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WO2000049007A1 - Derives acetamido acetonitriles en tant qu'inhibiteurs de la cathepsine l et/ou s - Google Patents

Derives acetamido acetonitriles en tant qu'inhibiteurs de la cathepsine l et/ou s Download PDF

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Publication number
WO2000049007A1
WO2000049007A1 PCT/GB2000/000532 GB0000532W WO0049007A1 WO 2000049007 A1 WO2000049007 A1 WO 2000049007A1 GB 0000532 W GB0000532 W GB 0000532W WO 0049007 A1 WO0049007 A1 WO 0049007A1
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Prior art keywords
alkyl
optionally substituted
carbamoyl
sulphamoyl
amino
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PCT/GB2000/000532
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English (en)
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WO2000049007A8 (fr
Inventor
Howard Tucker
Michael Stewart Large
John Oldfield
Craig Johnstone
Philip Neil Edwards
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Astrazeneca Ab
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Priority claimed from GBGB9903857.2A external-priority patent/GB9903857D0/en
Priority claimed from GBGB9916098.8A external-priority patent/GB9916098D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP00903848A priority Critical patent/EP1155010A1/fr
Priority to JP2000599747A priority patent/JP2002537293A/ja
Priority to AU25603/00A priority patent/AU2560300A/en
Publication of WO2000049007A1 publication Critical patent/WO2000049007A1/fr
Publication of WO2000049007A8 publication Critical patent/WO2000049007A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that are cysteine protease inhibitors and in particular compounds that are Cathepsin L inhibitors and or Cathepsin S inhibitors especially Cathepsin S inhibitors.
  • the invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents, to pharmaceutical compositions containing them and to a method of treating a Cathepsin L or Cathepsin S mediated disease state.
  • Cysteine proteases are enzymes important in normal cell physiology, but they are also associated with several disease states including inflammation, metastasis, tissue damage following myocardial infarction, bone resorption and muscle wasting in dystrophic diseases.
  • Cathepsins B, H, K, L, N and S are cysteinyl proteases involved in normal protein degradation and are normally located in the lysosomes of cells. However, when these enzymes are found outside the lysosomes they have been implicated as playing a causative role in a number of disease states including bone resorption disease such as osteoporosis.
  • Living bone is continuously being remodelled and replenished by the process of resorption and deposition of the protein matrix and calcium minerals. These events are facilitated by the osteoclast, which has the ability to degrade and demineralise the bone, and the osteoblast which is responsible for new bone generation. In normal situations these processes are intimately linked resulting in little alteration of bone mass.
  • pathological conditions exist in which there is an imbalance between their activities resulting in increased degradation and demineralisation of bone and the development of fragile and/or brittle bone structure, as seen during osteoporosis.
  • Cathepsins B, H, K, L, N and S have been further implicated as playing a causative role in other diseases such as rheumatoid arthritis, osteoarthritis, tumour metastasis, pneumocystitis, Crithidia fusiculata, malaria, trypanosoma brucei brucei, schistosomiasis, periodontal disease, metachromatic leukodystrophy and muscular dystrophy.
  • Cathepsins B, H, K, L, N and S either alone or together, have also been implicated as playing a causative role in chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention discloses compounds with inhibitory activity of cysteine proteases and in particular of Cathepsin L and or Cathepsin S.
  • the compounds of the invention are also useful in the treatment of chronic obstructive pulmonary disease (COPD). Accordingly the present invention provides a compound of formula (I):
  • Ar is optionally substituted phenyl, optionally substituted naphthyl, Het, C 3 . ⁇ 2 cycloalkyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d ⁇ alkoxy, d- ⁇ alkyl, nitro, C ⁇ . 6 alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, Ci. 6 alkanoyl, d. 6 alkanoyloxy, amino, C ⁇ .
  • alkyl 2 amino, d_ 6 alkyl, hydroxy, trifluoromethoxy, cyano, d_ 6 alkoxy, C ⁇ . 6 alkanoyl, C ⁇ . 6 alkanoyloxy, d_ 6 alkanoylamino, carboxy, carbamoyl, N-(d. alkyl)carbamoyl, N,N-(C 1 . alkyl) 2 carbamoyl, C ⁇ . 6 alkoxycarbonyl, mercapto, Cj. 6 alkylsulphanyl, d. 6 alkylsulphinyl, d. 6 alkylsulphonyl, sulphamoyl,
  • R 1 is H, d- ⁇ alkyl (optionally substituted with R 8 ), Cl-6 alkylsulphanyl (optionally substituted with R 8 ), C ⁇ alkenyl, R 8 , R 8 S- wherein R 8 is phenyl, C 3 . 12 cycloalkyl, Het or a 5- or 6- membered heteroaryl ring, all of which are optionally substituted by one or more groups chosen from Q- ⁇ alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C]. 6 alkoxy, C ⁇ . 6 alkanoyl, d- alkanoyloxy, amino, d.
  • 6 alkyl 2 sulphamoyl and benzyloxy, with the proviso that if R 1 is d. 6 alkylsulphanyl (optionally substituted with R 8 ) or R 8 S- then X is -SO 2 ⁇ (R 7 )-; R 2 is H or C ⁇ . 6 alkyl;
  • R 3 is H or Ci- ⁇ alkyl
  • R 4 is H, C ⁇ . 6 alkyl (optionally substituted with one or more of hydroxy, C ⁇ - 6 alkylsulphanyl, C ⁇ . 6 alkylsulphinyl, C]. alkylsulphonyl, R 9 , R 9 C ! - 6 alkylsulphanyl, R 9 C 1 . 6 alkylsulphinyl and R 9 C 1 . 6 alkylsulphonyl), or R 4 is C ⁇ - 6 alkoxy (optionally substituted with one or more of C 2 - 6 alkenyl, C 2 . 6 alkynyl, R 9 , R 9 C 2 - 6 alkenyl, R 9 C 2 .
  • R 4 is C 2 . 6 alkenyl, C 2 - alkynyl, d- 6 alkoxycarbonyl, carbamoyl, N-(C ⁇ - 6 alkyl)carbamoyl, N,N-(C ⁇ . 6 alkyl) 2 carbamoyl, R 9 -, R 9 S-, R 9 d. 6 alkylsulphanyl, N-(R 9 C ⁇ _ 6 alkyl)carbamoyl, N-(Hetd. 6 alkyl)carbamoyl, d. 6 alkanoylamino, C ⁇ . 6 alkylsulphanyl, C ⁇ .
  • R 5 is H or C ⁇ - 6 alkyl; Het is a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms; provided that: when R 1 is H or d_ 6 alkyl, X is O or S, and R 2 and R 3 are both hydrogen, then Ar is not pyrimid-4-yl; when R 1 and R 2 are both hydrogen, R 3 is C ⁇ - 6 alkyl, X is O, R 4 is hydrogen, C ⁇ _ 6 alkyl, phenyl or benzyl, and R 5 is hydrogen or d ⁇ alkyl, then Ar is not halophenyl; when R 1 and R 3 are both hydrogen, R 2 and R 5 are, independently, hydrogen or methyl, R 4 is unsubstituted pyrrolyl, thienyl or furyl, and X is O, then Ar is not 3-methyl-2,4- dichlorophenyl; when R 1 is hydrogen or C alkyl, R 2 is hydrogen or C
  • 'alkyl' includes straight chained and branched structures and ring systems.
