Patent EA-001432-B1 (EA)
Title: Matrix metalloproteinase inhibitors
Inventor: ALPEGIANI MARCO
IPC: C07D277/44
Filed: 1997-06-20
Abstract: 1. A compound which is a succinic amide derivative of formula (I)   wherein W is a -COOH or -CONHOH group; R <I>s either hydrogen, C1-C6 alkyl, phenyl, or benzyl; R<1> is either hydrogen or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl; aryl, especially phenyl and naphthyl; and aryl(lower alkyl), especially benzyl; these groups being either unsubstituted or substituted by one or more substituents, equal or different, selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro , amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or  -(CH2)m-heterocyclyl or -(CH2)m-cyclopropyl, wherein m is either zero, or an integer from one to three, and heterocyclyl represents a 3 to 6 membered heterocyclyl ring, simple or condensed with a benzene or naphthalene ring, containing at least one nitrogen atom; still preferably succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein such heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or  a group -(CH2)nCOOH or -(CH2)mCOOR<1>, wherein n may be 1, 2 or 3, m may be 0, 1, 2 or 3, and R<1> is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or a group selected from -(CH2)mSO2R<1>, -(CH2)mSO2NH2, -(CH2)mSO2N(Me)2, -(CH2)mSO2NHR<1>, wherein m, R<1> and possible substituents of such R<I> group are as defined above, -(CH2)mSO2-(4-morpholino), -(CH2)mSO2-(1-piperazino), or -(CH2)mSO2-(4-methyl-1-piperazino); or  a group -(CH2)nSO3H, wherein n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or  a group -C(O)-R<II>-C(O)R<III>, wherein -R<II>- represents a chemical bond, -CH2-, -CH2(CH2)mCH2- wherein m is as defined above, -CH=CH-, -CH2CH=CH-, phenylene (i.e., -C6H4-), -CH2CH=CH-C6H4-, -CH2CH2CH=CH-, CH2-CC-, -CH2CH2-CC-, -CH2CH2CH=CH-C6H4-, -CH2-CC-C6H4-, -CH2CH2-CC-C6H4, and R<III> is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or -C(O)-heterocyclyl, wherein heterocyclyl is as defined above, and wherein such heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or -C(O)-R<II>-heterocyclyl or -C(O)-R<II>-aryl, wherein R<II>, heterocyclyl , aryl and possible substituents of such heterocyclyl or aryl are as described above; or R and R1, taken together with the nitrogen atom to which they are attached, represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido, or phthalimido; R2 is C3 -C15 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group -R<II>-H, wherein R<II> is as defined above, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, C3 -C4 linear or branched alkyl, fluoro, chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy, carboxymethyl; or R2 is a group -R<II>-X-R<IV>, wherein R<II> is as defined above, R<IV> is C1-C6alkyl, C3-C7 cycloalkyl, C2-C6alkenyl, phenyl, phenyl (C1-C6)alkyl, or phenyl (C2-C6)alkenyl, said groups can be either unsubstituted or substituted by a group selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, and X is either a direct bond, or an oxygen atom, a sulfur atom, or a sulfinyl -S(O)-, sulfonyl -S(O)2 or carbamoyl group -CONH- or -NHCO-; R3 is the characterizing group of a natural or non-natural alpha-amino acid in which any functional group, if present, may be protected; R4 is either O-alkyl, wherein alkyl is a C1-C4 straight or branched alkyl group, especially methyl, ethyl and tert-butyl, or is O-phenyl, and derivatives thereof substituted by one to three substituents selected from C1-C4 straight or branched alkyl, chloro and methoxy; or R4 is -NH2, -NH(C1-C6alkyl), -NH-aryl, -NH-heterocyclyl; or R4 is -NH(C1-C6alkyl) substituted by phenvl or heterocyclyl; or R4 is -NH(C2-C6alkyl) substituted by a group selected from -CONH2, -NHCONH2, -SO2NH2, -NHSO2NH2, or derivatives thereof wherein the terminal nitrogen atom is substituted by one or two methyl groups, or derivatives thereof wherein the terminal nitrogen atom is part of a