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1. EP0763012 - SUCCINYL HYDROXAMIC ACID, N-FORMYL-N-HYDROXY AMINO CARBOXYLIC ACID AND SUCCINIC ACID AMIDE DERIVATIVES AS METALLOPROTEASE INHIBITORS

Office European Patent Office
Application Number 95920160
Application Date 26.05.1995
Publication Number 0763012
Publication Date 19.03.1997
Publication Kind B1
IPC
C07D 521/00
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
521Heterocyclic compounds containing unspecified hetero rings
A61K 31/16
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
16Amides, e.g. hydroxamic acids
A61K 31/165
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
16Amides, e.g. hydroxamic acids
165having aromatic rings, e.g. colchicine, atenolol, progabide
A61K 31/195
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
19Carboxylic acids, e.g. valproic acid
195having an amino group
A61K 31/20
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
19Carboxylic acids, e.g. valproic acid
20having a carboxyl group bound to an acyclic chain of seven or more carbon atoms, e.g. stearic, palmitic or arachidic acid
A61P 1/02
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
1Drugs for disorders of the alimentary tract or the digestive system
02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
CPC
A61P 1/02
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
1Drugs for disorders of the alimentary tract or the digestive system
02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 27/02
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
27Drugs for disorders of the senses
02Ophthalmic agents
A61P 29/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
29Non-central analgesic, antipyretic or anti-inflammatory agents, e.g antirheumatic agents; Non-steroidal anti-inflammatory drugs (NSAIDs)
A61P 43/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
43Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
C07C 237/22
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
237Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
02having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
22having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
C07C 259/06
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
259Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
04without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
06having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
Applicants BRITISH BIOTECH PHARM
Inventors MILLER ANDREW
BECKETT PAUL RAYMOND
MARTIN FIONNA M
WHITTAKER MARK
Designated States
Priority Data 9410802 28.05.1994 GB
9501226 26.05.1995 GB
9503754 24.02.1995 GB
Title
(DE) SUCCINYL HYDROXAMSÄURE-, N-FORMYL-N-HYDROXY-AMINOCARBONSÄURE- UND SUCCINSÄUREAMID-DERIVATE UND IHRE VERWENDUNG ALS METALLOPROTEASE-INHIBITOREN
(EN) SUCCINYL HYDROXAMIC ACID, N-FORMYL-N-HYDROXY AMINO CARBOXYLIC ACID AND SUCCINIC ACID AMIDE DERIVATIVES AS METALLOPROTEASE INHIBITORS
(FR) ACIDE SUCCINYLE HYDROXAMIQUE, ACIDE N-FORMYL-N-HYDROXY AMINO CARBOXYLIQUE ET DERIVES AMIDES DE L'ACIDE SUCCINIQUE EN TANT QU'INHIBITEURS DES METALLOPROTEASES
Abstract
(EN)
Compounds of general formula (I) wherein X is a -CO2H, -N(OH)CHO or -CONHOH group; R1 is hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; phenyl; substituted phenyl; phenyl(C1-C6)alkyl; substituted phenyl(C1-C6)alkyl; heterocyclyl; substituted heterocyclyl; heterocyclyl(C1-C6)alkyl; substituted heterocyclyl(C1-C6)alkyl; a group BSOnA- wherein n is 0, 1 or 2 and B is hydrogen or a (C1-C6)alkyl, phenyl, substituted phenyl, heterocyclyl, (C1-C6)acyl, phenacyl or substituted phenacyl group, and A represents (C1-C6)alkyl; amino; protected amino; acylamino; OH; SH; (C1-C6)alkoxy; (C1-C6)alkylamino; di-(C1-C6)alkylamino; (C1-C6)alkylthio; aryl (C1-C6)alkyl; amino(C1-C6)alkyl; hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or carboxy(C1-C6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-groups are optionally protected or the carboxyl-group amidated; lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino; R2 represents a linear saturated or unsaturated C13-C24 hydrocarbon chain, which chain (i) may be interrupted by one or more non-adjacent -O- or -S- atoms or -C(=O)-, -S($m(7)O)-, -S(=O)2- or -N(Rx)- groups wherein Rx is hydrogen, methyl or ethyl, provided that the maximum length of the chain is no more than 28 C, O, S and N atoms, and/or (ii) may be substituted with one ore more groups selected from C1-C6 alkyl, OH, OMe, halogen, NH2, NHCH3, N(CH3)2, CO2H, CO2CH3, COCH3, CHO, CONH2, CONHCH3, CON(CH3)2, CH2OH, NHCOCH3, provided that the maximum length of the chain is no more than 28 C, O, S and N atoms; R3 is the characterising side chain of a natural or non-natural $g(a) amino acid in which any functional groups may be protected, with the proviso that R3 does not represent hydrogen; R4 is hydrogen, C1-C6 alkyl, (C1-C4)perfluoroalkyl or a group D-(C1-C6 alkyl) wherein D represents hydroxy, (C1-C6)alkoxy, (C1-C6)alkylthio, acylamino, optionally substituted phenyl or heteroaryl, NH2, or mono- or di-(C1-C6 alkyl)amino; R5 is hydrogen or a (C1-C6)alkyl group; or a salt, hydrate or solvate thereof. The compounds are inhibitors of matrix metalloproteinases, especially gelatinases.