  • d. alkyl includes propyl, isopropyl, t-butyl, cyclopropyl and cyclohexyl.
  • references to individual alkyl groups such as 'propyl' are specific for the straight chained version only
  • references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only
  • references to individual cycloalkyl groups such as cyclohexyl are specific to the cyclic groups only.
  • a similar convention applies to other radicals, for example "aminoC 1 _ 6 alkyl" includes
  • halo refers to fluoro, chloro, bromo and iodo.
  • Het means, unless otherwise further specified, a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms. Examples of heteroatoms include nitrogen, oxygen and sulphur. Examples of “Het” include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl. Further examples of “Het” include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholino and morpholino. Preferably "Het” is morpholino.
  • “5- or 6- membered heteroaryl ring” means, unless otherwise further specified, a 5- or 6- membered ring that contains some degree of unsaturation, with up to four ring heteroatoms selected from nitrogen, oxygen and sulphur.
  • Examples of “5- or 6- membered heteroaryl ring” include thienyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrrolyl and pyrazolyl.
  • Examples of “5- membered heteroaryl ring” include thienyl, furyl, imidazolyl, thiazolyl and pyrrolyl.
  • Examples of “drete 6 alkanoyloxy” are acetoxy and propionyloxy. Examples of
  • d- 6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of “d. 6 alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of “d_ 6 alkanoylamino” include formamido, acetamido and propionylamino.
  • Examples of "C ⁇ . 6 alkylsulphanyl include methylthio and ethylthio.
  • 6 alkylsulphinyl include methylsulphinyl and ethylsulphinyl. Examples of "C ⁇ .
  • 6 alkylsulphonyl include mesyl and ethylsulphonyl.
  • Examples of “d. 6 alkanoyl” include acetyl and propionyl.
  • Examples of “d.. 6 alkylamino” include methylamino and ethylamino.
  • Examples of "N,N-(C ⁇ - 6 alkyl) 2 amino” include NN-dimethylamino, NN-diethylamino and N-ethyl-N-methylamino.
  • Examples of “C 2 - 6 alkenyl” are vinyl, allyl and 1-propenyl. Examples of "C 2 .
  • 6 alkynyl are ethynyl, 1-propynyl and 2-propynyl.
  • Examples of "N-(C 1 . 6 alkyl)aminoC 1 . 6 alkyl” are 2-N-methylaminoethyl and 3-N-ethylaminopropyl.
  • Examples of "N,N-(d. 6 alkyl) 2 aminoC ⁇ - 6 alkyl” are 2-(N,N-dimethylamino)ethyl and
  • N-(C ⁇ . 6 alkyl)carbamoyl are methylaminocarbonyl and ethylaminocarbonyl.
  • N,N-(C 1 .6alkyl) 2 carbamoyl are dimethylaminocarbonyl and methylethylaminocarbonyl.
  • N-(C ⁇ . 6 alkyl)sulphamoyl are N-methylsulphamoyl and N-ethylsulphamoyl.
  • R 9 d- 6 alkylsulphanyl include R 9 methylthio and R 9 ethylthio.
  • R 9 C 1 . 6 alkylsulphinyl include R 9 methylsulphinyl and R 9 ethylsulphinyl.
  • R 9 d. 6 alkylsulphonyl include R 9 mesyl and R 9 ethylsulphonyl.
  • R 9 C 2 . 6 alkenyl are R 9 vinyl and R 9 allyl.
  • Examples of “C 2 - 6 alkynyl” are R 9 ethynyl and R 9 propyn-l-yl.
  • Examples of “N-(R 9 C ⁇ - 6 alkyl)carbamoyl” are R 9 methylaminocarbonyl and R 9 ethylaminocarbonyl.
  • Examples of “N-(Hetd. 6 alkyl)carbamoyl” are morpholinomethylaminocarbonyl and 2- (piperidinoethyl)aminocarbonyl.
  • Examples of “C 3 . 12 cycloalkyl” are cyclopropyl, cyclopentyl and cyclohexyl.
  • substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
  • substituents are chosen from one or more halo, d. 6 alkoxy and d ⁇ alkyl
  • examples of possible combinations of substituents include 1) a bromo group, 2) two chloro groups, 3) a methoxy, ethoxy and propoxy substitutent, 4) a fluoro and a methoxy group, 5) a methoxy, a methyl and an ethyl group, and 6) a chloro, a methoxy and an ethyl group.
  • the present invention provides a compound of formula (I), wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, Het, C 3 . 12 cycloalkyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d. 6 alkoxy, C ⁇ _ 6 alkyl, nitro, d. 6 alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ _ alkanoyl, C ⁇ . 6 alkanoyloxy, amino, d- 6 alkylamino, N,N-(C ⁇ .
  • 6 alkyl amino, carboxy, carbamoyl, N-(Ci- 6 alkyl)carbamoyl, N,N-(d_ alkyl) 2 carbamoyl, d. 6 alkoxycarbonyl, mercapto, d. 6 alkylsulphanyl, d. alkylsulphinyl, C ⁇ . alkylsulphonyl, sulphamoyl, N-(d. 6 alkyl)sulphamoyl, N,N-(C 1 . alkyl) 2 sulphamoyl, aminod.. alkyl, N-(C ⁇ - 6 alkyl)aminoC ⁇ .
  • R 6 alkyl R 6 S-, R 6 C(O)- and R 6 CH 2 - wherein R 6 is phenyl which is optionally substituted by one or more groups chosen from d_ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ - 6 alkoxy, C ⁇ . 6 alkanoyl, d. 6 alkanoyloxy, amino, d. alkylamino, N,N-(C ⁇ . 6 alkyl) 2 amino, d.
  • alkanoylamino nitro, carboxy, carbamoyl, N-(C ⁇ _ 6 alkyl)carbamoyl, N,N-(C ⁇ - 6 alkyl) 2 carbamoyl, d_ alkoxycarbonyl, mercapto, d. 6 alkylsulphanyl, d. 6 alkylsulphinyl, C ⁇ . 6 alkylsulphonyl, sulphamoyl, N-(d- 6 alkyl)sulphamoyl and N,N-(C 1 .
  • alkanoylamino nitro, carboxy, carbamoyl, N-(d_ 6 alkyl)carbamoyl, N,N-(C 1 _ 6 alkyl) 2 carbamoyl, Ci- ⁇ alkoxycarbonyl, mercapto, d. 6 alkylsulphanyl, d.
  • 6 alkyl halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ _ 6 alkoxy, d. 6 alkanoyl, C ⁇ _ 6 alkanoyloxy, amino, d. 6 alkylamino, N,N-(C ⁇ - 6 alkyl) 2 amino, C]. alkanoylamino, nitro, carboxy, carbamoyl, N-(C]. 6 alkyl)carbamoyl, N,N-(C 1 . 6 alkyl) 2 carbamoyl, C ⁇ . 6 alkoxycarbonyl, mercapto, d ⁇ alkylsulphanyl, d. 6 alkylsulphinyl, d.
