WO1998004537A1 - Novel compounds and compositions for treating diseases associated with tryptase activity - Google Patents

Novel compounds and compositions for treating diseases associated with tryptase activity Download PDF

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Publication number
WO1998004537A1
WO1998004537A1 PCT/US1997/013422 US9713422W WO9804537A1 WO 1998004537 A1 WO1998004537 A1 WO 1998004537A1 US 9713422 W US9713422 W US 9713422W WO 9804537 A1 WO9804537 A1 WO 9804537A1
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Prior art keywords
alkylene
compound
hetero
formula
piperazinecarboxylate
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PCT/US1997/013422
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French (fr)
Inventor
Jeffrey Mark Dener
Elaine Yee-Lin Kuo
Ken Duane Rice
Vivian Rueywen Wang
Wendy Beth Young
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Arris Pharmaceutical Corporation
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Priority to SK85-99A priority Critical patent/SK8599A3/en
Priority to NZ333713A priority patent/NZ333713A/en
Priority to AU39670/97A priority patent/AU733621B2/en
Priority to SI9720047A priority patent/SI9720047A/en
Application filed by Arris Pharmaceutical Corporation filed Critical Arris Pharmaceutical Corporation
Priority to CA002262542A priority patent/CA2262542A1/en
Priority to HU0003267A priority patent/HUP0003267A3/en
Priority to JP50913698A priority patent/JP2001509787A/en
Priority to EEP199900036A priority patent/EE9900036A/en
Priority to EP97937066A priority patent/EP0934293A1/en
Publication of WO1998004537A1 publication Critical patent/WO1998004537A1/en
Priority to FI990171A priority patent/FI990171A/en
Priority to NO990433A priority patent/NO990433L/en
Priority to LVP-99-27A priority patent/LV12291B/en
Priority to LVP-00-31A priority patent/LV12459B/en
Priority to LVP-00-30A priority patent/LV12458B/en

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    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
    • C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D233/14—Radicals substituted by oxygen atoms

Definitions

  • This invention relates to novel methods and compositions for treating diseases associated with tryptase activity by administration of novel tryptase inhibitors.
  • Tryptase the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316: 1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific .antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol.
  • allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface.
  • Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation
  • mast cells e.g., superoxide, lipid derived mediators, etc.
  • large molecules e.g., proteoglycans, tryptase, chymase, etc.
  • the release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens.
  • the early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure.
  • This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase.
  • inflammatory cells e.g., eosinophils, neutrophils, lymphocytes, etc.
  • the late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes. Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al.
  • tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides.
  • Tryptase cleaves fibrinogen ⁇ -chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant.
  • Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis.
  • tryptase inhibitor protects against development of the late and airway hyper responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6): 1966- 1970). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.
  • This application relates to a compound of Formula I:
  • X 5 is (C 3 . M )cycloalkylene, hetero(C 3 . I4 )cycloalkylene, (C 6 . M )arylene or hetero(C 5 . , 4 )ary lene ;
  • X 4 and X 6 are independently (C 0 . 2 )alkylene
  • X 1 and X 9 are independently a covalent bond, -C(O)-, -C(O)0-, -OC(O)-, -C(O)N(R 3 )-, -N(R 3 )C(O)-, -S(O) 2 N(R 3 )-, -N(R 3 )S(O) 2 -, -OC(O)N(R 3 )-, -N(R 3 )C(O)O-, -N(R 3 )C(O)N(R 3 )- or -OC(O)O-, wherein each R 3 is independently hydrogen, (C,. 3 )alkyl or (C 3 .
  • X 1 and X 9 are not both covalent bonds;
  • X 3 and X 7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 3 )-, -N(R 3 )C(O)-,
  • X 2 and X 8 are independently (C,. g )alkylene, hetero(C,. 8 )alkylene, -X 10 -X n - or -X"-X l ⁇ -, wherein X 10 is (C 0 _ 4 )alkylene or hetero(C 3 . 4 )alkylene and X" is (C 3 . 8 )cycloalkyIene or hetero(C 3 . g )cycloalkylene;
  • R 1 is R 4 -X 12 - or R 5 -X 13 -, wherein:
  • R 4 is amino, amidino, guanidino, 1-iminoethyl or methylamino
  • X 12 is (C 4 - 6 )alkylene, hetero(C 4 . 6 )alkylene, heterooxo(C 4 . 6 )a!kylene, oxo(C 4 . 6 )alkylene or -X ,4 -X ,5 -X 16 -, wherein X' 5 is (C 3 . 6 )cycloalkylene, hetero(C 5 . 6 )arylene, hetero(C 3 .
  • X 14 is (C n )alkylene and X 16 is (C nl6 )alkylene, wherein the sum of nl4 .and n!6 is 0, 1, 2, 3 or 4,
  • R 5 is a group selected from azetidin-3-yl, bcnzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazoIin-3-yl, 2-methylimidazoI-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-I-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l ,4,5,6-tetr.ahydropyrimidin-2-yl, l,4,5
  • X 13 is (C 0 . 6 )alkylene, hetero(C 2 . 6 )alkylene, heterooxo(C 3 . 6 )alkylene, oxo(C 2 . 6 )alkylene or -X l7 -X l8 -X' 9 -, wherein X 18 is as defined above for X 15 , X 17 is
  • X 20 is (C 4 . 6 )alkylene, hetero(C 4 _ 6 )alkylene, heterooxo(C 4 . 6 )alkylene, oxo(C 4 . 6 )alkylene or -X 22 -X 23 -X 24 -, wherein X 23 is as defined above for X 15 , X 22 is (C ⁇ 22 )alkylene and X 24 is (C n2 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R 8 is amino then X 22 is not (C 4 . 6 )alkylene or oxa(C 4 . 6 )alkylene and n22 is not 1, 2, 3 or 4, R 9 is as defined above for R 5 and
  • X 2 ' is (C 0 . 6 )alkylene, hetero(C 2 . 6 )alkylene, heterooxo(C 3 . 6 )alkylene, oxo(C 2 . 6 )alkylene or -X 25 -X 26 -X 27 -, wherein X 26 is as defined above for X 15 , X 25 is (C n25 )alkylene and X 27 is (C n27 )alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,. 8 )alkyl, (C 3 ., )cycloalkyl, (C 6 ., 4 )aryl,
  • a second aspect of this application relates to a compound of Formula I:
  • X 4 -X 5 -X 6 together are (C 2 . )2 )alkylene or hetero(C 3 ., 2 )alkylene; X 1 and X 9 are independently a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O) ⁇ (R 3 )-,
  • each R 3 is independently hydrogen, (C,. 3 )alkyl or (C 3 . 8 )cycloalkyl, with the proviso that X 1 and X 9 are not both covalent bonds;
  • X 3 and X 7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R 3 )-, -N(R 3 )C(O)-. -S(O) 2 N(R 3 )-, -N(R 3 )S(O) 2 -, -OC(O)N(R 3 )-, -N(R 3 )C(O)0-, -N(R 3 )C(O)N(R 3 )- or -OC(O)0-, wherein R 3 is as defined above; X 2 and X 8 are independently (C,. 8 )alkylene, hetero(C,.
  • R 4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino
  • X 12 is (C 4 . 6 )alkylene, hetero(C 4 . 6 )alkylene, heterooxo(C 4 . 6 )alkylene, oxo(C 4 . 6 )alkylene or -X l4 -X l5 -X 16 -, wherein X 15 is (C 3 . 6 )cycIoalkylene, hetero(C 5 . 6 )arylene, hetero(C 3 .
  • R 5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yI imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, l-methylpiperid-4-yI, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl,
  • X 13 is (C 0 . 6 )alkylene, hetero(C 2 . 6 )alkylene, heterooxo(C 3 . 6 )alkylene, oxo(C 2 . 6 )alkylene or -X 17 -X ,8 -X' 9 -, wherein X 18 is as defined above for X 15 , X ,7 is (C nl7 )alkylene and X 18 is (C n , 8 )alkylene, wherein the sum of nl7 and nl8 is 0, 1 or 2; and
  • R 2 is R 8 -X 20 - or R 9 -X 21 -, wherein:
  • R 8 is as defined above for R 4
  • X 20 is (C 4 . 6 )alkylene, hetero(C 4 . 6 )alkylene, heterooxo(C 4 . 6 )alkylene, oxo(C 4 . 6 )alkylene or -X 22 -X 23 -X 24 -, wherein X 23 is as defined above for X 15
  • X 22 is (C n22 )alkylene
  • X 24 is (C n24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4,
  • R 9 is as defined above for R 5 and
  • X 21 is (C 0 . 6 )alkylene, hetero(C 2 . 6 )alkylene, heterooxo(C 3 . 6 )alkylene, oxo(C 2 . 6 )alkylene or -X 25 -X 6 -X 27 -, wherein X 26 is as defined above for X 15 , X 25 is (C n25 )alkylene and X 27 is (C n27 )alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,. 8 )alkyl, (C 3 ., 4 )cycloalkyl, (C 6 ., 4 )aryl,
  • a third aspect of this invention is a pharmaceutical composition which contains a compound of Formula I, or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof in admixture with one or more suitable excipients.
  • a fourth aspect of this invention is a method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutical ly effective amount of compound of Formula I or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.
  • a fifth aspect of this invention is the processes for preparing compounds of Formula I and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof as set forth in "Detailed Description of the Invention".
  • Alkanoyl means the radical -C(O)R, wherein R is alkyl as defined below, having overall the number of carbon atoms indicated (e.g., (C,. 8 )alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.).
  • Alkyl as in alkyl, arylalkyl, alkyloxy, alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having the number of carbon atoms indicated (e.g., (C
  • Alkylene means a straight, saturated or unsaturated hydrocarbon divalent radical having the number of carbon atoms indicated (e.g., (C Intel. 6 )alkylene includes methylene (-CH 2 -), ethylene (-(CH 2 ) 2 -), vinylene (-CH:CH-), ethynylene (-C ; C-), 2-propylene (-CH:CH-CH 2 -), 1 -propylene (-CH 2 -CH:CH-), tetramethylene (-(CH 2 ) 4 -), pentamethylene (-(CH ) 5 -) and hexamethylene (-(CH 2 ) 6 -), etc.).
  • the term (C 0 )alkylene is meant to represent a covalent bond.
  • Alkyloxy means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,. 8 )alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.).
  • Alkylthio means the radical -SR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,. 8 )alkylthio includes the radicals methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.).
  • Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.).
  • Aryl as in aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein the carbon atom with the free valence is a member of an aromatic ring, and any carbocylic ketone or thioketone derivative thereof (e.g., (C 6 .
  • l4 )aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, l,2,3,4-tetrahydronaphth-5-yl, 1-oxo-l ,2-dihydronaphth-6-yl, 1 -thioxo-1 ,2-dihydronaphth-7-yl, etc.).
  • “Arylene” means an aromatic monocyclic or polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of an aromatic ring, and any carbocylic ketone or thioketone derivative thereof (e.g., (C 6 .
  • arylene includes 1 ,4-phenylene, 1,3 -phenyiene, 1 ,4-naphthylene, 2,6-naphthylene, 1 ,4-anthracenylene, 2,6-anthracenylene, 1 ,6-phenanthrenylene, 1 ,2,3,4-tetrahydro-5,8-naphthylene, 1 -oxo-1 ,2-dihydro-5,7-naphthylene, l-thioxo-l,2-dihydro-5,8-naphthylene, etc.).
  • Aryloxy means the radical -OR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C 6 .. 4 )aryloxy includes the radicals phenoxy, naphthyloxy, anthracenyloxy, etc.).
  • Arylthio means the radical -SR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C 6 . 14 )arylthio includes the radicals phenylthio, naphthylthio, anthracenylthio, etc.).
  • Cycloalkyl as in cycloalkyl and cycloalkyloxy, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated. wherein the carbon atom with the free valence is a member of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C 3 _ )4 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl.
  • Cycloalkylene means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C 3 .
  • cycloalkylene includes 1 ,2-cyclopropylene, 1 ,2-cyclobutylene, 1,3-cyclobutylene, 1 ,2-cyclopentylene, 1 ,3-cycIopentylene, 1 ,4-cyclopentylene, 1 ,4-cyclohexylene, 3-cyclohexen- 1 ,2-ylene, 2,5-cyclohexadien- 1 ,4-ylene, l,4-bicyclo[2.2.2]octylene, l,2,3,4-tetrahydro-l,4-naphthylene, 5-oxo-l,3-cyclohexylene, 2,5-dioxo- 1 ,4-cyclohexylene, 5-thioxo- 1 ,4-cyclohexylene, etc.).
  • Cycloalkyloxy means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C 3 . 14 )cycloalkyloxy includes the radicals cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.).
  • Cycloalkylthio means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C 3 . ]4 )cycloalkylthio includes the radicals cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.).
  • Deprotecting refers to removing any protective groups present after the selective reaction has been carried out.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
  • Halo means fluoro, chloro, bromo or iodo.
  • Heteroalkylene means alkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated is replaced by a heteroatom chosen from N, O or S (e.g., azaalkylene, oxaalkylene and thiaalkylene, respectively), with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms.
  • hetero(C 3 . I2 )alkylene is meant to encompass aza(C 3 )alkylene which includes 3-azatrimethylene (-NHCH 2 CH 2 -), 2-azatrimethylene (-CH 2 -NH-CH 2 -), etc.; ⁇ -aza(C 2 .
  • alkylene which includes 2-azaethylene (-NH-CH 2 -), 3-azatrimethylene, 4-azatetramethylene (-NH-CH 2 -CH 2 -CH 2 -) and 5-azapentamethylene (-NH-CH 2 -CH 2 -CH 2 -CH 2 -); oxa(C 3 )alkylene which includes as 3-oxatrimethylene (-O-CH 2 -CH 2 -), 2-oxatrimethylene (-CH 2 O-CH 2 -), etc.; oxa(C 5 )alkylene such as 3-oxapentamethylene (-CH 2 -CH 2 *CH 2 -CH 2 -), etc.; thia(C 3 )alkylene which includes 3-thiatrimethylene (-S-CH 2 -CH 2 -), 2-thiatrimethylene (-CH 2 -S-CH 2 -), etc.; ⁇ -thia(C 2 .
  • alkylene which includes 2-thiaethylene (-NH-CH 2 -), 3-thiatrimethylene and 4-thiatetramethylene (-S-CH 2 -CH 2 -CH 2 -); diaza(C 6 )alkylene which includes 2,5-diazahexamethylene (-CH 2 -NH-CH 2 -CH 2 -NH-CH 2 -); azaoxa(C 6 )alkylene which includes 2,-oxa-5-azahexamethylene (-CH 2 -O-CH 2 -CH 2 -NH-CH 2 -); and the like.
  • Heteroarylene means arylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, O or S (e.g., hetero(C 5 . 6 )arylene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.).
  • Heterocycloalkylene means cycloalkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, O, or S (e.g., hetero(C 3 ., 4 )cycloalkylene includes 2,4-pyrrolidinylene, 2,4-pyrrolinylene, 2,4-imidazolinylene, 2,4-imidazolinylene, 3,5-pyrazolinylene, 1 ,4-piperidylene,
  • heterooxo(C 4 . 6 )alkylene is meant to encompass azaoxo(C 3 )alkylene which includes 2-aza-3-oxotrimethylene (-C(O)-NH-CH-,-), 3-aza-2-oxotrimethylene (-NH-C(O)-CH 2 -), etc.; oxaoxo(C 3 )alkylene which includes 2-oxa-3-oxotrimethylene (-C(O)O-CH 2 -),
  • 3-oxa-2-oxotrimethylene (-O-C(O)-CH 2 -), etc.; and thiaoxo(C 3 )alkylene which includes 2-thia-3-oxotrimethylene (-C-(O)-S-CH 2 -), 3-thia-2-oxotrimethylene (-S-C(O)-CH 2 -), etc.
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy
  • “Pharmaceutically acceptable N-Oxide” means compound in which nitrogens are in an oxidized state (i.e., O- ⁇ ) which are pharmaceutically acceptable, as defined below, and which possess the desired pharmacological activity.
  • the N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • “Pathology” of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, /7-chlorobenzene-sulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, 1 ,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, o-(4-hydroxybenzoyl)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, me
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, trometha ine and the like.
  • Phenyiene means the divalent aromatic radical -C 6 H 4 - and includes 1 ,4-phenylene,
  • “Pharmaceutically acceptable prodrug derivatives” means derivatives of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I.
  • Such prodrugs include compounds of Formula I which have N-acylated piperidyl (i.e., ⁇ (P)C 5 H 9 -), N-acylated azaalkylene (e.g., - ⁇ (P)-CH 2 -CH 2 -), N-acylated amino (i.e., - ⁇ H 2 (P)), N-acylated amidino (i.e.,-C(NP)-NHP, -C(NH)-NHP or -C(NP)-NH 2 ), N-acylated guanidino (i.e., - ⁇ HC( ⁇ P)- ⁇ HP, -NH-C(NH)-NHP or -NH-C(NP)-NH 2 ) groups, in which P is
  • Protective group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
  • Protecting agent means an agent which will react with a multifunctional compound and create a protective group at a reactive site.
  • Protected derivatives in reference to a compound or a group means a derivative of compound or group in which a reactive site or sites are blocked with protective groups.
  • Protected derivatives of compounds of Formula I are in themselves active as tryptase inhibitors and are useful in the preparation of other compounds of Formula I.
  • Suitable protecting groups for reactive nitrogen atoms include /ert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).
  • Symptomatology of a disease means any morbid phenomenon or departure from the normal in structure, function or sensation experienced by the patient and indicative of the disease, their production and the indications they furnish.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Treating" or “treatment” of a disease includes preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display symptoms of the disease, inhibiting the disease (i.e., arresting its development) or relieving the disease (i.e., causing regression of the disease).
  • q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • the compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides and amidines.
  • acids, esters, amides and amidines are named in accordance IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides and amidines.
  • a divalent radical by written description the order of the number prefixes signifies the orientation of its attachment.
  • the way in which the formula is presented signifies the orientation of attachment.
  • X 4 and X 6 each are a covalent bond
  • X 5 is cw-l,5-cyclooctylene a .
  • nd P is hydrogen
  • X 4 is a covalent bond
  • X 6 is methylene
  • X 5 is phenyiene and P is hydrogen
  • 1 ,4-tetr.amethylene 4-.amidinobenzylcarbamoyl-l-piperazinecarboxylate when X 3 and X 7 are each is -C(O)O- and X 4 -X 5 -X 6 is 1 ,4-tetramethylene (i.e., -CH 2 -CH 2 -CH 2 -CH 2 -); and N-4-amidinobenzyl-4- ⁇ 5-[4-(2-piperid-4-ylaminoethylcarbamoyl)piperid-l-ylcarbonyl]valeryl ⁇ - 1 -piperazinecarboxamide when X 3 and X 7 are each is -C(O)- and X 4 -X 5 -X 6 is 1 ,4-tetramethylene (i.e., X 3 and X
  • preferred compounds of Formula I are those in which X 5 is cw-l,5-cyclooctyiene and X 4 and X 6 each are a covalent bond, X -X 5 -X 6 together are (C 4 .
  • X 5 is 1 ,4-phenylene and X 4 and X 6 are (C 0 .,)ethylene;
  • X 1 and X 9 are independently a covalent bond, -C(O)-, - ⁇ HC(O)-, -C(O)NH-, -N(CH 3 )C(O)- or -S(O) 2 NH-, with the proviso that X' and X 9 are not both covalent bonds;
