EP1157003A1 - Inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles - Google Patents

Inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles

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Publication number
EP1157003A1
EP1157003A1 EP00903853A EP00903853A EP1157003A1 EP 1157003 A1 EP1157003 A1 EP 1157003A1 EP 00903853 A EP00903853 A EP 00903853A EP 00903853 A EP00903853 A EP 00903853A EP 1157003 A1 EP1157003 A1 EP 1157003A1
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EP
European Patent Office
Prior art keywords
alkyl
carbamoyl
optionally substituted
sulphamoyl
alkylsulphanyl
Prior art date
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Withdrawn
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EP00903853A
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German (de)
English (en)
Inventor
Howard Tucker
Michael Stewart Large
John Oldfield
Craig Johnstone
Philip Neil Edwards
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1157003A1 publication Critical patent/EP1157003A1/fr
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    • 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
    • C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • 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

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
  • US 5,055,451 discloses a series of peptidyl methyl ketones as thiol protease inhibitors;
  • WO 95/15749 discloses peptidyl ketones with heterocyclic leaving groups as cysteine protease inhibitors; the in vivo inhibition of Cathepsin B by peptidyl (acyloxy) methyl ketones was discussed in J. Med. Chem. 1994, 37, 1833-40 and these types of compounds as inhibitors of cysteine protease inhibitors were also discussed in J. Am. Chem. Soc, 1988, 110, 4429-4431 ; peptidyl diazomethyl ketones as specific inactivators of thiol proteinases was discussed in J. Biol.
  • 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 phenylC 1 . 6 alkyl) 2 CH-, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted heteroaryl ring, said optional substituents being chosen from one or more of halo, C ⁇ _ 6 alkoxy, ⁇ a-kyl, nitro, C ⁇ - 6 alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ alkanoyl, - ⁇ alkanoyloxy, amino, C ⁇ .
  • R 5 is phenyl which is optionally substituted by one or more groups chosen from Ci- 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, - ⁇ alkoxy, - ⁇ alkanoyl, C ⁇ _ 6 alkanoyloxy, amino, C ⁇ . 6 alkylamino, (C ⁇ .
  • R 1 is H or C ⁇ . 6 alkyl;
  • R 2 is H, C ⁇ .
  • R 4 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents on R 4 being chosen from one or more of C ⁇ _ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, Cj. 6 alkoxy, C ⁇ - 6 alkanoyl, amino, d- ⁇ alkylamino, (C 1 .
  • Het is a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms;
  • R 3 is H or Ci- ⁇ alkyl; or a pharmaceutically acceptable salt thereof.
  • 'alkyl' includes straight chained and branched structures and ring systems.
  • C ⁇ . 6 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.
  • aminoC ⁇ _ 6 alkyl includes 1-aminoethyl and 2-aminoethyl.
  • Het means, unless otherwise further specified, a fully saturated monocyclic 5 - 8 membered heterocyclic ring, with up to 4 ring heteroatoms. Examles of heteroatoms include nitrogen, oxygen and sulphur. Examples of “Het” include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, triazole (especially 1,2,3-triazole), piperazinyl and morpholinyl. Examples of “Het” include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
  • Heteroaryl ring means, unless otherwise further specified, a monocyclic- or bicyclic- 5-12 membered ring that contains some degree of unsaturation, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur.
  • heteroaryl ring include thienyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrrolyl, pyrazolyl, indolyl, benzimidazolyl, benzothiazolyl, quinolyl and isoquinolinyl.
  • Examples of "5- or 6- membered heteroaryl ring” include thienyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrrolyl and pyrazolyl.
  • C ⁇ _ 6 alkanoyloxy are acetoxy and propionyloxy.
  • Examples of “Ci_ 6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of “C ⁇ _ 6 alkoxy” include methoxy, ethoxy and propoxy. Examples of
  • 6 alkanoylamino include formamido, acetamido and propionylamino.
  • Examples of “C]. 6 alkylsulphanyl” include methylthio and ethylthio.
  • Examples of “Q-ealkylsulphinyl” include methylsulphinyl and ethylsulphinyl.
  • Examples of " - ⁇ alkylsulphonyl” include mesyl and ethylsulphonyl.