  • alkylsulphonyl sulphamoyl, N-(d. 6 alkyl)sulphamoyl and N,N-(C 1 . 6 alkyl) 2 sulphamoyl; and R 5 is H or C ⁇ - 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I), wherein Ar is optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, C ⁇ _ 6 alkyl, nitro, C ⁇ - 6 alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ - alkanoyl, C ⁇ - alkanoyloxy, amino, C ⁇ _ 6 alkylamino, N,N-(C ⁇ - 6 alkyl) 2 amino, carboxy, carbamoyl, N-(C ⁇ - 6 alkyl)carbamoyl, N,N-(C ⁇ - 6 alkyl) 2 carbamoyl, d- ⁇ alkoxycarbonyl, mercapto, C 1 - 6 alkylsulphanyl, d.
  • Ar is optionally substituted phenyl, optionally substitute
  • R 6 is phenyl which is optionally substituted by one or more groups chosen from C ⁇ _ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ - 6 alkoxy, C ⁇ - 6 alkanoyl, C ⁇ - 6 alkanoyloxy, amino, C ⁇ .
  • 6 alkyl 2 amino, d- 6 alkyl, hydroxy, trifluoromethoxy, cyano, C ⁇ . 6 alkoxy, d. 6 alkanoyl, Ci- ⁇ alkanoyloxy, C ⁇ . 6 alkanoylamino, carboxy, carbamoyl, N-(d. 6 alkyl)carbamoyl, N,N-(Ci_ alkyl) carbamoyl, d. 6 alkoxycarbonyl, mercapto, d. 6 alkylsulphanyl, C ! . 6 alkylsulphinyl, C ⁇ - 6 alkylsulphonyl, sulphamoyl, N-(d.
  • R 1 is H, d- ⁇ alkyl (optionally substituted with R 8 ), C 2 . 6 alkenyl, R 8 S- wherein R 8 is phenyl which is optionally substituted by one or more groups chosen from ddonating 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d. 6 alkoxy, d. 6 alkanoyl, d ⁇ alkanoyloxy, amino, N,N-(C ⁇ . 6 alkyl) 2 amino, d.
  • R 2 is H or Ci- ⁇ alkyl
  • R 3 is H or Ci- ⁇ alkyl
  • R 4 is H, C ⁇ - 6 alkyl (optionally substituted with one or more of hydroxy
  • R 4 is C ⁇ _ 6 alkoxy (optionally substituted with one or more of C 2 . 6 alkenyl, C 2 . 6 alkynyl, R 9 , R 9 C 2 . 6 alkenyl, R 9 C 2 - 6 alkynyl, Het and trifluoromethyl), or R 4 is C 2 - 6 alkenyl, C 2 .
  • R 9 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more of d_ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d- 6 alkoxy, d. 6 alkanoyl, Ci- ⁇ alkanoyloxy, amino, d. 6 alkylamino, N,N-(d- 6 alkyl) 2 amino, C ⁇ . 6 alkanoylamino, nitro, carboxy, carbamoyl, N-(C ⁇ - 6 alkyl)carbamoyl, N,N-(C 1 .
  • Ar is optionally substituted phenyl, optionally substituted naphthyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d ⁇ alkoxy, Ci- ⁇ alkyl, nitro, C]. 6 alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d- ⁇ alkanoyl, C ⁇ - 6 alkanoyloxy, amino, d-6alkylamino, N,N-(C 1 . 6 alkyl) 2 amino, carboxy, carbamoyl, N-(d. 6 alkyl)carbamoyl, /V,N-(C ⁇ .
  • R 6 alkyl R 6 S-, R 6 C(O)- and R 6 CH 2 - wherein R 6 is phenyl which is optionally substituted by one or more groups chosen from d. 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ _ alkoxy, d. alkanoyl, d. 6 alkanoyloxy, amino, d. 6 alkylamino, NN-(C 1 .
  • R 1 is H, C]. 6 alkyl (optionally substituted with R 8 ), C 2 ⁇ alkenyl, R 8 S- wherein R 8 is phenyl which is optionally substituted by one or more groups chosen from d_ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d_ 6 alkoxy, C 1 . 6 alkanoyl, d. 6 alkanoyloxy, amino, d_ 6 alkyl amino, N,N-(C ⁇ . 6 alkyl) 2 amino, C ⁇ . 6 alkanoylamino, nitro, carboxy, carbamoyl, N-(d.
  • R 4 is H, C ⁇ - 6 alkyl (optionally substituted with one or more of hydroxy, C ⁇ _ alkylsulphanyl, C ⁇ - 6 alkylsulphinyl, Ci- ⁇ alkylsulphonyl, R 9 , R 9 C ⁇ - 6 alkylsulphanyl, R 9 d- 6 alkylsulphinyl and R 9 d. 6 alkylsulphonyl), or R 4 is d. 6 alkoxy (optionally substituted with one or more of C 2 - 6 alkenyl, C . 6 alkynyl, R 9 , R 9 C 2 . 6 alkenyl, R 9 C 2 .
  • R 4 is C 2 _ 6 alkenyl, C 2 . 6 alkynyl, d. 6 alkoxycarbonyl, carbamoyl, N-(C,. 6 alkyl)carbamoyl, N,N-(d. 6 alkyl) 2 carbamoyl, R 9 -, R 9 S-, R 9 d- 6 alkylsulphanyl, N-(R 9 C ! . 6 alkyl)carbamoyl, N-(Hetd_ 6 alkyl)carbamoyl, d. 6 alkanoylamino,
  • Ar is an optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted 5 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d. 6 alkoxy, d_ 6 alkyl, nitro, C ⁇ . 6 alkanoylamino, trifluoromethyl, N,N-(C ⁇ . 6 alkyl) 2 amino and N,N-(C ⁇ - 6 alkyl) 2 aminoC 1 . 6 alkyl.
  • Ar is an optionally substituted phenyl, optionally substituted naphthyl, morpholino or an optionally substituted 5 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d- 6 alkoxy, C ⁇ . 6 alkyl, nitro, d. 6 alkanoylamino, trifluoromethyl, N.N- d-ealkyl ⁇ amino and N,N-(C ⁇ . 6 alkyl) 2 aminoC 1 . 6 alkyl with the proviso that when Ar is morpholino X cannot be - ⁇ (R 7 )- or -O-.
  • the 5-membered heteroaryl ring is, for example, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl or isothiazolyl.
  • the 5-membered ring is suitably thienyl.
  • Ar is an optionally substituted phenyl, optionally substituted naphthyl and optionally substituted thienyl said optional substituents being chosen from one or more fluoro, chloro, bromo, methoxy, methyl, nitro, acetylamino, trifluoromethyl, N,N-dimethylamino or N,N-dimethylaminomethyl.
  • Ar is an optionally substituted phenyl, optionally substituted naphthyl, morpholino and optionally substituted thienyl said optional substituents being chosen from one or more fluoro, chloro, bromo, methoxy, methyl, nitro, acetylamino, trifluoromethyl, N,N-dimethylamino or N,N-dimethylaminomethyl with the proviso that when Ar is morpholino X cannot be - ⁇ (R 7 )- or -O-.
  • Ar is phenyl which is optionally substituted with 1 to 3 fluoro, chloro or bromo.
  • Ar is morpholino or phenyl which is optionally substituted with 1 to 3 fluoro, chloro or bromo with the proviso that when Ar is morpholino X cannot be -N(R 7 )- or -O-.