  • X 3 and X 7 are independently -C(O)- or -C(O)O-;
  • X 2 and X 8 are independently -X'°-X"-, wherein X 10 is a covalent bond or methylene and X" is 4,1-piperidylene or 1 ,4-piperazinylene; R !
  • R 2 is R 8 -X 20 - or R 9 -X 21 -, wherein R 8 is amino, amidino, guanidino, methylamino or 1-iminoethyl
  • X 20 is -X 22 -X 23 -X 24 -, wherein X 23 is /n s-l ,4-cyclohexylene, 1 ,4-phenylene, 4,1- ⁇ yridylene, 1 ,4-piperidylene
  • X 22 is (C n22 )alkylene
  • X 24 is (C n24 )alkylene, wherein the sum of n22 and n24 is 1 or 2
  • R 9 is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-l-yl, 5-methylimid.azol-l-yl, l-methylpiperid-4-yl
  • More preferred compounds of Formula I are those in which X 5 is cw-l,5-cyclooctylene and X 4 and X 6 each are a covalent bond or X 4 -X 5 -X 6 together are (C 4 . 8 )alkylene; X 1 and X 9 are independently a covalent bond -C(O)-, -NHC(O)-, -C(O)NH- or -S(O) 2 NH-, with the proviso that X 1 and X 9 are not both covalent bonds; X 3 and X 7 are independently -C(O)- or -C(O)O-; X 2 and X 8 are independently -X'°-X n -, wherein X'° is a covalent bond or methylene and X" is 4,1-piperidylene or 1 ,4-piperazinylene; R 1 is R 4 -X 12 -, wherein R 4 is amidino or guanidino
  • Particularly preferred compounds of Formula I are those in which X 5 is cis-l ,5-cyclooctylene .and X 4 and X 6 each are a covalent bond; X 1 and X 9 are independently -C(O)- or - ⁇ HC(O)-; X 3 and X 7 each are -C(O)O-; X 2 and X 8 are independently -X' 0 -X"-, wherein X 10 is a covalent bond and X" is 1,4-piperazinylene; R' is R 4 -X 12 -, wherein R 4 is amidino or guanidino and X 12 is -X l4 -X l5 -X 16 -, wherein X 15 is 1 ,4-phenylene, X 14 is a covalent bond and X 16 is methylene; and R 2 is R 8 -X 20 - or R 9 -X 21 -, wherein R 8 is amino, X 20
  • Particularly preferred compounds of Formula 1 are those in which X 4 -X 5 -X 6 together are (C 4 . g )alkylene; X 1 and X 9 are independently -C(O)- or - ⁇ HC(O)-; X 3 and X 7 are independently -C(O)- or -C(O)O-; X 2 and X s each are -X l0 -X n -, wherein X'° is a covalent bond and X" is 1,4-piperazinylene; R 1 is R 4 -X 12 -, wherein R 4 is amidino or guanidino and X 12 is -X l4 -X l5 -X 16 -, wherein X 15 is 1 ,4-phenylene, X 14 is a covalent bond and X 16 is methylene; and R 2 is R 8 -X 20 -, wherein R 8 is amidino or guanidino and X 20 is
  • the compounds of this invention are tryptase inhibitors.
  • the compounds of Formula I are useful for treating diseases, particularly immunomediated inflammatory diseases in which tryptase activity contributes to the pathology and/or symptomatology of the disease.
  • immunomediated inflammatory diseases in which tryptase activity contributes to its pathology and/or symptomatology include asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis, inflammatory skin conditions, and the like.
  • Suitable in vitro assays for measuring tryptase activity and the inhibition thereof by compounds are known (e.g., see Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler
  • the assay will measures tryptase induced hydrolysis of peptide base substrate.
  • an in vitro assay for measuring tryptase activity see Example 33, infra.
  • Suitable in vivo models of inflammation are known to those of ordinary skill in the art.
  • compounds of Formula 1 will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of Formula I for the treatment of asthma may range from 0.1 micrograms per kilogram body weight ( ⁇ g/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 ⁇ g/kg/day to 0.1 mg/kg/day.
  • a therapeutically effective amount for a 80 kg asthmatic human patient may range from 10 ⁇ g/day to 10 mg/day, typically 0.1 mg/day to lO mg/day.
  • Therapeutic agents that may be useful for administration in combination with compounds of Formula I in treating asthma include ⁇ -adrenergic agonists (e.g., albuterol, terbutaline, formoterol, fenoterol, prenaline and the like), methylxanthines (e.g., caffeine, theophylline, aminophylline, theobromine and the like), cromoglycates (e.g., cromolyn, nedocromil, and the like) and corticosteroids (e.g., beclomethasome, triamcinolone, fiurisolide, dexamethasone and the like).
  • ⁇ -adrenergic agonists e.g., albuterol, terbutaline, formoterol, fenoterol, pren
  • compositions can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • Compressed gases may be used to disperse the active ingredient in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc.
  • Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso Remington's Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company.
  • a composition of a compound of Formula I for treating asthma will comprise from 0.0 l%w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients.
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • Representative pharmaceutical formulations containing a compound of Formula I arc described in Example 34.
  • the compounds of the invention are comprised of five distinct subunits (i.e., R'-, -X 2 -,
  • the subunits comprising the compounds of Formula I can be assembled individually or as larger combinations of subunits.
  • the following reaction schemes are representative methods for preparing compounds of Formula I. It is understood that the compounds of Formula 1 can be prepared by other analogous procedures.
  • R 2 -Y 9 -C(O)L or a protected derivative thereof, with a compound of the formula R 2 -Y 9 -C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y 9 is a bond, -O- or -N(R 3 )-, Y 8 is piperazin-1-yl, piperid-4-yl or HN(R 3 )-(C
  • X 4 , X 5 , X 6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary.
  • 1,4-piperidylene and X 9 is -NHC(O)- or in which X 8 is (C,. 8 )alkylene and X 9 is -NHC(O)N(R 3 )- can be prepared by reacting an appropriate compound of Formula 1. or a protected derivative thereof, with an isocyanate of the formula R 2 -NC(O), or a protected derivative thereof, and then deprotecting when necessary (for further details see Example 8, infra.).
  • X 1 is -C(O)N(R 3 )-, -OC(O)N(R 3 )- or -N(R )C(O)N(R 3 )- can be prepared by reacting a compound of Formula 2:
  • R 1 , R ⁇ R 3 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary.
  • R 1 equals R 2 ;
  • X 2 and/or X 8 is 1 ,4-piperazinylene or 1,4-piperidylene;
  • X 1 is -C(O)-, -OC(O)- or -N(R 3 )C(O)-;
  • X 9 is -C(O)-, -OC(O)- or -N(R 3 )C(O)- .and/or in which X 2 and/or X 8 is (C,.
  • X' is -C(O)N(R 3 )-, -OC(O)N(R 3 )- or -N(R 3 )C(O)N(R 3 )-; and X 9 -C(O)N(R 3 )-, -OC(O)N(R 3 )- or -N(R 3 )C(O)N(R 3 )- can be prepared by reacting a compound of Formula 3:
  • R'-Y'-C(O)L or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y 1 is a bond, -O- or -N(R 3 )-, Y 2 and Y 8 are independently piperazin- 1-yl, piperid-4-yl or HN(R 3 )-(C,. 8 )alkyl .and each R 1 , R ⁇ X 3 , X 4 , X 5 , X 6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary.
  • R 1 equals R 2 ;
  • X 2 and/or X 8 is 1 ,4-piper.azinylene or 1 ,4-piperidylene;
  • X 1 is -NHC(O)- and/or
  • X 9 is -NHC(O)- and/or in which X 2 and/or X 8 is (C,.
  • X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are as defined in the Summary of the Invention (for further details see
  • 4,1-piperidylene and X 3 and X 7 are independently -C(O)-, -C(O)O- or -C(O)N(R 3 )- or in which
  • X 2 and X 8 each are (C, .8 )alkylene or hetero(C-. 8 )alkylene and X 3 and X 7 are independently -N(R 3 )C(O)-, -N(R 3 )C(O)O- or -N(R 3 )C(O)N(R 3 )- can be prepared by reacting two or more molar equivalents of a compound of the formula R'-X'-Y 2 , or a protected derivative thereof, with a compound of Formula 6:
  • L is a leaving group
  • Y 3 and Y 7 are independently a bond, -O- or -N(R 3 )-
  • Y 2 is piperazin- 1-yl, piperid-4-yl, HN(R 3 )-(C,. 8 )alkyl or
  • acylation reactions described above can be carried out by reacting together an activated ester (e.g., an acid chloride derivative) and an appropriate nucleophile in the presence of a suitable organic base (e.g., N,N-diisopropylethylamine (DIEA), N-methylmorpholine, etc. preferably DIEA) and suitable solvent (e.g., N,N-dimethylform.amide (DMF), tetrahydrofuran
  • a suitable organic base e.g., N,N-diisopropylethylamine (DIEA), N-methylmorpholine, etc. preferably DIEA
  • suitable solvent e.g., N,N-dimethylform.amide (DMF), tetrahydrofuran
  • the acylation can be effected by reacting together an appropriate carboxylic acid and nucleophile in the presence of a suitable coupling reagent (e.g., l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc.) and a suitable solvent (e.g., DMF, etc.) at 20 to 30°C, typically at approximately 23 °C, for several minutes to 24 hours.
  • a suitable coupling reagent e.g., l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc.
  • a suitable solvent e.g., DMF, etc.
  • Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield.
  • a detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
  • the starting materials useful in preparing the compounds of Formula I and the intermediates useful in preparing the compounds of Formula I are commercially available or can be readily prepared by those of ordinary skill in the art.
  • intermediates useful in preparing the compounds of Formula I are conveniently prepared by the acylation reactions described above. When necessary suitable protection chemistry is employed to direct the reaction to the desired reactive site when multiple reactive sites are present in the starting materials.
  • a convenient starting material for preparing compounds of Formula I in which X 3 and X 7 each are -C(O)O- is a compound of Formula 7:
  • Compounds of Formula I in which R 4 is guanidino can be prepared by reacting a corresponding compound of Formula I in which R 4 is amino with cyanamide. The reaction is carried out by treating the amine with hydrogen chloride and then reacting neat with an excess of cyanamide at approximately 65 °C for about two hours (for further details see Example 15, infra.).
  • Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid.
  • the pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
  • the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form.
  • compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, etc.
  • Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • a suitable acid e.g., hydrochloric acid, etc.
  • the N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, /weta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0°C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, /weta-chloroperoxybenzoic acid, etc.
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as methylene chloride
  • Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, etc.
  • Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordin.ary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. 4: 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate,/j ⁇ r ⁇ -nitrophenyl carbonate, etc.).
  • a suitable carbamylating agent e.g., l,l-acyloxyalkylcarbonochloridate,/j ⁇ r ⁇ -nitrophenyl carbonate, etc.
  • Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley &
  • an aspect of this invention is a process for preparing compounds of Formula I, which process comprises: (a) reacting a compound of Formula 1 :
  • R 1 , R 2 , R 3 , X', X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I, in which X 8 is 1 ,4-piperazinylene or 1,4-piperidylene and X 9 is -C(O)-, -OC(O)- or -N(R 3 )C(O)- or in which X 8 is (C,. 8 )alkylene and X 9 is -C(O)N(R 3 )-, -OC(O)N(R 3 )- or -N(R 3 )C(O)N(R 3 )-;
  • 1,4-piperidylene and X 9 is -NHC(O)- or in which X 8 is (C,. 8 )alkylene and X 9 is -NHC(O)N(R 3 )-;
  • R 1 , R 2 , R 3 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 .and X 9 are as defined in the Summary of the Invention, .and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X 1 is -C(O)-, -OC(O)- or -N(R 3 )C(O)- or in which X 2 is (C,.
  • Y 2 and Y 8 are independently piperazin- 1 -yi, piperid-4-yl or HN(R 3 )-(C,. 8 )alkyl and each
  • R 1 , R 3 , X 3 , X 4 , X 5 , X 6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which R' equals R 2 ; X 2 and/or
  • X 8 is 1,4-piperazinylene or 1 ,4-piperidylene; X 1 is -C(O)-, -OC(O)- or -N(R 3 )C(O)-; and X 9 is
  • X 1 is -C(O)N(R 3 )-, -OC(O)N(R 3 )- or -N(R 3 )C(O)N(R 3 )-; and X 9 -C(O)N(R 3 )-, -OC(O)N(R 3 )- or
  • Y 1 is a bond, -O- or -N(R 3 )- and each R 1 , R 2 , R 3 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 .and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 1 is -N(R 3 )C(O)-, -N(R 3 )C(O)O- or -N(R 3 )C(O)N(R 3 )-;
  • X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1 ,4-piperazinylene or 4,1-piperidylene and X 3 is -C(O)-, -C(O)O- or -C(O)N(R 3 )- or in which X 2 is (C,. 8 )alkylene and
  • X 3 is -N(R 3 )C(O)-, -N(R 3 )C(O)O- or -N(R 3 )C(O)N(R 3 )-;
  • L is a leaving group
  • Y 3 and Y 7 are independently a bond, -O- or -N(R 3 )-
  • Y 2 is piperazin- 1-yl, piperid-4-yl, HN(R 3 )-(C,. 8 )alkyl or
  • X 2 and X 8 each are (C,. 8 )alkylene or hetero(C,. 8 )alkylene and X 3 and X 2 are independently -N(R 3 )C(O)-, -N(R 3 )C(O)O- or -N(R 3 )C(O)N(R 3 )-, respectively;
  • a reference to Formula I refers to such Formula wherein each R', R 2 , R ⁇ X', X 2 , X 3 , X 4 , X 5 , X 6 , X 7 X 8 and X 9 are as defined in their broadest definitions set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments. Examples:
  • Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to between 60 and 65 °C until the material completely melted and then /er/-butyl
  • 4-aminobenzylcarbamate hydrochloride (25.3 g, 97.8 mmol.), prepared as in Example 1 , was added directly to the liquid cyanamide giving a yellow solution. The solution was stirred 2 hours at between 60 and 65 °C and then water (100 mL) was added. The aqueous mixture was cooled to room temperature and washed with ethyl ether (1 L). The org.anic phase was back extracted with water (2x, 100 mL) and the combined aqueous layers were washed with ethyl ether (500 mL), cooled in an ice water bath and then basified with aqueous sodium hydroxide (10 M, 100 mL) giving an insoluble oil which slowly crystallized.
  • fer/-Butyl 4-guanidinobenzylcarbamate (41.77 g, 0.158 mol.), prepared as in Example 2, was treated with trifluoroacetic acid (TFA) (100 mL) for 30 minutes at room temperature.
  • TFA trifluoroacetic acid
  • the resulting nearly colorless liquid was concentrated in vacuo at 45 °C and the residue was triturated with ethyl ether (3x, 400 mL) and dried in vacuo to a colorless foam.
  • the residue was dissolved in methanol (200 mL) and then DIEA (55 mL, 0.32 mol, amount based on estimated excess TFA present) was added to the solution.
  • cis- 1 ,5-Cyclooctanediol (20.2 g, 0.14 mol.) was taken into acetonitrile (250 mL) and potassium carbonate (41.4 g, 0.3 mol.) was added to the mixture giving a suspension.
  • the suspension was cooled to 0°C under a nitrogen atmosphere and then phosgene (1.9M in toluene, 220 mL, 0.42 mol.) was added dropwise over one hour.
  • the suspension was warmed to room temperature and stirred 12 hours and then ether (1 L) was added.
  • the suspension was filtered free of insoluble salts and concentrated.
  • X' and X 9 each are -NHC(O)-
  • X 2 and X 8 each are 1 ,4-piperazinylene
  • X 3 and X 7 each are -C(O)O-
  • X 4 and X 6 each are a covalent bond
  • X 5 is cw-l,5-cyclooctylene. cis- 1 ,5-Cyclooctylene di(4-ter/-butoxycarbony 1- 1 -piperazinecarboxylate) (47.9 mg
  • terr-Butyl 4-aminomethyl-l -benzenecarbamate hydrochloride (3.39 g, 13.1 mmol), prepared as in Example 12, was taken into dichloromethane (120 mL) at 0°C and pyridine (4.3 mL, 53 mmol) and triphosgene (1.3 g, 4.4 mmol) was added. The mixture was allowed to warm to room temperature over 30 minutes and aqueous hydrochloric acid (0.5N, 100 mL) was added. The organic layer was dried (MgSO 4 ) and filtered.
  • R 2 is 3-imidazol-l-ylpropyl
  • X' and X 9 each are -NHC(O)-
  • X 2 and X 8 each are 1 ,4-piperazinylene
  • X 3 and X 7 each are -C(O)O-
  • X 4 and X 6 each are a covalent bond
  • X 5 is is- 1 , 5 -cycloocty lene .
  • the mixture was stirred under hydrogen (1 atm) for 17 hours at 23 °C.
  • the reaction mixture was placed under nitrogen and filtered.
  • 1,4-piperazinylene X 8 is 4,1-piperidylene, X 3 and X 7 each are -C(O)O-, X 4 and X 6 each are a covalent bond and X 5 is cw-l,5-cyclooctylene.
  • Triphosgene (30 mg, 0.10 mmol, 0.58 equiv) and pyridine (30 mL, 0.39 mmol, 2.1 equiv) were added to cw-l,5-cyclooctylene 1 -piperazinecarboxylate 4-[2-(l-/er/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l -piperidinecarboxylate (0.11 g, 0.18 mmol, 1.0 equiv), prepared as in Example 19, in dichloromethane (2 mL) at 0°C. The reaction mixture was stirred 3 hours at 0°C. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (Na 2 SO 4 ) and concentrated giving a brown oil residue.
  • 4-Piperazin- 1 -ylcarbonylmethylbenzamidine bis(trifluoroacetate) 80 mg; 0.17 mmol
  • DMF 1.0 mL
  • Tris buffer comprising: NaCl, 100 M; Tris, 50 mM; 2-[N-mo ⁇ holine]ethane sulfonic acid, 2.5 mM, CaCI 2 , 0.5 mM; DMSO, 10%; glycerol, 5%; polyoxyethylenesorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng/mL; and pH 8.2
  • Tris buffer comprising: NaCl, 100 M; Tris, 50 mM; 2-[N-mo ⁇ holine]ethane sulfonic acid, 2.5 mM, CaCI 2 , 0.5 mM; DMSO, 10%; glycerol, 5%; polyoxyethylenesorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng/mL; and pH 8.2
  • Allergic sheep characterized as dual responders i.e., displaying early and late phases of bronchoconstriction
  • antigen e.g., Ascaris suum
  • the sheep are administered test compound or vehicle by aerosol inhalation at 0.5 hours before .and at 4 and 24 hours post antigen challenge.
  • Specific lung resistance (SR L ) is monitored via an esophageal balloon catheter just prior to the first test compound or vehicle treatment and every 0.5 to 1 hour thereafter.
  • airway responsiveness is monitored 1 to 2 days prior to antigen challenge and just subsequent to administration of test compound or vehicle at 24 hours post antigen challenge.
  • airway responsiveness is defined as the cumulative dose of carbachol required to increase SR, by 400% (PC 400 ).
  • the PC 400 values are obtained by administering 0 to 30 breath units of 1% carbachol (10 mg in 1 mL of PBS) by aerosol inhalation until SR, was increased by 400%.
  • Sheep treated with vehicle exhibit early phase bronchoconstriction from 0 to 4 hours post antigen challenge and late phase bronchoconstriction from 4 to greater than 8 hours post antigen challenge.
  • vehicle treated sheep exhibit hyper responsiveness to carbachol (i.e., a 60% decrease in PC 400 is observed).
  • Sheep treated with tryptase inhibitors do not exhibit late phase broncoconstriction (i.e., at 4 to 8 hours post antigen challenge, SR L remained at basal levels). Further, sheep treated with tryptase inhibitors do not exhibit any hyper responsiveness to carbachol.

