Details for Patent: 5,510,496
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| Title: | Substituted pyrazolyl benzenesulfonamides |
| Abstract: | A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I: ##STR1## wherein R.sup.1 is selected from sulfamyl, fluoro, chloro, methyl, hydroxyl, methoxy and trifluoromethyl: wherein R.sup.2 is selected from hydrido, difiuoromethyl, trifluoromethyl, amido, dichloromethyl, trichloromethyl, pentafluoroethyl, cyano, heptatluoropropyl, difluorochloromethyl, methoxycarbonyl, dichlorofluoromethyl, N-phenylamido, N-3-fluorophenyl) amido, 2-pyridylamido, N-(4-methylphenyl)amido, hydroxypropyl, N-(3-chlorophenyl)amido, N-(4-methoxyphenyl)amido, hydroxymethyl, hydroxyethyl, carboxylpropyl, carboxymethyl and carboxyethyl; wherein R.sup.3 is selected from hydrido, methyl, triflouromethyl, fluoro, chloro and bromo; wherein R.sup.4 is selected from phenyl, biphenyl, pyrazinyl, cyclohexyl, cyclohexenyl and thienyl; and wherein R.sup.4 is optionally substituted at a substitutable position with one or more radicals selected from chloro, bromo, fluoro, methylthio, methylsulfonyl, morpholinyl, amino, methyl, ethyl, propyl, isopropyl, butyl, ethoxy, nitro, chloromethyl, trifluoromethoxy, trifluoroenhoxy, fluoromethyl, methoxy, difluoromethyl, trifluoromethyl, dichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, and difluoropropyl; or wherein R.sup.3 and R.sup.4 together form ##STR2## provided R.sup.2 and R.sup.3 are not both hydrido; or a pharmaceutically-acceptable salt thereof. |
| Inventor(s): | Talley; John J. (St. Louis, MO), Penning; Thomas D. (Elmhurst, IL), Collins; Paul W. (Deerfield, IL), Malecha; James W. (Libertyville, IL), Bertenshaw; Stephen R. (Brentwood, MO), Graneto; Matthew J. (St. Louis, MO) |
| Assignee: | G.D. Searle & Co. (Chicago, IL) |
| Filing Date: | Jun 01, 1995 |
| Application Number: | 08/456,441 |
| Claims: | 1. A compound of Formula I ##STR45## wherein R.sup.1 is sulfamyl; wherein R.sup.2 is selected from hydrido, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylalmido, N-alkyl-N-arylamido, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl, N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic; wherein R.sup.3 is selected from hydrido, alkyl, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido, N-monoarylamicio, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl, dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic, heterocycloalkyl and aralkyl; and wherein R.sup.4 is selected from aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl. amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; provided R.sup.2 and R.sup.3 are not identical radicals selected from hydrido, carboxyl and ethoxycarbonyl; further provided that R.sup.2 is not carboxyl when R.sup.3 is hydrido and when R.sup.4 is phenyl; and further provided that R.sup.3 is not hydrido or alkyl when R.sup.2 is haloalkyl; or a pharmaceutically-acceptable salt thereof. 2. Compound of claim 1 wherein R.sup.1 is sulfamyl; wherein R.sup.2 is selected from hydrido, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl, N, N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl and heterocyclic; wherein R.sup.3 is selected from alkyl, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylsulfamyl, N-arylsulfamyl, arylsulfonyl, N,N-dialkylsulfamyl, N-alkyl-N-arylsulfamyl, heterocyclic, heterocycloalkyl and aralkyl; and wherein R.sup.4 is selected from aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a pharmaceutically-acceptable salt thereof. 3. Compound of claim 2 wherein R.sup.2 is hydrido or haloalkyl; wherein R.sup.3 is selected from alkyl, halo, carboxyalkyl, N-monoalkyl-N-hydroxyamido, N-monoalkyl-N-hydroxyamidoalkyl and N-monoalkylamido; and wherein R.sup.4 is aryl optionally substituted at a substitutable position with halo; or a pharmaceutically-acceptable salt thereof. 4. Compound of claim 3 wherein R.sup.2 is selected from hydrido, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl; wherein R.sup.3 is selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, N-methylamido, N-ethylamido, N-isopropylamido, N-propylamido, N-butylamido, N-isobutylamido, N-tertbutylamido, N-pentylamido, N-cyclohexylamido, N-cyclopentylamido, carboxypropyl, carboxymethyl, carboxyethyl, N-methyl-N-hydroxyamido, N-methyl-N-hydroxyamidomethyl, N-methyl-N-hydroxyamidoethyl and N-methyl-N-hydroxyamidopropyl; and wherein R.sup.4 is phenyl optionally substituted at a substitutable position with one or more radicals selected from fluoro, chloro and bromo; or a pharmaceutically-acceptable salt thereof. 