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WO1995023790A1 - Cytokines inhibant des derives d'acide hydroxamique substitue par imidazole - Google Patents

Cytokines inhibant des derives d'acide hydroxamique substitue par imidazole Download PDF

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Publication number
WO1995023790A1
WO1995023790A1 PCT/US1995/002606 US9502606W WO9523790A1 WO 1995023790 A1 WO1995023790 A1 WO 1995023790A1 US 9502606 W US9502606 W US 9502606W WO 9523790 A1 WO9523790 A1 WO 9523790A1
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Prior art keywords
alkyl
hydrogen
6alkyl
phenyl
optionally substituted
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PCT/US1995/002606
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English (en)
Inventor
James Simpson Frazee
John Gerald Gleason
Brian Walter Metcalf
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Smithkline Beecham Corporation
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Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US08/702,528 priority Critical patent/US5665753A/en
Priority to JP7523024A priority patent/JPH09509940A/ja
Priority to EP95912688A priority patent/EP0748313A4/fr
Publication of WO1995023790A1 publication Critical patent/WO1995023790A1/fr

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    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D233/68—Halogen atoms

Definitions

  • This invention relates to novel compounds for both pharmaceutical and veterinary treatment of matrix-degrading metalloproteinase related disease states.
  • MMP matrix degrading metalloproteinases
  • diseases include rheumatoid arthritis, osteoarthritis, arthropathy, dermatological conditions, bone resorption, inflammatory diseases, tumor invasion or metastasis, in the promotion of wound healing, osteoporosis, rheumatoid arthritis, periodonititis, gingivitis, and corneal ulceration, gastric ulceration.
  • hydroxamic acid derivatives have been suggested as being useful as collagenase inhibitors, or for promoting tumor regression, such as those in the following patents and patent applications: US 4,599,361; EP 236872; WO 90/05716; WO 91/02716; WO 90/05719; WO 93/20047; EPO 0498 665 Al; and WO 93/21942.
  • the present invention relates to a series of novel imidazole substituted hydroxamic acid derivatives, and compositions useful thereof as inhibitors of matrix- degrading metalloproteinase.
  • the compounds of Formula (I) may be used in the treatment of disease states mediated thereby.
  • This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
  • This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Rl is hydrogen, hydroxy, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkenyl, phenyl, optionally substituted phenyl Ci-6 alkyl-, R7-S(O)nCi-6-alkyl-; n is 0 or an integer having a value of 1 or 2;
  • R7 is C 1-6 alkyl, phenyl, phenyl Ci-6 alkyl, heterocyclic, heterocyclic Ci-6 alkyl, heteroaryl, heteroaryl Ci-6 alkyl, Ci-6 alkyl carbonyl, or phenacyl, all of which may be optionally substituted one to four time independently from Cl-6 alkyl, Ci-6 alkoxy, hydroxy, thio Ci- ⁇ alkyl, amino, halogen, CF3 or nitro;
  • R2 is hydrogen, Ci-6alkyl, Cl-6 alkenyl, phenyl Ci-6 alkyl, cycloalkyl Cl-6 alkyl, or cycloalkenyl Ci-6 alkyl;
  • R3 is hydrogen or methyl;
  • R4 is hydrogen, Ci-6 alkyl, cyclopropyl, an amino acid residue, optionally substituted phenyl, optionally substituted phenyl ci-6 alkyl- , optionally substituted
  • Ci-6alkyl optionally substituted -Ci-6 alkyl oxyCi-6 alkyl phenyl, or an optionally substituted -Ci-6 alkyl oxy phenyl; wherein the phenyl or benzyl moiety is independently substituted one to four times by halogen, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, thiol, Ci-6alkylthio-, -NR12R13, -NHR a , -NO2, -C(O)2Rl4, -C(O)2NRi2Rl3, cyanoamino,