Abstract

The present invention relates to novel compounds which are typtase inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

Description

NOVEL COMPOUNDS AND COMPOSITIONS FOR TREATING DISEASES ASSOCIATED
WITH TRYPTASE ACTIVITY
This application claims the benefit of U.S. Provisional Application No. 60/023,139, filed
July 30, 1996.
Field of the Invention: This invention relates to novel methods and compositions for treating diseases associated with tryptase activity by administration of novel tryptase inhibitors.
Description of the Field: Tryptase, the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316: 1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific .antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol.
141 :563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase levels, a finding that provides some support for the hypothesis that release of proteinase from activated mast cells could contribute to lung destruction in smoker's emphysema. (Celenteron et al. (1988) Chest 94: 1 19-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Clin. Invest. 88:493-499). Asthma is recognized as an inflammatory disorder (Hood et al. (1984,)
In: Benjamin-Cummings, ed. Immunology 2nd ed.) and frequently is characterized by progressive development of hyper responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyper responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall. Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation
(e.g., superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.
The release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens. The early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes. Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al.
(1988) J Pharmacol. Exp. Ther. 248:947-951 ; and Tarn et al. (1990) Am. J. Respir. Cell Mol. Biol. 3:27-32) a . nd modulation of bronchial responsiveness to histamine (Sekizawa et al. (1989)
J. Clin. Invest. 83:175-179). These findings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase cleaves fibrinogen α-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, administration of tryptase inhibitor protects against development of the late and airway hyper responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6): 1966- 1970). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.
The disclosures of these and other documents referred to throughout this application are incoφorated herein by reference.
SUMMARY OF THE INVENTION
This application relates to a compound of Formula I:
R'-X'-X^X^X4
\
. X3
R2-X9-X8-X7-X6 '
in which:
X5 is (C3.M)cycloalkylene, hetero(C3.I4)cycloalkylene, (C6.M)arylene or hetero(C5. , 4)ary lene ;
X4 and X6 are independently (C0.2)alkylene;
X1 and X9 are independently a covalent bond, -C(O)-, -C(O)0-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyl, with the proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-,
-S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein R3 is as defined above; X2 and X8 are independently (C,.g)alkylene, hetero(C,.8)alkylene, -X10-Xn- or -X"-Xlϋ-, wherein X10 is (C0_4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkyIene or hetero(C3.g)cycloalkylene;
R1 is R4-X12- or R5-X13-, wherein:
R4 is amino, amidino, guanidino, 1-iminoethyl or methylamino, X12 is (C4-6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)a!kylene, oxo(C4.6)alkylene or -X,4-X,5-X16-, wherein X'5 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene, X14 is (Cn )alkylene and X16 is (Cnl6)alkylene, wherein the sum of nl4 .and n!6 is 0, 1, 2, 3 or 4,
R5 is a group selected from azetidin-3-yl, bcnzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazoIin-3-yl, 2-methylimidazoI-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-I-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l ,4,5,6-tetr.ahydropyrimidin-2-yl, l,4,5,6-tetrahydropyrimidin-4-yl and l,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.|4)cycloalkyl, (C6.14)aryl, (C6.]4)aryl(C )alkyl,
(C|.8)alkanoyl, (C..8)alkyloxy, (C6.I4)aryloxy, (C3.l4)cycIoalkyloxy, (C,.4)alkyloxy, (C,.8)alkylthio, (C3.l4)cycloalkyIthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.g)alkyl, (C].8)alkanoyl, (C3..4)cycloalkyl or
(C6.14)aryl and
X13 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -Xl7-Xl8-X'9-, wherein X18 is as defined above for X15, X17 is
(Cnι7)alkylene and X18 is (Cnl )alkylene, wherein the sum of n!7 and nl8 is 0, 1 or 2; and R2 is R8-X20- or R9-X21-, wherein: Rδ is amino, 1-iminoethyl or methylamino,
X20 is (C4.6)alkylene, hetero(C4_6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X15, X22 is (Cπ22)alkylene and X24 is (Cn2 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R8 is amino then X22 is not (C4.6)alkylene or oxa(C4.6)alkylene and n22 is not 1, 2, 3 or 4, R9 is as defined above for R5 and
X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3., )cycloalkyl, (C6.,4)aryl,
(C6-l4)aryl(Cι.4)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.14)cycloalkyloxy, (C|.4)alkyloxy, (C,.8)alkylthio, (C3.]4)cycloalkylthio, (C6.,4)arylthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R1, X2, X4, X6, Xs and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
A second aspect of this application relates to a compound of Formula I:
Figure imgf000007_0001
in which:
X4-X5-X6 together are (C2.)2)alkylene or hetero(C3.,2)alkylene; X1 and X9 are independently a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)Ν(R3)-,
-N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyl, with the proviso that X1 and X9 are not both covalent bonds;
X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-. -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)0-, wherein R3 is as defined above; X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)alkylene, -Xl0-X' '- or -X1 '-X'0-, wherein X10 is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene; R' is R -X12- or R5-X13-, wherein:
R4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino, X12 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -Xl4-Xl5-X16-, wherein X15 is (C3.6)cycIoalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene, X14 is (Cn]4)alkylene and X'ft is (C„|6)alkylene, wherein the sum of nl4 and nl 6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yI imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, l-methylpiperid-4-yI, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, l,4,5,6-tetrahydropyrimidin-4-yl and 1 ,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.,4)cycloalkyl, (C6.,4)aryl, (C6.14)aryl(C,.4)alkyl, (C--g)alkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.14)cycloalkyloxy, (C,.4)aIkyloxy,
(C,-8)alkylthio, (C3.,4)cycloalkylthio, (C6.l4)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.-4)cycloalkyl or (C6.14)aryl and
X13 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X17-X,8-X'9-, wherein X18 is as defined above for X15, X,7 is (Cnl7)alkylene and X18 is (Cn,8)alkylene, wherein the sum of nl7 and nl8 is 0, 1 or 2; and
R2 is R8-X20- or R9-X21-, wherein:
R8 is as defined above for R4, X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X15, X22 is (Cn22)alkylene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, R9 is as defined above for R5 and
X21 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X 6-X27-, wherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.,4)cycloalkyl, (C6.,4)aryl,
(C6.14)aryl(C,.4)alkyl, (C,.8)alkanoyl, (C,.8)aIkyloxy, (C6.14)aryloxy, (C3.14)cycloalkyloxy, (CM)alkyloxy, (C,.8)aIkylthio, (C3.l4)cycloalkylthio, (C6.l4)arylthio .and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R1, X2, X4, X6, X8 and R2 .and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
A third aspect of this invention is a pharmaceutical composition which contains a compound of Formula I, or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof in admixture with one or more suitable excipients.
A fourth aspect of this invention is a method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutical ly effective amount of compound of Formula I or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof. A fifth aspect of this invention is the processes for preparing compounds of Formula I and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof as set forth in "Detailed Description of the Invention".
DETAILED DESCRIPTION OF THE INVENTION
Definitions: Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: "Alkanoyl" means the radical -C(O)R, wherein R is alkyl as defined below, having overall the number of carbon atoms indicated (e.g., (C,.8)alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.). "Alkyl", as in alkyl, arylalkyl, alkyloxy, alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having the number of carbon atoms indicated (e.g., (C|.8)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, .sec-butyl, isobutyl, ter/-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.).
"Alkylene" means a straight, saturated or unsaturated hydrocarbon divalent radical having the number of carbon atoms indicated (e.g., (C„.6)alkylene includes methylene (-CH2-), ethylene (-(CH2)2-), vinylene (-CH:CH-), ethynylene (-C ; C-), 2-propylene (-CH:CH-CH2-), 1 -propylene (-CH2-CH:CH-), tetramethylene (-(CH2)4-), pentamethylene (-(CH )5-) and hexamethylene (-(CH2)6-), etc.). The term (C0)alkylene is meant to represent a covalent bond.
"Alkyloxy" means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,.8)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.).
"Alkylthio" means the radical -SR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,.8)alkylthio includes the radicals methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.).
"Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.). "Aryl", as in aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein the carbon atom with the free valence is a member of an aromatic ring, and any carbocylic ketone or thioketone derivative thereof (e.g., (C6.l4)aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, l,2,3,4-tetrahydronaphth-5-yl, 1-oxo-l ,2-dihydronaphth-6-yl, 1 -thioxo-1 ,2-dihydronaphth-7-yl, etc.). "Arylene" means an aromatic monocyclic or polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of an aromatic ring, and any carbocylic ketone or thioketone derivative thereof (e.g., (C6.14)arylene includes 1 ,4-phenylene, 1,3 -phenyiene, 1 ,4-naphthylene, 2,6-naphthylene, 1 ,4-anthracenylene, 2,6-anthracenylene, 1 ,6-phenanthrenylene, 1 ,2,3,4-tetrahydro-5,8-naphthylene, 1 -oxo-1 ,2-dihydro-5,7-naphthylene, l-thioxo-l,2-dihydro-5,8-naphthylene, etc.).
"Aryloxy" means the radical -OR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C6..4)aryloxy includes the radicals phenoxy, naphthyloxy, anthracenyloxy, etc.).
"Arylthio" means the radical -SR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C6.14)arylthio includes the radicals phenylthio, naphthylthio, anthracenylthio, etc.).
"Cycloalkyl", as in cycloalkyl and cycloalkyloxy, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated. wherein the carbon atom with the free valence is a member of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C3_)4)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl. bicyclo[2.2.2]octyl, 1 ,2,3,4-tetrahydronaphth-l -yl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).
"Cycloalkylene" means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C3.6)cycloalkylene includes 1 ,2-cyclopropylene, 1 ,2-cyclobutylene, 1,3-cyclobutylene, 1 ,2-cyclopentylene, 1 ,3-cycIopentylene, 1 ,4-cyclopentylene, 1 ,4-cyclohexylene, 3-cyclohexen- 1 ,2-ylene, 2,5-cyclohexadien- 1 ,4-ylene, l,4-bicyclo[2.2.2]octylene, l,2,3,4-tetrahydro-l,4-naphthylene, 5-oxo-l,3-cyclohexylene, 2,5-dioxo- 1 ,4-cyclohexylene, 5-thioxo- 1 ,4-cyclohexylene, etc.).
"Cycloalkyloxy" means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C3.14)cycloalkyloxy includes the radicals cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.). "Cycloalkylthio" means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C3.]4)cycloalkylthio includes the radicals cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.).
"Deprotecting" refers to removing any protective groups present after the selective reaction has been carried out. "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. "Halo" means fluoro, chloro, bromo or iodo.
"Heteroalkylene" means alkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated is replaced by a heteroatom chosen from N, O or S (e.g., azaalkylene, oxaalkylene and thiaalkylene, respectively), with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, hetero(C3.I2)alkylene is meant to encompass aza(C3)alkylene which includes 3-azatrimethylene (-NHCH2CH2-), 2-azatrimethylene (-CH2-NH-CH2-), etc.; ω-aza(C2.5)alkylene which includes 2-azaethylene (-NH-CH2-), 3-azatrimethylene, 4-azatetramethylene (-NH-CH2-CH2-CH2-) and 5-azapentamethylene (-NH-CH2-CH2-CH2-CH2-); oxa(C3)alkylene which includes as 3-oxatrimethylene (-O-CH2-CH2-), 2-oxatrimethylene (-CH2O-CH2-), etc.; oxa(C5)alkylene such as 3-oxapentamethylene (-CH2-CH2 *CH2-CH2-), etc.; thia(C3)alkylene which includes 3-thiatrimethylene (-S-CH2-CH2-), 2-thiatrimethylene (-CH2-S-CH2-), etc.; ω-thia(C2.4)alkylene which includes 2-thiaethylene (-NH-CH2-), 3-thiatrimethylene and 4-thiatetramethylene (-S-CH2-CH2-CH2-); diaza(C6)alkylene which includes 2,5-diazahexamethylene (-CH2-NH-CH2-CH2-NH-CH2-); azaoxa(C6)alkylene which includes 2,-oxa-5-azahexamethylene (-CH2-O-CH2-CH2-NH-CH2-); and the like.
"Heteroarylene" means arylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, O or S (e.g., hetero(C5.6)arylene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.).
"Heterocycloalkylene" means cycloalkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, O, or S (e.g., hetero(C3.,4)cycloalkylene includes 2,4-pyrrolidinylene, 2,4-pyrrolinylene, 2,4-imidazolinylene, 2,4-imidazolinylene, 3,5-pyrazolinylene, 1 ,4-piperidylene,
1 ,4-piperazinylene, 2,5-quinuclidinylene, 2,5-morpholinylene, 1.3-isoindolinylene, etc.). "Heterooxoalkylene" means alkylene, as defined above, wherein one of the number of carbon atoms indicated is replaced by a heteroatom chosen from N, O or S and a carbon atom adjacent to the heteroatom is replaced by a carbonyl group (C=O), e.g., azaoxoalkylene, oxaoxoalkylene and thiaoxoalkylene, respectively, with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, heterooxo(C4.6)alkylene is meant to encompass azaoxo(C3)alkylene which includes 2-aza-3-oxotrimethylene (-C(O)-NH-CH-,-), 3-aza-2-oxotrimethylene (-NH-C(O)-CH2-), etc.; oxaoxo(C3)alkylene which includes 2-oxa-3-oxotrimethylene (-C(O)O-CH2-),
3-oxa-2-oxotrimethylene (-O-C(O)-CH2-), etc.; and thiaoxo(C3)alkylene which includes 2-thia-3-oxotrimethylene (-C-(O)-S-CH2-), 3-thia-2-oxotrimethylene (-S-C(O)-CH2-), etc.
"Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy
(e.g., benzenesulfonyloxy .and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally substituted with one or more radicals" means that the group referred to may or may not be substituted in order to fall within the scope of the invention.
"Pharmaceutically acceptable N-Oxide" means compound in which nitrogens are in an oxidized state (i.e., O-Ν) which are pharmaceutically acceptable, as defined below, and which possess the desired pharmacological activity. The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. "Oxoalkylene" means alkylene, as defined above, wherein one of the number of carbon atoms indicated is replaced by a carbonyl group (C=O), e.g., oxo(C3)alkylene includes
3-oxotrimethylene (-C(O)-CH2-CH2-), etc.. "Pathology" of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salts" means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, /7-chlorobenzene-sulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, 1 ,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, o-(4-hydroxybenzoyl)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l -carboxylic acid), muconic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenyipropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid, /?-toluenesulfonic acid, trimethylacetic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, trometha ine and the like. "Phenyiene" means the divalent aromatic radical -C6H4- and includes 1 ,4-phenylene,
1,3 -phenyiene and the like.
"Pharmaceutically acceptable prodrug derivatives" means derivatives of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Such prodrugs include compounds of Formula I which have N-acylated piperidyl (i.e., Ν(P)C5H9-), N-acylated azaalkylene (e.g., -Ν(P)-CH2-CH2-), N-acylated amino (i.e., -ΝH2(P)), N-acylated amidino (i.e.,-C(NP)-NHP, -C(NH)-NHP or -C(NP)-NH2), N-acylated guanidino (i.e., -ΝHC(ΝP)-ΝHP, -NH-C(NH)-NHP or -NH-C(NP)-NH2) groups, in which P is a group selected from -C(O)R10, wherein R10 can be (CM0)alkyloxy or c .v-2-(CM0)alkanoyloxyphenylvinyl,
3-(C,.,0)alkanoyloxybutyryl, R"-X28-, wherein R" is carboxy and X28 is (C|-,0)alkylene or -C(O)-O-CH(R12)OC(O)R13, wherein R12 is hydrogen, (C 0)alkyl or (C3.10)cycloalkyl and R13 is (C 0)alkyl.
"Protective group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
"Protecting agent" means an agent which will react with a multifunctional compound and create a protective group at a reactive site.
"Protected derivatives" in reference to a compound or a group means a derivative of compound or group in which a reactive site or sites are blocked with protective groups. Protected derivatives of compounds of Formula I are in themselves active as tryptase inhibitors and are useful in the preparation of other compounds of Formula I. Suitable protecting groups for reactive nitrogen atoms include /ert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).
"Symptomatology" of a disease means any morbid phenomenon or departure from the normal in structure, function or sensation experienced by the patient and indicative of the disease, their production and the indications they furnish.
"Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
"Treating" or "treatment" of a disease includes preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display symptoms of the disease, inhibiting the disease ( i.e., arresting its development) or relieving the disease (i.e., causing regression of the disease).
The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%). The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides and amidines. Furthermore, for the purposes of this Application, when referring to a divalent radical by written description the order of the number prefixes signifies the orientation of its attachment. Similarly, when referring to a divalent radical by formula the way in which the formula is presented signifies the orientation of attachment. For example, a compound of Formula I in which R1 is 4-amidinobenzyl, X1 and X9 each are -NHC(O)-, X2 is 1 ,4-piperazinylene, X7 is -C(O)O-, X8 is 4,1-piperidylene and R2 is R9-X21, wherein R9 is piperid-4-yl and X21 is 3-azatrimethylene, is illustrated by the following formula:
Figure imgf000016_0001
which compound is named: c/'y-l,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-l-piperazinecarboxylate 4-(2-piperid-4-ylaminoethyIc.arbamoyl)-l -piperidinecarboxylate when X3 and X7 each are
-C(O)O-, X4 and X6 each are a covalent bond, X5 is cw-l,5-cyclooctylene a . nd P is hydrogen;
3-{4-[2-(l-{c/.y-5-[4-(4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyloxy]cyclooctyloxy- c;arbonyl}piperid-4-ylcarbonylamino)ethylamino]piperid-l-ylcarbonyl}propionic acid when X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond, X5 is cw-l,5-cyclooctylene and P is 3-carboxypropionyl; 4- [4-(4-amidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyljbenzy 1
4-(2-piperid-4-ylaminoethylcarbamoyl)-l-piperadinecarboxylate when X3 is -C(O)-, X7 is
-C(O)O-, X4 is a covalent bond, X6 is methylene, X5 is phenyiene and P is hydrogen; 1 ,4-tetr.amethylene 4-.amidinobenzylcarbamoyl-l-piperazinecarboxylate when X3 and X7 are each is -C(O)O- and X4-X5-X6 is 1 ,4-tetramethylene (i.e., -CH2-CH2-CH2-CH2-); and N-4-amidinobenzyl-4-{5-[4-(2-piperid-4-ylaminoethylcarbamoyl)piperid-l-ylcarbonyl]valeryl}- 1 -piperazinecarboxamide when X3 and X7 are each is -C(O)- and X4-X5-X6 is 1 ,4-tetramethylene (i.e., -CH2-CH2-CH2-CH2-).
Presently Preferred Embodiments:
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula I are preferred. For example, preferred compounds of Formula I are those in which X5 is cw-l,5-cyclooctyiene and X4 and X6 each are a covalent bond, X -X5-X6 together are (C4.8)alkylene or X5 is 1 ,4-phenylene and X4 and X6 are (C0.,)ethylene; X1 and X9 are independently a covalent bond, -C(O)-, -ΝHC(O)-, -C(O)NH-, -N(CH3)C(O)- or -S(O)2NH-, with the proviso that X' and X9 are not both covalent bonds; X3 and X7 are independently -C(O)- or -C(O)O-; X2 and X8 are independently -X'°-X"-, wherein X10 is a covalent bond or methylene and X" is 4,1-piperidylene or 1 ,4-piperazinylene; R! is R4-X12- or R5-X13-, wherein R4 is amidino, guanidino or methylamino, X12 is -Xl4-X15-X16-, wherein X15 is 1 ,4-phenylene or 1 ,4-piperidylene, X'4 is (C„ι4)alkylene and X16 is (Cn.6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2, R5 is piperid-4-yl and X13 is (C2.3)alkylene; and R2 is R8-X20- or R9-X21-, wherein R8 is amino, amidino, guanidino, methylamino or 1-iminoethyl, X20 is -X22-X23-X24-, wherein X23 is /n s-l ,4-cyclohexylene, 1 ,4-phenylene, 4,1-ρyridylene, 1 ,4-piperidylene, X22 is (Cn22)alkylene andX24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 1 or 2, R9 is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-l-yl, 5-methylimid.azol-l-yl, l-methylpiperid-4-yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yl or 1 ,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl and X21 is (C,.6)alkylene, ω-aza(C2.5)alkylene,
