Patent EA-001803-B1 (EA)
Title: Sulfonyl urea derivatives and their use in the control of interleukin-1 activity
Inventor: DOMBROSKI MARK ANTHOHY
IPC: A61P1/00
Filed: 1997-12-29
Abstract: 1. A compound of the formula     or a pharmaceutically acceptable salt thereof, wherein R' is 1,1-dioxo-1-thiochromanyl optionally substituted with (C1-C6)alkyl; 8-hydroxy-5,6,7,8-tetrahydronaphtyl, 8-oxo-5,6,7,8-tetrahydronaphtyl, 8-hydroxyimino-5,6,7,8-tetrahydronaphtyl, or phenyl, thienyl, 5,6,7,8-tetrahydronaphtyl, furanyl, indolyl, benzoimidazolyl, each of them is optionally substituted by 1-3 substituents, selected from the group: (C1-C6)alkyl, optionally substituted by 1-2 substituents, selected from hydroxy, amino, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl, phenyloxy, substituted with (C1-C6)acyl, hydroxy(C3-C6)cycloalkyl, halo, perfluoro(C1-C6)alkyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, aminosulfonyl, (C3-C7)cycloalkylaminosulfonyl, dioxolanyl, optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, amino, imidazolyl, furanyl, group of the formula   wherein u is 0, 1, R<19> is hydrogen, or (C1-C6)alkyl; R<20> is hydrogen, (C1-C6)alkyl, (C1-C6)carboxyalkyl or phenyl(C1-C6)alkyl; group of the formula   wherein s is 0 or 1; Y is hydrogen, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NR<9>R<10>, wherein R<9> and R<10> each independently is selected from hydrogen and (C1-C6)alkyl; R<2> is R<2> is phenyl or 1,2,3,5,6,7-hexahydroindacenyl, each of them is optionally substituted by 1-3 substituents, selected from the group consisting of halo, (C1-C6)alkyl (linear or branched), cyano, thienyl, phenyl, a group of the formula   wherein Y is (C1-C6)alkyl or amino. 2. A compound according to Claim 1, wherein R<1> is 8-hydroxy-5,6,7,8-tetrahydronaphtyl, 8-oxo-5,6,7,8-tetrahydronaphtyl, 8-hydroxyimino-5,6,7,8-tetrahydronaphtyl, indolyl, benzoimidazolyl, or phenyl, thienyl, furanyl, each of them is optionally substituted with halo, (C1-C6)alkyl, which is optionally substituted with 1-2 hydroxy, (C3-C7)cycloalkylaminosulfonyl, (C1-C6)alkylaminosulfonyl, dioxolanyl, which is optionally substituted with (C1-C6)alkyl, group of formula   wherein u is 0,1, R<19> is (C,-C6)alkyl; R<20> is hydrogen; or group of formula   wherein Y is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl. 3. A compound according to Claim 1, wherein said compound is selected from the group consisting of: 1-(4-chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-l-methyl-ethyl)benzenesulfonyl]-urea; 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-sulfonyl]-urea; 1-(1,2,3,5,6,7-hexahydro-4-aza-s-indacen-8-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(4-[1,3]dioxolan-2-yl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(2,6-diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(2,6-diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(4-acetyl-thiophene-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(1H-benzimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(4-acetyl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(4-fluoro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonyl]-urea; 1-(6-fluoro-1H-benzimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(4-chloro-2,6-diisopropyl-phenyl)-3-(lH-indole-6-sulfonyl)-urea; 1-(4-chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1H-indole-6-sulfonyl)-urea; 1-[1,2,3,5,6,7-hexahydro-s-indacen-u-yl)-3-(1H-indole-6-sulfonyl)-urea; 1-(5-fluoro-1H-indole-6-sulfonyl)-3-(1,2,3,5,6,7-hexanhydro-5-indacen-4-yl)-urea; 1-[4-chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1,3)dioxolan-2-yl)-benzenesulfonyl]-urea; 3-[3-[4-chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide; 1-[2-fluoro-5-(2-methyl-(1,3)dioxoian-2-yl)-benzenesulfonyl]-3-(1,2,3,5,6,7-hexahydro-indacen-4-yl)-urea; and 3-[3-(1,2,3,5,6,7-hexahydro-S-indacen-4-yl)-ureidosulfonyl]-N-methyl-benzenesulfonamide. 4. A pharmaceutical composition for the treatment of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzheimers disease, percussion injury, depression, atherosclerosis and osteoporosis in a mammal, including a human, comprising administering an amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatments or inhibition and a pharmaceutically acceptable carrier. 5. A method for treating a condition selected from the group consisting of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzheimers disease, percussion injury, depression, atherosclerosis and osteoporosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition. 6. The compound 4-(l-hydroxy-l-methyl-ethyl)-furan-2-sulfonamide.