  • Rl4C(O)-O- Ci-6 alkyl OH, Ci-6alkyl-C(O)2Rl4. Ci-6alkyl-oxy-Ci-6alkyl, C(O)Ci-6 alkylNRi2Rl3. or Ci-6alkyl-(O)2C-Ri4 ;
  • R a is hydrogen, Ci-6 alkyl, or the side chain of an amino acid
  • Rl4 is hydrogen, Cl-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci- alkyl, arylC 1 -6alkyl, heteroarylC 1 -6alkyl, or heterocyclic C 1 -6 alkyl;
  • R5 is hydrogen or Ci-6alkyl
  • R6 and R7 are independently hydrogen, halogen, CF3, Ci-6 alkyl, aryl, arylCi-6alkyl, heteroaryl, heteroarylCi-6alkyl, heterocyclic, heterocyclic Ci-6 alkyl, (CHR8)m' OH, (CHRs)m C(O)2RlO, (CHR 8 )m C(OH)(R9)2, (CRsR9)-OH, C(O)Rn, C(O)NRi2Rl3, C(O)2Rl0 > or NO2; or R6 and R7 can together form a fused C 2-4 alkylene, aryl or heteroaryl moiety; m is 0 or an integer having a value of 1 or 2; m' is an integer having a value of 1, 2, or 3;
  • R8 and Ro. are independently hydrogen, C ⁇ _4 alkyl or phenyl
  • RlO is hydrogen, Ci- alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci-6 alkyl, C5-7 cycloalkenyl, arylC 1 -6alkyl, heteroarylC 1 - ⁇ alkyl, heterocyclic, heterocyclic C 1.( ⁇ alkyl all of which may be optionally substituted by halogen, hydroxyl, -Ci-6alkoxy, -thioCi-6 alkyl, or CF3;
  • Rll is hydrogen, Cl-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci-6 alkyl, C5-7 cycloalkenyl, aryl, arylCi-6alkyl, heteroaryl, heteroarylC ⁇ _6alkyl, heterocyclic, heterocyclic Ci-6 alkyl all of which may be optionally substituted by halogen, hydroxyl, -Ci-6 alkoxy, -thioCi-6 alkyl, or CF3;
  • Rl2 and R13 are independently hydrogen, Ci- alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci-6 alkyl, aryl, arylC ⁇ _6alkyl, heteroaryl, heteroaryl Ci-6alkyl, heterocyclic, heterocyclic Ci-6 alkyl or R12 and R13 may together with the nitrogen to which they are attached form a 5 to 7 membered ring which may additionally contain another heteroatom selected from O/N/ or S; or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds, specifically racemic mixtures and stereoisomers thereof are included within the scope of the present invention.
  • Rl is hydrogen, hydroxy, or phenyl, benzyl, or R7-S(O)n Ci-6 alkyl- wherein the Ci-6 alkyl is preferably methylene.
  • R7 is preferably phenyl and n is 0.
  • R2 is Cl-6 alkyl, more preferably isobutyl.
  • R3 is hydrogen or methyl, preferably hydrogen.
  • R4 is hydrogen, Ci-6 alkyl, cyclopropyl, an amino acid residue, optionally substituted phenyl, optionally substituted phenyl ci-6 alkyl- , optionally substituted -Ci-6-alkyl-oxy Ci-6alkyl, optionally substituted -Ci-6 alkyl oxyCl-6 alkyl phenyl, or an optionally substituted -Ci-6 alkyl oxy phenyl; wherein the phenyl or benzyl moiety is independently substituted one to four times by halogen, Cl-6 alkyl, Ci-6 alkoxy, hydroxy, thiol, Ci-6alkylthio-, -NR12R13, -NHR a , -NO2, -C(O)2Rl4.
  • R6 and R7 are independently hydrogen, bromine, chlorine, CF3, Ci-6 alkyl, phenyl, (CHR8)m' OH, (CHRs)m C(O)2Rl ⁇ , (CHR8)m C(OH)(R9)2, (CR8R9)-OH, C(O)Rn, C(O)NRi2Rl3, C(O)2RlO, orNO2; or R6 and R7 can together form a fused C 2-4 alkylene, aryl or heteroaryl moiety.
  • the fused ring forms an (i.e., aryl) ring to result in a benzoimidazole moiety.
  • Rio is hydrogen, or Ci-6 alkyl
  • the alkyl is methyl or isopropyl.
  • Rl 1 is hydrogen, Cl-6 alkyl, or phenyl, preferably the alkyl is methyl or isopropyl.
  • R6 or R7 is (CHR8)m C(O)2RlO than m is preferably 0 or 2.
  • R6 or R7 is (CHR8)m OH than R8 is preferably hydrogen, methyl, isopropyl, or phenyl.
  • Ri is hydrogen or hydroxy
  • R2 is Ci-6 alkyl, more preferably isobutyl
  • R3 is hydrogen
  • R4 is hydrogen, methyl, t-butyl, ethyl, propyl, isobutyl, cyclopropyl or benzyl, preferably Ci- alkyl, more preferably isopropyl
  • R6 and R7 are hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, phenyl, benzyl, CF3, bromine, C(O)2CH3, C(H)O, CH2OH, CH(OH)CH3, CH(OH)isopropyl,