3-oxotrimethylene, ω-thia(C2.4)alkylene, 3-oxo-2-azatrimethylene, 3-aza-2-oxotrimethylene or -X25-X26-X27-, wherein X26 is 1 ,4-phenylene, X25 is (Cn25)alkylene and X24 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0 or 1 ; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
More preferred compounds of Formula I are those in which X5 is cw-l,5-cyclooctylene and X4 and X6 each are a covalent bond or X4-X5-X6 together are (C4.8)alkylene; X1 and X9 are independently a covalent bond -C(O)-, -NHC(O)-, -C(O)NH- or -S(O)2NH-, with the proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independently -C(O)- or -C(O)O-; X2 and X8 are independently -X'°-Xn-, wherein X'° is a covalent bond or methylene and X" is 4,1-piperidylene or 1 ,4-piperazinylene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X'2 is -X14-X,5-X16-, wherein X15 is 1 ,4-phenylene or 1 ,4-piperidylene, X14 is (Cnl4)alkylene and X'6 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2; and R2 is R8-X20- or R9-X21-, wherein R8 is amino or methylamino, X2ϋ is -X22-X23-X24-, wherein X23 is frα -l,4-cyclohexylene or 1 ,4-phenylene, X22 is (Cn22)alkylene and X16 is (Cn24)alkylene, wherein the sum of n22 and n24 is 1 or 2, R9 is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-yl or pyrid-4-yl and X21 is (C-_5)alkylene or 3-azatrimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula I are those in which X5 is cis-l ,5-cyclooctylene .and X4 and X6 each are a covalent bond; X1 and X9 are independently -C(O)- or -ΝHC(O)-; X3 and X7 each are -C(O)O-; X2 and X8 are independently -X'0-X"-, wherein X10 is a covalent bond and X" is 1,4-piperazinylene; R' is R4-X12-, wherein R4 is amidino or guanidino and X12 is -Xl4-Xl5-X16-, wherein X15 is 1 ,4-phenylene, X14 is a covalent bond and X16 is methylene; and R2 is R8-X20- or R9-X21-, wherein R8 is amino, X20 is -X22-X23-X24-, wherein X23 is trans- 1 ,4-cyclohexylene, X22 is a covalent bond and X24 is methylene, R9 is piperid-4-yl and X21 is ethylene or trimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula 1 are those in which X4-X5-X6 together are (C4.g)alkylene; X1 and X9 are independently -C(O)- or -ΝHC(O)-; X3 and X7 are independently -C(O)- or -C(O)O-; X2 and Xs each are -Xl0-Xn-, wherein X'° is a covalent bond and X" is 1,4-piperazinylene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X12 is -Xl4-Xl5-X16-, wherein X15 is 1 ,4-phenylene, X14 is a covalent bond and X16 is methylene; and R2 is R8-X20-, wherein R8 is amidino or guanidino and X20 is -X22-X23-X24-, wherein X23 is 1,4-phenylene, X22 is a covalent bond and X24 is methylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. Most preferred compounds of Formula I are the following:
4-guanidinobenzyl 4-{7-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]- heptanoyl } - 1 -piperazinecarboxamide ; 4-guanidinobenzyl 4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]octanoyl}- 1 -piperazinecarboxamide;
4-guanidinobenzyl 4- { 9-[4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonylj- nonanoyl } - 1 -piperazinecarboxamide; 4-amidinobenzyl
4-{7-[4-(4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]heptanoyl}- 1 -piperazinecarboxamide; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(2-piperid-4-y lethylcarbamoyl)- 1 -piperazinecarboxylate;
1 ,5-pentamethylene di[4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate]; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoy 1)- 1 -piperazinecarboxylate
4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; c«-l,5-cyclooctylene /rαrt5-4-(4-aminocyclohexylmethylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate; cis-\ ,5-cycIooctylene 4-(4-amidinophenylacetyI)-l -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; 1 ,4-tetramethylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate]; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -pipera. zinecarboxylate; 4-guanidinobenzyl
4- { 6- [4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyl]hexanoyl } - 1 -piperazinecarboxamide; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(4-piperid-4-ylbutyryI)- 1 -piperazinecarboxylate; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)- 1 -pipenazinecarboxylate; 4-guanidinobenzyl
4-{5-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]valeryl}- 1 -piperazinecarboxamide; 3-oxa-l,5-pentamethylene di[4-(4-guanidinophenylacetyl)piperazin-l-ylcarbonyl]; and cis- 1 ,5-cyclooctylene 4-(4-amidinophenylacetyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Pharmacology and Utility:
The compounds of this invention are tryptase inhibitors. As such the compounds of Formula I are useful for treating diseases, particularly immunomediated inflammatory diseases in which tryptase activity contributes to the pathology and/or symptomatology of the disease. For example, immunomediated inflammatory diseases in which tryptase activity contributes to its pathology and/or symptomatology include asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis, inflammatory skin conditions, and the like.
Suitable in vitro assays for measuring tryptase activity and the inhibition thereof by compounds are known (e.g., see Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler
373:1025-1030). Typically, the assay will measures tryptase induced hydrolysis of peptide base substrate. For further details of an in vitro assay for measuring tryptase activity see Example 33, infra.
Suitable in vivo models of inflammation are known to those of ordinary skill in the art.
For example, in vivo models for asthma are known (e.g., see Larsen (1991) Experimental Models of Reversible Airway Obstruction. In: West et al., eds. The Lung: Scientific Foundations Raven
Press, New York). For further details of an in vitro model of asthma see Example 2, infra.
Further, in vivo models of inflammatory skin conditions (Walsh et al. (1995) Br. J. Pharmacol. 114: 1343-1350; .and Armstrong et al. (1995) Prostaglandins 49: 205-224), arthritic conditions (Peacock et al. (1995) Cell Immunol. 160: 178-184; and Houri et al. (1995) Curr. Opin. Rheumatol. 7: 201-205) and gastrointestinal diseases (Anthony et al. (1995) Int. . Exp. Pathol. 76: 215-224.; .and Carter et al. (1995) Dig. Dis.Sci. 40: 192-197) are known. For further details of an in vivo assay for measuring asthmatic responses see Example 34, infra.
Administration and Pharmaceutical Compositions:
In general, compounds of Formula 1 will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I for the treatment of asthma may range from 0.1 micrograms per kilogram body weight (μg/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 μg/kg/day to 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg asthmatic human patient may range from 10 μg/day to 10 mg/day, typically 0.1 mg/day to lO mg/day. Therapeutic agents that may be useful for administration in combination with compounds of Formula I in treating asthma include β-adrenergic agonists (e.g., albuterol, terbutaline, formoterol, fenoterol, prenaline and the like), methylxanthines (e.g., caffeine, theophylline, aminophylline, theobromine and the like), cromoglycates (e.g., cromolyn, nedocromil, and the like) and corticosteroids (e.g., beclomethasome, triamcinolone, fiurisolide, dexamethasone and the like). In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given inflammatory disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
Compressed gases may be used to disperse the active ingredient in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc. Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso Remington's Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating asthma will comprise from 0.0 l%w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I arc described in Example 34.
Chemistry: The compounds of the invention are comprised of five distinct subunits (i.e., R'-, -X2-,
-X4-X5-X6-, -X8- and R2-) which subunits are connected via carbonyl, formyloxy, amide, sulfonamide, carbamate or urea linkages (i.e., -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-). Methods for forming such linking groups are known and suitable reagents are readily available (e.g., see, March, Advanced Organic Chemistry, 4th Ed. (Wiley 1992); Larock, Comprehensive Organic Transformations (VCH 1989); and Furniss et al., Vogel 's Textbook of Practical Organic Chemistry, 5th Ed.. (Longman 1989).
The subunits comprising the compounds of Formula I can be assembled individually or as larger combinations of subunits. The following reaction schemes are representative methods for preparing compounds of Formula I. It is understood that the compounds of Formula 1 can be prepared by other analogous procedures.
Compounds of Formula I in which X8 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X9 is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X8 is (C,.8)alkylene and X9 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)- can be prepared by reacting a compound of Formula 1 :
R'-X'-X2-X3-X4
\
Y8-X7-X6 '
or a protected derivative thereof, with a compound of the formula R2-Y9-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y9 is a bond, -O- or -N(R3)-, Y8 is piperazin-1-yl, piperid-4-yl or HN(R3)-(C|.8)alkyl, respectively, and each R1, R2, R\ X!, X2, X3,
X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary. Alternatively, compounds of Formula I in which X8 is 1 ,4-piperazinylene or
1,4-piperidylene and X9 is -NHC(O)- or in which X8 is (C,.8)alkylene and X9 is -NHC(O)N(R3)- can be prepared by reacting an appropriate compound of Formula 1. or a protected derivative thereof, with an isocyanate of the formula R2-NC(O), or a protected derivative thereof, and then deprotecting when necessary (for further details see Example 8, infra.).
In an analogous fashion, compounds of Formula I in which X2 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X' is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X2 is (C,.8)alkylene and
X1 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R )C(O)N(R3)- can be prepared by reacting a compound of Formula 2:
Y2-X3-X4
R2-X9-X8-X7-X6 ' or a protected derivative thereof, with a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y1 is a bond, -O- or -N(R3)-, Y2 is piperazin- 1 -yl, ρiperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R1, R\ R3, X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary. Alternatively, compounds of Formula I in which X2 is 1 ,4-piperazinylene or 1,4-piperidylene and X1 is -NHC(O)- or in which X2 is (C,.s)alkylene and X1 is -NHC(O)N(R3)- can be prep.ared by reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary (for further details see Example 14(b), infra.).
Compounds of Formula I in which R1 equals R2; X2 and/or X8 is 1 ,4-piperazinylene or 1,4-piperidylene; X1 is -C(O)-, -OC(O)- or -N(R3)C(O)-; and X9 is -C(O)-, -OC(O)- or -N(R3)C(O)- .and/or in which X2 and/or X8 is (C,.8)alkylene; X' is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-; and X9 -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)- can be prepared by reacting a compound of Formula 3:
Figure imgf000025_0001
or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y1 is a bond, -O- or -N(R3)-, Y2 and Y8 are independently piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl .and each R1, R\ X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary. Alternatively, compounds of Formula I in which R1 equals R2; X2 and/or X8 is 1 ,4-piper.azinylene or 1 ,4-piperidylene; X1 is -NHC(O)- and/or X9 is -NHC(O)- and/or in which X2 and/or X8 is (C,.8)alkylene and X1 is -NHC(O)N(R3)- and/or X9 is -NHC(O)N(R3)- can be prepared by reacting a compound of Formula 3, or a protected derivative thereof, with two or more molar equivalents of an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary (for further details see Ex∑imple 10, infra.).
Compounds of Formula I in which X1 is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)- can be prepared by reacting an amine of the formula R'-N(R3)H, or a protected derivative thereof, with a compound of Formula 4:
Figure imgf000026_0001
or a protected derivative, wherein L is a leaving group, Y1 is a bond, -O- or -N(R3)- and each R1, R2, R3, X2, X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention (for further details see Example 20, infra.). Compounds of Formula I in which X2 is 1 ,4-piperazinylene or 4,1-piperidylene and X3 is
-C(O)-, -C(O)O- or -C(O)N(R3)- or in which X2 is (C,.8)alkylenc and X3 is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)- can be prepared by reacting a compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 5:
Figure imgf000026_0002
or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)aIkyl, respectively, and each R1, R2, R3, X1, X2, X3,
X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention (for further details see
Example 31, infra.). Compounds of Formula I in which X2 and X8 each are 1 ,4-piperazinylene or
4,1-piperidylene and X3 and X7 are independently -C(O)-, -C(O)O- or -C(O)N(R3)- or in which
X2 and X8each are (C,.8)alkylene or hetero(C-.8)alkylene and X3 and X7 are independently -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)- can be prepared by reacting two or more molar equivalents of a compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 6:
LC(0)-Y3-X4
LC(0)Y7-X6
or a protected derivative thereof, wherein L is a leaving group, Y3 and Y7 are independently a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl, HN(R3)-(C,.8)alkyl or
HN(R3)-hetero(C,-8)alkyl, respectively, and each R1, X', X4, X5 and X6 are as defined in the
Summary of the Invention (for further details see Example 32, infra.). The acylation reactions described above can be carried out by reacting together an activated ester (e.g., an acid chloride derivative) and an appropriate nucleophile in the presence of a suitable organic base (e.g., N,N-diisopropylethylamine (DIEA), N-methylmorpholine, etc. preferably DIEA) and suitable solvent (e.g., N,N-dimethylform.amide (DMF), tetrahydrofuran
(THF), dichloromethane, etc.) at 20 to 30°C, typically at approximately 23 °C, for several minutes to 24 hours. Alternatively, the acylation can be effected by reacting together an appropriate carboxylic acid and nucleophile in the presence of a suitable coupling reagent (e.g., l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc.) and a suitable solvent (e.g., DMF, etc.) at
20 to 30°C, typically at approximately 23 °C, for several hours to several days. The reactions described above for the preparation of compounds of Formula I and the conditions for effecting the reactions are illustrative and one of ordinary skill in the art will recognize that other reaction conditions can be applied and different starting materials can be used to prepare the compounds of the invention.
Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. Generally, the starting materials useful in preparing the compounds of Formula I and the intermediates useful in preparing the compounds of Formula I are commercially available or can be readily prepared by those of ordinary skill in the art. For example, intermediates useful in preparing the compounds of Formula I are conveniently prepared by the acylation reactions described above. When necessary suitable protection chemistry is employed to direct the reaction to the desired reactive site when multiple reactive sites are present in the starting materials.
A convenient starting material for preparing compounds of Formula I in which X3 and X7 each are -C(O)O- is a compound of Formula 7:
Figure imgf000028_0001
in which each X4, X5 and X6 are as defined in the Summary of the Invention. For example, compounds of Formula 6 in which L is chloro can be prepared by reacting a corresponding diol
(e.g., cis-l,5-cyclooctanediol, tr.ans-l .4-cyclohexylendimeth.anol, 1,4-phenylenedimethanol, etc.) with triphosgene (for further details see Example 5, infra.). Intermediates useful in preparing compounds of Formula I in which such intermediate contains a amidino group can be prepared by treating a corresponding nitrile with hydrogen chloride in ethanol and then reacting with ammonia.
Additional Processes for Preparing Compounds of Formula I:
Compounds of Formula I in which R4 is guanidino can be prepared by reacting a corresponding compound of Formula I in which R4 is amino with cyanamide. The reaction is carried out by treating the amine with hydrogen chloride and then reacting neat with an excess of cyanamide at approximately 65 °C for about two hours (for further details see Example 15, infra.). Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
Alternatively, the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates. The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc). The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, /weta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0°C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordin.ary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. 4: 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate,/jαrø-nitrophenyl carbonate, etc.). Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
In summary, an aspect of this invention is a process for preparing compounds of Formula I, which process comprises: (a) reacting a compound of Formula 1 :
R'-X'-X2-X3-X4
\
. X5
Y8-X7-X6 '
or a protected derivative thereof, with a compound of the formula R2-Y9-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y9 is a bond, -O- or -N(R3)-, Y8 is piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R1, R2, R3, X', X2, X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I, in which X8 is 1 ,4-piperazinylene or 1,4-piperidylene and X9 is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X8 is (C,.8)alkylene and X9 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-;
(b) reacting a compound of Formula 1 , or a protected derivative thereof, with an isocyanate of the formula R2-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X8 is 1 ,4-piperazinylene or
1,4-piperidylene and X9 is -NHC(O)- or in which X8 is (C,.8)alkylene and X9 is -NHC(O)N(R3)-;
(c) reacting a compound of Formula 2:
γ2-χ3-χ4
R2-X9-X8-X7-X6 ^ or a protected derivative thereof, with a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y1 is a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R1, R2, R3, X3, X4, X5, X6, X7, X8 .and X9 are as defined in the Summary of the Invention, .and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X1 is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X2 is (C,.8)alkylene and X1 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R )C(O)N(R3)-; (d) reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula R'-NC(O), or a protected derivative thereof, .and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 1,4-piperidylene and X1 is -NHC(O)- or in which X2 is (C,.8)alkylenc .and X1 is -NHC(O)N(R3)-; (e) reacting a compound of Formula 3:
Y2-X3-X4
\
Y8-X7-X6'
or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R1-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, -O- or
-N(R3)-, Y2 and Y8 are independently piperazin- 1 -yi, piperid-4-yl or HN(R3)-(C,.8)alkyl and each
R1, R3, X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which R' equals R2; X2 and/or
X8 is 1,4-piperazinylene or 1 ,4-piperidylene; X1 is -C(O)-, -OC(O)- or -N(R3)C(O)-; and X9 is
-C(O)-, -OC(O)- or -N(R3)C(O)- and/or in which X2 and/or X8 is (C,.8)alkylene; X1 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-; and X9 -C(O)N(R3)-, -OC(O)N(R3)- or
-N(R3)C(O)N(R3)-;
(f) reacting a compound of Formula 3, or a protected derivative thereof, with two or more molar equivalents of an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necess-ary, to give a compound of Formula I in which R1 equals R2; X2 and/or X8 is 1 ,4-piperazinylene or 1,4-piperidylene; X1 is -NHC(O)- and/or X9 is -NHC(O)- and/or in which X2 and/or X8 is (C,.8)alkylene and X1 is -NHC(O)N(R3)- and/or X9 is -NHC(O)N(R3)-;
(g) reacting an amine of the formula R'-N(R3)H, or a protected derivative thereof, with a compound Formula 4:
Figure imgf000032_0001
or a protected derivative thereof, wherein L is a leaving group, Y1 is a bond, -O- or -N(R3)- and each R1, R2, R3, X2, X3, X4, X5, X6, X7, X8 .and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X1 is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)-;
(h) reacting a compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 5 :
Figure imgf000032_0002
or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R1, R2, R3, X', X2, X\
X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 4,1-piperidylene and X3 is -C(O)-, -C(O)O- or -C(O)N(R3)- or in which X2 is (C,.8)alkylene and
X3 is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)-;
(i) reacting 2 or more molar equivalents of compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 6:
Figure imgf000033_0001
or a protected derivative thereof, wherein L is a leaving group, Y3 and Y7 are independently a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl, HN(R3)-(C,.8)alkyl or
HN(R3)-hetero(Ct.8)alkyl and each R1, X1, X4, X5 and X6 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 and X8 each are 1 ,4-piperazinylene or 4, 1 -piperidylenc and X3 and X7 are independently -C(O)-,
-C(O)O- or -C(O)N(R3)- or in which X2 and X8 each are (C,.8)alkylene or hetero(C,.8)alkylene and X3 and X2 are independently -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)-, respectively;
