Patent EA-003294-B1 (EA)
Title: Metalloproteinase inhibitors, pharmaceutical compositions, their constituents, and their pharmaceutical use
Inventor: ZOOK Scott
IPC: C07D401/12
Filed: 1996-12-05
Abstract: 1. A compound of formula (1): wherein Z is O or S; Ar is monocyclic aryl or heteroaryl group, which is selected from a phenyl group, or five- or six-membered nitrogen- or oxygen-containing heteroaryl group unsubstituted or substituted by one or more suitable substituents, selected from the halogroups and cyanogroup; X is selected from S, S=O, O, N-R3 and N<+>(O<->)-R4 wherein R3 is hydrogen atom or C1-C6-alkyl group, wherein said alkyl group is a monovalent radical with straight or branched chain of carbon and hydrogen atoms having no unsaturation, C(O)-R17-group, C(O)O-R17 group, C(O)NHR17 group, SO2-R19 group, wherein R17 is C1-C4-alkyl group, the said alkyl group is a monovalent radical with straight or branched, having no unsaturation chain of carbon and hydrogen atoms, and where R19 is CH3 and R4 is C1-C7 alkyl group, wherein alkyl group is a monovalent radical with straight or branched, having no unsaturation chain of carbon and hydrogen atoms; and R1 and R2 are independently selected from a hydrogen atom, a C1-C7- alkyl group, a -C(O)O-R17 group, or a -C(O)NR17R18 group, wherein R17 is hydrogen or a C1-C4-alkyl group, and R18 is a hydrogen, and wherein each of said alkyl groups is a monovalent radical with straight or branched having no unsaturation chain of carbon and hydrogen atoms; a pharmaceutically acceptable prodrug of the indicated compound, its pharmaceutically acceptable salt or solvate. 2. A compound according to claim 1, differing by that X is N-R3; and R3 is a hydrogen atom or C1-C6-alkyl group, wherein said alkyl group is a monovalent radical with straight or branched having no unsaturation chain of carbon and hydrogen atoms, C(O)-R17-group, C(O)O-R17 group, C(O)NHR17 group, SO2-R19 group, wherein R17 is C1-C4-alkyl group, said alkyl group is a monovalent radical with straight or branched having no unsaturation chain of carbon and hydrogen atoms, and wherein R19 is CH3. 3. A compound according to claim 1, differing by that Ar is a phenyl group which is unsubstituted or substituted in the para position by a suitable substituent, selected from fluorine or chlorine. 4. A compound according to claim 1, wherein the hydrogen atom designated with "*" is in the R-configuration when X is O, N-R3 or N<+>(O<->)-R4 and in the S-configuration when X is S or S=O. 5. A compound as claimed in claim 1 differing by that it is 3(S)-N-hydroxy-4-(4-((pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; and pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs thereof. 6. A compound according to claim 1 which is selected from the group consisting of: 3(S)-N-hydroxy 4-(4-(4- imidazole-1-yl)phenoxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 3(S)-N-hydroxy-4-(4-(4- flourophenoxy)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 3(S)-N-hydroxy-4-(4-(4-imidazol-2-yl)phenoxy)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 3(S)-N-hydroxy-4-(4-(4-chlorophenoxy)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R)-3,3-Dimethyl-N-hydroxy-1-(4-(4-chlorophenoxyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-Dimethyl-N-hydroxy-1-(4-(4-fluorophenoxyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-Dimethyl-N-hydroxy-1-(4-(4-bromophenoxy)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-1-(4-(4-(chlorophenoxy)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R)-1-(4-(4-(fluorophenoxy)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 3(S)-N-hydroxy-4-(4-(4-chlorophenylsulfanyl)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 3(S)-N-hydroxy-4-(4-(4-fluorophenylsulfanyl)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R)-3,3-Dimethyl-N-hydroxy-1-(4-(4-fluorophenylsulfanyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-Dimethyl-N-hydroxy-1-(4-(4-chlorophenylsulfanyl)benzenesulfonyl)-piperazine-2-carboxarnide, 2(R)-1-(4-(4-fluorophenylsulfanyl)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R)-1-(4-(4-chlorophenylsulfanyl)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R),3(S)-N-hydroxy-4-(4-(pyrid-4-yl)oxy)benzenesulfonyl)-2-methyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R),3(S)-N-hydroxy-4-(4-(pyrid-4-yl)sulfonyl)benzenesulfonyl)-2-methyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R)-N-hydroxy-1-(4-(4-chlorophenoxy)benzenesulfonyl)-4-(methanesulfonyl)-piperazine-2-carboxamide, 2(R)-N-hydroxy-1-(4-(4-fluolorophenoxy)benzenesulfonyl)-4-(methanesulfonyl)-piperazine-2-carboxamide, 3(S)-N-hydroxy-4-(4-((pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide, compounds having the formula: and also pharmaceutically acceptable prodrugs, salts and solvates of the said compounds. 7. Pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable prodrug, salt or solvate thereof; and (b) a pharmaceutically acceptable carrier, diluent, vehicle or excipient. 8. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound as defined in claim 5 or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable carrier, diluent, vehicle or excipient. 9. A method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable prodrug, salt or solvate thereof. 10. A method according to claim 9 wherein the said disease condition is selected from the group of tumor growth, invasion or metastasis, or arthritis. 11. A method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in claim 5 or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof. 12. A method according to claim 11 wherein the said disease condition is selected from the group of tumor growth, invasion or metastasis, or arthritis.