Patent EA-003283-B1 (EA)
Title: N-hydroxy-2-(alkyl, aryl, or heteroaryl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl, or heteroarylamides as matrix metalloproteinase inhibitors
Inventor: VENKATESAN ARANAPAKAM MUDUMBAI
IPC: C07D211/12
Filed: 1998-08-26
Abstract: 1. A compound according to formula I wherein: R<1> is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, optionally substituted with one or two groups selected independently from R<5>; or heteroaryl- (CH2) 0-6- wherein the heteroaryl group is 5 to 6-membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R<5>; A is -S-,-SO-or -SO2-; R<2> and R<3>, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R<7> optionally having one or two double bonds; R<4> is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; phenyl or naphthyl optionally substituted with one or two groups selected independently from R<5>; C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, optionally substituted with one or two groups selected independently from R<5>; R<5> is H, C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alkylamine, C1-C12 perfluoro alkyl, S (O) n-C1-C6 alkyl, S (O) n-aryl where n is 0,1 or 2; OCOO C1-C6 alkyl, OCOOaryl, OCONR<6>, COOH, COO C1-C6 alkyl, COOaryI, CONR<6>R<6>, CONHOH, NR<6>R<6>, SO2NR<6>R<6>, NR<6>SO2aryl, -NR<6>CONR<6>R<6>, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2- C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3-C8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R<6> is H, C1-C18 alkyl optionally substituted with OH; C3-C6 alkenyl, C3-C6alkynyl, C1-C6 perfluoro alkyl, S (O) n-C1-C6 alkyl S (O) n aryl where n is 0,1 or 2; or CO-heteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and R<7> is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S (O) n-C1-C6-alkyl, S (O) n-aryl where n is 0,1 or 2; COO-C1-C6-alkyl, COOaryl, CONHR<6>, CONR<6>R<6>, CONHOH, SO2NR<6>R<6>, SO2CF3, SO2NH-heteroaryl, SO2NHCO-aryl, CONHSO2-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C1-C6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R<5>; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R<5>; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R<5>; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R<5>; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatoms selected from O, S or N-C1-C6 alkyl, optionally substituted with one or two groups selected independently from R<5>; or R<8>R<9>N-C1-C6-alkoxyaryl-C1-C6-alkyl where R<8> and R<9> are independently selected from C1-C6 alkyl or R<8> and R<9> together with the interposed nitrogen forms a 5-7-membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein: R<1> is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R<5>; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R<5>; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR<7>, optionally substituted with one to two groups selected independently from R<5>; or heteroaryl- (CH2) 0-6- wherein the heteroaryl group is 5 to 6-membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R<5>; A is-S-,-SO-or -SO2- ; R<2> and R<3>, taken with the carbon atom to which they are attached, form a 5 to 7-membered heterocyclic ring containing O, S or N-R<7> optionally having one or two double bonds; R<4> is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; phenyl or naphthyl optionally substituted with one or two groups selected independently from R<5>; C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R<5>; R<5> is H, F, Cl, Br, I, CN, CHO, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6alkenyloxy, C3-C6 alkynyloxy, C1-C6alkoxyheteroaryl, C1-C6alkoxyaryl, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylene dioxy, aryloxy-C1-C6 alkylamine, C1-C12 perfluoro alkyl, S (O)n-C1-C6 alkyl, S (O) n-aryl where n is 0,1 or 2; OCOO- C1-C6 alkyl, OCOOaryl, OCONR<6>, COOH, COO-C<1>-C<6> alkyl, COOaryl, CONR<6>R<6>, CONHOH, NR<6>R<6>, SO2NR<6>R<6>, NR<6>SO2-aryl, NR<6>CONR<6>R<6>, NHSO2CF3, SO2NH-heteroaryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl,CONHSO2-aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl; or saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>; wherein heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R<6> is H, C1 to C18 alkyl optionally substituted with OH; C3-C6 alkenyl, C3-C6alkynyl, C1-C6 perfluoro alkyl, S (O) n alkyl or aryl where n is 0,1, or 2; or CO-heteroaryl; wherein heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and R<7> is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S (O) n-alkyl, S (O) n-aryl where n is 0,1 or 2; COOalkyl, COOaryl, CONHR<6>, CONR<6>R<6>,CONHOH, SO2NR<6>R<6>, SO2CF3, SO2NH-heteroaryl, SO2NHCOaryl, CONHSO2alkyl, CONHSO2aryl, aryl, heteroaryl; wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group