  • Ar is phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl and 2,4,6-trichlorophenyl.
  • Ar is morpholino, phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl and 2,4,6-trichlorophenyl with the proviso that when Ar is morpholino X cannot be -N(R 7 )- or -O-.
  • Het is as defined above (that is it is: a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms; for example pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl).
  • X is -SO 2 ⁇ (R 7 )- the nitrogen atom is attached to the CR'R 2 group and the sulphur is attached to the Ar group.
  • X is -N(Me)-, -S-, -SO-, -SO 2 -, -O- and -SO 2 N(R 7 )- wherein R 7 is hydrogen, methyl, ethyl, propyl, isobutyl, cyanoethyl, morpholinoethyl, furylmethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl, where said phenylallyl or benzyl is optionally substituted with methoxy, nitro, chloro, trifluoromethyl, methyl or N,N-dimethylamino.
  • X is -O-, -SO 2 - and -SO 2 N(R 7 )- wherein R 7 is hydrogen, furylmethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl, where said benzyl is optionally substituted with methoxy, nitro, chloro, trifluoromethyl, methyl or N,N-dimethylamino.
  • X is -O-, -SO 2 - and -SO 2 ⁇ (R 7 )- wherein R 7 is hydrogen, fur-2- ylmethyl, thien-2-ylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, phenylallyl or benzyl, where said benzyl is optionally substituted with methoxy, nitro, chloro, trifluoromethyl, methyl or NN-dimethylamino.
  • R 7 is not hydrogen.
  • R 7 is optionally substituted benzyl wherein said optional substituents are as defined for R 10 above.
  • R 1 is hydrogen, C 2 . 6 alkenyl and C ⁇ - 6 alkyl which is optionally substituted with phenyl where said phenyl is optionally substituted by one or more groups chosen from halo, cyano, C ⁇ _ 6 alkoxy, nitro, d. 6 alkylsulphonyl and benzyloxy. More preferably R 1 is hydrogen, methyl, ethyl, propyl, isobutyl, 2-methylbut-2-ene and benzyl where said phenyl is optionally substituted with one group chosen from fluoro, chloro, methoxy, benzyloxy, mesyl, nitro and cyano.
  • R 1 is hydrogen and benzyl where said phenyl is optionally substituted with methoxy, fluoro, chloro, mesyl, nitro or cyano. More particularly R 1 is hydrogen, benzyl, 2-fluorobenzyl, 3-methoxybenzyl,
  • R 1 is hydrogen.
  • R 2 is hydrogen.
  • R 3 is hydrogen.
  • R 4 is hydrogen, d_ 6 alkyl (optionally substituted with d- 6 alkylsulphanyl,
  • Het is as defined above (that is it is: a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms; for example pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl).
  • R 4 is hydrogen, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, methylthio, ethylthio, isopropylthio, methylthiomethyl, methylthioethyl, ethynyloxy, propynyloxy, carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isobutylaminocarbonyl, furyl (optionally substituted with methyl), pyridyl, thienyl (optionally substituted with bromo or methyl), N-methylpyrrolyl, benzylaminocarbonyl, pyridylmethylaminocarbonyl and morpholinoethylaminocarbonyl.
  • R 4 is methoxy, isopropylthio, propynyloxy, furyl (optionally substituted with methyl) and thienyl.
  • R 4 is methoxy, isopropylthio, propyn-1-yloxy, fur-2-yl, 5-methylfur-2-yl and thien-2-yl.
  • R is an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more of d_ 6 alkyl and halo.
  • R 4 is optionally substituted thienyl or furyl said optional substituents being chosen from one or more of C ⁇ _ 6 alkyl and halo.
  • R 4 is thienyl
  • R 4 is thien-2-yl.
  • R 5 is hydrogen or methyl.
  • R 5 is hydrogen
  • Ar is an optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted 5 membered heteroaryl ring, said optional substituents being chosen from one or more of halo, d_ 6 alkoxy, d combat 6 alkyl, nitro, d. 6 alkanoylamino, trifluoromethyl, N,N-(C ⁇ . 6 alkyl) 2 amino and N ) N-(C 1 . 6 alkyl) 2 aminoC ⁇ . 6 alkyl;
  • R 1 is hydrogen, C 2 . 6 alkenyl or C ⁇ . 6 alkyl which is optionally substituted with phenyl where said phenyl is optionally substituted by one or more groups chosen from halo, cyano, d. alkoxy, nitro, C ⁇ . 6 alkylsulphonyl and benzyloxy;
  • R 4 is hydrogen, (optionally substituted with Ci- ⁇ alkylsulphanyl, C ⁇ - 6 alkylsulphinyl and d. 6 alkylsulphonyl), d. 6 alkoxy (optionally substituted with C 2 . alkynyl), d_ 6 alkoxycarbonyl, carbamoyl, N-(d.
  • R 9 is phenyl or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more of C ⁇ _ 6 alkyl or halo;
  • R 5 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is that of formula (I) wherein: Ar is phenyl which is optionally substituted with 1 to 3 fluoro, chloro or bromo;
  • X is -O-, -SO 2 - or -SO 2 ⁇ (R 7 )- wherein R 7 is hydrogen, furylmethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl, where said benzyl is optionally substituted with methoxy, nitro, chloro, trifluoromethyl, methyl or N,N-dimethylamino;
  • R 1 is hydrogen or benzyl where said phenyl is optionally substituted with methoxy, fluoro, chloro, mesyl, nitro or cyano;
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is methoxy, isopropylthio, propynyloxy, furyl (optionally substituted with methyl) and thienyl; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds are those of Examples 156-158 or a pharmaceutically acceptable salt thereof.
  • Especially preferred compounds are those of Examples 5, 19, 20, 27, 31, 38, 42, 43, 45, 46, 50, 51, 91, 92, 93, 94, 97, 98, 100, 101, 102, 104, 106, 108, 109, 1 1 1, 1 12, 1 14, 1 15, 116, 117, 120, 122, 126, 141, 143 or 146 or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as the methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example a sodium salt, an alkaline earth metal salt for example a calcium or a magnesium salt, an organic amine salt for example a salt with triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or an amino acid for example a lysine salt.
  • a preferred pharmaceutically acceptable salt is a sodium salt.
  • Some compounds of formula (I) may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I) which possess cysteine protease inhibitory activity.
  • the invention further relates to all tautomeric forms of the compounds of formula (I). It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. According to this aspect of the invention there is provided a process (in which variable groups are as defined for formula (I) unless otherwise stated) which comprises:
  • a suitable reactive derivative of an acid of the formula (II) is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate, an alcohol such as 1 - hydroxybenzotriazole or a uronium salt such as 2-(l-benzotriazolyl)-l,l,3,3- tetramethyluronium hexafluorophosphate(V); an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl
  • the reaction is preferably carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate or potassium carbonate, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine or diazabicyclo-[5.4.0]undec-7-ene.
  • a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate or potassium carbonate, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine or diazabicyclo-[5.4.0]undec-7-ene.
  • the reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, acetonitrile, tetrahydrofuran, 1 ,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin- 2-one or dimethylsulphoxide, and at a temperature in the range, for example, -78° to 150°C, conveniently at or near ambient temperature.
