Patent EA-004432-B1 (EA)
Title: 4,5-diaryl-3(2h)-furanone derivatives as cyclooxygenase-2 inhibitors
Inventor: SHIN SONG SEOG
IPC: C07D409/04
Filed: 2000-04-12
Abstract: 1. A compound of the following Formula I: wherein X represents halo, hydrido, or linear or branched C1-C10-alkyl; Y represents (C1-C10-alkyl)sulfonyl, aminosulfonyl, (N-acylamino)-sulfonyl, in which alkyl radical of acyl group is linear or branched and comprises from 1 to 10 carbon atoms, (N-alkylamino)sulfonyl, in which alkyl radical is linear or branched and comprises from 1 to 10 carbon atoms, or (C1-C10-alkyl)thio; Z represents oxygen or sulfur atom; R1 and R2 are selected independently from C1-C5-alkyl radicals, or form a 4 to 6-membered aliphatic or hetero cyclic group, taken together with the 2-position carbon atom of the 3(2H)-furanone ring; and AR represents a substituted or non-substituted aromatic group of 5 to 10 atoms; or a pharmaceutically-acceptable salt thereof. 2. A compound according to Claim 1, wherein X is selected from halo, hydrido and C1-C5-alkyl; Y is selected from (C1-C5-alkyl)sulfonyl, aminosulfonyl, (C1-C5-alkyl)sulfinyl, (lower N-acylamino)-sulfonyl, in which alkyl radical of acyl group comprises from 1 to 5 carbon atoms, (N-alkylamino)sulphonyl, in which alkyl radical comprises from 1 to 5 carbon atoms, and (C1-C5-alkyl)thio; Z is selected from oxygen and sulfur atom; wherein R1 and R2 are selected independently from lower alkyls, or R1 and R2 represent pentylidenyl (-CH2-CH2-CH2-CH2-), hexylidenyl (-CH2-CH2-CH2-CH2-CH2-), 4-tetrahydro-(4H)-pyranylidenyl (CH2-CH2-O-CH2-CH2-), 3-tetrahydrofuranylidenyl(-CH2-O-CH2-CH2-) or 3-oxetanylidenyl (-CH2-O-CH2-) to form a cycle taken together with the 2-position carbon atom of the 3(2H)-furanone ring; and AR represents a substituted or non-substituted aromatic group of 5 to 10 atoms, which is selected from, but not limited to, the aromatic groups encompassing wherein, each of R3 to R7, if present, is independently selected from hydrido, halo, C1-C10-alkyl, C1-C10-haloalkyl, C1-C10-alkoxy, C1-C10-haloalkoxy, acyl, in which alkyl radical comprises from 1 to 10 carbon atoms, nitro, amino, N-alkylamino, in which alkyl radical comprises from 1 to 10 carbon atoms, N,N-dialkylamino, in which alkyl radical comprises from 1 to 10 carbon atoms, N-acylamino, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, (haloacyl)amino, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, formyl, cyano, azido, hydroxy, (C1-C10-alkyl)thio, (C1-C10-alkyl)sulfonyl, phenyl, alkoxyalkyl, in which alkyl radical comprises from 1 to 10 carbon atoms and hydroxyalkyl, in which alkyl radical comprises from 1 to 10 carbon atoms or the adjacent two groups of R3 to R7 form, taken together, methylenedioxy; and wherein each of R8 to R19, if present, is selected from hydrido, halo, C1-C10-alkyl, acyl, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, C1-C10-haloalkyl, C1-C10-alkoxy, formyl, cyano, nitro, amino, azido and N-acylamino, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms; or a pharmaceutically-acceptable salt thereof. 3. A compound according to Claims 1 and 2, in which X is selected from fluoro, chloro, bromo, hydrido, methyl, ethyl and n-propyl; Y is selected from methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, aminosulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, (N-acetylamino)sulfonyl, (N-propionylamino)sulfonyl, (N-butyrylamino)sulfonyl, (N-methylamino)sulfonyl, (N-ethylamino)sulfonyl, methylthio, ethylthio, and n-propylthio; Z is selected from oxygen and sulfur atom; wherein R1 and R2 are selected independently from methyl and ethyl, or R1 and R2 represent, taken together, pentylidenyl (-CH2-CH2-CH2-CH2-), hexylidenyl (-CH2-CH2-CH2-CH2-CH2-), 4-tetrahydro-(4H)-pyranylidenyl (-CH2-CH2-O-CH2-CH2-), 3-tetrahydrofuranylidenyl (-CH2-O-CH2-CH2-), and 3-oxetanylidenyl (-CH2-O-CH2-) to form a cycle with the 2-position carbon atom of the 3 (2H)-furanone ring; each of R3 to R7, if present, is independently selected from hydrido, fluoro, chloro, bromo, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, trifluoromethoxy, difluoromethoxy, fluoromethoxy, acetyl, propionyl, n-butanoyl, iso-butanoyl, n-pentanoyl, nitro, amino, N-methylamino, N-ethylamino, N-n-propylamino, N,N-dimethylamino, N-acetylamino, N-propionylamino, N-(trifluoroacetyl)amino, formyl, hydroxy, methylthio, ethylthio, n-propylthio, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, phenyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl, or adjacent two groups of R3 to R7 form, taken together, methylenedioxy; and each of R8 to R19, if present, is selected from hydrido, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, acetyl, propionyl, methoxy, ethoxy, iso-propyloxy, n-propyloxy and formyl; or a pharmaceutically-acceptable salt thereof. 