  • the compounds of Formula (I) are those wherein Ri is hydrogen, or hydroxy; R2 is Ci-6alkyl; R3 is hydrogen;
  • R4 is hydrogen, Ci-6 alkyl, cyclopropyl, an amino acid residue, optionally substituted phenyl, optionally substituted phenyl ci-6 alkyl- , optionally substituted -C 1 -6-alkyl-oxy C 1 -6alkyl, optionally substituted -C 1 -6 alkyl oxyC 1 _6 alkyl phenyl, an optionally substituted -Ci-6 alkyl oxy phenyl, or phenyl-Ci- 6 alkyl-oxy Ci- 6 alkyl; wherein the phenyl or benzyl moiety is independently substituted one to four times by halogen, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, thiol, Ci-6alkylthio-, -NR12R13, -NHRa, -NO2, -C(O)2Rl4, -C(O)2NRi2Rl3, cyanoamino, Ri4C(O)-
  • Ci-6 alkyl OH O-, Ci-6 alkyl OH, C ⁇ _6alkyl-C(O)2Ri4, Ci- ⁇ alkyl-oxy-Ci- ⁇ alkyl, C(O)Ci-6 alkylNRi2Rl3> or Ci-6alkyl-(O)2C-Ri4 ;
  • R5 is hydrogen or methyl, Ci-6alkyl;
  • R6 and R7 are independently hydrogen, bromine, chlorine, CF3, Ci-6 alkyl, phenyl, (CHR8)m * OH, (CHRs)m C(O)2RlO, (CHR 8 )m C(OH)(R9)2, (CR8R9)-OH,
  • R6 and R7 can together form a fused C 2-4 alkylene, aryl or heteroaryl moiety; m is an integer having a value of 1, 2, or 3; m' is 0 or an integer having a value of 1 or 2; R8 and R9 are independently hydrogen, C1-4 alkyl, or phenyl; RlO is hydrogen, or Ci-6 alkyl; Rl 1 is hydrogen, Ci-6 alkyl, or phenyl;
  • Rl2 and R13 are independently hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci-6 alkyl, aryl, arylCi-6alkyl, heteroaryl, heteroarylC ⁇ _6alkyl, heterocyclic, heterocyclic Cl-6 alkyl or R12 and R13 may together with the nitrogen to which they are attached form a 5 to 7 membered ring which may additionally contain another heteroatom selected from O N/ or S; or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and
  • pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent Yi in R3 comprises a carboxy group.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to Formula (I).
  • halo all halogens, that is chloro, fluoro, bromo and iodo;
  • alkyl both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, .sec-butyl, i-r ⁇ -butyl, tert-butyl, and the like;
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to 7 carbons, which contains an unsaturated bond, including but not limited to cyclopentenyl, cyclohexenyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”) - a 5- 10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, thiophene, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole;
  • heterocyclic (on its own or in any combination, such as “heterocyclylalkyl”) - a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine;
  • aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-6 alkyl as defined above unless otherwise indicated.
  • amino acid residue is used herein to mean a characteristic side chain attached to the -CH(NH2)COOH moiety in the following R or S amino acids, glycine, phenyl glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid.
  • Compounds of Formula (I) are imidazole derivatives which may be readily prepared using procedures well known to those of skill in the art such as may be found in US 4,599,361; EP 236872; WO 90/05716; WO 91/02716; WO 90/05719; WO 93/20047; EPO 0498 665 Al; and WO 93/21942 whose disclosures are hereby incorporated by reference, or may be prepared by analogous methods to those indicated herein below.
  • Monoesters of a dicarboxylic acid such as 1 -Scheme- 1 may be prepared according to procedures found in European Pat App. 0498 665-Al, in particular see Example 1C, page 11 thereof.
  • 1 -Scheme- 1 is coupled with a suitable amine (a), in this case a substituted aminomethyl imidazole which is available from any ⁇ -amino acid as in Scheme 3.
  • a suitable amine
  • the coupling is carried out using any standard coupling agent used in peptide synthesis, in this case "BOP" reagent to give 2-Scheme-l.