  • a suitable inert solvent or diluent for example methylene chloride, acetonitrile, tetrahydrofuran, 1 ,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin- 2-one or dimethylsulphoxide, and at a temperature in the range, for example, -78° to 150°C, conveniently at or near ambient temperature.
  • L is a displaceable group.
  • a suitable displaceable group L is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the reaction is preferably carried out in the presence of a suitable base as defined hereinbefore such as potassium carbonate.
  • a suitable inert solvent or diluent as defined hereinbefore such as N,N-dimethylformamide and at a temperature in the range of -0 to 100°C conveniently 25°C to 100°C.
  • a dehydration reaction may conventionally be carried out by reaction with a reagent such as trifluoroacetic anhydride.
  • the reaction can conveniently be conducted in the presence of a suitable base as defined hereinbefore such as, for example, triethylamine.
  • the reaction is also preferably carried out in a suitable inert solvent or diluent, as defined hereinbefore such as dichloromethane and at a temperature in the range, for example, -10°C to reflux conveniently 10°C to reflux.
  • the reaction can conveniently be conducted in the presence of a suitable base as defined hereinbefore such as potassium carbonate, in a suitable inert solvent or diluent as defined hereinbefore such as acetonitrile and at a temperature in the range of 25°C to reflux, conveniently 50°C to reflux.
  • a suitable base as defined hereinbefore such as potassium carbonate
  • a suitable inert solvent or diluent as defined hereinbefore such as acetonitrile
  • the necessary starting materials for the procedures described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, by techniques which are analogous to the above described procedures or by techniques which are analogous to the procedures described in the examples.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and a Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with.a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. Many of the intermediates defined herein are novel, for example, those of the formula
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease in a warm blooded animal, such as man.
  • a method of treating a Cathepsin L or Cathepsin S mediated disease state in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg "1 to 100 mgkg " of the compound, preferably in the range of 5 mgkg "1 to 20 mgkg “1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. Inhibition of Cathepsin L and S.
  • the pharmaceutically-acceptable compounds of the present invention are useful in the inhibition of Cathepsin L and Cathepsin S, having a good activity in vitro against human Cathepsin L, human Cathepsin S and rabbit Cathepsin L.
  • Cathepsin L activity was measured based on the method of Barrett and Kirschke (1981 Methods in Enzymology, 80, 535-561), using the fluorogenic substrates NCBz-Phe-Arg- NHMec. Inhibitors were identified by their ability to decrease the generation of the fluorescent leaving group (NHMec). Briefly the assay was as follows: rHuman Cathepsin L or rabbit Cathepsin L (0.025 pmoles) was pre-incubated with or without test compound in 0.1M sodium acetate buffer pH4.5, lOmM cysteine, 0.1% BRIJTM 35 at 25°C for 15 minutes in a solid black 96 well plate.
  • Synthetic substrate 20 ⁇ M NCBz- Phe-Arg-NHMec
  • 20 ⁇ M NCBz- Phe-Arg-NHMec was added and the mixture incubated at 37°C for 30 minutes.
  • the reaction was stopped by the addition of 0.1M sodium chloroacetate pH 4.3.
  • Fluorescence was determined using a Fluoroskan II plate reader; excitation 355nm, emission 460nm.
  • Compound potency was determined from the raw fluorescence data by calculating the IC 50 against each enzyme using a PC graph drawing software package. Cathepsin S assay.
  • Recombinant human Cathepsin S was cloned and expressed in Baculovirus, by the following method.
  • the cDNA sequence for human Cathepsin S is available in the EMBL database Accession Number M90696. This database sequence was used to prepare, by PCR on mRNA from human tissues, a recombinant plasmid carrying an insert with a DNA sequence identical to that of Cathepsin S in the EMBL database (Ace. no. M90696).
  • the techniques for mRNA isolation, PCR and cloning are standard techniques known by those skilled in the art. Sequence determination of the recombinant insert was carried out using established DNA sequencing techniques.
  • the PCR was done so as to introduce an EcoRI cloning site 5' of the 'ATG' of
  • BacTM Expression System commercially available from Gibco BRL -Life Technologies (cat. no. 10359-016)). This recombinant construct was used to generate, by standard techniques, a recombinant baculovirus capable of expressing preprocathepsin S.
  • Procathepsin S was found in the insect cell medium and acid activated.
  • the medium was mixed with an equal volume of lOOmM Sodium Acetate buffer pH 4.5, 5mM dithiothreitol (DTT) and 5mM EDTA and incubated for one hour at 37°C method of Maubach et al (Eur. J. Biochem., 250, 745-750, 1997).
  • the pH of insect cell medium (10ml) containing procathepsin S was adjusted to 4.5 with glacial acetic acid and DTT and EDTA added to 5mM. The sample was then incubated at 37°C for 150min to enable conversion to the active enzyme. Ammonium sulphate was then added to 80% saturation and a pellet obtained by centrifugation. This pellet was redissolved in 2ml buffer A (lOOmM Tris, 500mM NaCl, ImM EDTA, pH7.5) and mixed in a batch wise fashion with lOO ⁇ l thiopropyl-Sepharose for 15min at 4°C. The non bound fraction was removed by a brief centrifugation and the gel washed with 2x1 ml buffer A. Cathepsin S was then eluted by batch mixing with 0.4ml 20mM DTT in buffer A for 15min at 4°C.
  • Cathepsin S activity was measured based on the method of Maubach et al (Eur. J. Biochem., 250, 745-750, 1997), using the fluorogenic substrate Z-Val-Val-Arg-NHMec. Inhibitors were identified by their ability to decrease the generation of the fluorescent leaving group (NHMec). Briefly the assay was as follows: rHuman Cathepsin S (1.5 nmoles) was pre-incubated with or without compounds in 50mM Potassium phosphate buffer pH 6.0-6.2, 20mM Na 2 EDTA, 0.1% BRUTM at 25°C for 5 minutes in a solid black 96 well plate.
  • Synthetic substrate 20 ⁇ M Z-Nal-Nal-Arg-NHMec
  • 20 ⁇ M Z-Nal-Nal-Arg-NHMec was added and the mixture incubated at 30°C for 20 minutes.
  • the reaction was stopped by the addition of 0.1M sodium chloroacetate pH 4.3.
  • Fluorescence was determined using a Fluoroskan II plate reader; excitation 355nm, emission 460nm.
  • Compound potency was determined from the raw fluorescence data by calculating the IC 5 o against Cathepsin S using a PC graph drawing software package.
  • the compounds of this invention When tested in the above in-vitro tests the compounds of this invention give IC 50 S in the range 1-10,000 nM.
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO- ⁇ 6 ) as the solvent unless otherwise stated;
  • melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymo ⁇ hism may result in isolation of materials with different melting points in some preparations.
  • Oxalyl chloride (0.39 g) was added to a suspension of 2,3-dichlorophenoxyacetic acid
  • Examples 60-131 were prepared according to the method of Example 1 using the appropriate sulphonamide containing acids and substituted aminoacetonitriles.
  • Examples 159-167 were prepared by adapting a suitable method disclosed herein.