(j) optionally reacting a compound of Formula I in which R4 is amino with cyanamide to give a compound of Formula I in which R4 is guanidino; (k) optionally further converting a compound of Formula I into a pharmaceutically acceptable salt;
(1) optionally further converting a salt form of a compound of Formula I to non-salt form; (m) optionally further converting -an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(n) optionally further an N-oxide form of a compound of Formula I its unoxidized form; (o) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(p) optionally further converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
In any of the above processes, a reference to Formula I refers to such Formula wherein each R', R2, R\ X', X2, X3, X4, X5, X6, X7 X8 and X9 are as defined in their broadest definitions set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments. Examples:
EXAMPLE 1 tert-Butyl 4-aminobenzylcarbamate hydrochloride
4-Aminobenzylamine (50.34 g, 0.412 mol) in dichloromethane (200 mL) was placed in a one liter 3 neck round bottom flask fitted with a mechanical stirring apparatus and the solution was cooled to 0°C. di-/er/-Butyl dicarbonate (89.9 g, 0.412 mol.) in dichloromethane (200 mL) was added dropwise to the solution over 30 minutes and the resulting suspension was stirred 2 hours at 0°C giving a nearly homogeneous solution. The dichloromethane solution subsequently was washed with aqueous sodium hydroxide (1.0 M, 500 mL) and then water (500 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo giving a yellow oil. The oil was taken into ethyl ether : methanol (2:1, 225 mL) and the solution was cooled to 0°C, acidified with hydrogen chloride in dioxane (4.0 M, 115 mL, 0.412 mol.) and combined with ethyl ether (200 mL) giving a thick pale yellow precipitate. The precipitate was collected by filtration and washed with additional ethyl ether (500 mL). Drying in vacuo gave /er/-butyl 4--aminobenzylcarbamate hydrochloride (100.23 g, 0.387 mol, 94% yield) as a pale yellow solid; 'H-NMR (300MHz, DMSO-d6): 10.40-10.20 (br s, 3H), 7.40 (tr, 1H), 7.30 (s, 4H), 4.10 (d, 2H), 1.40 (s, 9H).
EXAMPLE 2
/er/-Butyl 4-guanidinobenzylcarbamate
Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to between 60 and 65 °C until the material completely melted and then /er/-butyl
4-aminobenzylcarbamate hydrochloride (25.3 g, 97.8 mmol.), prepared as in Example 1 , was added directly to the liquid cyanamide giving a yellow solution. The solution was stirred 2 hours at between 60 and 65 °C and then water (100 mL) was added. The aqueous mixture was cooled to room temperature and washed with ethyl ether (1 L). The org.anic phase was back extracted with water (2x, 100 mL) and the combined aqueous layers were washed with ethyl ether (500 mL), cooled in an ice water bath and then basified with aqueous sodium hydroxide (10 M, 100 mL) giving an insoluble oil which slowly crystallized. The crystals were collected by filtration washed with water. Drying in vacuo gave rer/-butyl 4-guanidinobenzylcarbamate (18.3 g, 69.24 mmol, 70.8% yield) as a colorless crystalline solid; 'H-NMR (300MHz, DMSO-dfi): 9.70 (s, 1H), 7.42 (tr, 1H), 7.40 (s, 4H), 7.25 (d, 2H), 7.15 (d, 2H), 4.10 (d, 2H), 1.40 (s, 9H).
EXAMPLE 3 /erf-Butyl 4-chlorocarbonyl- 1 -piperazinecarboxylate
Triphosgene (25 g, 84.2 mmol) was taken into dichloromethane (200 mL) and the resulting solution cooled to 0°C. A mixture of /er/-butyl 1 -piperazinecarboxylate (40 g, 214.8 mmol) and pyridine (35 mL, 432.7 mmol) in dichloromethane (100 mL) then was added dropwise to the triphosgene solution and the reaction mixture was allowed to warm to room temperature over 30 minutes. The mixture was quenched with aqueous hydrochloric acid (0.1N, 200 mL) and the aqueous phase was washed with dichloromethane (50 mL). The combined organic layers were dried (MgSO4) and filtered. Concentrating in vacuo gave /cr/-butyl
4-chlorocarbonyl- 1 -piperazinecarboxylate (45.6 g, 71.6 mmol, 85% yield) as a yellow solid; 'H-NMR (300MHz, CDC13): 3.70 (m, 211), 3.60 (m, 2H), 3.50 (m, 4H), 1.50 (s, 9H).
EXAMPLE 4
/er/-Butyl 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate trifluoroacetate
fer/-Butyl 4-guanidinobenzylcarbamate (41.77 g, 0.158 mol.), prepared as in Example 2, was treated with trifluoroacetic acid (TFA) (100 mL) for 30 minutes at room temperature. The resulting nearly colorless liquid was concentrated in vacuo at 45 °C and the residue was triturated with ethyl ether (3x, 400 mL) and dried in vacuo to a colorless foam. The residue was dissolved in methanol (200 mL) and then DIEA (55 mL, 0.32 mol, amount based on estimated excess TFA present) was added to the solution. The mixture was cooled to 0°C and then /er/-butyl 4-chlorocarbonyl- 1 -piperazinecarboxylate (39.3 g, 0.158 mol.), prepared as in Example 3, in dichlorometh∑me (120 mL) was added. An additional amount of DIEA (30 mL) was added and the reaction mixture was allowed to warm to room temperature, stirred 12 hours and concentrated in vacuo giving an orange oil. The oil was combined with water (200 mL) giving a thick precipitate. Recrystallization of the precipitate from acetonitrile and ether gave /er/-butyl 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate trifluoroacetate (62.0 g, 0.126 mol, 80% yield) as a pale yellow solid; 'H-NMR (300MHz, DMSO-d6): 10.15 (s, 1H), 9.10 (br s, 2H), 7.65 (s, 4H), 7.40 (tr, 1H), 7.25 (dd AB, 4H), 4.25 (d, 2H), 3.55 (m, 4H), 3.10 (s, 4H); Electrospray LRMS: Calculated for CI3H20N6O: MH( : 277.4; MHJ2/2: 139.2, Found: MH+: 277.4; MH2 +2/2: 139.3.
EXAMPLE 5 cis-l ,5-Cyclooctylene di(chloroformate)
cis- 1 ,5-Cyclooctanediol (20.2 g, 0.14 mol.) was taken into acetonitrile (250 mL) and potassium carbonate (41.4 g, 0.3 mol.) was added to the mixture giving a suspension. The suspension was cooled to 0°C under a nitrogen atmosphere and then phosgene (1.9M in toluene, 220 mL, 0.42 mol.) was added dropwise over one hour. The suspension was warmed to room temperature and stirred 12 hours and then ether (1 L) was added. The suspension was filtered free of insoluble salts and concentrated. Recrystallization of the residue from hexane gave cw-l,5-cyclooctylene di(chloroformate) as a colorless crystalline solid. Further purification can be effected with silica gel flash chromatography using hexane:ethyl ether (10: 1) as eluent; 'H-NMR (300MHz, CDC13): 5.00-4.85 (m, 2H), 2.20-1.60 (m, 12H).
EXAMPLE 6 cis- 1 ,5-Cyclooctylene chloroformate 4-/er/-butoxycarbonyl- 1 -piperazinecarboxylate
cis- 1 ,5-Cyclooctylene di(chloroformate) (1.91 g, 7.1 mmol), prepared as in Example 5, in dichloromethane (25 mL) was added dropwise to a mixture of tert-butyl 1 -piperazinecarboxylate (1.3 g, 7.1 mmol) and DIEA (1.3 mL, 7.1 mmol) in dichloromethane (25 mL). The mixture was stirred 15 minutes at room temperature and then a workup with 0.1 M aqueous hydrochloric acid was performed. The dichloromethane layer was dried (MgSO4), filtered and concentrated. Purifying from the residue by silica gel flash chromatography using ethyl ether and hexanes as eluent gave cw-l,5-cyclooctylene chloroformate 4-/er/-butoxycarbonyl-l -piperazinecarboxylate (660 mg, 1.6 mmol, 22% yield) as a colorless oil; 'H-NMR (300MHz, CDC13): 5.00-4.90 (m, 1H), 4.80-4.70 (m, 1H), 3.40 (s, 8H), 2.05-1.40 (m, 12), 1.40 (s, 9H). EXAMPLE 7 cis- 1 ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-/er/-butoxycarbonyl- 1 -piperazinecarboxylate
ter/-Butyl 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate trifluoroacetate (383.7 mg, 1.06 mmol), prepared as in Example 4, was treated with trifluoroacetic acid (1 mL) neat for 10 minutes at room temperature. The mixture was concentrated in vacuo giving a colorless oil. The oil was then taken into water (15 mL) and the pH of the aqueous solution was adjusted to between 7 and 8 with 5M aqueous sodium hydroxide added dropwise. cw-l,5-Cyclooctylene chloroformate 4-/er/-butoxycarbony]-l -piperazinecarboxylate (444.7 mg, 1.06 mmol), prepared as in Example 6, in THF (10 mL) was added to the aqueous solution and the pH was continually adjusted with IM aqueous sodium hydroxide added dropwise until no further change in pH was observed. The mixture was concentrated in vacuo removing the bulk of THF and then ethyl ether (5 L) and 5M aqueous sodium hydroxide (sufficient to adjust the pH to 14) was added giving a thick white suspension. The suspension was allowed to stand for 15 to 30 minutes at room temperature and then the precipitate was collected by filtering and washed with water (2x, 15 mL). Drying in vacuo gave cis-\ ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-/cr/-butoxycarbonyl- 1 -piperazinecarboxylate (527 mg, 0.82 mmol, 77% yield) as a colorless solid; 'H-NMR
(300MHz, DMSO-d6): 7.05 (d, 2H), 7.00 (tr, 1H), 6.70 (d, 2H), 5.10 (br, 311), 4.65 (m, 2H), 4.15 (d, 2H), 3.30 (s, 16H), 1.90-1.40 (m, 12H), 1.40 (s, 9H).
EXAMPLE 8 cis- 1 ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate trifluoroacetate (Compound 1)
The following is the preparation of a compound of Formula I in which R' is 4-guanidinobenzyl, R2 is 2-piperid-4-ylethyl, X' and X9 each are -NHC(O)-, X2 and X8 each are 1 ,4-piperazinylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is cis- 1 ,5-cyclooctylene.
cis- 1 ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyI)- 1 -piperazinecarboxylate
4-/er/-butoxycarbonyl-l -piperazinecarboxylate (818 mg, 1.24 mmol.), prepared as in Example 7, was treated with TFA (2 mL) neat for 10 minutes. The mixture was concentration in vacuo giving a colorless oil. The residue was triturated with ethyl ether (2x, 10 mL) and dried in vacuo giving a colorless foam. The residue was then taken into DMF (2 mL) and then DIEA (700 mL, 4.0 mmol.) and /er/-butyl 4-(2-isocy.anatoethyl)-l-piperidinecarboxylate (3.2 mL, 0.39 M in DMF, 1.25 mmol.) were added. The mixture was stirred 12 hours and then concentrated in vacuo. The residue was triturated with water (2x, 5 mL) and dried in vacuo giving a yellow solid. The solid was then treated with TFA (2 mL) and the mixture was concentrated in vacuo. The residue was taken into water. Purifying from the aqueous mixture by preparative reverse phase HPLC gave cw-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate as an amorphous colorless solid; Plasma Desorption LRMS: Calculated for C35H55N,oO6: MH^: 712.9, Found: MH+: 713.2.
Proceeding as in Example 8 and substituting different starting materials the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 2); Calculated for C35H50N10O6: MH+: 707.9, Found: MH+: 707.7; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-piperidylmethylcarbamoyl)-l -piperazinecarboxylate (Compound 3); Calculated for C34H53N10O6: MH+: 698.9, Found: MH+: 699.7; cis- 1 ,5-cyclooctylene 4-(/rfl«.y-4-aminocyclohexylmethyIcarbamoyl)- 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate (Compound 4); Calculated for C35H55N10O6: MH+: 712.9, Found: MH': 713.6; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 3-piperid-4-ylpropylcarbamoyl-l -piperazinecarboxylate (Compound 5); Calculated for
C36H58NIOO6: MH+: 727.9 Found: MH+: 727.9; 4-[4-(2-piperid-4-ylethylcarbamoyi)piperazin- 1 -ylcarbonyl]benzyl
4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 6); Calculated for
C34H48N10O5: MH+: 677.8 Found: MH+: 677.6; 4-[4-(3-piperid-4-ylpropylcarbamoyl)piperazin-l -ylcarbonyl jbenzyl
4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 7); Calculated for
C35H50N10O5: MH+: 691.9 Found: MH+: 691.5; 4-[4-(4-piperid-4-ylbutylcarbamoyl)piperazin- 1 -ylcarbonyljbenzyl
4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 8); Calculated for
C36H52N,0O5: MH+: 705.9 Found: MH+: 705.9; 4-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]benzyI
4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 9); Calculated for
C34H48N10O5: MH+: 677.8 Found: MH+: 677.7; 4-[4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyl]benzyl
4-(3-piperid-4-ylpropylcarbamoyl)-l -piperazinecarboxylate (Compound 10); Calculated for
C35H50NIOO5: MH+: 691.9 Found: MH+: 691.3; 4-[4-(2-piperid-4-ylethylcarbamoyl)piperazin- 1 -ylcarbonylmethyl]benzyl
4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 1 1 ); Calculated for
C35H50NIOO5: MH1: 691.9 Found: MH : 692.1 ; 4-[4-(3-piperid-4-ylpropylcarbamoyl)piperazin-l-ylcarbonylmethyl]benzyl
4-(4-guanidinobenzylc^bamoyI)-l -piperazinecarboxylate (Compound 12); Calculated for
C36H52N10O5: MH+: 705.9 Found: MH+: 705.6; c/.y-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate
4-(4-methylaminomethylbenzylcarbamoyl)-l -piperazinecarboxylate (Compound 13); Calculated for C37H54NI0O6: MH+: 735.9 Found: MH+: 735.7; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate
4-(2-piperid-4-ylethylcarb,amoyl)-l -piperazinecarboxylate (Compound 14); Calculated for
C35H55N9O6: MH+: 698.9, Found: MH+: 698.2; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate 4-(3-piperid-4-ylpropylcarbamoyl)-l -piperazinecarboxylate (Compound 15); Calculated for
C36H57N9O6: MH+: 712.9, Found: MH : 712.3; cis-\ ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate
4-(4-imidazol-l-ylbutylcarbamoyl)-l -piperazinecarboxylate (Compound 16); Calculated for
C35H53N,,O6: MH^: 724.9, Found: MH+: 724.5; cis- 1 ,5-cyclooctylene 4-(4-gu∑ιnidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(4-imidazolin-2-ylaminobutylcarbamoyl)-l-piperazinecarboxylate (Compound 17); Calculated for C35H56Nl2O6: MH+: 741.9, Found: MH+: 741.7; cz.y- 1,5-cyclooctylene 4-(/rα«s-4-aminocyclohexylmethylcarbamoyl)-
1 -piperazinecarboxylate 4-(4-guanidinobenzyIcarbamoyl)- 1 -piperazinecarboxylate
(Compound 18); Calculated for C35H56NI0O6: MH+: 713.9 Found: MH+: 714.1; cis- 1 ,5-cyclooctylene 2-( 1 -/er/-butryryloxymethoxycarbonylpiperid-4-yl)ethylcarbamoyl-
1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
(Compound 19); Calculated for C42H66N10Ol0: MH+: 872.1, Found: MH+: 871.8; cw-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate
4-[2-(l-methylpiperid-4-yl)ethylcarbamoyl]-l -piperazinecarboxylate (Compound 20); Calculated for C36H58N10O6: MH2 272: 364.0, Found: MH2 272: 364.3; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(3-imidazoIin-2-ylaminopropylcarbamoyl)-l -piperazinecarboxylate (Compound 21);
Calculated for C34H54NI2O6: MH+: 727.9, Found: MH+: 728.0; cw-l,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate
4-[l-(l-iminoethyl)piρerid-4-yImethylcarbamoyl]-l -piperazinecarboxylate (Compound 22);
Calculated for C36H57NnO6: MH+: 740.9, Found: MH+: 740.5; cis- 1 ,5-cyclooctylene 4-(4-gu.anidinobenzoylaminomethyl)- 1 -piperidinecarboxy late
4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 23); Calculated for
C36H„N9O6: MH+: 712.9, Found: MH+: 71 1.6; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
2-(l-methoxycarbonylpiperid-4-yl)ethylcarbamoyl-l -piperazinecarboxylate (Compound 24);
Calculated for C37H57N9Og: MH+: 756.9, Found: MH+: 756.7; and 3-{4-[2-(4-{cw-5-[4-(4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyloxy]cyclooctyloxy- carbonyl }piperazin- 1 -ylcarbonylamino)ethyl]piperid- 1 -ylcarbonyl } propionic acid (Compound 25); Calculated for C39H60N9O9: MH+: 799.0, Found: MH+: 798.6.
Proceeding as in Example 8 and replacing the isocyanate with an activated ester the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-imidazol-4-ylacetyl- 1 -piperazinecarboxylate (Compound 26); Calculated for
C32H46Nl0O6: MH+: 667.8, Found: MH+: 667.7; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(E-3-imidazol-4-ylacryloyl)-l -piperazinecarboxylate (Compound 27); Calculated for
C33H46Nl0O6: MH+: 679.9, Found: MH+: 679.8; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(3-imidazol-4-ylpropionyl)-l -piperazinecarboxylate (Compound 28); Calculated for
C33H48N10O6: MH+: 681.8, Found: MH+: 681.7; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzy lcarbamoy 1)- 1 -piperazinecarboxylate
4-(5-imidazol-l-ylvaleryl)-l -piperazinecarboxylate (Compound 29); Calculated for
C35H52NI0O6: MH+: 709.9, Found: MH+: 709.5; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(6-imidazol-l-ylhexanoyl)-l -piperazinecarboxylate (Compound 30); Calculated for
C36H54N10O6: MH+: 723.9, Found: MH+: 723.4; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(4-imidazol-l-ylmethylphenylacetyl)-l -piperazinecarboxylate (Compound 31); Calculated for
C39H52N10O6: MH+: 757.9, Found: MH+: 757.2; cis-l ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate
4-(4-imidazol-l-ylmethylbenzoyl)-l -piperazinecarboxylate (Compound 32); Calculated for
C38H50NI0O6: MH+: 743.9, Found: MH+: 743.7; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(3-imidazol-l-ylmethylbenzoyl)-l -piperazinecarboxylate (Compound 33); Calculated for C38H50NI0O6: MH+: 743.9, Found: MH+: 743.6; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(7-imidazol- 1 -ylheptanoyl)- 1 -piperazinecarboxylate (Compound 34); Calculated for C37H56NιrA: MH+: 737.9, Found: MH+: 737.6; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-[6-(2-methylimidazol-l-yl)hexanoyl]-l -piperazinecarboxylate (Compound 35); Calculated for C37H56N,0O6: MH+: 737.9, Found: MH+: 737.3; cis- 1 ,5-cyclooctylene 4-(4-gu.anidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-imidazol-l-ylphenoxyacetyl)-l -piperazinecarboxylate (Compound 36); Calculated for C38H50N10O7: MH+: 759.9, Found: MH+: 759.3; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-[6-(4-methylimidazol- 1 -yl)hexanoyl]- 1 -piperazinecarboxylate and cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-[6-(5-methyIimidazol-l-yl)hexanoyl]-l -piperazinecarboxylate as a mixture (Compound 37); Calculated for C37H56Nl0O6: MH+: 737.9, Found: MH+: 738.2; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l -piperazinecarboxylate (Compound 38); Calculated for C36H57N906: MH+: 712.9 Found: MH+: 712.4; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacety 1)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l -piperazinecarboxylate (Compound 39); Calculated for C36H56N8O6: M rV: 697.9, Found: MH+: 697.5; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethyl)(methyl)carbamoyl-l -piperazinecarboxylate (Compound 40); Calculated for C36H58N10O6: MH+: 727.9, Found: MH+: 727.6; cw-l,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(2-piperid-4-ylethyI)(methyl)carbamoyl-l -piperazinecarboxylate (Compound 41); Calculated for C36H57N9O6: MH+: 712.9, Found: MH+: 712.7; cis-l ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(2-piperid-4-ylethoxycarbonyl)-l -piperazinecarboxylate (Compound 42); Calculated for C35H55N9O7: MH+: 714.9, Found: MH+: 714.5; cw-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(4-imidazol-l-ylphenylacetyl)-l -piperazinecarboxylate (Compound 43); Calculated for C38H50N10O6: MH : 743.9, Found: MH+: 743.6; cis-\ ,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l -piperazinecarboxylate (Compound 44); Calculated for C36H53N9O6: MW: 708.9, Found: MH+: 708.8; cw-l ,5-cyclooctylene 4-(4-gu£inidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(3-pyrid-4-ylthiopropionyl)-l -piperazinecarboxylate (Compound 45); Calculated for C35H49N9O6: MH+: 724.9, Found: MH+: 724.4; cis-\ ,5-cyclooctylene 4-(4-guanidinobenzylcarbonyl)- 1 -piperazinecarboxylate 4-pyrid-4-ylthioacetyl-l -piperazinecarboxylate (Compound 46); Calculated for C34H47N9O6: MH+: 710.9, Found: MH+: 710.8; cis-l ,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(3-pyrid-4-ylthiopropionyl)-l -piperazinecarboxylate (Compound 47); Calculated for C35H48N8O6: MH+: 709.9, Found: MH+: 709.3; cis-\ ,5-cyclooctylene 4-(4-gu*anidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l -piperazinecarboxylate (Compound 48); Calculated for C36H54N10O6: MH+: 723.9, Found: MH+: 723.5; c/'s-l ,5-cyclooctylene 4-(benzoimidazol-6-ylcarbonyl)-l -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 49); Calculated for C35H47NIOO6: MH+: 703.8, Found: MH+: 703.4; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l -piperazinecarboxylate (Compound 50); Calculated for C36H53N9O6: MH+: 708.9, Found: MH+: 708.6; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzoylaminomethy 1)- 1 -piperidinecarboxy late 4-(6-imidazol-4-yIhexanoyl)-l -piperazinecarboxylate (Compound 51 ); Calculated for C37H54N8O6: MH+: 707.9, Found: MH+: 707.5; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacety 1)- 1 -piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l -piperazinecarboxylate (Compound 52); Calculated for C35H52N10O6: MH+: 708.9 Found: MH+: 708.4; cis- 1 ,5-cyclooctyIene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-pyrid-4-ylcarbamoylacetyl-l -piperazinecarboxylate (Compound 53); Calculated for C35H47N9O7: MH+: 706.8, Found: MH+: 706.3; cis-\ ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(3-pyrid-4-ylaminopropionyl)-l -piperazinecarboxylate (Compound 54); Calculated for C35H50N,0O6: MH+: 707.9, Found: MH+: 707.3; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 3-[pyrid-4-yl(/er/-butoxycarbonyl)amino]propionyl- 1 -piperazinecarboxylate (Compound 55); Calculated for C40H58N-0O8: MH2 272: 404.5, Found: MH2 2+/2: 404.2; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(3-piperazin-l-ylcarbonylpropionyl)-l -piperazinecarboxylate (Compound 56); Calculated for C35H54N,0O7: MH+: 727.9, Found: MH+: 727.5; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-piperid-l-ylcarbonylaminoacetyl-l -piperazinecarboxylate (Compound 57); Calculated for C35H54Nl0O7: MH+: 727.9, Found: MH+: 727.5; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)- 1 -piperazinecarboxylate 4-(5-imidazol-4-ylvaleryl)-l -piperazinecarboxylate (Compound 58); Calculated for C35H52N10O6: MH+: 