  • Examples of “C ⁇ - 6 alkanoyl” include acetyl and propionyl.
  • Examples of “C ⁇ - 6 alkylamino” include methylamino and ethylamino.
  • N,N-(C 1 - 6 alkyl) 2 amino examples include N,N-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 ⁇ . 6 alkyl)sulphamoyl” are N-methylsulphamoyl and N-ethylsulphamoyl. Examples of "N,N-(C 1 .
  • 6 alkyl) 2 aminoC 1 - 6 alkyl are 2-(N,N-dimethylamino)ethyl and 3-(N,N-diethylamino)propyl.
  • R 4 C). 6 alkylsulphanyl include R 4 methylthio and 2- R 4 ethylthio.
  • R 4 C 1 . 6 alkylsulphinyl include R 4 methylsulphinyl and 2- R 4 ethylsulphinyl.
  • Examples of "R 4 C 1 . alkylsulphonyl” include R 4 mesyl and 2- R 4 ethylsulphonyl. Examples of R 4 C 2 .
  • 6 alkenyl are R 4 vinyl and R 4 allyl.
  • C 2 . 6 alkynyl are R 4 ethynyl and R 4 propyn-l-yl.
  • Examples of "N-(R 4 Ci_ 6 alkyl)carbamoyl” are N-(R 4 methyl)aminocarbonyl and N-(2-R 4 ethyl)aminocarbonyl.
  • Examples of "N-(HetC ⁇ . 6 alkyl)carbamoyl” are morpholinomethylaminocarbonyl and 2- (piperidinoethyl)aminocarbonyl.
  • 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, ⁇ alkoxy and Ci- ⁇ 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 phenylC 1 . 6 alkyl) 2 CH-, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted heteroaryl ring, said optional substituents being chosen from one or more of halo, - ⁇ alkoxy, - ⁇ alkyl, nitro, C ⁇ alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, - ⁇ alkanoyl, C ⁇ ⁇ alkanoyloxy, amino, C ⁇ ⁇ alkylamino, N,N-(C ⁇ - 6 alkyl) 2 amino, carboxy, carbamoyl, N-(C ⁇ _ 6 alkyl)carbamoyl, N,N-(C 1 - 6 alkyl) 2 carbamoyl, C ⁇ alkoxycarbonyl, mercapto, C ⁇ _ 6 alkyls
  • R 5 is phenyl which is optionally substituted by one or more groups chosen from Ci- ⁇ alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, ⁇ alkoxy, d- ⁇ alkanoyl, - ⁇ alkanoyloxy, amino, C ⁇ . 6 alkylamino, N,N-(C ⁇ - alkyl) 2 amino, Cj- ⁇ alkanoylamino, nitro, carboxy, carbamoyl, N-tCi-ealky carbamoyl, N,N-(C].
  • R 1 is H or Ci-ealkyl
  • R 2 is H, C ⁇ . 6 alkyl (optionally substituted with one or more hydroxy, d. 6 alkylsulphanyl, d. 6 alkylsulphinyl, d- 6 alkylsulphonyl, R 4 , R 4 C 1 . 6 alkylsulphanyl, R 4 C ⁇ . 6 alkylsulphinyl and R 4 C 1 . 6 alkylsulphonyl), or R 2 is d_ 6 alkoxy (optionally substituted with one or more C 2 . 6 alkenyl, C 2 . 6 alkynyl, R 4 , R 4 C 2 . 6 alkenyl, R 4 C 2 .
  • R 2 is C 2 . 6 alkenyl, C 2 . 6 alkynyl, d_ 6 alkoxycarbonyl, carbamoyl, N-(d. 6 alkyl)carbamoyl, N,N-(C ⁇ . 6 alkyl) 2 carbamoyl, trifluoromethoxy, R 4 -, R 4 S-, R ⁇ - ⁇ alkylsulphanyl, N-(R 4 C 1 . 6 alkyl)carbamoyl, N-(HetC ⁇ _ 6 alkyl)carbamoyl, d.
  • R 4 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents on R 4 being chosen from one or more of d. 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ - alkoxy, d. 6 alkanoyl, d. 6 alkanoyloxy, amino, d. 6 alkylamino, N,N-(C 1 .