morpholino, pyrrolidino, piperazino, or N-methylpiperazino ring; or R4 is -NH(C2-C6alkyl) substituted by amino, protected amino, mono (C1-C6)alkylamino, di(C1-C6) alkylamino, guanidino, morpholino, piperazino or N-methylpiperazino; or R3 and R4 taken together are a group of the formula -(CH2)m-NH-, where m is integer from 5 to 12, optionally interrupted by a -NR5- group, wherein R5 is selected from hydrogen, C1-C6alkyl, C1 -C6 alkoxycarbonyl, aryl, aryl (C1-C6)alkyl, or aryl (C1-C6) alkoxycarbonyl, or interrupted by a group -C6H4-O-, or interrupted by an indole ring linked through its C-3 and nitrogen atoms; and wherein the alkyl, alkenyl, phenyl, cycloalkyl, heterocyclyl and characterizing groups in any of the above definitions of R1, R2, R3, R4 and A can be either unsubstituted or substituted by one or more substituents; and the salts, prodrugs, solvates and hydrates thereof, with the proviso that, when -NRR1 is -NH2, protected amino or acylamino , R3 is tert-butyl and R4 is either amino or alkylamino, then R2 is different from isobutyl. 2. A compound as claimed in claim 1 having the formuia (I')   wherein: W is a -COOH or -CONHOH group; R is either hydrogen, methyl, ethyl, or benzyl; R<I> is either hydrogen or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl; aryl, especially phenyl and naphthyl; and aryl(lower alkyl), especially benzyl; these groups being either unsubstituted or substituted by one or more substituents, equal or different, selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro. bromo. nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or -(CH2)m-heterocyclyl or -(CH2)m-cyclopropyl, wherein m is either zero or an integer from one to three, and heterocyclyl represents a 3 to 6 membered heterocyclyl ring, simple or condensed with a benzene or naphthalene ring, containing at least one nitrogen atom; still preferably succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein such heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or group -(CH2)nCOOH or a group -(CH2)mCOOR<1>, wherein n may be 1, 2 or 3, m may be 0, 1, 2 or 3, and R<1> is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or a group selected from -(CH2)mSO2R<1>, -(CH2)mSO2NH2, -(CH2)m-SO2N(Me)2, -(CH2)mSO2NHR<1>, wherein m, R<1> and possible substituents of such R<1> group are as defined above, or a group -(CH2)mSO2-(4-morpholino), -(CH2)mSO2-(1-piperazino), or -(CH2)mSO2-(4-methyl-1-piperazino); or  a group -(CH2)nSO3H wherein n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or group -C(O)-R<II>-C(O)R<III>, wherein -R<II>- represents a chemical bond, -CH2-, -CH2(CH2)mCH2- wherein m is as defined above, -CH=CH-, -CH2CH=CH-, phenylene (i.e., -C6H4-), -CH2CH=CH-C6H4-, -CH2CH2CH=CH-, CH2-CC-, -CH2CH2-CC-, -CH2CH2CH=CH-C6H4-, -CH2-CC-C6H4-, -CH2CH2-CC-C6H4-, and R<III> is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or -C(O)-heterocyclyl, wherein heterocyclyl is as defined above, and wherein such heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromo, chloro, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy and nitro; or -C(O)-R<II>-heterocyclyl or -C(O)-R<II>-aryl, wherein R<II>, heterocyclyl, aryl and possible substituents of such heterocyclyl or aryl are as described above; or R and R1, taken together with the nitrogen atom to which they are attached, represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido,or phthalimido; R2 is C3 -C15 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group -R<II>-H, wherein R<II> is as defined above, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, C3-C4 linear or branched alkyl, fluoro, chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy, carboxymethyl; or R2 is a group -R<II>-X-R<IV>, wherein R<II> is as defined above, -X- is a direct bond, -O-, -S-, -SO-, -SO2, -CONH- or -NHCO-, and R<IV> is C1-C6 alkyl, C2-C6 alkenyl, methyl, ethyl, propyl, butyl, phenyl or benzyl, the benzene ring of the phenyl