708.9, Found: MH+: 709.4; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)- 1 -piperidinecarboxylatc 4-(3-piperazin-l-ylcarbonylpropionyl)-l -piperazinecarboxylate (Compound 59); Calculated for C36H54N8O7: MH+: 711.9, Found: MH+: 711.4; cis-\ ,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)- 1 -piperidinecarboxylate 4-piperid-4-ylcarbonylaminoacetyl-l -piperazinecarboxylate (Compound 60); Calculated for C36H54N8O7: MH+: 711.9, Found: MH+: 711.4; cis- 1 ,5-cyclooctylene 4-[3-(2-aminopyrimidin-5-yl)propionyl]-l -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 61); Calculated for C34H49N,,O6: MH+: 708.8, Found: MH+: 708.4; cw-l,5-cyclooctylene 4-[3-(6-aminopyrid-3-yl)propionyI]-l -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyi)-l -piperazinecarboxylate (Compound 62); Calculated for C35H50NIOO6: MH+: 707.8, Found: MIL: 707.4; cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-[4-(4-pyrid-4-ylthio)butyryl]-l -piperazinecarboxylate (Compound 63); Calculated for C36H51N9O6: MH+: 738.9, Found: MH+: 738.4; cis- 1 ,5-cyclooctylene 4-[3-(2-amino-2,4-dioxo- 1 ,2,3,4-tetrahydropyrimidin-5-yl)propionyl]- 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 64); Calculated for C34H48N10O8: MH+: 725.8, Found: MH+: 725.2; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l -piperazinecarboxylate (Compound 65); Calculated for C36H56N8O6: MH+: 697.9, Found: MH+: 697.4; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)- 1 -piperidinecarboxylatc 4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate (Compound 66); Calculated for C37H57N7O6: MH+: 696.9, Found: MH+: 696.4; cis- 1 ,5-cyclooctylene 4-( 1 -amidinopiperid-4-ylacetyl)- 1 -piperidinecarboxylate 4-(6-imidazol- 1 -ylhexanoyl)- 1 -piperazinecarboxylate (Compound 67); Calculated for C35H57N9O6: MH*: 700.9, Found: MH+: 700.5; cis- 1 ,5-cyclooctylene 4-( 1 -amidino-4-piperidylacetyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l -piperazinecarboxylate (Compound 68); Calculated for CjjHβoNgOβ: MW: 689.9, Found: MH+: 689.4; cis- 1 ,5-cyclooctylene 4-( 1 -amidino-4-piperidylacetyl)- 1 -piperazinecarboxylate 4-(6-imidazol-l -ylhexanoyl)- 1 -piperazinecarboxylate (Compound 69); Calculated for C35H57N9O6.MH+: 700.9, Found: MH+: 700.4; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l -piperazinecarboxylate (Compound 70); Calculated for C36H53N9O6: MH+: 708.9, Found: MH+: 708.4; cis-\ ,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-l -piperidinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l -piperazinecarboxylate (Compound 71); Calculated for C37H54NgO6: MH+: 707.9, Found: MH+: 707.4; cis- 1 ,5-cyclooctylene 4-(4-<amidinophenylacetyl)- 1 -piperazinecarboxylate 4-(6-imidazol-l -ylhexanoyl)-! -piperazinecarboxylate (Compound 72); Calculated for C36H52N8O6: MH+: 693.9, Found: MH+: 693.4; cis- 1 ,5-cyclooctylene 4-(4-amidinophenylacetyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l -piperazinecarboxylate (Compound 73); Calculated for C36H55N7O6: MH+: 682.9, Found: MH+: 682.4; cis- 1 ,5-cyclooctylene 4-(4-amidinophenylacetyI)- 1 -piperazinecarboxylate 4-(6-imidazol-4-yIhexanoyl)-l -piperazinecarboxylate (Compound 74); Calculated for C36H52N8O6: MH+: 693.9 MH+: 693.4; and cw-l ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-[4-(2-(l-/er/-butylcarbonyloxymethoxycarbonyl)piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate (Compound 75); Calculated for C42H65N9O|0: MH+: 857.0 Found: MH+: 856.6.
EXAMPLE 9 cis- 1 ,5-cyclooctylene di(4-/er/-butoxyc∑ιrbonyl- 1 -piperazinecarboxylate)
cw-l,5-Cyclooctylene di(chloroformate) (3.69 g, 13.7 mmol.), prepared as in Example 5, and DIEA (7.2 mL, 41 mmol.) were taken into DMF (25 mL) and /cr/-butyl 1 -piperazinecarboxylate (5.1 g, 27.4 mmol.) was added. The mixture was stirred 12 hours at room temperature and then concentrated in vacuo giving a semi-solid residue. The residue was partitioned between dichloromethane (50 mL) and water (50 mL) and the dichloromethane layer was washed with 0.1N aqueous hydrochloric acid (2x, 25 mL), dried (MgSO4) and filtered. Concentrating in vacuo gave c/'.f-l,5-cyclooctylene di(4-/er/-butoxycarbonyl-
1 -piperazinecarboxylate) as an amorphous solid; 'H-NMR (300MHz, CDC13): 4.80 (m, 211), 3.40 (br s, 16H), 2.00-1.40 (m, 12H), 1.40 (s, 18H).
EXAMPLE 10 cis-l ,5-cyclooctylene di[4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate]
(Compound 76)
The following is the preparation of a compound of Formula I in which R' and R2 each are
2-piperid-4-ylethyl, X' and X9 each are -NHC(O)-, X2 and X8 each are 1 ,4-piperazinylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is cw-l,5-cyclooctylene. cis- 1 ,5-Cyclooctylene di(4-ter/-butoxycarbony 1- 1 -piperazinecarboxylate) (47.9 mg,
0.088 mmol.), prepared as Example 9, was treated with TFA ( 1 mL) neat for 10 minutes giving a colorless oil. The mixture was concentrated in vacuo and the residue was triturated with ethyl ether (2x, 5 mL) and repeatedly dried in vacuo giving an amoφhous solid. The solid residue was taken into DMF (5 mL) and DIEA (100 mL, 0.5 mmol.) and then tert-b tyl 4-(2-isocyanatoethyl)-l -piperidinecarboxylate (460 mL, 0.39 M in DMF, 0.18 mmol.) was added to the solution. The mixture was stirred 12 hours and concentrated in vacuo. The residue was triturated with water (2x, 5 mL) and dried in vacuo giving a yellow solid. The solid was treated with TFA (2 mL) and the mixture was concentrated in vacuo. The residue was taken into water. Purifying from the aqueous mixture by preparative reverse phase HPLC followed by lyophillization gave c/.ϊ-l,5-cyclooctylene di[4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate] as a colorless amoφhous solid; Electrospray LRMS: Calculated for C34H60N8O6: MH+: 677.9, Found: MH+: 677.6.
Proceeding as in Example 10 and substituting different starting materials cis-\ ,5-cyclooctylene di[4-(4-methylarninornethylbenzylcarbamoyl)- 1 -piperazinecarboxylate] (Compound 77) was prepared; Calculated for C38H56N8Oή: MH+: 721.9, Found: MH+: 721.7.
Proceeding as in Example 10 and replacing the isocyanate with an activated ester the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene di[4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate]
(Compound 78); Calculated for C36H62N6O6: MW: 675.9, Found: MH+: 675.6; and
/?αrα-dimethy lenepheny lene di [4-(4-piperid-4-y Ibutyry 1)- 1 -piperazinecarboxylate] (Compound 79); Calculated for C36H56N6O6: MH+: 669.9, Found: MH+: 669.4.
EXAMPLE 11 /cr/-Butyl 4-(3-imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate
/er -Butyl 4-chlorocarbonyl-l -piperazinecarboxylate (188 mg, 0.76 mmol.), prepared as in Example 3, was taken into dichloromethane (10 mL) and DIEA (150 mL, 0.86 mmol) was added. l-(3-Aminopropyl)imidazole (100 mL, 0.84 mmol) was added by syringe and the mixture was stirred 12 hours. Dichloromethane (10 mL) was added to the mixture and the organic layer was washed with water (lx, 10 mL), dried (MgSO4) and filtered. Concentrating gave tert-butyl 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (230 mg, 0.68 mmol, 90% yield) as a colorless oil; 'H-NMR (300MHz, DMSO-d6): 7.60 (s, IH), 7.20 (s, IH), 6.85 (s, IH), 6.60 (tr, IH), 3.95 (tr, 2H), 3.30 (s, 8H), 3.00 (q, 2H), 1.80 (m, 2H), 1.40 (s, 9H). EXAMPLE 12 /er/-Butyl 4-aminomethyl-l -benzenecarbamate hydrochloride
4-Aminobenzylamine (5.56 g, 45.6 mmol.) was taken into water (45 mL) and citric acid
(9.63 g, 50 mmol) was added to the solution. Di-/cr/-butyl dicarbonate (9.94 g, 45.5 mmol) in dioxane (20 mL) was added dropwise to the solution and the mixture was stirred 48 hours at room temperature giving a yellow suspension. The suspension was filtered and the aqueous solution was basified with excess solid sodium carbonate and extracted with ethyl acetate (3x, 35 mL). The combined extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated in vacuo giving a white solid. The solid was taken into methanol (30 mL), the solution was acidified with hydrogen chloride in dioxane (4M, 8.4 mL, 33.6 mmol.) and then ethyl ether (100 mL) was added giving a suspension. The particulate matter was isolated by filtration. Drying in vacuo gave tert-butyl
4-aminomethyl- 1 -benzenecarbamate hydrochloride (7.2 g, 27.8 mmol, 61% yield) as a colorless solid; 'H-NMR (300MHz, DMSO-d6): 9.43 (s, IH), 8.20 (br s, 3H), 7.40 (dd AB, 4H), 3.92 (m, 2H), 1.50 (s, 9H).
EXAMPLE 13 /er/-Butyl 4-isocyanatomethyl-l -benzenecarbamate:
terr-Butyl 4-aminomethyl-l -benzenecarbamate hydrochloride (3.39 g, 13.1 mmol), prepared as in Example 12, was taken into dichloromethane (120 mL) at 0°C and pyridine (4.3 mL, 53 mmol) and triphosgene (1.3 g, 4.4 mmol) was added. The mixture was allowed to warm to room temperature over 30 minutes and aqueous hydrochloric acid (0.5N, 100 mL) was added. The organic layer was dried (MgSO4) and filtered. Concentrating gave /er/-butyl 4-isocyanatomethyl-l -benzenecarbamate (2.7 g, 1 1 mmol, 84% yield) as a yellow solid; 'H-NMR (300MHz, CDC13): 7.29 (dd AB, 4H), 6.55 (br s, IH), 4.40 (s, 2H), 1.55 (s, 9H). EX AMPLE 14 cis- 1 ,5-Cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(3-imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate
(Compound 80)
The following is the preparation of a compound of Formula I in which R' is 4-aminobenzyl, R2 is 3-imidazol-l-ylpropyl, X1 and X9 each are -NHC(O)-, X2 and X8 each are 1 ,4-piperazinylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is cis- 1 ,5-cyclooctylene. (a) ter/-Butyl 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (225 mg,
0.67 mmol), prepared as in Example 1 1 , was treated with TFA (1 mL) neat for 10 minutes. The mixture was concentrated in vacuo and the residue was taken into dichloromethane ( 10 mL) and an excess of DIEA (1.0 mL) was added to the solution. cw-1.5-Cyclooctylene chloroformate 4-terr-butoxycarbonyl- 1 -piperazinecarboxylate (279 mg, 0.67 mmol), prepared as in Example 6, in dichloromethane (5 mL) was added to the solution and the mixture was stirred for 1 hour. Additional dichloromethane (10 mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (lx, 10 mL), dried (MgSO4) and filtered. Concentrating gave crude cw-l,5-cyclooctylene 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate /er/-butoxycarbonyl- 1 -piperazinecarboxylate adduct as a colorless foam.
(b) The adduct prepared in Part (a) was treated with TFA (1 mL) neat for 10 minutes and then the mixture was concentrated in vacuo. The residue was taken into DMF (10 mL) and an excess of DIEA (1.5 mL) and tert-butyl 4-isocyanatomethyl- 1 -benzenecarbamate ( 165 mg, 0.67 mmol.), prepared as in Example 13 were added. The mixture was stirred 12 hours and concentrated in vacuo. The residue was treated with TFA neat and mixture was concentrated in vacuo. The residue was taken into water (15 mL) and the aqueous solution was extracted with ethyl ether (lx, 1 mL). The aqueous layer was basified with 1.0M aqueous sodium hydroxide and then extracted with dichloromethane. The dichloromethane was dried (MgSO4) and filtered. Concentrating in vacuo gave cis-l ,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-
1 -piperazinecarboxylate 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate as a colorless foam; 'H-NMR (300MHz, CDC13): 7.45 (s, IH), 7.10 (d, 2H), 7.05 (s, IH), 6.90 (s, 1H), 6.60 (d, 2H), 4.85-4.70 (m, 4H), 4.30 (d, 2H), 4.00 (tr, 2H), 3.50-3.30 (m, 18H), 2.00 (m, 2H), 1.90-1.50 (m, 12H).
Proceeding as in Example 14 and substituting different starting materials the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -pipereizinecarboxylate 4-(2-pyrid-4-ylethylcurb.amoyl)-l -piperazinecarboxylate (Compound 81 ); cis- 1 ,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(3-piperid-4-ylpropyl)-l -piperidinecarboxylate (Compound 82); and cis- 1 ,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(4-piperid-4-ylbutyl)-l -piperidinecarboxylate (Compound 83).
EXAMPLE 15 cis- ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate
4-(3-imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate
(Compound 84)
The following is the preparation of a compound of Formula I in which R' is
4-guanidinobenzyl, R2 is 3-imidazol-l-ylpropyl, X' and X9 each are -NHC(O)-, X2 and X8 each are 1 ,4-piperazinylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is is- 1 , 5 -cycloocty lene . cis- 1 ,5-Cyclooctylene 4-(4-aminobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate, prepared in Example 14, was taken into methanol and ethyl ether and an excess of hydrogen chloride (4M in dioxane) was added. The mixture was concentrated and dried in vacuo. An excess of cyanamide (1.0g) was added and the mixture was heated at 65 °C for two hours giving a yellow solution. The mixture was allowed to cool to room temperature and triturated with ethyl ether (3x, 10 mL). The insoluble residue was taken into water. Purifying from the aqueous mixture by preparative reverse phase HPLC gave cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate as a colorless amoφhous solid; Electrospray LRMS: Calculated for C34H51NnO6: MH+: 710.9, Found: MH+: 710.6.
Proceeding as in Example 15 and substituting different starting materials the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(2-pyrid-4-ylethylcarbamoyI)-l -piperazinecarboxylate (Compound 85); Calculated for C35H50N10O6: MH+: 707.9 Found: MH+: 707.6; cis-\ ,5-cyclooctylene 3-piperid-4-ylpropyl-l -piperidinecarboxylate
4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate (Compound 86); and cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-piperid-4-ylbutyl-l -piperidinecarboxylate (Compound 87); Calculated for C37H60N8O5: MH+: 697.9, Found: MH': 697.7.
EXAMPLE 16 cis- 1 ,5-cyclooctylene chloroformate 4-benzyloxycarbony 1- 1 -piperazinecarboxylate
Benzyl 1 -piperazinecarboxylate (1.0 g, 4.53 mmol, 1.0 equiv) and DIEA (0.88 mL, 4.98 mmol, 1.1 equiv) in dichloromethane (25 mL) was added dropwise to cw-l,5-cyclooctylene di(chloroformate) (1.2 g, 4.53 mmol, 1.0 equiv), prepared as in Example 5, in dichloromethane (25 mL) at 0°C. The reaction mixture was stirred for 22 hours while allowing to warm to room temperature. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (Na2SO4) over sodium sulfate and concentrated. Purifying the residue by flash column chromatography, eluting with 20 and 30% ethyl acetate in hexanes, gave α's-l,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-l -piperazinecarboxylate (0.81 g, 1.81 mmol, 40%) as a yellow oil;
IR: 2939 (s), 2863 (m), 1770 (s), 1732 (s), 1696 (s); Η NMR (300 MHz, CDC15): 7.35 (s, 5 H), 5.15 (s, 2 H), 4.95 (m, 1 H), 4.75 (m, 1 H), 3.45 (s, 8 H), 1.50 - 2.05 (m, 12 H). EXAMPLE 17 l-[cw-5-(4-Benzyloxyc^bonylpiperazin-l-ylcarbonyloxy)cyclooctyloxycarbonyl]- 4-piperidinecarboxylic acid
Isonipecotic acid (75 mg, 0.58 mmol, 1.1 equiv) and DIEA (0.23 mL, 1.33 mmol, 2.5 equiv) were added to cw-l,5-cyclooctylene chloroformate 4-benzyloxycarbonyl- 1 -piperazinecarboxylate (0.24 g, 0.53 mmol, 1.0 equiv), prepared as in Example 16, in dichloromethane (10 mL) at 0°C giving a white suspension. The suspension was stirred for 18 hours while allowing to warm to room temperature. The reaction mixture was partitioned between dichloromethane and 0.05N aqueous hydrochloric acid. Concentrating the organic layer gave crude 1 -[cw-5-(4-benzyloxycarbonylpiperazin-l -ylcarbonyloxy)cyclooctyloxycarbonyl]- 4-piperidinecarboxylic acid (0.36 g) as a colorless oil; 'H NMR (300 MHz, CDC13): 7.35 (s, 5 H), 5.15 (s, 2 H), 4.75 (m, 2 H), 3.90 (m, 1 H), 3.45 (s, 8 H), 2.75 (m, 1 H), 2.50 (m, 3 H), 1.50-1.90 (m, 16 H).
EXAMPLE 18 cis- 1 ,5-Cyclooctylene 4-benzyloxycarbony 1- 1 -piperazinecarboxylate
4-[2-( 1 -/er/-butoxycarbonylpiperid-4-y l)ethy lcarbamoyl]- 1 -piperidinecarboxylate
1-Hydroxybenzotriazole hydrate (80 mg, 58.3 mmol, 1.1 equiv), /er/-butyl 4-(2-aminoethyl)-l -piperidinecarboxylate hydrochloride (0.14 g, 0.53 mmol, 1.0 equiv) and 4-methylmoφholine (0.15 mL, 1.33 mmol, 2.5 equiv) were added to a solution of crude 1 -[c/'.s-5-(4-benzyloxyc.arbonylpiperazin- 1 -ylcarbonyloxy)cyclooctyloxycarbonyl]- 4-piperidinecarboxylic acid (0.36 g, 0.53 mol, 1.0 equiv), prepared as in Example 17, in DMF (5 mL). l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol, 1.25 equiv) was added to the reaction mixture at 0 °C. The solution was stirred for 1.5 hours at 0°C and for 3 days at 23 °C. The reaction mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water (two portions) and saturated aqueous sodium chloride. The organic layer was dried (Na2SO4) and concentrated. Purifying from the residue by flash column chromatography, eluting with 3% methanol in dichloromethane, gave c/s-l,5-cyclooctylene 4-benzyloxycarbonyl- 1 -piperazinecarboxylate 4-[2-( 1 -rer/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]- 1 -piperidinecarboxylate (0.15 g, 0.2 mmol, 37% over two steps) as a yellow oil; 'H NMR (300 MHz, CDC13): 7.35 (s, 5 H), 5.15 (s, 2 H), 4.80 (m, 2 H), 4.10 (m, 4 H), 3.45 (m, 10 H), 3.30 ( , 2 H), 2.70 (m, 2 H), 1.50-1.90 (m, 23 H), 1.45 (s, 9 H); Electrospray LRMS: calcd for C40H62N5O9 (MH+): 756.97, obtained: 757.0.
EXAMPLE 19 cis- 1 ,5-Cyclooctylene 1 -piperazinecarboxylate 4-[2-( 1 -/er/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l -piperidinecarboxylate
Ethanol (3 mL) was added to cw-l,5-cyclooctylene 4-benzyloxycarbonyl-
1 -piperazinecarboxylate 4-[2-( 1 -/er/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]- 1 -piperidinecarboxylate (0.15 g, 0.20 mmol, 1.0 equiv), prepared as in Example 18, and 5% palladium on carbon (75 mg, 0.50 wt equiv) under nitrogen. The mixture was stirred under hydrogen (1 atm) for 17 hours at 23 °C. The reaction mixture was placed under nitrogen and filtered. Concentrating the filtrate gave cw-l,5-cyclooctylene 1 -piperazinecarboxylate 4-[2-( 1 -ter/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]- 1 -piperidinecarboxylate (110 mg,
0.18 mmol, 90%) as a colorless oil; 'H NMR (300 MHz, CDC13): 5.5 (m, 1 H), 4.9 (m, 2 H), 4.75 (m, 1 H), 4.1 (m, 4 H), 3.45 (m, 4 H), 3.25 (m, 2 H), 2.60-2.85 (m, 8 H), 2.10 (m, 1 H), 1.50-1.95 (m, 23 H), 1.45 (s, 9 H); Electrospray LRMS: calcd for C32H56N5O7 (MH+): 622.83, obtained: 622.7.
EXAMPLE 20 cis-l ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperidinecarboxylate
(Compound 88)
The following is the preparation of a compound of Formula I in which R' is 4-guanidinobenzyl, R2 is 2-piperid-4-ylethyl, X1 and X9 each are -NHC(O)-, X2 is
1,4-piperazinylene, X8 is 4,1-piperidylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is cw-l,5-cyclooctylene. Triphosgene (30 mg, 0.10 mmol, 0.58 equiv) and pyridine (30 mL, 0.39 mmol, 2.1 equiv) were added to cw-l,5-cyclooctylene 1 -piperazinecarboxylate 4-[2-(l-/er/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l -piperidinecarboxylate (0.11 g, 0.18 mmol, 1.0 equiv), prepared as in Example 19, in dichloromethane (2 mL) at 0°C. The reaction mixture was stirred 3 hours at 0°C. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (Na2SO4) and concentrated giving a brown oil residue.
4-Guanidinobenzylamine dihydrochloride (43 mg, 0.20 mmol, 1.1 equiv) and DIEA (0.16 mL, 0.90 mmol, 5.0 equiv) in DMF (2 mL) were added to the residue giving a suspension. The suspension was stirred 18.5 hours at 23 °C and concentrated. The residue was taken into 50% TFA in dichloromethane (4 mL) and the mixture was stirred 45 minutes at 23 °C. The reaction mixture was concentrated and the residue was triturated with ether and dried in vacuo. Purifying from the residue by preparative reverse phase HPLC and lyophillization gave cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperidinecarboxylate as a colorless amoφhous solid; Electrospray LRMS: calcd for C36HS8N9O6 (MH4): 712.91, obtained: 712.8
Proceeding as in Example 20 and substituting different starting materials the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-(4-guanidinophenyIacety 1)- 1 -piperazinecarboxylate 4-(3-imidazol-4-ylpropylcarbamoyl)-l -piperazinecarboxylate (Compound 89); Calculated for
C34H50N10O6: MH+: 695.9, Found: MH+: 695.4; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate
4-(2-imidazol-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 90); Calculated for
C33H48NIOO6: MH+: 681.3, Found: MW: 680.9; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate
4-(3-imidazol-l -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (Compound 91); Calculated for
C34H50N10O6: MH+: 695.9, Found: MH+: 694.9; cis- 1 ,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate
4-(4-imidazol-l-ylbutylcarbamoyl)-l -piperazinecarboxylate (Compound 92); Calculated for
C35H53N10O6: MH+: 709.9, Found: MH+: 709.4; and cis- 1 ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate
4-(3-imidazoI-l-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 93); Calculated for
C35H5,NIOO6: MFI+: 709.9, Found: MH+: 710.4.
EXAMPLE 21
3-Piperid-4-ylpropionic acid hydrochloride
4-Pyridineacrylic acid hydrochloride (12.0 g; 64.6 mmol) and 1.37 g of platinum oxide was suspended in acetic acid (80 mL) and hydrogenated 12 hours at 50 to 60 psi. The mixture was diluted with water and filtered through a pad of celite. The solids were washed with water (200 mL) and the combined filtrate .and washings were concentrated in vacuo giving a white solid. The solid was suspended in a small amount of methanol and the mixture was diluted with diethyl ether (200 mL). The particulate matter was isolated by filtration and washed with diethyl ether and hexane. Air-drying gave 3-piperid-4-ylpropionic acid hydrochloride (1 1.3 g; 58.1 mmol, 90%) as a colorless solid; 'H-NMR (300 MHz; DMSO-d6): 8.75 (br s, 2H), 3.15 (d, 2H), 2.75 (t, 2H) 2.2 (t, 2H), 1.75 (d, 2H), 1.45 (t, 2H), 1.25 (br q, 2H).