  • alkyl 2 amino, d_ 6 alkanoylamino, nitro, carboxy, carbamoyl, N-(d. 6 alkyl)carbamoyl, N,N-(d. 6 alkyl) 2 carbamoyl, d_ 6 alkoxycarbonyl, mercapto, d-ealkylsulphanyl, C ⁇ _ 6 alkylsulphinyl, C]. alkylsulphonyl, sulphamoyl, N-(d- 6 alkyl)sulphamoyl and N,N-(C 1 . 6 alkyl) 2 sulphamoyl; and
  • R 3 is H or C ⁇ _ 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein Ar is phenyl substituted with 1 to 3 chloro or methyl moieties, or naphthyl substituted with 1 bromo atom; R 1 is H or d_ 6 alkyl; R 2 is H, d- 6 alkyl (optionally substituted with one or more hydroxy, Ci. 6 alkylsulphanyl, d- 6 alkylsulphinyl, d ⁇ alkylsulphonyl, R 4 , R 4 d. 6 alkylsulphanyl, R 4 d combat 6 alkylsulphinyl or R 4 d. 6 alkylsulphonyl), C].
  • alkylsulphanyl N-(R 4 d- 6 alkyl)carbamoyl, N-(HetC ⁇ . 6 alkyl)carbamoyl, d_ 6 alkanoylamino, C].
  • alkylsulphanyl Ci- ⁇ alkylsulphinyl or Cj. 6 alkylsulphonyl;
  • R 4 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents on R 4 being chosen from one or more of d_ 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ _ 6 alkoxy, d.
  • Ar is optionally substituted phenyl or optionally substituted naphthyl said optional substituents being chosen from one or more of halo and d. 6 alkyl.
  • Ar is phenyl substituted with 1 to 3 chloro or methyl moieties, or naphthyl substituted with 1 bromo group. Particularly Ar is phenyl substituted with 2 chloro groups or naphthyl substituted with
  • Ar is 2,6-dichlorophenyl or l-bromo-napth-2-yl.
  • R 1 is hydrogen
  • R 2 is hydrogen, d_ 6 alkoxy (optionally substituted with one or more C 2 . alkynyl, R 4 , R 4 C 2 . 6 alkenyl, R 4 C 2 . 6 alkynyl or Het), d- 6 alkanoylamino, trifluoromethoxy, d_ 6 alkylsulphanyl or R 4 wherein R 4 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more d. 6 alkyl groups.
  • 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 2 is hydrogen, d. 6 alkoxy (optionally substituted with one or more halogen, C 2 . 6 alkynyl, R 4 , R 4 C 2 . 6 alkenyl, R 4 C 2 . 6 alkynyl or Het), d_ 6 alkanoylamino, C ⁇ - 6 alkylsulphanyl or R 4 ;
  • R 4 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more Cj.
  • R 4 is optionally substituted: phenyl, pyridyl, triazolyl, pyrazolyl, furyl or thienyl.
  • Het is pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl. More preferably R 2 is hydrogen, methoxy, ethoxy, propoxy, 3-phenylprop-2-ynyloxy,
  • the present invention provides a compound of formula (I) wherein R 2 is hydrogen, methoxy, ethoxy, propoxy, 3-phenylprop-2-ynyloxy, 3-phenylprop-2-enyloxy, 2-morpholinoethoxy, acetamido, 2,2,2-trifluoroethoxy, methylthio, ethylthio, wo-propylthio, 2-propynyloxy, pyridylmethoxy, optionally substituted pyrazolyl, optionally substituted triazolyl, optionally substituted furyl, optionally substituted thienyl where said optional substituents are chosen from 1 or 2 methyl groups or said 5-membered ring is fused to a benzene ring (to form, for example, a benzotriazolyl bicyclic ring system).
  • R 2 is methoxy, ethoxy, ⁇ -propoxy, 2-morpholinoethoxy, 2-propynyloxy and isopropylthio.
  • R 3 is hydrogen.
