyl, 2-dιmethylamιnosulfonyl- 1 -ethyl, 2- methanesulfanyl-2-propyl, 2-hydroxy-2-propyl, 4-(2-pyπdylcarbonylamιno- 1 -butyl, 2- (dιmethylammocarbonyl)-l -ethyl, 2-methanesulfonyl-l -ethyl, l-(2-pyπdylmethoxy)-l -ethyl, 1-benzyloxy-l -ethyl, 2-phenyl-l -ethyl, l-(3-pyndylmethoxy)-l -ethyl, 4-pyndylmethyl, 4- methoxybenzyl, 3-mdolemethyl, 2-ιndolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2- phenyl-2-propyl;
R5 is hydrogen; and R(, is methyl, 2-( 1 -pyrrohdino)- 1 -ethyl, 2-pyπdylmethyl, 3-pyπdylmefhyl,
4- pyπdylmethyl, cyclopropyl, cyclopentyl, 2-(4-moφholmo)-l -ethyl, 3-(4-moφhohno)-l- propyl, 3-(4-methylpιperazme)-l -propyl, 2-(4-methylpιperazme)-l -ethyl, 2-(2-pyndyl)-l- ethyl, 2-(3-pyπdyl)-l -ethyl, 2-(4-pyπdyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tnfluoroethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
5. A compound of the formula:
Figure imgf000120_0001
(II) where Ri , R3,and R5 are as defined above claim 4 and where R2 is benzyl, 5-phenyl-l-
pentyl or 5-(4-chlorophenyl)-l-pentyl;
R4 is 1-methylbenzyl, benzyl, 2,2-dιmethyl-l -propyl, 4-pyπdylmethyl, 4-methoxybenzyl, 3- indolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3-naphthylmethyl, or 2-phenyl-2-propyl; and R6 is hydrogen, 2-(2 -pyridyl)- 1 -ethyl, 2-(3 -pyridyl)- 1 -ethyl, 2-(4-pyπdyl)- 1 -ethyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
6. A compound of the formula:
Figure imgf000121_0001
(II) where
R, is methyl, ethyl, n-propyl, isopropyl, or 3,3,3-trifluoro-l-propyl;
R2 is 3-phenyl-l-propyl, 3-(4-chlorophenyl)-l -propyl, 3-(4-fluorophenyl)-l -propyl, 3- (4-frifluoromethylphenyl)-l -propyl, or 3-(thiophene-2-yl)- 1 -propyl;
R3 is hydrogen;
R┬╗ is tert-butyl or 1-phenyl-l -ethyl;
R5 is hydrogen; and
R6 is methyl, 2-(l-pyrrolidino)-l -ethyl, 2-pyridylmethyl, 3-pyridylmethyl, or 4- pyridylmethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
7. A compound of the formula:
Figure imgf000122_0001
(II) where Ri , R3,and R5 are as defined above in claim 6 and where R2 is 3-(4-methylphenyl)-l-
propyl, 3-(4-phenoxyphenyl)-l-propyl,or 5-phenyl-l-pentyl; i is benzyl, 4-fluorobenzyl, 2-butyl, cyclohexyl, or isopropyl; and R is 2-(4-moφhohno)-l -ethyl, 3-(4-moφhohno)-l -propyl, tetraethyleneglycolyl methyl ether, 2-(2-pyπdyl)-l -ethyl, 2-(3 -pyridyl)- 1 -ethyl, or 2-(4-pyπdyl)-l -ethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
8. A compound of claim 1, wherein the compound is selected from the compounds listed in Table 1A.
9. A compound of claim 1, wherein the compound is selected from the compounds listed in Table IB.
10. A compound of claim 1, wherein the compound is selected from the compounds listed in Table 2A.
1 1. A compound of claim 1 , wherein the compound is selected from the compounds listed in Table 2B.
12. A compound of formula (II) as claimed in any one of claims 1 to 1 1 for use in therapy.
13. A pharmaceutical composition comprising a pharmaceutically acceptable earner and a pharmacologically effective amount of a compound as claimed in any one of claims 1 to l l.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the as claimed in any one of claims 1 to 1 1 sufficient to inhibit a matrix metalloprotease.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 11 sufficient to inhibit the cellular release of mature tumor necrosis factor alpha.
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 11 sufficient to inhibit the shedding of cell surface protein ectodomains.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 11 sufficient to inhibit CD23 proteolysis.
18. A pharmaceutical composition comprising a pharmaceutically acceptable earner and a pharmacologically effective amount of the compound as claimed m any one of claims 1 to 1 1, sufficient to cause a decrease in malignant growth.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 11, sufficient to treat arthritis.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 11, sufficient to treat diabetes.
21. A method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 11.
22. A method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to l l.
23. A method of inhibition of shedding of cell surface protein ectodomains, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 11.
24. A method of inhibition of CD23 proteolysis, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 11.
25. Use of a compound as claimed m any one of claims 1 to 11 m the preparation of a medicament for inhibiting the intracellular release of mature tumor necrosis factor alpha.
26. Use of a compound as claimed in any one of claims 1 to 11 m the preparation of a medicament for inhibiting a matrix metalloprotease.
27. Use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for inhibiting the shedding of cell surface protein ectodomains.
28. Use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for inhibiting CD23 proteolysis.
29. Use of a compound as claimed m any one of claims 1 to 11 in the preparation of a medicament for inhibiting the growth of tumor metastases.
30. Use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for treating arthritis.
31. Use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for treating diabetes.
PCT/US1999/019303 1998-08-26 1999-08-25 Formamides as therapeutic agents WO2000012083A1 (en)

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JP2000567200A JP2002523454A (en) 1998-08-26 1999-08-25 Formamides as therapeutic agents

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US60/097,956 1998-08-26
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