  • ester group in 2-Scheme- I is deprotected using standard reagents, in this case trifluoroacetic acid as its own solvent of TFA in chloroform or TFA in methylene chloride.
  • the carboxylic acid 3 ⁇ Scheme- 1 is coupled with a suitably protected hydroxylamine, in this case O- benzylhydroxylamine, using "BOP" reagent as the coupling agent in solvents such as water, aqueous hydrochloric acid, acetic acid, ethyl acetate, the various alcohols, such as ethanol, methanol or isopropanol.
  • solvents such as water, aqueous hydrochloric acid, acetic acid, ethyl acetate, the various alcohols, such as ethanol, methanol or isopropanol.
  • the protecting group on the hydroxamic acid 4 ⁇ Scheme- 1 is removed using standard conditions, in this case catalytic hydrogenation over a palladium catalyst, and gave the final product 5-Scheme-l.
  • the dianion of the diester is alkylated with /-butyl bromide to give 2-Scheme-2.
  • R2 is isobutyl and Rl is hydroxyl
  • the solvents such as THF, ether, or dimethoxy ethane are suitably used, and a primary or secondary bromide derivative of R2 may be used.
  • the esters can be cleaved under standard hydrolytic conditions, in this case with aqueous NaOH, (or NaOH in aq. alcohols or aq.
  • THF THF
  • ⁇ -hydroxy carboxylic acid can be protected as the acetonide, in this case by reaction of the hydroxy acid with dimethoxypropane under acid catalysis, in this case using p-toluenesulfonic acid.
  • 3-Scheme-2 is first coupled with pentafluorophenol using a standard coupling agent, in this case a water soluble diimide (WSDI), specifically l-ethyl-3-dimethylaminopropyl-carbodiimide methiodide in organic solvents such as the halogenated hydrocarbons, tetrahydrofuran, ethyl acetate, toluene, benzene, acetone, ethers, acetonitrile and DMF; and the resultant active ester is coupled with a suitably substituted aminomethyl imidazole obtained from the procedure of 4-Scheme 4 in solvents such as DMF or chlorinated hydrocarbons.
  • a standard coupling agent in this case a water soluble diimide (WSDI), specifically l-ethyl-3-dimethylaminopropyl-carbodiimide methiodide in organic solvents such as the halogenated hydrocarbons, tetrahydro
  • R3 is hydrogen
  • R4 is isopropyl
  • R6 and R7 are hydrogen
  • R5 as a hydrogen is suitably protected, this compound being derived from valine.
  • the acetonide protecting group in 4-Scheme-2 can be removed under acidic conditions, in this case with aqueous HCl in ethylene glycol or any suitable alcohol.
  • compounds wherein R3 and/or R5 is methyl can suitably be prepared.
  • the free carboxylic acid in 5-Scheme-2 can be coupled under standard conditions with a suitably protected hydroxylamine, in this case O-benzyl-hydroxylamine, to give the protected hydroxamic acid 6-Scheme-2.
  • Simultaneous deprotection of the hydroxamic acid and the imidazole can be accomplished using conditions appropriate to the protecting groups, in this case catalytic hydrogenation over a palladium catalyst to give the final product 7-Scheme-2.
  • ⁇ -amino acid including phenylglycine (which produces the final product of formula (I) wherein R4 is phenyl), but in this case tert-leucine is illustrated for R4 as a t-butyl group (tert-leucine is available from Aldrich Chemical Co.) which amino acid can have the nitrogen protected as a carbamate, in this case a carbobenzyloxy group, using standard conditions, such as in aq. THF, or alternatively this can be done under anhydrous condition such as triethylamine as a base and chlorinated solvents, to give 2-Scheme-3.
  • tert-leucine is illustrated for R4 as a t-butyl group (tert-leucine is available from Aldrich Chemical Co.) which amino acid can have the nitrogen protected as a carbamate, in this case a carbobenzyloxy group, using standard conditions, such as in aq. THF, or alternatively this can be done under anhydrous