EXAMPLE 22 3-(l-/ert-Butyoxycarbonylpiperid-4-yl)propionic acid 3-Piperid-4-ylpropionic acid (5.07 g; 26.2 mmol), prepared as in Example 21, was dissolved in 2N aqueous NaOH (40 mL; 80 mmol). THF (40 mL) and then di(/er/-butyl)dic.arbonate (6.21 g; 28.4 mmol) was added giving a suspension. The suspension was stirred 22 hours, diluted with water and concentrated in vacuo. The residue was washed with diethyl ether (2x, 100 mL) and the aqueous phase was acidified to pH 2-3 with 1.ON aqueous KHSO4 and extracted with ethyl acetate (3x, 200 L). The combined organic phases were washed with brine and dried (Na SO4). Concentrating in vacuo gave 3-[4-(l-/er/-butoxycarbonyl)-4-piperidyl]propionic acid (6.21 g; 24.1 mmol, 92%) as a colorless oil that crystallized on standing; 'H-NMR (300 MHz, CDC13): 4.10 (br d, 2H), 2.65 (br t, 2H), 2.35 (t, 2H), 1.70-1.50 (m, 3H), 1.45 (s, 9H), 1.20-0.95 (m, 2H).
EXAMPLE 23 /er/-Butyl 4-benzyloxyc.arbonyl- 1 -piperazinecarboxylate
/er/-Butyl 1 -piperazinecarboxylate (2.01 g; 10.8 mmol) and DIEA (2.0 mL; 1.48 g; 1 1.5 mmol) in 50 mL of ice cold dichloromethane was treated with benzyl chloroformate (2.0 mL; 2.39 g; 14.0 mmol). The mixture was stirred for 42 hours and then partitioned between ethyl acetate and 0.5N KHSO4. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4) and concentrated. Purifying from the residue by chromatography over silica gel (ethyl acetate:hexane, 1 :3) gave /er/-butyl 4-benzyloxycarbonyl- 1 -piperazinecarboxylate (3.33 g; 10.4 mmol, 96%) as a colorless solid; 'H-NMR (300 MHz, CDC13): 7.35 (br s, 5H), 5.13 (s, 2H), 3.55-3.25 (m, 8H), 1.45 (s, 9H). EXAMPLE 24 Benzyl 1 -piperazinecarboxylate hydrochloride
ter/-Butyl 4-benzyloxycarbonyl- 1 -piperazinecarboxylate ( 1.01 g; 3.16 mmol), prepared as in Example 23, was suspended in 4 mL of ethyl acetate. The suspension was cooled in an ice water bath and 4N hydrogen chloride (12 mL in 1,4-dioxane) was added giving a solution. The solution was stirred for 30 minutes on the ice bath and then for 30 minutes at room temperature. The reaction mixture was diluted with diethyl ether (75 mL) giving a precipitate. The precipitate was isolated by filtration and washed with diethyl ether. Drying in vacuo gave benzyl 1 -piperazinecarboxylate hydrochloride (740 mg; 2.78 mmol, 88%) as a colorless solid; 'H-NMR (300 MHz, DMSO-d6): 9.25 (br s, 2H), 7.33 (s, 5H), 5.06 (s, 2H), 3.58 (br s, 4H), 3.04 (t, 4H).
EXAMPLE 25 tert-Butyl 4-[2-(4-benzyloxycarbonyIpiperazin- 1 -ylcarbonylamino)ethyl]-
1 -piperidinecarboxylate
3-[4-(l-/er/-Butoxycarbonyl)-4-piperidyl]propionic acid (2.16 g; 8.4 mmol), prepared as in Example 22, in dry benzene (28 mL) was treated with triethylamine (1.35 mL; 951 mg; 9.40 mmol) and diphenylphosphoryl azide (2.05 mL; 2.62 g; 9.53 mmol). The reaction mixture was gradually heated to reflux and kept at reflux for 3.5 hours. The mixture was cooled to room temperature then added dropwise to a suspension of benzyl 1 -piperazinecarboxylate hydrochloride (2.44 g; 9.19 mmol), prepared as in Example 24, and triethylamine (1.40 mL; 1.02g; 10.0 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred for 43 hours and diluted with ethyl acetate and 0.5N KHSO4. The organic layer was washed with water, aqueous sodium bicarbonate and brine, dried (Na SO4) and concentrated. Purifying from the residue by chromatography on silica gel (ethyl acetate-hexane, 4: 1; then pure ethyl acetate) gave r/-butyl 4-[2-(4-benzyloxycarbonylpiperazin- 1 -ylcarbonylamino)ethyl]- 1 -piperidinecarboxylate (3.84 g; 8.1 mmol, 96%) as a white solid; 'H-NMR (300 MHz, CDC13): 7.35 (s, 5H), 5.15 (s, 2H), 4.50 (br t, IH), 4.05 (br s, 2H), 3.55-3.45 (m, 4H), 3.40-3.30 (m, 4H), 3.25 (q, 2H), 2.65 (t. 2H), 1.70 (s, 2H), 1.45 (s, 11H), 1.20-1.00 (m, 2H). EXAMPLE 26 cis- 1 ,5-Cyclooctylene chloroformate 4-[2-(4-/er/-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]- 1 -piperazinecarboxylate
tert-Buty 4-[2-(4-benzyloxycarbonylpiperazin- 1 -ylcarbonylamino)ethyl]-
1 -piperidinecarboxylate (2.03 g; 4.28 mmol), prepared as in Example 25, and 10% palladium-on-carbon (570 mg) suspended in ethanol (19 mL) was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered and the catalyst was washed with ethanol.
The filtrate and washings were concentrated in vacuo and the residue was dissolved in dichloromethane (30 mL) and treated with DIEA (500 mL). The solution was added dropwise to cw-l,5-cyclooctylene di(chloroformate) (4.15g; 15.4 mmol), prepared as in Example 5, in ice cold dichloromethane (75 mL). The reaction mixture was stirred overnight and diluted with 0.5N aqueous KHSO4 and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine, dried (Na2SO4) .and concentrated.
Purifying from the residue by chromatography on silica gel (ethyl acetatc-hexane, 3:1 ; then pure ethyl acetate) gave cis- 1 ,5-cyclooctylene chloroformate
4-[2-(4-/er/-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-l -piperazinecarboxylate (1.02 g;
1.8 mmol, 42%) as a pale yellow oil; 'H-NMR (300 MHz, CDC13): 5.00-4.90 (m, IH), 4.85-4.75 (m, IH), 4.35 (br t, IH), 4.05 (br d, 2H), 3.50-3.40 (m, 4H), 3.35-3.30 (m, 4H), 3.25 (q, 2H), 2.65
(t, 2H), 2.05-1.55 (m, 17H), 1.40 (s, 9H), 1.25-1.00 (m, 2H).
EXAMPLE 27 4-Cyanophenylacetic acid
2-(4-Cyanophenyl)ethanol (5.00 g; 34.0 mmol) was dissolved in acetone (140 mL) and cooled to 10-15°C. A solution of CrO3 in aqueous H2SO4 was added dropwise, while keeping the internal temperature below 30°C, until an orange color persisted giving a suspension. The suspension was stirred for 45 minutes and filtered. The solids were washed with acetone (150 mL) and the combined filtrate and washings were stirred with 2-propanol (20 mL ) for 30 minutes. The mixture w∑is filtered .and the filtrate was concentrated in vacuo. The residue was taken intoethyl acetate and the solution was washed with 0.5N aqueous KHSO4, water and brine and concentrated. The residue was dissolved in dichlorometha. ne and the solution was treated with sodium hydroxide (1.56 g) in water (100 mL). The aqueous phase was extracted with dichloromethane and acidified to pH 1-2 with concentrated aqueous hydrochloric acid giving a precipitate. The precipitate was washed with water and air-dried. Drying in vacuo gave 4-cyanophenylacetic acid (3.36 g; 20.7 mmol, 61%) as a white powder; 'H-NMR (300 MHz, CDC13): 7.63 (d, 2H), 7.40 (d, 2H), 3.72 (s, 2H).
EXAMPLE 28 tert-Butyl 4-(4-cyanophenylacetyl)- 1 -ρiper.azinecarboxylate
A mixture of 4-cyanophenylacetic acid (890 mg; 5.52 mmol), prepared as in Example 27, ethylene dichloride (1.16 g; 6.07 mmol) and 1 -hydroxybenzotriazole hydrate (820 mg; 6.07 mmol) was suspended in THF ( 18 mL) and tert-butyl 1 -piperazinecarboxylate ( 1.04 g; 5.60 mmol) and DIEA were added to give a homogenous solution. The solution was concentrated in vacuo and the residue was treated with 0.2N KHSO . The mixture was filtered and the solid collected was washed with water. Drying in vacuo gave tert-butyl 4-(4-cyanophenylacetyl)- 1 -piperazinecarboxylate (1.68 g; 5.1 mmol, 92%) as a solid; 'H-NMR (300 MHz, CDC13): 7.70 (d, 2H), 7.35 (d, 2H), 3.80 (s, 2H), 3.70-3.60 (m, 2H), 3.45-3.30 (m, 6H), 1.40 (s, 9H).
EXAMPLE 29 tert-Butyl 4-[4-(N-hydroxyamidino)phenylacetyl]- 1 -piperazinecarboxylate
tert-Butyl 4-(4-cyanophenylacetyI)-l -piperazinecarboxylate (1.68 g; 5.1 mmol), prepared as in Example 28, in dry ethanol (10 mL) was treated with hydroxylamine hydrochloride (461 mg; 6.63 mmol) and triethylamine (924 mL, 671 mg; 6.63 mmol). The mixture was heated at reflux for 3.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol, filtered and the filtrate cooled overnight giving a crystalline product. The crystals were isolated by Alteration and washed with cold ethanol. Air-drying gave tert-butyl 4-[4-(N-hydroxyamidino)phenylacetyl]-l -piperazinecarboxylate (1.62 g; 4.5 mmol, 88%); 'H-NMR (300 MHz, DMSO-d6): 9.60 (s, IH) 7.60 (d, 2H), 7.20 (d, 2H), 5.75 (s, 2H), 3.70 (s, 2H), 3.40 (br s, 4H), 3.25 (br s, 4H), 1.40 (s, 9H).
EXAMPLE 30
4-piperazin- 1 -ylcarbonylmethylbenzamidine bis(trifluoroacetate)
tert-Butyl 4-[4-(N-hydroxyamidino)phenylacetyl]-l -piperazinecarboxylate (653 mg; 1.81 mmol), prepared as in Example 29, and 10% palladium-on-carbon (200 mg) were suspended in acetic acid (12 mL) and hydrogen was bubbled through the suspension overnight. The reaction mixture was filtered and the catalyst was washed with acetic acid. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in TFA. The solution stood for 1 hour and then was concentrated in vacuo. The residue was co-evaporated from a mixture of dichloromethane and methanol and then suspended in diethyl ether. The paniculate matter was collected by filtration. Drying gave 4-piperazin-l -ylcarbonylmethylbenzamidine bis(trifluoroacetate) (1.04 g; 1.81 mmol, 100%) as a white solid; 'H-ΝMR (300 MHz, DMSO-d6): 9.30 (d, 4H), 9.15 (br s, 2H), 7.70 (d, 2H), 7.40 (d, 2H), 3.85 (s, 2H), 3.65 (br d, 4H), 4.20-3.90 (m, 4H).
EXAMPLE 31 cis- 1 ,5-Cyclooctylene 4-(4-amidinophenylacetyl)-l -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyI)- 1 -piperazinecarboxylate
(Compound 94)
The following is the preparation of a compound of Formula I in which R1 is 4-amidinobenzyl, R2 is 2-piperid-4-ylethyI, X1 is -C(O)- and X9 is -NHC(O)-, X2 and X8 each are
1,4-piperazinylene, X3 and X7 each are -C(O)O-, X4 and X6 each are a covalent bond and X5 is cis- 1 ,5-cyclooctylene. 4-Piperazin- 1 -ylcarbonylmethylbenzamidine bis(trifluoroacetate) (80 mg; 0.17 mmol), prepared as in Example 30, was dissolved in DMF (1.0 mL) and the solution was treated with
DIEA (150 mL). c/5-l,5-Cyclooctylene chloroformate 4-[2-(4-tert-butoxycarbonylpiperazin- 1 -yI)ethylcarbamoyl]- 1 -piperazinecarboxylate ( 100 mg), prepared as in Example 26, in DMF (1.0 mL) was added and the mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in dichloromethane and TFA (1 : 1) and the mixture was concentrated in vacuo. The residue was triturated with diethyl ether giving a foam residue. Purifying from the residue by preparative reverse phase HPLC and lyophilization of the pure fractions gave c/.s-l,5-cyclooctylene 4-(4-amidinophenylacetyl)-l -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate as a colorless solid; Electrospray
LRMS: Calculated for C35H54N8O8: MH+: 683.9; MH2 +2/2: 342.5,, Found: MH+: 683.8;
MH2 +72: 342.3.
Proceeding as in Example 31 and substituting different starting materials the following compounds of Formula I were prepared:
cis- 1 ,5-cyclooctylene 4-( 1 -amidinopiperid-4-ylacetyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 95); Calculated for C34H59N9O6: MH+: 690.9, Found: MH+: 690.6; cis- 1 ,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)- 1 -piperidinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 96); Calculated for C36H56N8O6: MH+: 697.9, Found: MH+: 697.7; cis-\ ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-yl)ethylcarbamoyl]-l -piperazinecarboxylate (Compound 97); Calculated for C35H55N9O6: MH': 698.9, Found: MH+: 698.7; cw-l ,5-cyclooctylene 4-(4-amidinophenylsulfonylaminomethyl)-l -piperidinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 98); Calculated for C35H56N8O7: MH+: 733.9, Found: MH+: 733.4; cis- 1 ,5-cyclooctylene 4-[2-( 1 -amidinopiperid-4-yl)ethylcarbamoyl]- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoy 1)- 1 -piperazinecarboxylate (Compound 99); Calculated for C35H62N!0O6: MH+: 719.9, Found: MH': 719.5; cis- 1 ,5-cyclooctylene 4-(4-amidinophenylcarbamoy lmethy 1)- 1 -piperidinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate (Compound 100); Calculated for C36H56N8O6: MH+: 697.9, Found: MH': 695.6; cz'.y-l ,5-cyclooctylene 4-(4-N-methoxycarbonylamidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethy lcarbamoy 1)- 1 -piperazinecarboxylate (Compound 101); Calculated for C37H57Ν9O8: MH' : 756.9, Found: MH+: 756.4; and cι.ϊ-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate 3-piperid-4-ylpropyl-l -piperidinecarboxylate (Compound 102); Calculated for C36H58N8O5: MH+: 683.9 Found: MH+: 683.3.
EXAMPLE 32 1 ,5-Pentamethylene di[4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate]
(Compound 103)
The following is the preparation of a compound of Formula I in which R' and R2 each are 4-guanidinobenzyl, X1 and X9 each are -NHC(O)-, X2 and X8 each are 1 ,4-piperazinylene, X3 and X7 each are -C(O)O- and X4-X6-X5 together are 1 ,5-pentamethylene. tert-Butyl 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate trifluoroacetate (306 mg, 0.62 mmol.) was treated with neat trifluoroacetic acid (ImL) at room temperature over ten minutes to give a colorless homogeneous solution. The liquid was concentrated and the oily residue triturated with diethyl ether (3x lOmL) followed by drying in vacuo to a colorless foam.
The deprotected piperazine salt was then taken into DMF (2.5 mL) followed by addition of diisopropylethylamine (0.5 mL, 3.1 mmol.) and 1 ,5-n-pentylene di(chloroformate) (70 mg,
0.31 mmol.) and the mixture was allowed to stir for one hour at room temperature. The reaction mixture was concentrated and the residue was triturated with diethyl ether (3x lOmL) followed by drying in vacuo. The crude material was taken into water (5 mL) and purified by preparative reverse phase HPLC and lyophilization to give 1,5-n-pentylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate] as a colorless amoφhous solid; Electrospray LRMS: Calculated for C33H48N12O6: MH+: 709.8,, Found: MH+: 709.3.
Proceeding as in Example 32 and substituting different starting materials the following compounds of formula I were prepared:
1 ,4-tetramethylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate)
(Compound 104); Calculated for C32H46N12O6: MH+: 695.8, Found: MH+: 695.8; 4-guanidinobenzyl 4- {5-[4-(4-guanidinobenzylcarbamoyl)piperazin-l -ylcarbonyl] valeryl } - 1 -piperazinecarboxamide
(Compound 105); Calculated for C32H46N12O4: MH+: 663.8, Found: MH': 663.4; 4-guanidinobenzyl 4-{6-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]hexanoyl}-
1 -piperazinecarboxamide (Compound 106); Calculated for C33H 8N,2O4: MH+: 677.8,
Found: MW: 611 A; 4-gU U idinobenzyl
4- { 7-[4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyljheptanoyl } -
1 -piperazinecarboxamide (Compound 107); Calculated for C34H50N12O4: MH': 691.9, Found: MH+: 691.5;
4-gu-anidinobenzyl
4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]octanoyl}- 1 -piperazinecarboxamide (Compound 108); Calculated for C37H57N9O8: MH+: 756.9,
Found: MH+: 756.4; 4-guanidinobenzyl 4- { 9-[4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbony l]nonanoyl } - 1 -piperazinecarboxamide (Compound 109); Calculated for C36H 4N12O4: MH+: 719.9, Found: MH+: 719.5;
4-amidinobenzyI 4- { 7- [4-(4-amidinobenzy lcarbamoy l)piperazin- 1 -ylcarbony l]heptanoy 1 } -
1 -piperazinecarboxamide (Compound 1 10); Calculated for C34H48N10O4: MH+: 661.8, Found: MH': 661.3; 1 ,5-pentamethylene di[4-(4-guanidinophenylacetyl)piperazin-l -ylcarbonyl]
(Compound 1 1 1); Calculated for C33H46N,0O4: MH+: 647.8, Found: MH* : 647.3; 1 ,6-hexamethylene di[4-(4-guanidinophenylacetyl)piperazin- 1 -ylcarbonyl] (Compound 1 12); Calculated for C34H48N,0O4: MHJ 661.8, Found: MIL: 661 ; 1 ,7-heptamethylene di [4-(4-gu.anidinophenylacetyl)piperazin- 1 -ylcarbonyl] (Compound 1 13); Calculated for C35H50N10O4: MW: 675.9, Found: MH+: 675.4; and 3-oxa-l ,5-pentamethylene di[4-(4-guanidinophenylacetyl)piperazin-l -ylcarbonyl]
(Compound 1 14); Calculated for C32H44N10O7: MW : 681.8. Found: MW : 681.4.
EXAMPLE 32 In Vitro Assay of Tryptase Inhibition
Mixtures of human tryptase (15 μg/mL) and test compound (varying concentrations) in Tris buffer (comprising: NaCl, 100 M; Tris, 50 mM; 2-[N-moφholine]ethane sulfonic acid, 2.5 mM, CaCI2, 0.5 mM; DMSO, 10%; glycerol, 5%; polyoxyethylenesorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng/mL; and pH 8.2) were incubated for 1 hour at room temperature and then Tosyl-Gly-Pro-Lys-pαrα-nitroanilide was added such that the final concentration of the assay mixture was 0.5 mM. Hydrolysis of the substrate was followed spectrophotometrically at (405 nm) for 5 minutes. Apparent inhibition constants (K,) were calculated from the enzyme progress curves using standard mathematical models. Human tryptase can be purified from human lung and skin tissue samples (e.g., see
Smith et al. (1984) J. Biol. Chem. 59: 1 1046-1 1051 ; and Braganza et al. (1991) Biochem. 30: 4997-5007) and human mast cell line or obtained commerically (e.g., ICN Biomedicals, Irvine California; Athens Research & Technology, Athens, Georgia). Porcine intestinal mucosa heparin and Tosyl-Gly-Pro-Lys-pαra-nitroanilide can be obtained from Sigma Chemical Company.
Proceeding as described in this application or by methods known to those of ordinary skill the following compounds of Formula I were prepared and tested for tryptase inhibitory activity:
Compound 1, K ,=0.003 μM; Compound 2, K=0.8μM; Compound 3, K =0.07μM; Compound 4, K,=0.001 μM; Compound 5, K,=0.2μM; Compound 6, K,=lμM;
Compound 7, K =0.3μM; Compound 8, K,=4μM; Compound 9, K,=0.4μM;
Compound 10, K,=l μM; Compound 11, K=0.09μM; Compound 12, K,=0.2μM; Compound 13, K =0.02μM; Compound 14, K,=0.004μM; Compound 15, K =0.5μM;
Compound 16, K,=0.9μM; Compound 17, K=lμM; Compound 18, K=0.08μM;
Compound 19, K,=1.2μM; Compound 20, K =3.4μM; Compound 21, K,=0.5μM; Compound 22, K=0.2μM; Compound 23, K =4μM; Compound 24, ,=0.3μM;
Compound 25, K,=0.002μM; Compound 26, K,=19μM; Compound 27, K,=2μM;
Compound 28, K=4μM; Compound 29, K=lμM; Compound 30, K=0.031 μM; Compound 31, K,=lμM; Compound 32, K=2μM; Compound 33, K,=l μM;
Compound 34, K=3μM; Compound 35, K=0.8μM; Compound 36, K ,=0.6μM;
Compound 37, K,=0.07μM; Compound 38, K=0.004μM; Compound 39, K ,=0.004μM; Compound 40, K=4μM; Compound 41, K=0.7μM; Compound 42, K=0.02μM;
Compound 43, K ,=0.4μM; Compound 44, K=0.02μM; Compound 45, ,=0.08μM;
Compound 46, K =l μM; Compound 47, K,=0.3μM; Compound 48, K,=0.09μM; Compound 49, K =2μM; Compound 50, K,=0.08μM; Compound 51, K =l μM;
Compound 52, K,=0.04μM; Compound 53, K=6μM; Compound 54, K,=0.1 μM;
Compound 55, K,=2μM; Compound 56, K,=10μM; Compound 57, K=2μM; Compound 58, K,-=0.1 μM; Compound 59, K=0.5μM; Compound 60, K =5μM;
Compound 61 , K=41 μM; Compound 62, K=0.2μM; Compound 63, K,=2μM; Compound 64, K,=lμM; Compound 65, K,=0.001μM; Compound 66, K,=0.02μM;
Compound 67, K=3μM; Compound 68, K,=0.04μM; Compound 69, K,=0.5μM; Compound 70, K,=0.05μM; Compound 71, K,=0.8μM; Compound 72, K=0.1μM;
Compound 73, K,=0.002μM; Compound 74, K,=0.04μM; Compound 75, K,=0.01 μM;
Compound 76, K=0.1μM; Compound 77, K,=6μM; Compound 78, K=0.1μM; Compound 79, K = 1 μM; Compound 84, K=0.06μM; Compound 85, K ,=0.9μM;
Compound 86, K,-0.08μM; Compound 87, K,=0.05μM; Compound 88, K -0.1μM;
Compound 89, K=0.1 μM; Compound 90, K,*-=l μM; Compound 91, K=0.1μM; Compound 92, K=0.1 μM; Compound 93, K=0.02μM; Compound 94, K,=0.007μM;
Compound 95, K,=0.02μM; Compound 96, =0.02μM; Compound 97, K =0.0009μM;
Compound 98, K =0.03μM; Compound 99, K =0.05μM; Compound 100, K=0.009μM; Compound 101, K,=0.04μM; Compound 102, K,=0.08μM; Compound 103, K=0.001 μM;
Compound 104, K,=0.003μM; Compound 105, K,=0.04μM; Compound 106, K =0.004μM;
Compound 107, K=0.0001μM; Compound 108, K=0.0005μM; Compound 109 K =0.0007μM; Compound 1 10, K =0.0008μM; Compound 1 11, K,-=0.3μM; Compound 1 12, K =0.09μM;
Compound 1 13 K,=0.005μM; and Compound 1 14, K,=0.058μM.
EXAMPLE 33 In Vivo Assay of Asthma
Allergic sheep characterized as dual responders (i.e., displaying early and late phases of bronchoconstriction) are challenged with antigen (e.g., Ascaris suum). The sheep are administered test compound or vehicle by aerosol inhalation at 0.5 hours before .and at 4 and 24 hours post antigen challenge. Specific lung resistance (SRL) is monitored via an esophageal balloon catheter just prior to the first test compound or vehicle treatment and every 0.5 to 1 hour thereafter.
In addition, airway responsiveness is monitored 1 to 2 days prior to antigen challenge and just subsequent to administration of test compound or vehicle at 24 hours post antigen challenge. For the puφoses of this application, airway responsiveness is defined as the cumulative dose of carbachol required to increase SR, by 400% (PC400). The PC400 values are obtained by administering 0 to 30 breath units of 1% carbachol (10 mg in 1 mL of PBS) by aerosol inhalation until SR, was increased by 400%.
Sheep treated with vehicle exhibit early phase bronchoconstriction from 0 to 4 hours post antigen challenge and late phase bronchoconstriction from 4 to greater than 8 hours post antigen challenge. In addition, vehicle treated sheep exhibit hyper responsiveness to carbachol (i.e., a 60% decrease in PC400 is observed).
Sheep treated with tryptase inhibitors do not exhibit late phase broncoconstriction (i.e., at 4 to 8 hours post antigen challenge, SRL remained at basal levels). Further, sheep treated with tryptase inhibitors do not exhibit any hyper responsiveness to carbachol.
EXAMPLE 34 Representative Pharmaceutical Formulations Containing a Compound of Formula I.
ORAL FORMULATION
Compound of Formula I 10-100 mg
Citric Acid Monohydrate 105 mg
Sodium Hydroxide 18 mg
Flavoring
Water q.s. to lOO mL
INTRAVENOUS FORMULATION
Compound of Formula I 0.1 - 10 mg
Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg
Sodium Hydroxide 0.18 mg
Water for Injection q.s. to 1.0 mL TABLET FORMULATION
Compound of Formula I 1 %
Microcrystalline Cellulose 73%
Stearic Acid 25%
Colloidal Silica 1%.