  • Ar is optionally substituted phenyl or optionally substituted naphthyl said optional substituents being chosen from one or more of halo and d_ alkyl;
  • R 1 is hydrogen;
  • R 2 is hydrogen, d_ 6 alkoxy (optionally substituted with C 2 _ 6 alkynyl, R 4 C 2 . 6 alkenyl, R 4 C 2 . 6 alkynyl or Het), d. 6 alkanoylamino, trifluoromethoxy, Cj- 6 alkylsulphanyl or R 4 wherein R 4 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl ring said optional substituents being chosen from one or more d_ 6 alkyl groups; and R is hydrogen; or a pharmaceutically acceptable salt thereof.
  • 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).
  • a further preferred class of compounds is that of formula (I) wherein: Ar is phenyl substituted with 2 chloro groups or naphthyl substituted with 1 bromo group;
  • R 1 is hydrogen
  • R is methoxy, ethoxy, n-propoxy, 2-morpholinoethoxy, 2-propynyloxy or isopropylthio; and R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein Ar is phenyl optionally substituted with halogen (such as chlorine) or C M alkyl (such as methyl), or naphthyl optionally substituted by halogen (such as bromo); R 1 and R 3 are both hydrogen; and R 2 is hydrogen, d- 6 alkoxy (optionally substituted by halogen (such as fluorine), pyridinyl or morpholinyl), d-6 alkylthio, C 2 . 6 alkenyloxy (optionally substituted by phenyl), C 2 .
  • halogen such as chlorine
  • C M alkyl such as methyl
  • halogen such as bromo
  • R 1 and R 3 are both hydrogen
  • R 2 is hydrogen, d- 6 alkoxy (optionally substituted by halogen (such as fluorine), pyridinyl or morpholinyl), d-6 alkylthio, C 2 . 6 alkenyloxy (option
  • Preferred compounds are those of Examples 1 - 26 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein Ar is phenyl disubstituted with halogen (such as chlorine), or naphthyl monosubstituted by halogen (such as bromo); R and R are both hydrogen; and R is Cj. 6 alkoxy (optionally substituted by morpholinyl), d_ 6 alkylthio or C 2 . 6 alkynyloxy; or a pharmaceutically acceptable salt.
  • R 2 is, for example, methoxy, ethoxy, n-propoxy, .s ⁇ -propylthio, 2- propynyloxy or 2-morpholinoethoxy.
  • Especially preferred compounds are those of Examples 1, 3, 5, 8, 10, 16 or 19 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, NN-dibenzylethylamine or an amino acid for example a lysine salt.
  • 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-ethylpiper
  • 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, 1,3,3- tetramethyluronium hexafluorophosphate(V); an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenyl
  • 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, morpholine 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, morpholine 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.
  • 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 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.
  • reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • 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.
  • 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 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 also provides a compound of the formula wherein Ar is (optionally substituted phenylC 1 .
  • R 5 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 ⁇ 6 alkanoyl, d. 6 alkanoyloxy, amino, C ⁇ _ 6 alkylamino, (C 1 . 6 alkyl) 2 amino, nitro, carboxy, carbamoyl, N-(d_ 6 alkyl)carbamoyl, N,N-(d_ 6 alkyl) carbamoyl, C 1 .
  • R 4 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents on R 4 being chosen from one or more of d. 6 alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d- 6 alkoxy, d- ⁇ alkanoyl, d. 6 alkanoyloxy, amino, d. 6 alkylamino, (C 1 .
  • R 3 is H or C ⁇ _ 6 alkyl; or a pharmaceutically acceptable salt thereof; for use as a medicament.
  • the present invention provides the use of a compound of the formula (I), wherein Ar is (optionally substituted phenylC 1 _ 6 alkyl) 2 CH-, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted heteroaryl ring, said optional substituents being chosen from one or more of halo, Cj. 6 alkyl, nitro, C ⁇ _ alkanoylamino, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, C ⁇ _ 6 alkanoyl, d_ 6 alkanoyloxy, amino, d_ 6 alkylamino, (C 1 .
  • R 5 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, d_ 6 alkanoyloxy, amino, d_ 6 alkylamino, (C 1 . 6 alkyl) 2 amino, d.