  • Trifluoroacetic anhydride (0.12 ml) was added dropwise to a stirred mixture of 2- [2- (2,4,6-trichlorophenoxy)acetamido]-2-methoxyacetamide (98 mg) in pyridine (3 ml) at -15°C. The mixture was allowed to warm to ambient temperature then poured into ice-water and extracted with ether. The organic phase was washed with brine, dried and evaporated to dryness under reduced pressure to give 2-[2-(2,4,6-trichlorophenoxy)acetamido]-2- methoxyacetonitrile (70 mg).
  • N-bromosuccinimide (42 mg) was added to a stirred solution of 2-[2-(2,4- dichlorophenoxy)acetamido]-2-isopropylthio acetonitrile (52 mg) in propargyl alcohol (1.5 ml). The mixture was allowed to warm to room temperature and evaporated to dryness under reduced pressure and the residue was partitoned between ethyl acetate and water. The organic phase was separated, dried and evaporated to dryness under reduced pressure.
  • Pentachlorophenoxy acetic acid A mixture of pentachlorophenol (5 g), acetone (80 ml), methyl bromoacetate (1.74 ml) and potassium carbonate (7.8 g) was stirred at reflux for 3 hours, cooled, filtered and the filtrate was evaporated to dryness under reduced pressure to give methyl-2-
  • 2,4-Dichlorophenoxyacetylchloride (1.2 g) was added dropwise to a stirred, ice cooled mixture of 2-S-methionine amide hydrochloride (0.91 g), N,N-dimethylformamide (10 ml) and 4-methyl mo ⁇ holine (0.8 ml) was stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted with chloroform. The extract was washed successively with water, 1M hydrochloric acid and brine, dried and evaporated to dryness under reduced pressure.
  • N-(N-Mo ⁇ holinosulphonyl)-N(benzyl)glycine methyl ester (Method L) (1.3 g) was dissolved in ethanol (25 ml) and aqueous 2M sodium hydroxide (9.9 ml) was added and the mixture stirred at ambient temperature for 20 hours. The reaction mixture was reduced to small volume, diluted with water (25 ml) , acidified with 2M HC1 and extracted with dichloromethane (3x25 ml). The combined dichloromethane extracts were dried. The solvent was removed and the residue was triturated with isohexane to give the title compound, 0.9g.

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Abstract

L'invention concerne un composé correspondant à la formule (I) dans laquelle Ar, R?1, R2, R3, R4 et R5¿ possèdent les notations données dans la description. Elle concerne également une composition comprenant un composé correspondant à la formule (I) ainsi qu'un excipient ou diluant; elle concerne encore l'emploi d'un composé correspondant à la formule (I) à dans la fabrication d'un médicament utile pour inhiber une cystéine protéase chez un animal de sang chaud, l'emploi d'un tel composé dans la fabrication d'un médicament utile dans le traitement du syndrome respiratoire obstructif chronique, chez un animal de sang chaud, ainsi qu'un procédé de traitement d'une pathologie induite par la cathepsine L ou S, consistant à administrer à un mammifère nécessitant un tel traitement une dose efficace d'un composé correspondant à la formule (I).
PCT/GB2000/000532 1999-02-20 2000-02-16 Derives acetamido acetonitriles en tant qu'inhibiteurs de la cathepsine l et/ou s WO2000049007A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP00903848A EP1155010A1 (fr) 1999-02-20 2000-02-16 Derives acetamido acetonitriles en tant qu'inhibiteurs de la cathepsine l et/ou s
JP2000599747A JP2002537293A (ja) 1999-02-20 2000-02-16 カテプシンｌおよび／またはカテプシンｓの阻害剤としてのアセタミドアセトニトリル誘導体
AU25603/00A AU2560300A (en) 1999-02-20 2000-02-16 Acetamido acetonitrile derivatives as inhibitors of cathepsin l and/or cathepsins

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9903857.2A GB9903857D0 (en) 1999-02-20 1999-02-20 Chemical compounds
GB9903857.2 1999-07-10
GBGB9916098.8A GB9916098D0 (en) 1999-07-10 1999-07-10 Chemical compounds
GB9916098.8 1999-07-10

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WO2000049007A1 true WO2000049007A1 (fr) 2000-08-24
WO2000049007A8 WO2000049007A8 (fr) 2001-03-15

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JP (1) JP2002537293A (fr)
AU (1) AU2560300A (fr)
WO (1) WO2000049007A1 (fr)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1159273A1 (fr) * 1999-03-02 2001-12-05 Boehringer Ingelheim Pharmaceuticals Inc. Composes utiles en tant qu'inhibiteurs reversibles de la cathepsine s
WO2002050052A1 (fr) * 2000-12-20 2002-06-27 Syngenta Participations Ag N-acyl aminoacetonitriles aux proprietes pesticides
US6455502B1 (en) 1999-03-15 2002-09-24 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
WO2002100849A3 (fr) * 2001-06-08 2003-10-16 Boehringer Ingelheim Pharma Nouveaux nitriles utilises comme inhibiteurs reversibles de cysteine proteases
US6642239B2 (en) 2000-02-10 2003-11-04 Novartis Ag Dipeptide nitrile cathepsin K inhibitors
JP2003533506A (ja) * 2000-05-15 2003-11-11 ノバルティス アクチエンゲゼルシャフト Ｎ−置換ペプチジルニトリル
WO2004022526A1 (fr) * 2002-09-04 2004-03-18 Merck Frosst Canada & Co. Inhibiteurs de proteases a cysteine de type cathepsine
WO2003086325A3 (fr) * 2002-04-05 2004-07-01 Boehringer Ingelheim Pharma Cyanamides utiles en tant qu'inhibiteurs reversibles des cysteine proteases
US6812237B2 (en) 2000-05-15 2004-11-02 Novartis Ag N-substituted peptidyl nitriles as cysteine cathepsin inhibitors
EP1452522A3 (fr) * 1999-03-15 2005-02-09 Axys Pharmaceuticals, Inc. Nouveaux composés et composiitons comme inhibiteurs de proteases
WO2004089395A3 (fr) * 2003-04-01 2005-02-17 Aventis Pharma Inc Utilisation d'un inhibiteur de la cathepsine-s ou -b afin de traiter ou de prevenir les maladies pulmonaires obstructives chroniques
US6878706B1 (en) 2002-04-05 2005-04-12 Boehringer Ingelheim Pharmaceuticals Inc. Cyanamides useful as reversible inhibitors of cysteine proteases
EP1248612A4 (fr) * 2000-01-06 2005-09-07 Merck Frosst Canada Inc Nouveaux composes et compositions utilises comme inhibiteurs de protease
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
EP1482924A4 (fr) * 2002-03-05 2006-03-08 Merck Frosst Canada Inc Inhibiteurs de cathepsine cysteine protease
