Patent EA-003319-B1 (EA)
Title: Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
Inventor: TALLEY JOHN J
IPC: A61K31/415
Filed: 1997-04-11
Abstract: 1. A compound of Formula I wherein A is a ring substituent selected from C4-C8 cycloalkenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrrolyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from C1-C20alkyl, halo-C1-C20alkyl, hydroxy-C1-C20alkyl, C1-C20alkylcarbonyloxy-C1-C20alkyl and oxo groups; wherein R<1> is radical selected from pyridyl and phenyl; wherein R<1> is optionally substituted at a substitutable position with one or more radicals selected from C1-C20alkyl, halo, C1-C10alkoxy; wherein R<2> is hydrogen; wherein R<2> is radical selected from C1-C20alkyl, acyl, carboxy-C1-C20alkyl, carboxy-C1-C20-alkylcarbonyl, C1-C10alkoxycarbonyl, C1-C10alkoxy-C1-C20-alkylcarbonyl, C1-C10alkoxycarbonyl-C1-C20-alkylcarbonyl, C1-C10alkoxycarbonyl-carbonyl, amino-C1-C20alkylcarbonyl and C1-C10alkylcarbonylamino-C1-C10alkylcarbonyl, or a pharmaceutically acceptable salt thereof. 2. Compound of Claim 1 wherein A is a ring substituent selected from cyclopencenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrrolyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from C1-C10alkyl, halo-C1-C6alkyl, C1-C6hydroxyalkyl, C1-C10alkylcarbonyloxy-C1-C10alkyl and oxo groups; wherein R<1> is radical selected from pyridyl and phenyl; wherein R<1> is optionally substituted at a substitutable position with one or more radicals selected from C1-C10alkyl, halo, C1-C10alkoxy; wherein R<2> is hydrogen; wherein R<3> is radical selected from C1-C10alkyl, C1-C10-alkylcarbonyl, benzoyl, formyl, carboxy-C1-C10alkyl, carboxy-C1-C10alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6alkoxyC1-C10 alkylcarbonyl, C1-C6alkoxycarbonyl-C1-C10 alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, amino-C1-C10alkylcarbonyl and C1-C10alkylcarbonylamino-C1-C10alkylcarbonyl, or a pharmaceutically acceptable salt thereof. 3. Compound of Claim 2 wherein A is a ring substituent selected from cyclopentyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrrolyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, difluoromethyl, hydroxymethyl, acetoxymethyl and oxo groups. wherein R<1> is radical selected from pyridyl and phenyl; wherein R<1> is optionally substituted at a substitutable position with one or more radicals selected from methyl, chlorine, and methoxy; wherein R<2> is hydrogen; wherein R<3> is radical selected from methyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, benzoyl, formyl, carboxymethyl, carboxyethylcarbonyl, methoxycarbonyl, tert-butoxycarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxymethylcarbonyl, methoxycarbonylmethylcarbonyl, methoxycarbonylcarbonyl, aminomethylcarbonyl, methylcarbonylaminomethylcarbonyl; or a pharmaceutically acceptable salt thereof. 4. Compound of Claim 3 selected from compounds and their pharmaceutically acceptable salts, of the group consisting of N-([4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl] propanamide; N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl] butanamide; N-[[4-[1,5-dimethyl)-3-phenyl-1H-pyrazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl] acetamide; N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H imidazol-1-yl)phenyl]sulfonyl] acetamide; N-[[4-i2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H imidazol-1-yl]phenyl]sulfonyl] acetamide; N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H imidazol-1-yl]phenyl]sulfonyl] butanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl] butanamide; N-[[4-[2-(3-chloro-5-mechylphenyl)-4-(trifluoromethyl)-1H imidazol-1-yl]phenyl]sulfonyl] acetamide; N-[[4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]phenyl]sulfonyl]acetamide; 2-methyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]benzamide; 2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]butanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]pentanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide; 3-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; 2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]butanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[3-(difluoromethyl)-6-fluoro-1,5-dihydro-7-methoxy-[2]benzothiopyrano[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[6-fluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-mechoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl] acetamide; N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide; methyl [[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]oxoacetate; 2-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl] acetamide; N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]butanamide; 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenylsulfonyl]amino]-4-oxobutanoic acid; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]formamide; 1,1-dimethylethyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine; 2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; 2-(acetylamino)-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; methyl 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-4-oxobutanoate; methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate; N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester; N-[[4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]acetamide; methyl-3-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-3-oxopropanoate; 4-[5-(3-bromo-5-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl]-N-methylbenzenesulfonamide; N-(1,1-dimethylethyl)-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-N-methylbenzenesulfonamide; N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; N-[[4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[5-(acetoxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; 1,1-dimethylethyl-N-[2-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-2-oxoethyl]carbamate; N-[[4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]phenyl]sulfonyl]acetamide; 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-methylbenzenesulfonamide; N-[[4-[3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl]phenyl]sulfonyl]propanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-trifluoromethylimidazol-1-yl]phenyl]sulfonyl]propanamide; 4-[2-(4-fluorophenyl)cyclopenten-1-yl]-N-methylbenzenesulfonamide; and N-[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyl]propanamide. 5. A compound of Formula I wherein A is a ring substituent selected from C4-C8 cycloalkenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrrolyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from C1-C20alkyl, halo-C1-C20alkyl, hydroxy-C1-C20alkyl, C1-C20alkylcarbonyloxy-C1-C20alkyl and oxo groups; wherein R<4> is radical selected from pyridyl and phenyl; wherein R<4> is optionally substituted at a substitutable position with one or more radicals selected from C1-C20alkyl, halo, C1-C10alkoxy; wherein R<5> is radical selected from hydrogen, C1-C20alkyl, phenyl, carboxy-C1-C20alkyl, C1-C10alkoxy, C1-C10alkoxy-C1-C20-alkyl, C1-C10alkoxycarbonyl-C1-C20-alkyl, C1-C10 alkoxycarbonyl, amino-C1-C20alkyl, C1-C20alkylcarbonylamino-C1-C20alkyl, or a pharmaceutically-acceptable salt thereof. 6. Compound of Claim 1 wherein A is a ring substituent selected from cyclopentenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrrolyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from C1-C10alkyl, halo-C1-C6alkyl, C1-C6hydroxyalkyl, C1-C10alkylcarbonyloxy-C1-C10alkyl and oxo groups; wherein R<4> is radical selected from pyridyl and phenyl; wherein R<4> is optionally substituted at a substitutable position with one or more radicals selected from C1-C10alkyl, halo, C1-C6alkoxy; wherein R<5> is radical selected from hydrogen , phenyl, , carboxy-C1-C10-alkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C10alkyl, C1-C6alkoxycarbonyl-C1-C10 alkyl, C1-C6alkoxycarbonyl, amino-C1-C10alkyl and C1-C10alkylcarbonylamino-C1-C10alkyl or a pharmaceutically-acceptable salt thereof. 7. Compound of Claim 6 wherein A is a ring substituent selected from cyclopentenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, difluoromethyl, hydroxymethyl, acetoxymethyl and oxo groups, wherein R<4> is selected from pyridyl and phenyl, wherein R<4> is optionally substituted at a substitutable position with one or more radicals selected from methyl, fluorine, chlorine, and methoxy; wherein R<5> is radical selected from hydrogen, phenyl, methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, methoxy, tert-butoxy, methoxyethyl, ethoxymethyl, methoxymethyl, carboxyethyl,