(FR)
Composés de la formule générale (I), ou un de leurs sels, hydrates ou solvates, dans laquelle X représente un groupe -CO2H, -N(OH)CHO ou -CONHOH; R1 représente hydrogène; alkyle C1-C6; alcényle C2-C6; phényle; phényle substitué; phényle alkyle C1-C6, phényle alkyle C1-C6 substitué, hétérocyclyle, hétérocyclyle substitué, hétérocyclyle alkyle C1-C6, hétérocyclyle alkyle C1-C6 substitué, un groupe BSOnA- dans lequel n vaut 0, 1 ou 2 et B représente hydrogène ou un groupe alkyle C1-C6, phényle, phényle substitué, hétérocyclyle, acyle C1-C6, phénacyle ou phénacyle substitué, A représente lakyle C1-C6, amino amino protégé, acylamino, OH, SH, alcoxy C1-C6, alkylamino C1-C6, di-alkylamino C1-C6, alkylthio C1-C6, aryle alkyle C1-C6, amino alkylo C1-C6, hydroxy alkyle C1-C6, mercapto alcoyle C1-C6 ou carboxy alkyle C1-C6 où les groupes amino-, hydroxy-, mercapto- ou carboxyle- sont éventuellement protégés, ou le groupe carboxyle- est amidé; alkyle inférieur substitué par carbamoyle, mono(alkyle inférieur)carbamoyle, di(alkyle inférieur)carbamoyle, di(alkyle inférieur)amino, ou carboxy-alcanoylamino inférieur; R2 représente un chaîne hydrocarbure C13-C24 linéaire saturée ou insaturée, laquelle (i) peut être interrompue par un ou plusieurs atome(s) -O- ou -S- non adjacent(s), ou des groupes -C(=O)-, -S($m(7)O)-, -S(=O)2- ou -N(Rx)- où Rx représente hydrogène, méthyle ou éthyle, à condition que la longueur maximum de la chaîne ne dépasse pas 28 atomes C, O, S et N, et/ou (ii) peut être substituée par un ou plusieurs groupes choisis parmi alcoyle C1-C6, OH, OMe, halogène, NH2, NHCH3, N(CH3)2, CO2H, CO2CH3, COCH3, CHO, CONH2, CONHCH3, CON(CH3)2, CH2OH, NHCOCH3, à condition que la longueur maximum de la chaîne ne dépasse pas 28 atomes C, O, S et N; R3 représente la chaîne latérale charactérisante d'un acide amine $g(a) naturel ou non dans lequel l'un quelconque des groupes fonctionnels peut être protégé, à condition que R3 ne représente pas hydrogène; R4 représente hydrogène, alkyle C1-C6, perfluoroalkyle C1-C4, ou un groupe D-(alkyle C1-C6) dans lequel D représente hydroxy, alcoxy C1-C6, alkylthio C1-C6, acylamino, phényle ou hétéroaryle éventuellement substitué, NH2, ou mono ou di(alkyle C1-C6)amino; R5 représente hydrogène ou un groupe alkyle C1-C6. Ces composés sont des inhibiteurs des métalloprotéases matricielles, notamment des enzymes gélatinolytiques.