Claims

WE CLAIM:
1. A compound of Formula I :
Figure imgf000071_0001
in which:
X5 is (C3.14)cycloalkylene, hetero(C3.14)cycloalkylene, (C6.|4)arylene or hetero(C5-|4)arylene;
X4 and X6 are independently (C0.2)alkylene;
X' and X9 are independently a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(0)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R )C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C._3)alkyl or (C3.8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds; X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-,
-S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)0-, wherein R3 is as defined above; X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)alkylene, -X'°-X"- or -X"-X,ϋ-, wherein X'° is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene; R' is R -X12- or R5-X'3-, wherein:
R4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino, X12 is (C .6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X14-X,5-X16-, wherein X15 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene, X14 is (Cn,4)alkylene and X16 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yI, 1 -methylpiperid-3-yI, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piper.azin- 1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yI, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,4,5,6-tetrahydropyrimidin-4-yl and 1 ,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.14)cycloalkyl, (C6.I4)aryl, (C6.)4)aryl(C,.4)alkyl, (C|.8)alkanoyl, (C,.8)aIkyloxy, (C6.l4)aryloxy, (C3.14)cycloalkyloxy, (Cμ4)alkyloxy,
(C,.8)alkylthio, (C3.14)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.14)cycloalkyl or (C6_M)aryl, and X'3 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X'7-X18-X'9-, wherein X'8 is as defined above for X'5, X,7 is (Cnl7)alkylene and X'8 is (Cn|8)alkylene, wherein the sum of nl7 and nl 8 is 0, 1 or 2; and
R2 is R -X20- or R9-X2'-, wherein:
R8 is amino, 1 -iminoethyl or methylamino, X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)a!kylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22 is (Cn22)alkylene and X24 is (Cn2 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R8 is amino then X22 is not (C4.6)alkylene or oxa(C4.6)alkylene and n22 is not 1 , 2, 3 or 4,
R9 is as defined above for R5 and X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Ct.8)alkyl, (C3.,4)cycloalkyl, (C6.14)aryl, (C6.I4)aryl(CM)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.,4)cycloalkyloxy, (C )alkyloxy, (C,.8)aIkylthio, (C3.14)cycIoalkylthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R', X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
2. The compound of Claim 1 in which:
X5 is cw-l,5-cyclooctylene and X4 and X6 each are a covalent bond or X5 is 1 ,4-phenylenc and X4 and X6 are (C0.,)ethylene;
X1 and X9 are independently a covalent bond, -C(O)-, -ΝHC(O)-, -C(O)NH-, -N(CH3)C(O)- or -S(O)2NH-; X3 and X7 are independently -C(O)- or -C(O)O-;
X2 and X8 are independently -X'°-X"-, wherein: X'° is a covalent bond or methylene and X" is 4,1-piperidylene or 1,4-piperazinylene;
R' is R4-X'2- or R5-X13-, wherein:
R4 is amidino, guanidino or methylamino, X'2 is -X'4-X,5-X16-, wherein X'5 is 1 ,4-phenylene or 1 ,4-piperidylene, X'4 is
(Cn,4)alkylene and X'6 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2, R5 is piperid-4-yl and X ' 3 is (C2.3)alkylene; and
R2 is R8-X20- or R9-X2'-, wherein:
R8 is amino, methylamino or 1-iminoethyl, X20 is -X22-X23-X24-, wherein X23 is trans- 1 ,4-cyclohexylene, 1 ,4-phenylene.
4,1-pyridylene, 1.4-piperidylene, X22 is (Cn22)alkylene andX24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 1 or 2, R9 is benzoimidazol-5-yl, imid.azol-1 -yl, imidazol-4-yl, 2-imidazolin-2-yI,
4-methylimidazol-l-yI, 5-methylimid-azol-l-yl, 1 -methylpiperid-4-yl, piperid-4-yl, piper.azin-1-yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yl or 1 ,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl and X2' is (C,.6)alkylene, ω-aza(C2.5)alkylene, 2-aza-3-oxotrimethylene,
3-aza-2-oxotrimethylene, 3-oxotrimethylene, ω-thia(C2.4)alkylene or -X25-X26-X27-, wherein X26 is 1 ,4-phenylene, X25 is (Cn25)alkylene and X24 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0 or 1 ; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
3. The compound of Claim 2 in which X5 is cis-\ ,5-cyclooctylene and X4 and X6 each are a covalent bond; X' and X9 arc independently a covalent bond, -C(O)-, -ΝHC(O)-, -C(O)NH- or -S(O)2NH-; X3 and X7 are independently -C(O)- or -C(O)O-; R' is R4-X12-, wherein R4 is amidino or guanidino; and R2 is R8-X20- or R -X2'-, wherein R8 is amino or methylamino, X23 is trans- 1 ,4-cyclohexylene or 1 ,4-phenylene, R9 is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-yl or pyrid-4-yl and X21 is (C,.5)alkylene or 3-azatrimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
4. The compound of Claim 3 in which X' and X9 are independently -C(O)- or -ΝHC(O)-; X3 and X7 each are -C(O)O-; X2 and X8 each are -X'ϋ-X"-, wherein X'° is a covalent bond and X" is 1 ,4-piperazinylene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X'2 is -X'4-Xl5-X16-, wherein X15 is 1 ,4-phenylene, X14 is a covalent bond and X'6 is methylene; and R2 is R8-X20- or R9-X2'-, wherein R8 is amino, X20 is -X22-X23-X24-, wherein X23 is tri s- 1,4-cyclohexylene, X22 is a covalent bond and X24 is methylene, R9 is piperid-4-yl and X2' is ethylene or trimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
5. The compound of Claim 4 in which X1 and X9 each are -ΝHC(O)-, R' is 4-amidinobenzyl and R2 is 2-piperid-4-ylethyl, namely c/s-l,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1-piper.azinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
6. The compound of Claim 4 in which X' is -ΝHC(O)-, X9 is -C(O)-, R1 is
4-amidinobenzyl and R2 is 3-piperid-4-yIpropyl, namely c/.y-l,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
7. The compound of Claim 4 in which X1 and X9 each are -ΝHC(O)-, R' is 4-guanidinobenzyl and R2 is trtfMS-4-aminocyclohexylmethyl, namely c/.v-l,5-cyclooctylene trα«^-4-(4-aminocyclohexylmethylcarbamoyl)-l-piperazinecarboxylatc 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
8. The compound of Claim 4 in which X' and X9 each are -C(O)-, R' is 4-amidinobenzyl and R2 is 3-piperid-4-ylpropyl, namely -l,5-cyclooctylene 4-(4-amidinophenylacetyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-
1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
9. The compound of Claim 4 in which X' and X9 each are -ΝHC(O)-, Rl is
4-guanidinobenzyl and R2 is 2-piperid-4-ylethyl, namely cw-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
10. The compound of Claim 4 in which X' is -ΝHC(O)-, X9 is -C(O)-, R1 is 4-guanidinobenzyl and R2 is 3-piperid-4-ylpropyl, namely cis-l ,5-cyclooctylene
4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
1 1. The compound of Claim 4 in which X' is -C(O)-, X9 is -ΝHC(O)-, R' is
4-guanidinobenzyl and R2 is 2-piperid-4-ylethyl, namely c/5-l,5-cyclooctylene 4-(4-guanidinophenylacetyl)- 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
12. The compound of Claim 4 in which X' and X9 each are -C(O)-, R' is 4-guanidinobenzyl .and R2 is 3-piperid-4-ylpropyl, namely c .s*-l,5-cyclooctylene
4-(4-guanidinophenylacetyI)- 1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyry 1)- 1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
13. The compound of Claim 4 in which X1 is -C(O)-, X9 is -ΝHC(O)-, R' is 4-amidinobenzyl and R2 is 2-piperid-4-ylethyl, namely cw-l,5-cyclooctylene 4-(4-amidinophenylacetyl)- 1 -piperazinecarboxylate
4-(2-piperid-4-ylethylcarbamoyl)-l -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable excipient.
15. A method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I:
Figure imgf000077_0001
in which: X5 is (C3.]4)cycloalkylene, hetero(C3.,4)cycloalkylene, (C6.,4)arylene or hetero(C5.,4)arylene;
X4 and X6 are independently (C0.2)alkylene; X' and X3 independently are a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-,
-N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyl; X7 and X9 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-,
-S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)0-, wherein R3 is as defined above; X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)aikylenc, -X'°-X"- or -X"-X'0-, wherein X10 is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene; R' is R4-X12- or R5-X13-, wherein:
R4 is amino, amidino, guanidino, 1-iminoethyl or methylamino, X'2 is (C4.6)alkylene, hetero(C4.6)aIkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X'4-X'5-X'6-, wherein X'5 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloa!kylene or phenyiene, X'4 is (Cnl4)alkylene and X'6 is (Cnι6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l -yl, piperid-3-yl, piperid-4-yl, piperazin- 1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, l,4,5,6-tetrahydropyrimidin-4-yl and l,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.14)cycloalkyl, (C6.l4)aryl, (C6.14)aryl(C )alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy,
(C6.14)aryloxy, (C3.,4)cycloalkyloxy, (C )alkyloxy, (C,.8)alkylthio, (C3.,4)cycloalkylthio, (C6.,4)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.14)cycloalkyl or (C6.)4)aryl and
X'3 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X'7-X'8-X'9-, wherein X'8 is as defined above for X'5, X'7is (CnI7)alkylene and X'8 is (C_)8)alkylene, wherein the sum of nl 7 and nl8 is 0, 1 or 2; and
R2 is R8-X20- or R9-X21-, wherein:
R8 is amino, 1-iminoethyl or methylamino, X20 is (C4.6)alkylene, hetero(C4.6)alky!ene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22is (Cn22)alkylene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R8 is amino then X22 is not (C4.6)alkylene or oxa(C4.6)alkylene and n22 is not 1, 2, 3 or 4,
R9 is as defined above for R5 and X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X'5, X25 is (Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3..4)cycloalkyl, (C6.,4)aryl, (C6.l4)aryl(C,.4)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.l4)aryloxy, (C3.l4)cycloalkyloxy,
(C,.4)alkyloxy, (C,.8)alkylthio, (C3.,4)cycloalkylthio, (C6.,4)arylthio and -NR6R7, wherein R6 .and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R', X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.
16. The method of Claim 15 in which the disease is selected from asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis and inflammatory skin conditions.
17. The method of Claim 16 in which the disease is asthma.
18. The method of Claim 17 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a aerosolized pharmaceutically acceptable carrier suitable for administration as an inhalant.
19. The method of Claim 18 in which the pharmaceutical composition further comprises a therapeutically effective amount of a β-adrenergic agonist, a methylxanthine, a cromoglycate or a corticosteroid.
20. The method of Claim 19 in which the β-adrenergic agonist is selected from albuterol, terbutaline, formoterol, fenoterol and prenaline, the methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the cromoglycate is selected from cromolyn and nedocromil and the corticosteriod is selected from beclomethasome, triamcinolone, flurisolide and dexamethasone.
21. The method of Claim 16 in which the disease is rheumatoid arthritis or conjunctivitis.
22. The method of Claim 21 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration.
23. A compound o f Formula I :
Figure imgf000080_0001
in which: X4-X5-X6 together are (C2.12)alkylene or hetero(C3.12)alkylene;
X' and X9 are independently a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds;
X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)0-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein R3 is as defined above;
X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)alkylenc, -X'°-X"- or -X"-X10-, wherein X'° is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene;
R' is R4-X'2- or R5-X13-, wherein: R4 is amino, amidino, guanidino, 1-iminoethyl or methylamino,
X12 is (C4.6)alkylene, hetero(C4^)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X'4-X15-X'6-, wherein X'5 is (C3.6)cycloalkylene, hetero(C5_6)arylene, hetero(C3.5)cycloalkylene or phenyiene, X'4 is (Cn,4)alkylene and X'6 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4,
R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl,
2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, l-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin- 1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,4,5,6-tetrahydropyrimidin-4-yl and l ,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.I4)cycloalkyl, (C6.14)aryl, (C6.14)aryl(C,.4)alkyl,
(C,.8)alkanoyl, (C,.8)aIkyloxy, (C6.14)aryloxy, (C3.14)cycloalkyloxy, (CM)alkyloxy, (C,.8)alkylthio, (C3.14)cycloalkyIthio, (C6.l4)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C-_8)alkanoyl, (C3-,4)cycloalkyl or
(C6.14)aryl and
X'3 is (C0.6)alkylene, hetero(C2_6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X'7-X'8-X19-, wherein X18 is as defined above for X'5, X'7is
(Cnl7)alkylene and X'8 is (Cnl8)alkylene, wherein the sum of nl7 and nl8 is 0, 1 or 2; and R2 is R8-X2ϋ- or R9-X21-, wherein: R8 is as defined above for R4,
X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22 is (Cn22)alkylene and X24 is (Cn2 )alkylene, wherein the sum of n22 and n24 is 0, 1 , 2, 3 or 4,
R9 is as defined above for R5 and
X21 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X'5, X25 is
(Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3., )cycloalkyl, (C6.l4)aryl, (C6.14)aryl(C,.4)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.,4)cycloalkyloxy, (C,.4)alkyloxy, (C,.8)alkylthio, (C3.]4)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein
R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R1, X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
24. The compound of Claim 23 in which:
X4-X5-X6 together are (C2.,0)alkylene or hetero(C3.,o)aIkylene; X' and X9 are independently a covalent bond, -C(O)-, -NHC(O)-, -C(O)NH-,
-N(CH3)C(O)- or -S(O)2NH-;
X3 and X7 are independently -C(O)- or -C(O)O-; X2 and X8 are independently -X'°-X' '-, wherein X'° is a covalent bond or methylene and
X" is 4,1-piperidylene or 1,4-piperazinylene; R' is R4-X12- or R5-X13-, wherein: R4 is -amidino, guanidino or methylamino,
X'2 is -X'4-Xl5-X16-, wherein X'5 is 1 ,4-phenylene or 1 ,4-piperidylene, X'4 is (Cnl4)alkylene and X'6 is (Cn.6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2, R5 is piperid-4-yl and
X'3 is (C2.3)alkylene; and R2 is R8-X20- or R9-X21-, wherein: R8 is amino, amidino, guanidino, methylamino or 1-iminoethyl,
X20 is -X22-X23-X24-, wherein X23 is trans- 1 ,4-cyclohexylene, 1 ,4-phenylene, 4,1-pyridylene, 1 ,4-piperidylene, X22 is (Cn22)alkylcne and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 1 or 2,
R9 is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-4-yl, piperid-4-yl, piperazin- 1-yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yl or
1 ,4,5,6-tetr.ahydro-2-dioxopyrimidin-5-yl and
X2' is (C,.6)alkylene, ω-aza(C2.5)alkylene, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, ω-thia(C2.4)alkylene or -X25-X26-X27-, wherein X26 is 1 ,4-phenylene, X25 is (C_25)alkylene and X24 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0 or 1 ; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
25. The compound of Claim 24 in which X4-X5-X6 together are (C4.8)alkylene or hetero(C4.I0)alkylene; X1 and X9 are independently a covalent bond, -C(O)-, -NHC(O)-, -C(O)NH- or -S(O)2NH-; X3 and X7 are independently -C(O)- or -C(O)O-; R! is R4-X12-, wherein R4 is amidino or guanidino; and R2 is R8-X20- or R9-X21-, wherein R8 is amino, amidino, guanidino or methylamino, X23 is trα«^-l,4-cycIohexylene or 1 ,4-phenylene, R9 is imid.azol-1-yl, imidazol-4-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-yl or pyrid-4-yl and X21 is (C,.5)alkylene or 3-azatrimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
26. The compound of Claim 25 in which X' and X9 are independently -C(O)- or -ΝHC(O)-; X3 and X7 are independently -C(O)- or -C(O)O-; X2 and X8 each are -X'°-X"-, wherein X10 is a covalent bond and X" is 1 ,4-piperazinylene; R' is R4-X'2-, wherein R4 is amidino or guanidino and X'2 is -Xl4-X15-X16-, wherein X15 is 1 ,4-phenylene, X'4 is a covalent bond and X'6 is methylene; and R2 is R8-X20-, wherein R8 is amidino or quanidino and X20 is
-X22-X23-X24-, where X23 is 1 ,4-phenylene, X22 is a covalent bond and X24 is methylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
27. The compound of Claim 26 in which X4-X5-X6 together are hexamethylene; X' and X9 each are -ΝHC(O)-, X3 and X7 each are -C(O)- and R' and R2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl
4- {7-[4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyl]heptanoyl } -
1 -piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
28. The compound of Claim 26 in which X4-X5-X6 together are heptamethylene; X' and X9 each are -ΝHC(O)-, X3 and X7 each are -C(O)- and R' and R2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl
4- { 8- [4-(4-guanidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyljoctanoyl } -
1 -piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
29. The compound of Claim 26 in λvhich X4-X5-X6 together are octamethylenc; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(O)- and R' and R2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl
4- { 9- [4-(4-guanidinobenzy lcarbamoyl)piperazin- 1 -ylcarbonyljnonanoy 1 } -
1 -piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
30. The compound of Claim 26 in which X"-X5-X6 together are hexamethylene; X1 and X9 each are -ΝHC(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-amidinobcnzyl, namely 4-amidinobenzyl
4-{7-[4-(4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]heptanoyl}- 1 -piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
31. The compound of Claim 26 in which X4-X5-X6 together are pentamethylene; X1 and X9 each are -ΝHC(O)-, X3 and X7 each are -C(0)0- and R1 and R2 each are 4-guanidinobenzyl, namely 1,5-pentamethylene di[4-(4-guanidinobenzy!carbamoyl)- 1 -piperazinecarboxylate]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
32. The compound of Claim 26 in which X4-X5-X6 together are tetramethylene; X' and X9 each are -ΝHC(O)-, X3 and X7 each are -C(O)O- and R1 and R2 each are 4-guanidinobenzyl, namely 1,5 -tetramethylene di[4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
33. The compound of Claim 26 in which X4-X5-X" together are pentamethylene; X1 and X9 each are -ΝHC(O)-, X3 and X7 each are -C(O>- and R1 and R2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- { 6- [4-(4-amidinobenzylcarbamoyl)piperazin- 1 -ylcarbony 1 jhexanoy I } - 1 -piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
34. The compound of Claim 26 in which X4-X5-X6 together are 3-oxatetramethylene;
X' and X9 each are -C(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-amidinobenzyl, namely 3-oxa-l,5-pentamethylene di[4-(4-guanidinophenylacetyl)piperazin-l -ylcarbonyl]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 23 in combination with a pharmaceutically acceptable excipient.
36. A method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I:
Figure imgf000085_0001
in which: X4-X5-X6 together are (C2.,2)alkylene or hetero(C3.|2)alkylene;
X' and X9 are independently a covalent bond, -C(O)-, -C(O)0-, -OC(O)-, -C(O)Ν(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C-.3)a!kyl or (C3.8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds;
X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(0)N(R3)- or -OC(O)O-, wherein R3 is as defined above; X2 and X8 are independently (C,.8)alkylene, hetero(C,.8)alkylene, -X'°-X"- or -X"-X10-, wherein X'° is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene;
R' is R4-X12- or R5-X'3-, wherein:
R4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino, X12 is (C .6)alkylene, hetero(C4.6)alkylcne, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X'4-X'5-X16-, wherein X'5 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene, X14 is (Cn,4)alkylene and X'6 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 , 2, 3 or 4,
R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yI, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin- 1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, ρyrimidin-5-yl, pyrrolidin-3-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,4,5,6-tctrahydropyrimidin-4-yl and l ,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3_.4)cycloalkyl, (C6.,4)aryl, (C6.,4)aryl(CM)alkyl,
(C,.8)aIkanoyl, (C,.8)alkyloxy, (C6.,4)aryloxy, (C3.l4)cycloalkyloxy, (C,.4)alkyloxy, (C,.8)alkylthio, (C3-,4)cycloalkylthio, (C6..4)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.,4)cycloalkyl or
(C6.I4)aryl and
X'3 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X'7-X'8-X'9-, wherein X'8 is as defined above for X'5, X'7 is
(Cn,7)alkylene and X'8 is (Cn,8)alkylene, wherein the sum of nl7 .and nl8 is 0, 1 or 2; and R2 is R8-X20- or R9-X21-, wherein: R8 is as defined above for R4,
X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22 is (Cn22)alkylene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, R9 is as defined above for R5 and
X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is
(Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.g)alkyl, (C3.M)cycloalkyl, (C6.14)aryl, (C6.14)aryl(C,.4)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.14)aryloxy, (C3.,4)cycloalkyloxy, (C,.4)alkyloxy, (C,.8)alkyIthio, (C3.l4)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein
R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R', X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.
37. The method of Claim 36 in which the disease is selected from asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis and inflammatory skin conditions.
38. The method of Claim 37 in which the disease is asthma.
39. The method of Claim 38 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a aerosolized pharmaceutically acceptable carrier suitable for administration as an inhalant.
40. The method of Claim 39 in which the pharmaceutical composition further comprises a therapeutically effective .amount of a β-adrenergic agonist, a methylxanthine, a cromoglycate or a corticosteroid.
41. The method of Claim 40 in which the β-adrenergic agonist is selected from albuterol, terbutaline, formoterol, fenoterol and prenaline, the methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the cromoglycate is selected from cromolyn and nedocromil and the corticosteriod is selected from beclomethasome, triamcinolone, flurisolide and dexamethasone.
42. The method of Claim 37 in which the disease is rheumatoid arthritis or conjunctivitis.
43. The method of Claim 42 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration.
44. A process for preparing a compound of Formula I :
Figure imgf000089_0001
in which:
X5 is (C3.,4)cycloalkylene, hetero(C3.14)cycloalkylene, (C6.,4)arylene or hetero(C5.M)arylene and X4 and X6 are independently (C0.2)alkylene or X4-X5-X6 together arc (C2_ ! 2)alky lene or hetero( C3. , 2)alky lene ;
X1 and X9 are independently a covalent bond, -C(O)-, -C(O)0-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R3)C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds;
X3 and X7 are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -S(O)2N(R3)-, -N(R3)S(O)2-, -OC(O)N(R3)-, -N(R )C(O)O-, -N(R3)C(O)N(R3)- or -OC(O)O-, wherein R3 is as defined above;
X2 and X8 are independently (C,.8)alkylene, hetero(C,-„)alkylene, -X'°-X"- or -X' '-X10-, wherein X10 is (C0.4)alkylene or hetero(C3.4)alkylene and X" is (C3.8)cycloalkylene or hetero(C3.8)cycloalkylene;
R1 is R4-X'2- or R5-X13-, wherein: R4 is amino, amidino, guanidino, 1-iminoethyl or methylamino,
X12 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X'4-X!5-X'6-, wherein X'5 is (C3.6)cycloalkylene, hetero(C5.6)arylene, hetero(C3.6)cycloalkylene or phenyiene,
X'4 is (Cn14)alkylene and X'6 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yl, 4-methylimida. zol-l-yl, 5-methylimid.azol-l-yl, l-methylpiperid-3-yl, l-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin- 1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,4,5,6-tetrahydropyrimidin-4-yl and l,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.,)alkyl, (C3.14)cycloalkyl, (C6.14)aιyl, (C5.14)aryl(C,.4)alkyl, (C,.8)alkanoyl, (C1.8)alkyloxy, (C6-,4)aryloxy, (C3.,4)cycloalkyloxy, (C,.4)alkyloxy, (C,.8)alkylthio, (C3.14)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (C,.8)alkyl, (C,.8)alkanoyl, (C3.,4)cycloalkyl or (C6.,4)aryl and X'3 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)alkylene or -X17-X'8-X'9-, wherein X18 is as defined above for X'5, X'7 is (C„ι7)alkylene and X'8 is (Cn)8)alkylene, wherein the sum of nl7 and nl 8 is 0, 1 or 2; and R2 is R8-X20- or R9-X21-, wherein:
R8 is amino, 1-iminoethyl or methyla. mino, X20 is (C4.6)alkylene, hetero(C4.6)alkylenc, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X'5, X22 is
(Cn22)alkylene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0, 1 , 2, 3 or 4, with the proviso that when R8 is amino then X22 is not (C4.6)alkylene or oxa(C4.6)alkylene and n22 is not 1, 2, 3 or 4,
R9 is as defined above for R5 and
X2' is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3_6)alkylene, oxo(C2.6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X'5, X25 is
(Cn25)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenyiene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.|4)cycloalkyl, (C6..4)aryl, (C6.14)aryl(C )alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.14)aryloxy, (C3.14)cycloalkyloxy, (C )alkyloxy, (C,._8)alkylthio, (C3.l4)cycloalkylthio, (C6.I4)arylthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R1, X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof, which process comprises:
(a) reacting a compound of Formula 1 :
Figure imgf000091_0001
or a protected derivative thereof, with a compound of the formula R -Y9-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y9 is a bond, -O- or -Ν(R3)-, Y8 is piperazin- 1 -yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R', R2, R3, X', X2, X3,
X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I, in which X8 is 1 ,4-piperazinylene or
1,4-piperidylene and X9 is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X8 is (C,.8)alkylene and
X9 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-; (b) reacting a compound of Formula 1 , or a protected derivative thereof, with .an isocyanate of the formula R2-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X8 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X9 is -NHC(O)- or in which X8 is (C,.8)alkylene and X9 is -NHC(O)N(R3)-;
(c) reacting a compound of Formula 2 :
Y2-X3-X4 R2-X9-X8-X7-X6 or a protected derivative thereof, with a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, -O- or -N(R3)-, Y2 is piperazin- 1 -yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R', R2, R\ X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 1 ,4-piperidylene and X1 is -C(O)-, -OC(O)- or -N(R3)C(O)- or in which X2 is (C,.8)alkylene and X1 is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-; (d) reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 1,4-piperidylene and X' is -NHC(O)- or in which X2 is (C,.8)alkylene and X1 is -NHC(O)N(R3)-; (e) reacting a compound of Formula 3 :
Figure imgf000092_0001
or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R'-Y'-C(O)L, or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, -O- or
-N(R3)-, Y2 and Y8 are independently piperazin- 1-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl and each
R', R3, X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which R' equals R2; X2 and/or
X8 is 1 ,4-piperazinylene or 1 ,4-piperidylene; X1 is -C(O)-, -OC(O)- or -N(R3)C(O)-; and X9 is
-C(O)-, -OC(O)- or -N(R3)C(O)- and/or in which X2 and/or X8 is (C,.8)alkylene; X' is -C(O)N(R3)-, -OC(O)N(R3)- or -N(R3)C(O)N(R3)-; and X9 -C(O)N(R3)-, -OC(O)N(R3)- or
-N(R3)C(O)N(R3)-;
(f) reacting a compound of Formula 3, or a protected derivative thereof, with two or more molar equivalents of an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which R' equals R2; X2 and/or X8 is 1 ,4-piperazinylene or 1 ,4-piperidylene; X' is -NHC(O)- and/or X9 is -NHC(O)- and/or in which X2 and/or X8 is (C,.8)alkylene and X1 is -NHC(O)N(R3)- and/or X9 is -NHC(O)N(R3)-;
(g) reacting an amine of the formula R'-N(R3)H, or a protected derivative thereof, with a compound Formula 4:
Figure imgf000093_0001
4
or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, -O- or -N(R3)- and each R', R2, R\ X2, X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X' is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R )C(O)N(R3)-;
(h) reacting a compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 5 :
Figure imgf000093_0002
or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -O- or -N(R3)-, Y2 is piperazin- 1 -yl, piperid-4-yl or HN(R3)-(C..8)alkyl, respectively, and each R', R2, R3, X', X2, X3,
X4, X5, X6, X7, Xs and X9 are as defined in the Sumrr ry of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1 ,4-piperazinylene or 4,1-piperidylene and X3 is -C(O)-, -C(O)O- or -C(O)N(R3)- or in which X2 is (C,.8)alkylene and
X3 is -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)-;
(i) reacting 2 or more molar equivalents of compound of the formula R'-X'-Y2, or a protected derivative thereof, with a compound of Formula 6:
Figure imgf000094_0001
or a protected derivative thereof, wherein L is a leaving group, Y3 and Y7 are independently a bond, -O- or -N(R3)-, Y2 is piperazin- 1-yl, piperid-4-yl, HN(R3)-(C,.8)alkyl or
HN(R3)-hetero(C,.8)alkyl and each R', X1, X4, X5 and X6 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 and X8 each are 1 ,4-piperazinylene or 4,1-piperidylene and X3 and X7are independently -C(O)-,
-C(O)O- or -C(O)N(R3)- or in which X2 and X8 each are (C,.8)alkylene or hetero(C,.8)alkylene and X3 and X2 are independently -N(R3)C(O)-, -N(R3)C(O)O- or -N(R3)C(O)N(R3)-, respectively;
(j) optionally reacting a compound of Formula I in which R4 is amino with cyanamide to give a compound of Formula I in which R4 is guanidino; (k) optionally further converting a compound of Formula I into a pharmaceutically acceptable salt;
(1) optionally further converting a salt form of a compound of Formula I to non-salt form; (m) optionally further converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(n) optionally further an N-oxide form of a compound of Formula I its unoxidized form; (o) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(p) optionally further converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
PCT/US1997/013422 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with tryptase activity WO1998004537A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
HU0003267A HUP0003267A3 (en) 1996-07-30 1997-07-30 Heteroaryl derivatives, pharmaceutical compositions containing them and process for producing them
AU39670/97A AU733621B2 (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with tryptase activity
SI9720047A SI9720047A (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with tryptase activity
EEP199900036A EE9900036A (en) 1996-07-30 1997-07-30 Novel compounds and compositions for the treatment of diseases associated with tryptase activity
CA002262542A CA2262542A1 (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with tryptase activity
NZ333713A NZ333713A (en) 1996-07-30 1997-07-30 Compounds for treating diseases associated with tryptase activity
JP50913698A JP2001509787A (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases involving tryptase activity
SK85-99A SK8599A3 (en) 1996-07-30 1997-07-30 Disubstituted cyclic compound, process for its preparation, pharmaceutical composition and method of the treatment of an animal
EP97937066A EP0934293A1 (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with tryptase activity
FI990171A FI990171A (en) 1996-07-30 1999-01-29 Novel compounds and compositions for the treatment of diseases related to tryptase activity
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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999040073A2 (en) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Tryptase inhibitors
WO1999040083A2 (en) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Bifunctional tryptase inhibitors
WO2000014097A2 (en) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyranoses
WO2001010848A2 (en) * 1999-08-10 2001-02-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Diazocin-dione derivatives and their use s tryptase inhibitors
WO2001019809A1 (en) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Tryptase inhibitors
US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
WO2001036386A1 (en) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Diabetic remedy containing dipiperazine derivative
WO2001046168A1 (en) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Tryptase inhibitors
WO2002060895A1 (en) * 2001-01-31 2002-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Diazocine derivatives and their use as tryptase inhibitors
WO2002066420A2 (en) * 2001-02-21 2002-08-29 Altana Pharma Ag Tryptase inhibitors
WO2002074733A2 (en) * 2001-03-15 2002-09-26 Altana Pharma Ag Tryptase-inhibitors
WO2002074732A2 (en) * 2001-03-15 2002-09-26 Altana Pharma Ag Tryptase-inhibitors
US6815557B2 (en) 1999-12-20 2004-11-09 Altana Pharma Ag Tryptase inhibitors
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6833140B2 (en) 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US6962941B2 (en) 2001-06-19 2005-11-08 Altana Pharma Ag Tryptase inhibitors
US7060716B2 (en) 2001-02-21 2006-06-13 Altana Pharma Ag Tryptase inhibitors
WO2010069595A1 (en) * 2008-12-19 2010-06-24 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8394857B2 (en) 2008-12-19 2013-03-12 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of inflammatory skin diseases
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US10464920B2 (en) 2015-07-06 2019-11-05 Inserm (Institute National De La Santé Et De La Recherche Médicale Vicinal primary diamines associated with metal and/or free radical chelation motifs, and active against carbonyl and oxidative stress, and use thereof
CN110869362A (en) * 2017-05-12 2020-03-06 国立研究开发法人理化学研究所 Modified class A GPCR binding compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19955476A1 (en) * 1999-11-18 2001-05-23 Boehringer Ingelheim Pharma Bis-basic compounds as tryptase inhibitors, process for their preparation and their use as medicaments

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845242A (en) * 1987-04-28 1989-07-04 Georgia Tech Research Corporation Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
WO1994020527A1 (en) * 1993-03-12 1994-09-15 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1995032945A1 (en) * 1994-06-01 1995-12-07 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell mediated conditions
WO1996009297A1 (en) * 1994-09-23 1996-03-28 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell inflammatory condition
US5525623A (en) * 1993-03-12 1996-06-11 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1996030353A1 (en) * 1995-03-24 1996-10-03 Arris Pharmaceutical Corporation Reversible protease inhibitors
WO1996040737A1 (en) * 1995-06-07 1996-12-19 Arris Pharmaceutical Corporation Reversible cysteine protease inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845242A (en) * 1987-04-28 1989-07-04 Georgia Tech Research Corporation Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
WO1994020527A1 (en) * 1993-03-12 1994-09-15 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
US5525623A (en) * 1993-03-12 1996-06-11 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1995032945A1 (en) * 1994-06-01 1995-12-07 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell mediated conditions
WO1996009297A1 (en) * 1994-09-23 1996-03-28 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell inflammatory condition
WO1996030353A1 (en) * 1995-03-24 1996-10-03 Arris Pharmaceutical Corporation Reversible protease inhibitors
WO1996040737A1 (en) * 1995-06-07 1996-12-19 Arris Pharmaceutical Corporation Reversible cysteine protease inhibitors

Cited By (46)

* Cited by examiner, † Cited by third party
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US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
WO1999040083A2 (en) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Bifunctional tryptase inhibitors
WO1999040073A3 (en) * 1998-02-06 1999-11-11 Max Planck Gesellschaft Tryptase inhibitors
WO1999040083A3 (en) * 1998-02-06 1999-11-11 Max Planck Gesellschaft Bifunctional tryptase inhibitors
US6489327B1 (en) * 1998-02-06 2002-12-03 Max-Planck-Gesellschaft Zur Fordrungder Wisenschaften, E.V. Tryptase inhibitors
US6613769B1 (en) * 1998-02-06 2003-09-02 Max-Planck-Gesellschaft zur Föderung der Wissenschaften. e.V. Tryptase inhibitors
WO1999040073A2 (en) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Tryptase inhibitors
WO2000014097A2 (en) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyranoses
WO2000014097A3 (en) * 1998-09-04 2000-07-20 Byk Gulden Lomberg Chem Fab Novel pyranoses
WO2001010848A3 (en) * 1999-08-10 2001-12-06 Byk Gulden Lomberg Chem Fab Diazocin-dione derivatives and their use s tryptase inhibitors
WO2001010848A2 (en) * 1999-08-10 2001-02-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Diazocin-dione derivatives and their use s tryptase inhibitors
US6673786B1 (en) 1999-08-10 2004-01-06 Altana Pharma Ag Tryptase inhibitors
WO2001019809A1 (en) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Tryptase inhibitors
US6960588B1 (en) 1999-09-14 2005-11-01 Altana Pharma Ag Tryptase inhibitors
AU778965B2 (en) * 1999-09-14 2004-12-23 Altana Pharma Ag Tryptase inhibitors
WO2001036386A1 (en) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Diabetic remedy containing dipiperazine derivative
US6815557B2 (en) 1999-12-20 2004-11-09 Altana Pharma Ag Tryptase inhibitors
AU783217B2 (en) * 1999-12-20 2005-10-06 Altana Pharma Ag Tryptase inhibitors
WO2001046168A1 (en) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Tryptase inhibitors
WO2002060895A1 (en) * 2001-01-31 2002-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Diazocine derivatives and their use as tryptase inhibitors
US6924305B2 (en) 2001-01-31 2005-08-02 Altana Pharma Ag Diazocine derivatives and their use as tryptase inhibitors
US7060716B2 (en) 2001-02-21 2006-06-13 Altana Pharma Ag Tryptase inhibitors
WO2002066420A2 (en) * 2001-02-21 2002-08-29 Altana Pharma Ag Tryptase inhibitors
US7101911B2 (en) 2001-02-21 2006-09-05 Altana Pharma Ag Tryptase inhibitors
WO2002066420A3 (en) * 2001-02-21 2003-02-27 Altana Pharma Ag Tryptase inhibitors
WO2002074732A2 (en) * 2001-03-15 2002-09-26 Altana Pharma Ag Tryptase-inhibitors
WO2002074733A3 (en) * 2001-03-15 2003-09-25 Altana Pharma Ag Tryptase-inhibitors
WO2002074732A3 (en) * 2001-03-15 2003-10-30 Altana Pharma Ag Tryptase-inhibitors
WO2002074733A2 (en) * 2001-03-15 2002-09-26 Altana Pharma Ag Tryptase-inhibitors
US6833140B2 (en) 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6962941B2 (en) 2001-06-19 2005-11-08 Altana Pharma Ag Tryptase inhibitors
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8906412B2 (en) 2004-11-04 2014-12-09 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
RU2484813C2 (en) * 2008-12-19 2013-06-20 Мерц Фарма Гмбх Унд Ко. Кгаа Derivatives of 1-amino-alkylcyclohexane for treatment of diseases, mediated by mast cells
US8680149B2 (en) 2008-12-19 2014-03-25 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US8399519B2 (en) 2008-12-19 2013-03-19 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US8394857B2 (en) 2008-12-19 2013-03-12 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of inflammatory skin diseases
WO2010069595A1 (en) * 2008-12-19 2010-06-24 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US10464920B2 (en) 2015-07-06 2019-11-05 Inserm (Institute National De La Santé Et De La Recherche Médicale Vicinal primary diamines associated with metal and/or free radical chelation motifs, and active against carbonyl and oxidative stress, and use thereof
CN110869362A (en) * 2017-05-12 2020-03-06 国立研究开发法人理化学研究所 Modified class A GPCR binding compounds
EP3623368A4 (en) * 2017-05-12 2021-04-07 Riken Class a gpcr-binding compound modifier

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