WO1998004537A1 - Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase - Google Patents

Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase 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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English (en)
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 NZ333713A priority Critical patent/NZ333713A/xx
Priority to SI9720047A priority patent/SI9720047A/sl
Priority to AU39670/97A priority patent/AU733621B2/en
Priority to SK85-99A priority patent/SK8599A3/sk
Application filed by Arris Pharmaceutical Corporation filed Critical Arris Pharmaceutical Corporation
Priority to CA002262542A priority patent/CA2262542A1/fr
Priority to EEP199900036A priority patent/EE9900036A/xx
Priority to EP97937066A priority patent/EP0934293A1/fr
Priority to JP50913698A priority patent/JP2001509787A/ja
Priority to HU0003267A priority patent/HUP0003267A3/hu
Publication of WO1998004537A1 publication Critical patent/WO1998004537A1/fr
Priority to FI990171A priority patent/FI990171A/fi
Priority to NO990433A priority patent/NO990433L/no
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

L'invention concerne de nouveaux composés qui sont des inhibiteurs de tryptase, leurs sels et N-oxydes acceptables sur le plan pharmaceutique, leurs utilisations en tant qu'agents thérapeutiques et leurs procédés de préparation.
PCT/US1997/013422 1996-07-30 1997-07-30 Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase WO1998004537A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EEP199900036A EE9900036A (et) 1996-07-30 1997-07-30 Uued ühendid ja kompositsioonid trüptaasi aktiivsusega seotud haiguste raviks
AU39670/97A AU733621B2 (en) 1996-07-30 1997-07-30 Novel compounds and compositions for treating diseases associated with 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
JP50913698A JP2001509787A (ja) 1996-07-30 1997-07-30 トリプターゼ活性に関わる病気を処置するための新規の化合物及び組成物
CA002262542A CA2262542A1 (fr) 1996-07-30 1997-07-30 Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase
SI9720047A SI9720047A (sl) 1996-07-30 1997-07-30 Nove spojine in sestavki za zdravljenje bolezni, povezanih z delovanjem triptaze
EP97937066A EP0934293A1 (fr) 1996-07-30 1997-07-30 Nouveaux composes et compositions servant a traiter des maladies associees a l'activite de tryptase
NZ333713A NZ333713A (en) 1996-07-30 1997-07-30 Compounds for treating diseases associated with tryptase activity
HU0003267A HUP0003267A3 (en) 1996-07-30 1997-07-30 Heteroaryl derivatives, pharmaceutical compositions containing them and process for producing them
FI990171A FI990171A (fi) 1996-07-30 1999-01-29 Uusia yhdisteitä ja koostumuksia tryptaasiaktiivisuuden liittyvien tautien hoitamiseksi
NO990433A NO990433L (no) 1996-07-30 1999-01-29 Nye forbindelser og blandinger for behandling av sykdommer i forbindelse med tryptase-aktivitet
LVP-99-27A LV12291B (en) 1996-07-30 1999-02-18 COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF TRIPTASE ACTIVITY-RELATED DISEASES
LVP-00-31A LV12459B (en) 1996-07-30 2000-02-25 COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF TRIPTASE ACTIVITY-RELATED DISEASES
LVP-00-30A LV12458B (en) 1996-07-30 2000-02-25 COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF TRIPTASE ACTIVITY-RELATED DISEASES

Applications Claiming Priority (4)

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US2313996P 1996-07-30 1996-07-30
US60/023,139 1996-07-30
US89577297A 1997-07-17 1997-07-17
US08/895,772 1997-07-17

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JP (1) JP2001509787A (fr)
KR (1) KR20000029679A (fr)
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AU (1) AU733621B2 (fr)
CA (1) CA2262542A1 (fr)
CZ (1) CZ29799A3 (fr)
EE (1) EE9900036A (fr)
FI (1) FI990171A (fr)
HU (1) HUP0003267A3 (fr)
LV (1) LV12291B (fr)
NO (1) NO990433L (fr)
NZ (1) NZ333713A (fr)
PL (1) PL331465A1 (fr)
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Cited By (24)