  • amino acid derivatives of interest can be prepared in accordance with the procedures illustrated in WO93/02057, in particular, Example 1(a) whose disclosure is hereby incorporated by reference.
  • the carboxyl group of 2_ Scheme-3 is activated by formation of an active ester, in this case the pentafluorophenyl ester, the coupling between the carboxylic acid and the phenol being carried out with any water soluble diimide, in solvents such as halogenated hydrocarbons, tetrahydrofuran, ethyl acetate, toluene, benzene, acetone, ethers, acetonitrile and DMF, in this case the WSDI is l-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p- toluene-sulfonate.
  • the active ester is coupled with N,O-dimethylhydroxylamine to give the amide 3-Scheme-3.
  • the amide is reduced to the aldehyde, in this case using LiAlH- 4 at reduced temperatures, in this case -55°, in solvents such as THF, ether, or dimethoxy ethane, to give the aldehyde of 4-Scheme-3.
  • Condensation of the aldehyde with glyoxal and ammonia in any alcoholic solvent gives the imidazole 5-Scheme-3. and the protecting group is removed using conditions appropriate for the particular protecting group, in this case catalytic hydrogenation over a palladium catalyst to give the substituted aminomethyl imidazole, 6-Scheme-3. used in scheme 1.
  • * is a protected site with a carbobenzyloxy moiety
  • a is a protected carbobenzyloxy amino group
  • b is methyl, i.e. the amino is group is NHCH3
  • a substituted aminomethyl imidazole such as available from the procedures outlined in Scheme 3 herein, in this case (lS)-l-amino-l-isopropyl-l-(imidazo-2-yl)methane, _ .
  • Scheme-4. can have the amino group protected, in this case as the t-butoxycarbonyl group, by reaction with a suitable derivatizing agent, in this case di-t-butyl- pyrocarbonate in chlorinated solvents, or alcohols.
  • the NH of the imidazole in compound 2-Scheme-4 can be blocked by alkylation, in this case alkylation is carried out under basic conditions with benzyl chloromethyl ether, and alternative solvents such as DMF or acetone, to give the doubly protected compound 3-Scheme-4.
  • the protecting group on the primary amine is selectively removed, in this case with trifluoroacetic acid (neat or in chlorinated solvents), and the resulting trifluoroacetate salt of the amine is neutralized with a base to give the product 4-Scheme-4.
  • the hydrogen may be removed and replaced with a methyl group (for R3) with NaH and Mel and the reaction scheme proceeds accordingly, or (for R5 other than hydrogen) using the intermediate of 2-Scheme-4 and methyl iodide instead of benzylchloromethyl ether, and working up accordingly will produce suitably substituted compounds.
  • R3 as other than hydrogen
  • the intermediate of 5-Scheme-3 may be used as intermediates to make other R5 alkyl groups.
  • compositions of formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.
  • Example 1(f) The compound of Example 1(f) can be reacted with O-benzylhydroxylamine hydrochloride in the presence of Et 3 N and benzotriazolo-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate in CH 2 C1 2 in a manner analogous to that of Example 1(c) to give the titled compound.
  • Example 1(g) (2S, 3R, rS)-N,2-dihydroxy-3-[r-isopropyl-r-(imidazol-2- yl)methylaminocarbonyl]-5-methyl hexanamide
  • the compound of Example 1(g) can be deprotected by hydrogenating a solution of the compound in MeOH over a 10% Pd/C catalyst in an analogous manner to that of Example 1(d), to give the titled compound.
  • Example 3(g) can be reacted with HCl in a mixture of H 2 O and ethylene glycol in a manner analagous to that of Example 2(f) to give the titled compound.
  • Example 3(h) The compound of Example 3(h) can be reacted with O-benzylhydroxylamine hydrochloride in the presence of Et 3 N and benzotriazolo-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate in CH C1 in a manner analogous to that of Example 1(c) to give the titled compound.