US7012075B2 (en) 2001-03-02 2006-03-14 Merck & Co., Inc. Cathepsin cysteine protease inhibitors
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
WO2006034004A3 (fr) * 2004-09-17 2006-11-23 Axys Pharm Inc Procedes et produits intermediaires permettant de preparer des inhibiteurs de la cysteine protease
WO2006128287A1 (fr) * 2005-06-02 2006-12-07 Merck Frosst Canada Ltd. Derives de fluoroalkylamine utilises comme inhibiteurs de la cathepsine
WO2007017088A1 (fr) * 2005-07-25 2007-02-15 Novartis Ag Composés amidonitrile
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7326719B2 (en) 2003-03-13 2008-02-05 Boehringer Ingelheim Pharmaceuticals, Inc. Cathepsin S inhibitors
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
US7465745B2 (en) 2003-03-13 2008-12-16 Boehringer Ingelheim Pharmaceuticals, Inc. Cathepsin S inhibitors
EP2198879A1 (fr) 2008-12-11 2010-06-23 Institut Curie Agent modulateur de CD74 pour la régulation de la migration de cellules dendritiques et dispositif pour l'étude de la capacité de motilité d'une cellule
EP2251007A2 (fr) 2002-09-24 2010-11-17 Novartis AG Agonistes du récepteur de la sphingosine-1-phosphate (S1P) pour son utilisation dans le traitement des maladies démyélinisantes
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
WO2014076038A1 (fr) * 2012-11-14 2014-05-22 F. Hoffmann-La Roche Ag Nouveaux dérivés d'acétamide en tant qu'antagonistes des canaux trp
WO2015037747A1 (fr) * 2013-09-13 2015-03-19 Nihon Nohyaku Co., Ltd. Agent anticancéreux comportant un composé d'aminoacétonitrile en tant que principe actif
EP3011958A1 (fr) 2008-06-20 2016-04-27 Novartis AG Compositions pédiatriques pour le traitement de la sclérose en plaques
CN116589425A (zh) * 2022-12-29 2023-08-15 百放英库医药科技(北京)有限公司 组织蛋白酶l抑制剂
WO2024037520A1 (fr) * 2022-08-16 2024-02-22 中国科学院上海药物研究所 Composé amide et son procédé de préparation, composition pharmaceutique et utilisation associée

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7297714B2 (en) * 2003-10-21 2007-11-20 Irm Llc Inhibitors of cathepsin S
US7423176B2 (en) * 2004-04-13 2008-09-09 Cephalon, Inc. Bicyclic aromatic sulfinyl derivatives

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010298A1 (fr) * 1978-10-23 1980-04-30 BASF Aktiengesellschaft Dérivés 1,2,4-triazol-1-yliques, leur préparation, fongicides, procédé de préparation de fongicides et méthode de lutte contre les champignons
DE3001433A1 (de) * 1979-01-16 1980-07-17 Produits Ind Cie Fse Phenoxy- und thiophenoxy-nitrile und deren verwendung als herbizide
US4567267A (en) * 1981-06-15 1986-01-28 American Home Products Corporation α-Phenyl-2-(aza)benzothiazolylthioglycolic acids and derivatives thereof
EP0262393A1 (fr) * 1986-08-29 1988-04-06 Shell Internationale Researchmaatschappij B.V. Dérivés d'acides aryloxycarboniques, leur préparation et leur utilisation
EP0272671A2 (fr) * 1986-12-22 1988-06-29 Sandoz Ltd. Aryloxy et arylacyloxy méthyl cétones comme inhibiteurs de thiol protéase
JPH03218347A (ja) * 1989-11-10 1991-09-25 Nippon Soda Co Ltd カルボン酸アミド誘導体及びその製造方法
JPH05286937A (ja) * 1992-04-10 1993-11-02 Mitsubishi Petrochem Co Ltd 置換ピリジルオキシカルボン酸アミド誘導体およびそれを含有する農業用殺菌剤
JPH06211766A (ja) * 1993-01-18 1994-08-02 Mitsubishi Petrochem Co Ltd アルコキシカルボン酸アミド誘導体およびそれを含有する農業用殺菌剤
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
WO1995015749A1 (fr) * 1993-12-08 1995-06-15 Prototek, Inc. Inhibiteurs de cysteine protease contenant des groupes partants heterocycliques
WO1998018766A1 (fr) * 1996-10-31 1998-05-07 Kumiai Chemical Industry Co., Ltd. Derives d'amine pyrimidinyloxyalcanoique et fongicides pour usage agricole et horticole
WO1999054287A1 (fr) * 1998-04-20 1999-10-28 American Cyanamid Company Procede ameliore de production de derives n-(1-cyanoalkyl)-2-pnenoxypropionamide

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010298A1 (fr) * 1978-10-23 1980-04-30 BASF Aktiengesellschaft Dérivés 1,2,4-triazol-1-yliques, leur préparation, fongicides, procédé de préparation de fongicides et méthode de lutte contre les champignons
DE3001433A1 (de) * 1979-01-16 1980-07-17 Produits Ind Cie Fse Phenoxy- und thiophenoxy-nitrile und deren verwendung als herbizide
US4567267A (en) * 1981-06-15 1986-01-28 American Home Products Corporation α-Phenyl-2-(aza)benzothiazolylthioglycolic acids and derivatives thereof
EP0262393A1 (fr) * 1986-08-29 1988-04-06 Shell Internationale Researchmaatschappij B.V. Dérivés d'acides aryloxycarboniques, leur préparation et leur utilisation
EP0272671A2 (fr) * 1986-12-22 1988-06-29 Sandoz Ltd. Aryloxy et arylacyloxy méthyl cétones comme inhibiteurs de thiol protéase
JPH03218347A (ja) * 1989-11-10 1991-09-25 Nippon Soda Co Ltd カルボン酸アミド誘導体及びその製造方法
JPH05286937A (ja) * 1992-04-10 1993-11-02 Mitsubishi Petrochem Co Ltd 置換ピリジルオキシカルボン酸アミド誘導体およびそれを含有する農業用殺菌剤
JPH06211766A (ja) * 1993-01-18 1994-08-02 Mitsubishi Petrochem Co Ltd アルコキシカルボン酸アミド誘導体およびそれを含有する農業用殺菌剤
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
WO1995015749A1 (fr) * 1993-12-08 1995-06-15 Prototek, Inc. Inhibiteurs de cysteine protease contenant des groupes partants heterocycliques
WO1998018766A1 (fr) * 1996-10-31 1998-05-07 Kumiai Chemical Industry Co., Ltd. Derives d'amine pyrimidinyloxyalcanoique et fongicides pour usage agricole et horticole
WO1999054287A1 (fr) * 1998-04-20 1999-10-28 American Cyanamid Company Procede ameliore de production de derives n-(1-cyanoalkyl)-2-pnenoxypropionamide

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 015, no. 500 (C - 0895) 18 December 1991 (1991-12-18) *
PATENT ABSTRACTS OF JAPAN vol. 018, no. 075 (C - 1163) 8 February 1994 (1994-02-08) *
PATENT ABSTRACTS OF JAPAN vol. 018, no. 575 (C - 1268) 4 November 1994 (1994-11-04) *
PICKEN P P ET AL: "Inhibition of bovine cathepsin B by amino acid-derived nitriles", BIOCHEMICAL SOCIETY TRANSACTIONS,GB,COLCHESTER, ESSEX, vol. 18, no. 2, April 1990 (1990-04-01), pages 316, XP002108054, ISSN: 0300-5127 *
SUZUE ET AL: "Hepatic agents. I. Synthesis of aminoacyl (and hydroxyacyl)aminoacetonitriles", CHEMICAL AND PHARMACEUTICAL BULLETIN,JP,TOKYO, vol. 16, no. 8, August 1968 (1968-08-01), pages 1417 - 1432, XP002108053, ISSN: 0009-2363 *

