Patent ID: 6559185
Filing Date: 2003-05-06
Classification: A61P,C07C,C07D

Abstract:
A method of treating a complication induced by diabetes by inhibition of aldose reductase which comprises administering to a patient in need thereof an aldose reductase inhibiting amount of a compound of the formula: in whichA is C6-C10-aryl or an optionally aromatic or non-aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N; X is halogen, cyano, C1-C7-alkyl, trifluoromethyl, C2-C7-alkoxy or trifluoromethoxy; R1 and R2, which are identical or different, are hydrogen atoms, a C1-C7-alkyl group, a C3-C12-cycloalkyl group, a trifluoromethyl group, a C1-C7-alkoxy group or R1 and R2 together form an alkylene chain â€”(CH2)râ€”, where r is chosen from 2, 3 and 4; p is chosen from 0, 1, 2, 3, 4 and 5; Z is a bond, the divalent radical â€”COâ€”NHâ€” in which the carbonyl function is linked to R3, the divalent radical â€”SO2â€”NHâ€” in which the sulfonyl function is linked to R3, a C2-C7-alkenylene radical, a sulfur atom, the sulfinyl radical or the sulfonyl radical; R3 is a hydrogen atom; a halogen atom; a tri-(C1-C7-alkyl)silyl group; a C1-C7-alkyl group optionally substituted with one or more identical or different Y radicals; a C6-C10-aryl group optionally substituted with one or more identical or different Y radicals; a C6-C10-aryloxy group optionally substituted with one or more identical or different Y radicals; a C3-C12-cycloalkyl group optionally substituted with one or more identical or different Y radicals; an aromatic or non-aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, the heterocycle being optionally substituted with one or more identical or different Y radicals, or R3 is indanyl or 2-[(4-nitromethylcarbonyl-3-chlorophenyl)aminocarbonyl]-1-(phenyl)ethyl; or R5 and R3 together form a bond; Y is a halogen atom, C1-C7-alkyl, C1-C7-alkoxy, trifluoromethyl, carboxy, carbamoyl, (C1-C7)alkylcarbamoyl, di-(C1-C7)alkylcarbamoyl, C1-C7-alkoxycarbonyl, amino, C1-C7-alkylamino, di-(C1-C7)-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C3-C12-cycloalkyl, sulfo, C1-C7-alkylthio, C1-C7-alkylsulfinyl, C1-C7-alkylsulfonyl, C2-C8-alkylcarbonyl, C2-C8-alkylthiocarbonyl, C2-C8-alkylcarbonylamino, or C6-C10-aryl; E is a divalent radical chosen from: (i) â€”COâ€”NR4â€” in which the carbonyl group is linked to â€”(CR1R2)pâ€” and R4 is the radical â€”(CH2)qâ€”R5 where q is chosen from 0 and 1; and where R5 is a hydrogen atom, a C1-C7-alkyl group, a C6-C10-aryl group or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, N and S; or R5 and R3together form a bond; (ii) â€”SO2â€”NR4â€” in which the sulfonyl group is linked to â€”(CR1R2)pâ€” and R4 is as defined above; (iii) â€”NR4â€” in which R4 is as defined above; (iv) â€”CH&boxH;Nâ€” in which the nitrogen atom is linked to A; and (v) an oxygen atom; n is 0 or 1; with the proviso that at least one of the following variables is defined as follows: A is an aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, Z is a sulfur atom, sulfinyl radical or sulfonyl radical, R3 is an aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, the heterocycle being optionally substituted with one or more identical or different Y radicals, or R3 is indanyl, E is â€”COâ€”NR4 wherein R5 is an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, or E is â€”NR4â€”, â€”CH&boxH;Nâ€” or an oxygen atom; when n is 1, with the further proviso that â€”A(X)â€”(E)nâ€”(CR1R2)pâ€”Zâ€”R3 is not halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl, 4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl, 2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substituted with a group X and optionally substituted 2-fluorophenyl as defined above, and with the further proviso that, when A is pyridyl, X is methyl and n is equal to 1, then E is not â€”NR4â€”, with the further proviso that the compound of formula I is not 3,5-dimethyl-1-nitroacetylpyrazole; or an addition salt thereof with a pharmaceutically acceptable carrier.