5. Compound of claim 4 selected-from compounds, and their pharmaceutically acceptable salts, of the group consisting of 4-[5-(4-bromophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide; 1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide; methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-aminophenyl)-1H-pyrazole-3-carboxyl ate ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxyl ate; 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide; 4-[5-phenyl-3-(3 -hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide; N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carbo xamide; N-[4-methoxyphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyraz ole-3-carboxamide; N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazo le-3-carboxamide; N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazo le-3-carboxamide N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4- fluorophenyl)-1H-pyrazole-3-carboxamide; 4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-propanoic acid; 4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(bromo)-1H-pyrazol-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazol-yl]benzenesulfonamide; methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxy late; 4-[5-(4-chlorophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide; N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-c arboxamide; N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carbo xamide; N-methyl-N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole -3-carboxamide; N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carbo xamide; N-methyl-N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol e-3-carboxamide; 4-[5-(4-chlorophenyl)-3-(nitro)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(amidino)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(methylsulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide 4-[5-(4-chlorophenyl)-3-(methylsulfamyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4- chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-4-fluoro-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-fluorophenyl)-3-chloro-1H-pyrazol-1-yl]benzenesulfonamide; N-methyl-N-hydroxy-1-[4-(aminosulfonyl)phenyl]-5-(4- fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-4-ethanamide; 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-4-acetic acid; and N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-4-carboxamide. 6. A compound of Formula II ##STR46## wherein R.sup.2 is selected from hydrido, haloalkyl, alkoxycarbonyl, cyano, amido, arylamido, carboxyalkyl and hydroxyalkyl; wherein R.sup.3 is hydrido or halo; and wherein R.sup.4 is selected from aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydrido, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; provided R.sup.3 is not hydrido when R.sup.2 is haloalkyl; or a pharmaceutically-acceptable salt thereof. 7. Compound of claim 6 wherein R.sup.2 is selected from hydrido, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, amido, N-phenylamido, N-(3-fluorophenyl)amido, N-(4-methylphenyl)amido, N-(3-chlorophenyl)amido, N-(4-methoxyphenyl)amido, 2-pyridylamido, hydroxypropyl, hydroxymethyl, hydroxyethyl, carboxypropyl, carboxymethyl and carboxyethyl; wherein R.sup.3 is selected from hydrido, fluoro, chloro, iodo and bromo; and wherein R.sup.4 is selected from phenyl, biphenyl, pyrazinyl, cyclohexyl, cyclohexenyl and thienyl; wherein R.sup.4 is optionally substituted at a substitutable position with one or more radicals selected from chloro, bromo, fluoro, methylthio, methylsulfonyl, morpholinyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl; or a pharmaceutically-acceptable salt thereof. 8. Compound of claim 7 selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of 4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-bromophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide; 1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide; methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-aminophenyl)-1H-pyrazole-3-carboxyl ate; ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxyl ate; 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide; 4-[5-phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide; N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carbo xamide; N-[4-methoxyphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyraz ole-3-carboxamide; N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazo le-3-carboxamide; N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazo le-3-carboxamide; N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazo le-3-carboxamide; 4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamid e; and 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-propanoic acid. |