  • Example 3(i) (2S, 3R, rS)-N,2-dihydroxy-3-[2',2'-dimethyl-r-(imidazol-2- yl)propylaminocarbonyl]-5-methyl hexanamide
  • the compound of Example 3(i) can be deprotected by hydrogenating a solution of the compound in MeOH over a 10% Pd/C catalyst in an analogous manner to that of Example 1(d), to afford the titled compound.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a matrix-degrading metalloproteinases.
  • Compounds of formula (I) are capable of inhibiting metalloproteinases involved in tissue degradation, such as collagenase, stromelysin, gelatinase and collagenase (IV).
  • tissue degradation such as collagenase, stromelysin, gelatinase and collagenase (IV).
  • the role of these metalloproteinases in well known in the art and management of these metalloproteinases would be useful to treat a wide variety of disease states and conditions thereof.
  • diseases involving tissue degradation which includes arthopathy, such as rheumatoid arthritis, osteoporosis, inflammatory disease, dermatological diseases, bone reasorption disease, inhibition of angiogenesis, regression of tumors and therefore in treatment of cancers caused thereby, and corneal ulceration.
  • the present invention provides a method of treating a matrix- degrading metalloproteinase mediated disease which comprises administering an effective matrix-degrading inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is to a method of treating a collagenase mediated disease state or where coUagenolytic activity is important.
  • compounds of formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated coUagenolytic activity by such mammal's cell.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of formula (I) may be administered in conventional dosage forms prepared by combining a compound of formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono- stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • Compounds of formula (I) may be administered topically, that is by non- systemic administration.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or f ungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • total daily dosage for oral administration will be from about 250mg to about 5000mg.
  • a suitable daily dosage will be from about 0. Img/kg to about 300 mg/kg of total body weight, preferably from about 1 to 100 mg/kg.
  • the daily parenteral in particular intra-articularly into the affected joint, will be from about .5mg/kg to lOOmg/kg, resulting in a daily administration of about 1 mg to 5 grams of compound for a 70kg mammal.
  • the daily topical dosage regimen will be similar to parenteral of .5mg to lOOmg/kg and typically be in the range of lOmg to lOOmg of compound.
  • For administration to the eyes .1 to lmg of compound per administration.
  • the optimal quantity and spacing of individual dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the collagenase inhibitory activity of compounds of the present invention are determined by the in vitro assays as described by the procedure of Cawston and
  • Example 1 Barrett, Anal. Biochem. 99, 340-345 (1979), and as described in US patent 5,240,598 or 4,599361 whose disclosures are hereby incorporated by reference.
  • the compound of Example 1 was found to be an effective inhibitor of collagenase activity.
  • the stromelysin inhibitory activity of the compounds of Formula (I) may be determined by the procedure of Cawston et al., Biochem. J., 195, 159-165 (1981), whose disclosure is hereby incorporated by reference.
  • Additional testing for anti-inflammatory and chondroprotective effects of the compounds of Formula (I) may also be done using the adjuvant arthritis (AA) rat model which is well known to those of skill in the art.
  • AA adjuvant arthritis