4. A compound according to Claim 1, which is represented by the following Formula II: wherein Y represents (C1-C10-alkyl)sulfonyl; aminosulfonyl, (C1-C10-alkyl)sulfinyl, (N-acylamino)-sulfonyl, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, (N-alkylamino)sulfonyl, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, or (C1-C10-alkyl)thio; Z represents oxygen or sulfur atom; R1 and R2 are selected independently from lower alkyl radicals; and each of R3 to R7, if present, is independently selected from hydrido, halo, C1-C10-alkyl, C1-C10-haloalkyl, C1-C10-alkoxy, C1-C10-haloalkoxy, acyl, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, nitro, amino, N-alkylamino, in which alkyl radical comprises from 1 to 10 carbon atoms, N,N-dialkylamino, in which alkyl radical comprises from 1 to 10 carbon atoms, N-acylamino, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, N-(haloacyl)amino, in which alkyl radical of acyl group comprises from 1 to 10 carbon atoms, formyl, cyano, azido, (C1-C10-alkyl)thio, hydroxy, alkylthio, (C1-C10-alkyl)sulfonyl, phenyl, alkoxyalkyl, in which alkyl radical comprises from 1 to 10 carbon atoms, and hydroxyalkyl, in which alkyl radical comprises from 1 to 10 carbon atoms, or two adjacent groups of R3 and R7 form, taken together, methylenedioxy; or a pharmaceutically-acceptable salt thereof. 5. A compound according to Claim 4, in which Y is selected from (C1-C10-alkyl)sulfonyl, aminosulfonyl, (C1-C5-alkyl)sulfinyl, (N-acylamino)sulfonyl, in which alkyl radical of acyl group comprises from 1 to 5 carbon atoms, (N-alkylamino)sulfonyl, in which alkyl radical comprises from 1 to 5 carbon atoms, and (C1-C5-alkyl)thio; Z is selected from oxygen and sulfur atom; R1 and R2 are independently selected from methyl and ethyl radical; and wherein each of R3 to R7, if present, is independently selected from hydrido, halo, C1-C5-alkyl, C1-C5-haloalkyl, C1-C5-alkoxy, C1-C5-haloalkoxy, acyl, in which alkyl radical of acyl group comprises from 1 to 5 carbon atoms, nitro, amino, N-alkylamino, in which alkyl radical comprises from 1 to 5 carbon atoms, N,N-dialkylamino, in which alkyl radical comprises from 1 to 5 carbon atoms, N-acylamino, in which alkyl radical of acyl group comprises from 1 to 5 carbon atoms, (haloacyl)amino, in which alkyl radical of acyl group comprises from 1 to 5 carbon atoms, formyl, cyano, azido, hydroxy, C1-C5-alkylthio, C1-C5-alkylsulfonyl, phenyl, C1-C5-alkoxyalkyl and hydroxyalkyl, in which alkyl radical comprises from 1 to 5 carbon atoms, or two adjacent groups of R3 to R7 form, taken together, methylenedioxy; or a pharmaceutically-acceptable salt thereof. 6. A compound according to Claim 5, in which Y is selected from methylsulfonyl, aminosulfonyl, methylsulfinyl, (N-acetylamino)sulfonyl, (N-propionylamino)sulfonyl, (N-butyrylamino)sulfonyl, (N-methylamino)sulfonyl, (N-ethylamino)sulfonyl, and methylthio; Z is selected from oxygen and sulfur atom; R1 and R2 are independently selected from methyl and ethyl radical; and each of R3 to R7, if present, is independently selected from hydrido, fluoro, chloro, bromo, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoromethoxy, acetyl, propionyl, n-butanoyl, iso-butanoyl, n-pentanoyl, nitro, amino, N,N-dimethylamino, N-acetylamino, N-propionylamino, formyl, hydroxy, methylthio, ethylthio, n-propylthio, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, phenyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl, or adjacent two groups of R3 to R7 form, taken together, methylenedioxy; or a pharmaceutically-acceptable salt thereof. 7. A compound according to Claim 6, which is selected from the following group of specific compounds: 2,2-Dimethyl-5-{4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)-furanone; 2,2-Dimethyl-4-(2-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 2,2-Dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 2,2-Dimethyl-4-(4-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 2,2-Dimethyl-4-(3-fluoro-4-phenylphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(2,4-Difluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(2,5-Difluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(3,4-Difluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(3,5-Difluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(2-Chlorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(3-Chlorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(4-Chlorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(3-Chloro-4-fluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone; 4-(3-Chloro-5-fluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phen