Oxa- and thiadiazoles and their use as metalloproteinase inhibitors

A method for the preparation of a medicament for the treatment or prophylaxis of diseases mediated by MMPs comprising adding to a medicament formulation a compound having formula (IA) or (IB)

• wherein
• W represents HO(C═O)—, HONH(C═O)— or H(C═O)N(OH)—;
• X represents —O— or —S—;
• R1 represents
• hydrogen;
• —OH or —SH;
• fluoro or chloro;
• —CF3;
• (C1-C6)alkyl;
• (C1-C6)alkoxy;
• (C2-C6)alkenyl;
• phenyl or substituted phenyl;
• phenyl(C1-C6)alkyl or substituted phenyl(C1-C6)alkyl;
• phenyl(C2-C6)alkenyl or substituted phenyl(C2-C6)alkenyl heterocyclyl or substituted heterocyclyl;
• heterocyclyl(C1-C6)alkyl or 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, substituted heterocyclyl, (C1-C6)acyl, phenacyl or substituted phenacyl group, and A represents (C1-C6)alkylene;
• —NH2, (C1-C6)alkylamino or di(C1-C6)alkylamino;
• amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or carboxy(C1-C6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated;
• or
• a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, halo, cyano (—CN), —CO2H, —CO2R, —CONH2, —CONHR, —CON(R)2, —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO2R wherein R is C1-C6 alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
• R2 represents a group R10-(X1)p-(ALK)m- wherein
• R10 represents hydrogen, or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C1-C12)alkyl, (C1-C12)alkoxy, hydroxy, mercapto, (C1-C12)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH2, —COORA, —NHCORA, —CONHRA, —NHRA, —NRARB, or —CONRARB wherein RA and RB are independently a (C1-C12)alkyl group and
• ALK represents a straight or branched divalent C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S-linkages,
• X1 represents —NH—, —O— or —S—, —NRc or —NCORc wherein Rc is a (C1-C12)alkyl group, and
• m and p are independently 0 or 1;
• R3 is C1-C6 alkyl, phenyl, 2,3-, or 4-pyridyl, 2- or 3-thienyl, 2,- 3-, or 4-hydroxyphenyl, 2,- 3-, or 4-methoxyphenyl, 2,3-, or 4-pyridylmethyl, benzyl, 2,3-, or 4-hydroxybenzyl, 2,- 3-, or 4-benzyloxybenzyl, 2,- 3-, or 4- C1-C6 alkoxybenzyl, or benzyloxy(C1-C6 alkyl)-;
• or
• the characterizing group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated;
• or
• a group -[Alk]nR6 where Alk is a (C1-C6)alkyl or (C2-C6)alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R7) groups [where R7 is a hydrogen atom or a (C1-C6)alkyl group], n is 0 or 1, and R6 is an optionally substituted cycloalkyl or cycloalkenyl group;
• or
• a benzyl group substituted in the phenyl ring by a group of formula —OCH2COR8 where R8 is hydroxyl, amino, (C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenyl(C1-C6)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid;
• or
• a heterocyclic(C1-C6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C1-C6)alkoxy, cyano, (C1-C6)alkanoyl, trifluoromethyl(C1-C6)alkyl, hydroxy, formyl, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, mercapto, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or (C1-C6)alkylphenylmethyl;
• or
• a group —CRaRbRc in which:
• each of Ra, Rb and Rc is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, (C3-C8)cycloalkyl;
• or
• Rc is hydrogen and Ra and Rb are independently phenyl or heteroaryl such as pyridyl;
• or
• Rc is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or (C3-C8)cycloalkyl, and Ra and Rb together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring;
• or Ra, Rb and Rc together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl);
• or
• Ra and Rb are each independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or a group as defined for Rc below other than hydrogen, or Ra and Rb together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and Rc is hydrogen, —OH, —SH, halogen, —CN, —CO2H, (C1-C4)perfluoroalkyl, —CH2OH, —CO2(C1-C6)alkyl, —O(C1-C6)alkyl, —O(C2-C6)alkenyl, —S(C1-C6)alkyl, —SO(C1-C6)alkyl, —SO2(C1-C6)alkyl, —S(C2-C6)alkenyl, —SO(C2-C6)alkenyl, —SO2(C2-C6)alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO2— and W represents a phenyl, phenylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylalkyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO2H, —CO2(C1-C6)alkyl, —CONH2, —CONH(C1-C6)alkyl, —CONH(C1-C6 alkyl)2, —CHO, —CH2OH, (C1-C4)perfluoroalkyl, —O(C1-C6)alkyl, —S(C1-C6)alkyl, —SO(C1-C6)alkyl, —SO2(C1-C6)alkyl,
• —NO2, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, —NHCO(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or benzyl;
• R4 represents optionally substituted
• C1-C6 alkyl,
• C2-C6 alkenyl,
• C2-C6 alkynyl,
• C1-C3 perfluoroalkyl,
• cycloalkyl,
• cycloalkyl(C1-C6 alkyl),
• cycloalkenyl,
• cycloalkenyl(C1-C6 alkyl)-,
• phenyl,
• phenyl(C1-C6 alkyl)-,
• naphthyl,
• non-aryl heterocyclyl,
• non-aryl heterocyclyl(C1-C6)alkyl-,
• heteroaryl;
• or
• heteroaryl(C1-C6 alkyl)-;
• or a pharmaceutically acceptable salt, hydrate or solvate thereof.