Patent EA-003127-B1 (EA)
Title: Heteroaryl succinamides and their use as metalloproteinase inhibitors
Inventor: BENDER STEVEN L
IPC: A61P1/00
Filed: 1997-10-06
Abstract: 1. A compound of formula I: wherein: X is a single bond or -C(O)CH2-; Y is -CH(OH)-; R1 is H, phenyl, optionally substituted C3-alkyl, cyano group, fluoro or pyridinyl; biphenyl, optionally substituted cyano group, or carbamoyl; or pyridinyl; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10, wherein R10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12, wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R3 is H or an alkyl group, or R2 and R3, together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R5 is C(O)NHOH, C(O)OR13, or N(OH)CHO; R13 is H, or C3-alkyl group, and is a heteroaryl group having five ring atoms, containing one N atom only as the heteroatom; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound of Claim 1, characterized in that R2 and R3 together with atoms to with they are attached, form cycloalkyl group or a pharmaceutically acceptable salt or solvate thereof. 2. A compound of formula I: wherein X is a single bond or -C(O)CH2-; Y is -C(O)-; R1 is H, phenyl, optionally substituted C3-alkyl, cyano group, fluoro or pyridinyl; biphenyl, optionally substituted cyano group, or carbamoyl; or pyridinyl; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10, wherein R10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12, wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R3 is an alkyl group, or an O-alkyl group; R2 and R3, together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R5 is C(O)NHOH, C(O)OR13, or N(OH)CHO; R13 is H, or C3-alkyl group, and is a heteroaryl group having five ring atoms, containing one N atom only as the heteroatom; or a pharmaceutically acceptable salt or solvate thereof, with proviso, that if compound of formula (I) is: wherein R1 and R5 are such as determined above; W is H, OH, halo group, alkyl group or O-alkyl group, and, more over, wherein, if m is 2, 3 or 4, n is 1, 2, 3 or 4, and A is CH2, O, NH or N-alkyl; or if m is 4, 5 or 6, n is 0, and A is -CHJ-, wherein J is carboxylic, alkoxycarbonyl or carbamoyl group; or a pharmaceutically acceptable salt or solvate thereof, then is pyrrolyl. 4. A compound of Claim 3, wherein R2 and R3, together with the atoms to which they are attached form a heterocycloalkyl group. 5. A compound of Claim 3, wherein R5 is C(O)OR13, wherein R13 is H, or C3-alkyl group. 6. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 3 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. 7. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. 8. A compound of formula I: wherein X is a single bond or -C(O)CH2-; Y is a single bond; R1 is H, phenyl, optionally substituted C3-alkyl, cyano group, fluoro or pyridinyl; biphenyl, optionally substituted cyano group, or carbamoyl; or pyridinyl; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10, wherein R10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12, wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R3 is heteroaryl group; R5 is C(O)NHOH, C(O)OR13 or N(OH)CHO; R13 is H, or C3-alkyl group, and is a heteroaryl group having five ring atoms, containing one N atom only as the heteroatom; or a pharmaceutically acceptable salt or solvate thereof, 9. The compound of Claim 8, wherein R3 is a heteroaryl group of formula wherein R21 and R22 together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof. 10. The compound of Claim 8, wherein R3 is a heteroaryl group of formula wherein R21 and R22 are independently selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C(O)O-alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable, salt or solvate thereof. 11. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 8 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. 12. The compound of formula or a pharmaceutically acceptable, salt or solvate thereof. 13. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 12 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. 14. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 12 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. 15. A compound selected from the group: 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid; N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid; N-(2-hydroxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid; 3(R)-[3-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl] succinamic acid; N-(2(R)-hydroxyindan-1(R)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl] succinamic acid; N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid; N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl] succinamic acid; N<1>-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-N<4>-hydroxy-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl] succinamide; 3(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid; 3(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl) succinamic acid; 3(R)-[3-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid; 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid; N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(S)-[1-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-3-yl] succinamic acid; and N<1>-hydroxy-N<4>-methyl-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamide; and the pharmaceutically acceptable salts and solvates thereof. 16. A compound of the formula I: wherein X is a single bond or -C(O)CH2-; Y is -CH(OH)-; R1 is H, phenyl, optionally substituted C3-alkyl, cyano group, fluoro or pyridinyl; biphenyl, optionally substituted cyano group, or carbamoyl; or pyridinyl; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10, wherein R10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12, wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R3 is H; R5 is C(O)NHOH, C(O)OR13 or N(OH)CHO; R13 is H, or C3-alkyl group, and is a heteroaryl group having five ring atoms, containing one N atom only as the heteroatom; or a pharmaceutically acceptable salt or solvate thereof. 17. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in Claim 15 or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.