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EP1159273A1 (fr) * 1999-03-02 2001-12-05 Boehringer Ingelheim Pharmaceuticals Inc. Composes utiles en tant qu'inhibiteurs reversibles de la cathepsine s
US6455502B1 (en) 1999-03-15 2002-09-24 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
US6476026B1 (en) 1999-03-15 2002-11-05 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
US6593327B2 (en) 1999-03-15 2003-07-15 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
EP1452522A3 (fr) * 1999-03-15 2005-02-09 Axys Pharmaceuticals, Inc. Nouveaux composés et composiitons comme inhibiteurs de proteases
EP1248612A4 (fr) * 2000-01-06 2005-09-07 Merck Frosst Canada Inc Nouveaux composes et compositions utilises comme inhibiteurs de protease
US6642239B2 (en) 2000-02-10 2003-11-04 Novartis Ag Dipeptide nitrile cathepsin K inhibitors
JP2003533506A (ja) * 2000-05-15 2003-11-11 ノバルティス アクチエンゲゼルシャフト Ｎ−置換ペプチジルニトリル
US6812237B2 (en) 2000-05-15 2004-11-02 Novartis Ag N-substituted peptidyl nitriles as cysteine cathepsin inhibitors
WO2002050052A1 (fr) * 2000-12-20 2002-06-27 Syngenta Participations Ag N-acyl aminoacetonitriles aux proprietes pesticides
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7012075B2 (en) 2001-03-02 2006-03-14 Merck & Co., Inc. Cathepsin cysteine protease inhibitors
WO2002100849A3 (fr) * 2001-06-08 2003-10-16 Boehringer Ingelheim Pharma Nouveaux nitriles utilises comme inhibiteurs reversibles de cysteine proteases
US6982263B2 (en) 2001-06-08 2006-01-03 Boehringer Ingelheim Pharmaceuticals, Inc. Nitriles useful as reversible inhibitors of cysteine proteases
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
JP2008115177A (ja) * 2002-03-05 2008-05-22 Merck Frosst Canada Ltd カテプシンシステインプロテアーゼ阻害剤
US8318748B2 (en) 2002-03-05 2012-11-27 Merck, Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
AU2003219953B8 (en) * 2002-03-05 2008-09-25 Axys Pharmaceuticals, Inc. Cathepsin cysteine protease inhibitors
US7375134B2 (en) 2002-03-05 2008-05-20 Axys Pharmaceuticals, Inc. Cathepsin cysteine protease inhibitors
EP1482924A4 (fr) * 2002-03-05 2006-03-08 Merck Frosst Canada Inc Inhibiteurs de cathepsine cysteine protease
US7973037B2 (en) 2002-03-05 2011-07-05 Axys Pharmaceuticals, Inc. Cathepsin cysteine protease inhibitors
AU2003219953B2 (en) * 2002-03-05 2007-11-01 Axys Pharmaceuticals, Inc. Cathepsin cysteine protease inhibitors
WO2003086325A3 (fr) * 2002-04-05 2004-07-01 Boehringer Ingelheim Pharma Cyanamides utiles en tant qu'inhibiteurs reversibles des cysteine proteases
US6878706B1 (en) 2002-04-05 2005-04-12 Boehringer Ingelheim Pharmaceuticals Inc. Cyanamides useful as reversible inhibitors of cysteine proteases
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
US7279478B2 (en) 2002-09-04 2007-10-09 Merck Frosst Canada & Co. Cathepsin cysteine protease inhibitors
WO2004022526A1 (fr) * 2002-09-04 2004-03-18 Merck Frosst Canada & Co. Inhibiteurs de proteases a cysteine de type cathepsine
EP2251007A2 (fr) 2002-09-24 2010-11-17 Novartis AG Agonistes du récepteur de la sphingosine-1-phosphate (S1P) pour son utilisation dans le traitement des maladies démyélinisantes
EP2255798A2 (fr) 2002-09-24 2010-12-01 Novartis AG Agonistes du récepteur de la sphingosine-1-phosphate (S1P) pour son utilisation dans le traitement de la névrite optique
US7465745B2 (en) 2003-03-13 2008-12-16 Boehringer Ingelheim Pharmaceuticals, Inc. Cathepsin S inhibitors
US7326719B2 (en) 2003-03-13 2008-02-05 Boehringer Ingelheim Pharmaceuticals, Inc. Cathepsin S inhibitors
WO2004089395A3 (fr) * 2003-04-01 2005-02-17 Aventis Pharma Inc Utilisation d'un inhibiteur de la cathepsine-s ou -b afin de traiter ou de prevenir les maladies pulmonaires obstructives chroniques
US7737300B2 (en) * 2004-09-17 2010-06-15 Virobay, Inc. Processes and intermediates preparing cysteine protease inhibitors
WO2006034004A3 (fr) * 2004-09-17 2006-11-23 Axys Pharm Inc Procedes et produits intermediaires permettant de preparer des inhibiteurs de la cysteine protease
WO2006128287A1 (fr) * 2005-06-02 2006-12-07 Merck Frosst Canada Ltd. Derives de fluoroalkylamine utilises comme inhibiteurs de la cathepsine
WO2007017088A1 (fr) * 2005-07-25 2007-02-15 Novartis Ag Composés amidonitrile
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
EP3011958A1 (fr) 2008-06-20 2016-04-27 Novartis AG Compositions pédiatriques pour le traitement de la sclérose en plaques
EP3545953A1 (fr) 2008-06-20 2019-10-02 Novartis AG Compositions pédiatriques pour le traitement de la sclérose en plaques
EP2198879A1 (fr) 2008-12-11 2010-06-23 Institut Curie Agent modulateur de CD74 pour la régulation de la migration de cellules dendritiques et dispositif pour l'étude de la capacité de motilité d'une cellule
US9359337B2 (en) 2012-11-14 2016-06-07 Hoffmann-La Roche Inc. Acetamide derivatives
CN104812740A (zh) * 2012-11-14 2015-07-29 霍夫曼-拉罗奇有限公司 作为trp通道拮抗剂的新乙酰胺衍生物
WO2014076038A1 (fr) * 2012-11-14 2014-05-22 F. Hoffmann-La Roche Ag Nouveaux dérivés d'acétamide en tant qu'antagonistes des canaux trp
WO2015037747A1 (fr) * 2013-09-13 2015-03-19 Nihon Nohyaku Co., Ltd. Agent anticancéreux comportant un composé d'aminoacétonitrile en tant que principe actif
US9907778B2 (en) 2013-09-13 2018-03-06 Pitney Pharmaceuticals Pty Limited Anticancer agent comprising aminoacetonitrile compound as active ingredient
US10292960B2 (en) 2013-09-13 2019-05-21 Pitney Pharmaceuticals Pty Limited Anticancer agent comprising aminoacetonitrile compound as active ingredient
WO2024037520A1 (fr) * 2022-08-16 2024-02-22 中国科学院上海药物研究所 Composé amide et son procédé de préparation, composition pharmaceutique et utilisation associée
CN116589425A (zh) * 2022-12-29 2023-08-15 百放英库医药科技(北京)有限公司 组织蛋白酶l抑制剂

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EP1155010A1 (fr) 2001-11-21
AU2560300A (en) 2000-09-04
WO2000049007A8 (fr) 2001-03-15
JP2002537293A (ja) 2002-11-05

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