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Abstract

La présente invention se rapporte à une série de nouveaux dérivés d'acide hydroxamique substités par imidazole, et à des compositions utilisées comme inhibiteurs de métalloprotéinases dégradant la matrice, notamment la collagénase.
PCT/US1995/002606 1994-03-03 1995-03-03 Cytokines inhibant des derives d'acide hydroxamique substitue par imidazole WO1995023790A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/702,528 US5665753A (en) 1994-03-03 1995-03-03 Cytokine inhibiting imidazole substituted hydroxamic acid derivatives
JP7523024A JPH09509940A (ja) 1994-03-03 1995-03-03 サイトカイン阻害性イミダゾール置換ヒドロキサム酸誘導体
EP95912688A EP0748313A4 (fr) 1994-03-03 1995-03-03 Cytokines inhibant des derives d'acide hydroxamique substitue par imidazole

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9404046A GB9404046D0 (en) 1994-03-03 1994-03-03 Novel compounds
GB9404046.6 1994-03-03

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WO1995023790A1 true WO1995023790A1 (fr) 1995-09-08

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033176A1 (fr) * 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Nouveaux composes d'acides hydroxamiques et d'aminocarboxylates servant d'inhibiteurs des metalloproteases et du tnf
WO1997019075A1 (fr) * 1995-11-22 1997-05-29 Darwin Discovery Limited Composes de mercaptoalkylpeptidyl possedant un substituant imidazole et leur utilisation comme inhibiteurs de metalloproteinases matricielles (mmp) et/ou du facteur de necrose tumorale (tnf)
WO1997019053A1 (fr) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Inhibiteurs de metaloproteinases
WO1997025981A1 (fr) * 1996-01-17 1997-07-24 Smithkline Beecham Plc Utilisation medicale
WO1998005635A1 (fr) * 1996-08-07 1998-02-12 Darwin Discovery Limited Derives de l'acide hydroxamique et de l'acide carboxylique dotes d'une activite inhibitrice vis a vis des mmp et du tnf
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
WO2002041886A1 (fr) * 2000-11-23 2002-05-30 British Biotech Pharmaceuticals Ltd Derives d'acide ydroxamyque ou de n-formyl hydroxylamine utilises comme inhibiteurs de la polypeptide deformylase bacterienne permettant de traiter des infections bacteriennes
WO2002050046A1 (fr) * 2000-12-21 2002-06-27 Pfizer Limited Acides 3-ox(adi)azolylpropanohydroxamiques utiles en tant qu'inhibiteurs de la procollagene c-proteinase
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6566384B1 (en) 1996-08-07 2003-05-20 Darwin Discovery Ltd. Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity
WO2003070711A1 (fr) * 2002-02-22 2003-08-28 Vernalis (Oxford) Ltd Oxa- et thiadiazoles et leur utilisation comme inhibiteurs de la metalloproteinase
US6645993B2 (en) 2001-03-30 2003-11-11 Warner-Lambert Company 3-heterocyclylpropanohydroxamic acid PCP inhibitors
US6716861B2 (en) 2000-12-21 2004-04-06 Pfizer, Inc. 3-ox(adi)azolylpropanohydroxamic acids useful as procollagen C-proteinase inhibitors
WO2004101537A1 (fr) * 2003-05-17 2004-11-25 British Biotech Pharmaceuticals Ltd Inhibiteurs de metalloproteinases
CN114957160A (zh) * 2022-03-28 2022-08-30 北京理工大学 一种2,4,5-三取代噻唑化合物、制备方法及其应用

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US4996358A (en) * 1986-03-11 1991-02-26 Hoffmann-La Roche Inc. Hydroxylamine bearing amino acid derivatives as collagenase inhibitors
US5240958A (en) * 1988-11-23 1993-08-31 British Bio-Technology Limited Hydroxamic acid based collagenase inhibitors
US5300674A (en) * 1991-02-07 1994-04-05 British Bio-Technology Limited P2'-modified hydroxamic acid collagenase inhibitors
US5304604A (en) * 1988-11-23 1994-04-19 British Bio-Technology Limited Hydroxamic acid collagenase inhibotors

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GB9215665D0 (en) * 1992-07-23 1992-09-09 British Bio Technology Compounds
AU671724B2 (en) * 1993-03-16 1996-09-05 British Biotech Pharmaceuticals Limited Hydroxamic acid derivatives as metalloproteinase inhibitors

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US4996358A (en) * 1986-03-11 1991-02-26 Hoffmann-La Roche Inc. Hydroxylamine bearing amino acid derivatives as collagenase inhibitors
US5240958A (en) * 1988-11-23 1993-08-31 British Bio-Technology Limited Hydroxamic acid based collagenase inhibitors
US5304604A (en) * 1988-11-23 1994-04-19 British Bio-Technology Limited Hydroxamic acid collagenase inhibotors
US5300674A (en) * 1991-02-07 1994-04-05 British Bio-Technology Limited P2'-modified hydroxamic acid collagenase inhibitors