  • R 1 is H or d ⁇ alkyl
  • R 2 is H, d_ 6 alkyl (optionally substituted with one or more hydroxy, d- ⁇ alkylsulphanyl, C ⁇ . 6 alkylsulphonyl, R 4 , R 4 C 1 . 6 alkylsulphanyl, R 4 d. 6 alkylsulphinyl or R 4 d_ alkylsulphonyl), d_ 6 alkoxy (optionally substituted with one or more halogen,
  • R 4 is optionally substituted phenyl, or an optionally substituted 5 or 6 membered heteroaryl ring, said optional substituents on R 4 being chosen from one or more of d- alkyl, halo, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, d ⁇ alkoxy, d. 6 alkanoyl, d.
  • the invention further 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 (COPD) in a warm blooded animal, such as man.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • the invention also 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 L in a warm blooded animal, such as man.
  • the present invention further provides 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 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. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • 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 "1 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.
  • 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.
  • Rabbit Cathepsin L was purified from rabbit liver as described by Maciewicz R. A. and Etherington D. J. (Biochem. J. (1988) 256, 433-440) except the liver homogenate supernatant was concentrated by fractionation with (NHU) 2 SO (20-80% saturation), and the pellet taken up and dialysed against 20mM NaAcetate pH 5.5, ImM ethylenediaminetetraacetic acid (EDTA). The supernatant was then applied to a CM Sepharose ion exchange column and Cathepsin L eluted by gradient elution (0.25-0.75M NaCl). Fraction activity was determined using the 5 synthetic substrate NCBz-Phe-Arg-NHMec as described.
  • Cathepsin L fractions were pooled and desalted on a Sephacryl SI 00 column. Active fractions were pooled, adjusted to 20% saturation (NH 4 ) 2 SO 4 and concentrated on a phenyl sepharose column. The remaining purification steps were as described.
  • Cathepsin L activity was measured based on the method of Barrett and Kirschke (1981).
  • the PCR was done so as to introduce an EcoRI cloning site 5' of the 'ATG' of Cathepsin S and an Xbal cloning site 3' of the 'Stop' codon.
  • the PCR product was cloned between the EcoRI and Xbal sites of the baculovirus transfer vector pFASTBAC-1 (Bac-to- Bac Expression System commercially available from Gibco BRL -Life Technologies ( cat no 5 10359-016)). This recombinant construct was used to generate, by standard techniques, a recombinant baculovirus capable of expressing preprocathepsin S.
  • Cathepsin S was tested for the baculoviral constructs by infection of two insect cell lines : Sf9 cells (ATCC No CRL-1711) and T.ni cells (Invitrogen, Cat No B855-02). 10 Purification of Cathepsin S Method 1.
  • 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 15 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
  • 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-Nal-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% Brij at 25°C for 5 minutes in a solid black 96 well plate.
  • Synthetic substrate 20 ⁇ M Z-Val-Val-Arg-NHMec
  • 20 ⁇ M Z-Val-Val-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 50 against Cathepsin S using a PC graph drawing software package.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60°C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
  • 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 250 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; polymorphism may result in isolation of materials with different melting points in some preparations.
  • Trifluoroacetic anhydride (0.51 ml) was added dropwise to a stirred mixture of 2-(2,6- dichlorobenzamido)-2-propoxyacetamide (360 mg) in pyridine (5 ml) at -10°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. The residue was triturated with hexane and the insoluble solid collected to give 2-(2,6-dichlorobenzamido)-2-propoxyacetonitrile (235 mg).
  • Example 17 2-(l-bromo-2- naphthoylamino)-2-isopropylthioacetamide as starting material to give 2-(l-bromo-2- naphthoylamino)-2-isopropylthioacetonitrile.
  • Example 17 2-(2.4-Dichlorobenzamido)-2-isopropylthioacetonitrile
  • Example 18 The process described in Example 2 was repeated using 2-(2,4-dichlorobenzamido)-2- isopropylthioacetamide as starting material to give 2-(2,4-dichlorobenzamido)-2- isopropylthioacetonitrile.
  • Example 18 Example 18
  • Example 20 2-(2,4-Dichlorobenzamido)-2-methoxyacetonitrile The process described in Example 19 was repeated using 2-(2,4-dichlorobenzamido)-2- isopropylthioacetonitrile as starting material to give 2-(2,4-dichlorobenzamido)-2- methoxyacetonitrile.