* Cited by examiner, † Cited by third party
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WO1999040073A2 (fr) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Inhibiteurs de la tryptase
WO1999040083A2 (fr) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Inhibiteurs de la tryptase
WO2000014097A2 (fr) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyranoses
WO2001010848A2 (fr) * 1999-08-10 2001-02-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
WO2001019809A1 (fr) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de la tryptase
US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
WO2001036386A1 (fr) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Traitement du diabete contenant un derive de dipiperazine
WO2001046168A1 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
WO2002060895A1 (fr) * 2001-01-31 2002-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de diazocine et leur utilisation en tant qu'inhibiteurs de tryptase
WO2002066420A2 (fr) * 2001-02-21 2002-08-29 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074732A2 (fr) * 2001-03-15 2002-09-26 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074733A2 (fr) * 2001-03-15 2002-09-26 Altana Pharma Ag Inhibiteurs de la tryptase
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 (fr) * 2008-12-19 2010-06-24 Merz Pharma Gmbh & Co. Kgaa Dérivés de 1-amino-alkylcyclohexane dans le traitement de maladies médiées par des mastocytes
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 (zh) * 2017-05-12 2020-03-06 国立研究开发法人理化学研究所 A类gpcr结合性化合物改性体

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DE19955476A1 (de) * 1999-11-18 2001-05-23 Boehringer Ingelheim Pharma Bis-basische Verbindungen als Tryptase-Inhibitoren, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel

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WO1994020527A1 (fr) * 1993-03-12 1994-09-15 Arris Pharmaceutical Corporation Compositions et procedes pour le traitement d'affections inflammatoires immunoresultantes
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Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
WO1999040083A2 (fr) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Inhibiteurs de la tryptase
WO1999040083A3 (fr) * 1998-02-06 1999-11-11 Max Planck Gesellschaft Inhibiteurs de la tryptase
WO1999040073A3 (fr) * 1998-02-06 1999-11-11 Max Planck Gesellschaft Inhibiteurs de la tryptase
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 (fr) * 1998-02-06 1999-08-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Inhibiteurs de la tryptase
WO2000014097A2 (fr) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyranoses
WO2000014097A3 (fr) * 1998-09-04 2000-07-20 Byk Gulden Lomberg Chem Fab Nouvelles pyranoses
WO2001010848A3 (fr) * 1999-08-10 2001-12-06 Byk Gulden Lomberg Chem Fab Inhibiteurs de tryptase
WO2001010848A2 (fr) * 1999-08-10 2001-02-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
US6673786B1 (en) 1999-08-10 2004-01-06 Altana Pharma Ag Tryptase inhibitors
WO2001019809A1 (fr) * 1999-09-14 2001-03-22 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de la tryptase
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 (fr) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Traitement du diabete contenant un derive de dipiperazine
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 (fr) * 1999-12-20 2001-06-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de tryptase
WO2002060895A1 (fr) * 2001-01-31 2002-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de diazocine et leur utilisation en tant qu'inhibiteurs de tryptase
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 (fr) * 2001-02-21 2002-08-29 Altana Pharma Ag Inhibiteurs de la tryptase
US7101911B2 (en) 2001-02-21 2006-09-05 Altana Pharma Ag Tryptase inhibitors
WO2002066420A3 (fr) * 2001-02-21 2003-02-27 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074733A2 (fr) * 2001-03-15 2002-09-26 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074733A3 (fr) * 2001-03-15 2003-09-25 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074732A3 (fr) * 2001-03-15 2003-10-30 Altana Pharma Ag Inhibiteurs de la tryptase
WO2002074732A2 (fr) * 2001-03-15 2002-09-26 Altana Pharma Ag Inhibiteurs de la tryptase
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 (ru) * 2008-12-19 2013-06-20 Мерц Фарма Гмбх Унд Ко. Кгаа Производные 1-амино-алкилциклогексана для лечения заболеваний, опосредованных тучными клетками
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 (fr) * 2008-12-19 2010-06-24 Merz Pharma Gmbh & Co. Kgaa Dérivés de 1-amino-alkylcyclohexane dans le traitement de maladies médiées par des mastocytes
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 (zh) * 2017-05-12 2020-03-06 国立研究开发法人理化学研究所 A类gpcr结合性化合物改性体
EP3623368A4 (fr) * 2017-05-12 2021-04-07 Riken Modificateur de composé de liaison de gpcr de classe a

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NZ333713A (en) 2000-12-22
HUP0003267A2 (hu) 2001-06-28
EE9900036A (et) 1999-08-16
LV12291B (en) 2000-04-20
SK8599A3 (en) 2000-03-13
NO990433L (no) 1999-03-25
EP0934293A1 (fr) 1999-08-11
CZ29799A3 (cs) 1999-06-16
JP2001509787A (ja) 2001-07-24
FI990171A (fi) 1999-03-23
NO990433D0 (no) 1999-01-29
KR20000029679A (ko) 2000-05-25
FI990171A0 (fi) 1999-01-29
CN1073103C (zh) 2001-10-17
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SI9720047A (sl) 1999-08-31
AU3967097A (en) 1998-02-20
CN1226892A (zh) 1999-08-25

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