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See also references of EP0748313A4 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703092A (en) * 1995-04-18 1997-12-30 The Dupont Merck Pharmaceutical Company Hydroxamic acid compounds as metalloprotease and TNF inhibitors
WO1996033176A1 (fr) * 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Nouveaux composes d'acides hydroxamiques et d'aminocarboxylates servant d'inhibiteurs des metalloproteases et du tnf
US6048841A (en) * 1995-11-22 2000-04-11 Darwin Discovery, Ltd. Peptidyl compounds
WO1997019075A1 (fr) * 1995-11-22 1997-05-29 Darwin Discovery Limited Composes de mercaptoalkylpeptidyl possedant un substituant imidazole et leur utilisation comme inhibiteurs de metalloproteinases matricielles (mmp) et/ou du facteur de necrose tumorale (tnf)
WO1997019053A1 (fr) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Inhibiteurs de metaloproteinases
WO1997025981A1 (fr) * 1996-01-17 1997-07-24 Smithkline Beecham Plc Utilisation medicale
WO1998005635A1 (fr) * 1996-08-07 1998-02-12 Darwin Discovery Limited Derives de l'acide hydroxamique et de l'acide carboxylique dotes d'une activite inhibitrice vis a vis des mmp et du tnf
US6566384B1 (en) 1996-08-07 2003-05-20 Darwin Discovery Ltd. Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity
US6118001A (en) * 1996-08-07 2000-09-12 Darwin Discovery, Ltd. Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity
AU730464B2 (en) * 1996-08-07 2001-03-08 Darwin Discovery Limited Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
WO2002041886A1 (fr) * 2000-11-23 2002-05-30 British Biotech Pharmaceuticals Ltd Derives d'acide ydroxamyque ou de n-formyl hydroxylamine utilises comme inhibiteurs de la polypeptide deformylase bacterienne permettant de traiter des infections bacteriennes
US7173053B2 (en) 2000-11-23 2007-02-06 British Biotech Pharmaceuticals Limited N-formyl hydroxylamine derivatives as inhibitors of bacterial polypeptide formylase for treating microbial infections
WO2002050046A1 (fr) * 2000-12-21 2002-06-27 Pfizer Limited Acides 3-ox(adi)azolylpropanohydroxamiques utiles en tant qu'inhibiteurs de la procollagene c-proteinase
US6716861B2 (en) 2000-12-21 2004-04-06 Pfizer, Inc. 3-ox(adi)azolylpropanohydroxamic acids useful as procollagen C-proteinase inhibitors
US7214694B2 (en) 2000-12-21 2007-05-08 Pfizer Inc 3-ox(adi)azolylpropanohydroxamic acids useful as procollagen C-proteinase inhibitors
US6645993B2 (en) 2001-03-30 2003-11-11 Warner-Lambert Company 3-heterocyclylpropanohydroxamic acid PCP inhibitors
US6831088B2 (en) 2001-03-30 2004-12-14 Pfizer Inc. 3-heterocyclypropanohydroxamic acid PCP inhibitors
WO2003070711A1 (fr) * 2002-02-22 2003-08-28 Vernalis (Oxford) Ltd Oxa- et thiadiazoles et leur utilisation comme inhibiteurs de la metalloproteinase
EA007609B1 (ru) * 2002-02-22 2006-12-29 Верналис (Оксфорд) Лтд. Окса- и тиадиазолы и их применение в качестве ингибиторов металлопротеиназ
US7358265B2 (en) 2002-02-22 2008-04-15 Vernalis (R&D) Ltd Oxa-and thiadiazoles and their use as metalloproteinase inhibitors
WO2004101537A1 (fr) * 2003-05-17 2004-11-25 British Biotech Pharmaceuticals Ltd Inhibiteurs de metalloproteinases
CN114957160A (zh) * 2022-03-28 2022-08-30 北京理工大学 一种2,4,5-三取代噻唑化合物、制备方法及其应用

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EP0748313A4 (fr) 1997-06-11
EP0748313A1 (fr) 1996-12-18
GB9404046D0 (en) 1994-04-20

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