  • Example 21 2-( 1 -Bromo-2-naphthoylamino)acetonitrile
  • N,N-Dimethylformamide (0.05 ml) was added to a stirred mixture of l-bromo-2- naphthoic acid (2 g) , dichloromethane (20 ml) and oxalyl chloride ( (0.9 ml) and the mixture was stirred for 1 hour then evaporated to dryness under reduced pressure.

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Abstract

La présente invention concerne, d'une part un composé représenté par la formule générale (I) dans laquelle R?1, R2, R3¿ et Ar sont tels que présentés dans la description, et d'autre part une composition comprenant un composé représenté par la formule générale (I) et un excipient ou un diluant. L'invention concerne également, d'une part un composé représenté par la formule générale (I) et convenant comme médicament, et d'autre part l'utilisation d'un composé représenté par la formule générale (I) pour la fabrication d'un médicament destiné à l'inhibition d'une protéase à cystéine chez un animal à sang chaud. L'invention concerne enfin, d'une part l'utilisation d'un composé représenté par la formule générale (I) pour la fabrication d'un médicament destiné au traitement d'une affection pulmonaire obstructive chronique chez un animal à sang chaud, et d'autre part un traitement d'un état pathologique à médiation par cathepsine L ou S chez un mammifère, ce traitement consistant en l'administration d'une quantité suffisante d'un composé représenté par la formule générale (I) à un mammifère justifiant d'un tel traitement.
EP00903853A 1999-02-20 2000-02-16 Inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles inhibiteurs de protease a cysteine a base d'aminoacetonitriles acyles Withdrawn EP1157003A1 (fr)

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JP2002539192A (ja) 1999-03-15 2002-11-19 アクシス・ファーマシューティカルズ・インコーポレイテッド プロテアーゼ阻害剤としての新規な化合物及び組成物
AU779855B2 (en) * 2000-01-06 2005-02-17 Axys Pharmaceuticals, Inc. Novel compounds and compositions as protease inhibitors
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
MXPA03005601A (es) * 2000-12-22 2004-12-02 Axys Pharm Inc Nuevos compuestos y composiciones como inhibidores de catepsina.
CN1324008C (zh) 2001-09-14 2007-07-04 安万特药物公司 作为组织蛋白酶抑制剂的新化合物和组合物
WO2003042197A1 (fr) 2001-11-14 2003-05-22 Aventis Pharmaceuticals Inc. Nouveaux composes et compositions jouant le role d'inhibiteurs de cathepsine s
KR100962972B1 (ko) 2002-07-26 2010-06-09 주식회사유한양행 1-페닐피페리딘-3-온 유도체 및 그의 제조방법
TWI376363B (en) 2002-09-24 2012-11-11 Novartis Ag Pharmaceutical combination for treating demyelinating disease
JP4690319B2 (ja) * 2003-06-30 2011-06-01 メルク フロスト カナダ リミテツド カテプシンシステインプロテアーゼ阻害剤
EP2240491B1 (fr) 2008-01-09 2015-07-15 Amura Therapeutics Limited DÉRIVÉS DE TÉTRAHYDROFURO(2,3-b)PYRROL-3-ONE COMME INHIBITEURS DE CYSTÉINE PROTÉINASES
KR20170081755A (ko) 2008-06-20 2017-07-12 노파르티스 아게 다발성 경화증을 치료하기 위한 소아용 조성물
PL3904350T3 (pl) * 2018-04-12 2024-02-19 Bayer Aktiengesellschaft Pochodne N-(cyklopropylometylo)-5-(metylosulfonylo)-N-{1-[1-(pirymidyn-2-ylo)-1H-1,2,4-triazol-5-ilo]etylo}benzamidu oraz odpowiednie pochodne pirydyno-karboksyamidu jako pestycydy

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GB2095237B (en) * 1981-03-19 1985-04-03 Ici Plc Herbicidal and fungicidal substituted n-furyl or thienyl-methyl amides
JPS60169454A (ja) * 1984-02-15 1985-09-02 Mitsui Toatsu Chem Inc アミド置換プロパルギルオキシアセトニトリル誘導体
JPS60255759A (ja) * 1984-05-31 1985-12-17 Mitsui Toatsu Chem Inc アミド置換フルオロエトキシアセトニトリル誘導体、その製造法およびそれらを有効成分とする除草剤および農園芸用殺菌剤
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