Details for Patent: 6,492,411
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| Title: | Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation |
| 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 II: ##STR1## wherein R.sup.2 is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R.sup.3 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and wherein R.sup.4 is selected from aralkenyl, 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, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; provided R.sup.2 and R.sup.3 are not both hydrido; further provided that R.sup.2 is not carboxyl or methyl when R.sup.3 is hydrido and when R.sup.4 is phenyl; further provided that R.sup.4 is not triazolyl when R.sup.2 is methyl; further provided that R.sup.4 is not aralkenyl when R.sup.2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R.sup.4 is not phenyl when R.sup.2 is methyl and R.sup.3 is carboxyl; and further provided that R.sup.4 is not unsubstituted thienyl when R.sup.2 is trifluoromethyl; or a pharmaceutically-acceptable salt thereof. |
| Inventor(s): | Talley; John J (St. Louis, MO), Penning; Thomas D (Elmhurst, IL), Collins; Paul W (Deerfield, IL), Rogier, Jr.; Donald J (St. Louis, MO), Malecha; James W (Libertyville, IL), Miyashiro; Julie M (Chicago, IL), Bertenshaw; Stephen R (Brentwood, MO), Khanna; Ish K (Vernon Hills, IL), Graneto; Matthew J (St. Louis, MO), Rogers; Roland S (Richmond Heights, MO), Carter; Jeffery S (Chesterfield, MO), Docter; Stephen H. (Mt. Prospect, IL), Yu; Stella S (Morton Grove, IL) |
| Assignee: | G. D. Searle & Co. (Chicago, IL) |
| Filing Date: | Apr 17, 2002 |
| Application Number: | 10/125,325 |
| Claims: | 1. A method for the treatment of headache in a subject in need of such treatment, wherein the method comprises administering to the subject an asthma treating-effective amount of a compound having the structure of Formula I: ##STR101## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is sulfamyl; R.sup.2 is haloalkyl; R.sup.3 is selected from the group consisting of H and alkyl; and R.sup.4 is selected from the group consisting of aryl, cycloalkyl, and cycloalkenyl; wherein R.sup.4 is optionally substituted with one or more radicals selected from the grou0p consisting of halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkkylamido, 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. 2. The method of claim 1 wherein: R.sup.2 is lower haloalkyl; R.sup.3 is H; and R.sup.4 is selected the group consisting of from aryl, cycloalkyl, and cycloalkenyl; wherein R.sup.4 is optionally substituted with one or more radicals selected from the group consisting of halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, amido, N-mono(lower alkyl)amido, N-monoarylamido, N,N-di(lower alkyl)amido, N-(lower alkyl)-N-arylamido, halo(lower alkyl), hydroxyl, lower alkoxy, hydroxy(lower alkyl, halo(lower alkoxy), sulfamyl, N-(lower alkyl)sulfamyl, amino, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, heterocyclic, nitro and acylamino; or a pharmaceutically-acceptable salt thereof. 3. The method of claim 1 wherein: R.sup.2 is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, chlorodifluoromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl; and R.sup.4 is selected the group consisting of phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R.sup.4 is optionally substituted with one or more radicals selected from the group consisting of fluoro, chloro, bromo, methylthio, methylsulfinyl, cyano, carboxyl, amido, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, N-methylamido, N-ethylamido, N-isopropylamido, N-propylamido, N-butylamido, N-isobutylamido, N-tert-butylamido, N-pentylamido,N-cyclohexylamido, N-cyclopentylamido, N,N-dimethylamido, N-methyl-N-ethylamido, pyrrolidinoamido, piperidinoamido, N-phenylamido, N-(3-fluorophenyl)amido, N-(4-methylphenyl)amido, N-(3-chlorophenyl)amido, N-(4-methoxyphenyl)amido, 2-pyridylamido, N-methyl-N-phenylamido, N-methyl-N-pyridylamido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, chlorodifluoromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, sulfamyl, methylsulfamyl, amino, nitro, methylamino, dimethylamino, formylamino, acetamino, trifluoroacetamino, and morpholino. 4. The method of claim 3 where in the compound is selected from the group consisting of: 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de; 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[3-(difluoromethyl)-5-(4-[methylthio}phenyl)-1H-pyrazol-1-yl]benzenesulfo namide; 4-[5-(2,4-[difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf onamide; 4-[5-(2,6-[difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf onamide; 4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonam ide; 4-[5-(4-chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo namide; 4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonami de; 4-[5-(4-biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[3-(difluoromethyl)phenyl)-5-(4-(morpholino)phenyl)-1H-pyrazol-1-yl]benze nesulfonamide; 4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[3-(difluoromethyl)-5-(4-(trifluoromethyl]phenyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(4-chlorophenyl)-3-(dichlorofluoromenthyl)-1H-pyrazol-1-yl]benzenesulf onamide; 4-[5-(3,5-dichlorofluoromenthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen esulfonamide; 4-[5-(2,4,6-trifluoromethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide; 4-[5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide; 4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de; 4-[5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de; 4-[5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo namide; 4-[5-(3,4-methylenedioxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide; 4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon amide; 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes ulfonamide; 4-[5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de; 4-[5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo namide; 4-[5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ; 4-[5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona mide; 4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf onamide; 4-[5-(2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(4-N-methylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide; 4-[5-(4-N,N-dimethylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen esulfonamide; 4-[5-(4-N-formylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide; 4-[5-(4-N-acetaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo namide; 4-[5-(4-N-methylsulfonamidophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benz enesulfonamide; 4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide; 4-[5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; 4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid e; 4-[5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de; or a pharmaceutically acceptable salt thereof. 5. The method of claim 4 where the compound is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami de, or a pharmaceutically-acceptable salt thereof. |
