Method for treating an inflammatory disease by administering a 1,2,3,4-tetrahydroquinoxaline compound containing a phenyl group having a sulfonic acid ester structure introduced therein as a substituent

Abstract

A method for treating a non-ocular inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof: R 1 represents: R 2 represents a lower alkyl group, a lower cycloalkyl group or an aralkyl group; R 3 represents a lower alkyl group; R 4 , R 5 , R 6 or R 7 each represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group or a nitro group; m, n, p or q each represents 0, 1 or 2; in the case where m, n, p or q is 2, each of R 4 , R 5 , R 6 or R 7 is the same or different.

1 . A method for treating a non-ocular inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof: 
       
         
           
           
               
               
           
         
         R 1  represents the following formula (2a), (3a), (4a) or (5a): 
       
       
         
           
           
               
               
           
         
         R 2  represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower cycloalkyl group or a substituted or unsubstituted aralkyl group; 
         R 3  represents a lower alkyl group; 
         R 4 , R 5 , R 6  or R 7  each represents a halogen atom, a substituted or unsubstituted lower alkyl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a cyano group or a nitro group; 
         m, n, p or q each represents 0, 1 or 2; and 
         in the case where m, n, p or q is 2, each of R 4 , R 5 , R 6  or R 7  is the same or different. 
       
     
     
         2 . The method according to  claim 1 , wherein in the formula (1),
 R 1  represents the following formula (2a), (3a), (4a) or (5a):   
       
         
           
           
               
               
           
         
         R 2  represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower cycloalkyl group or a substituted or unsubstituted aralkyl group; 
         R 3  represents a lower alkyl group; 
         R 4  represents a halogen atom, a lower alkyl group, a lower alkoxy or a nitro group; 
         R 5  represents a halogen atom, a lower alkyl group, or a lower alkoxy group; 
         R 6  represents a lower alkyl group or a lower alkoxy group; 
         R 7  represents a halogen atom or a lower alkyl group; 
         m, n or p represents 1 or 2; 
         in the case where m, n or p is 2, each of R 4 , R 5  or R 6  is the same or different; and 
         q represents 0 or 1. 
       
     
     
         3 . The method according to  claim 1 , wherein in the formula (1),
 R 1  represents the following formula (2b-1), (2b-2), (2b-3), (3b-1), (3b-2), (4b-1) or (5b-1):   
       
         
           
           
               
               
           
         
         R 2  represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower cycloalkyl group or a substituted or unsubstituted aralkyl group; and 
         R 3  represents a methyl group. 
       
     
     
         4 . A method for treating a non-ocular inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of
 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-methylsulfonyloxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-propylsulfonyloxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-methylsulfonyloxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-benzylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-butylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-ethylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-(4-isopropylsulfonyloxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[4-(3-chlorobenzylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(4-methylbenzylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro quinoxalin-2-one,   7-[4-(4-chlorobenzylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-(4-isobutylsulfonyloxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[4-(2-chlorobenzylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(2-methylbenzylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclohexylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(3-methylbenzylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isobutylsulfonyloxy-2-methoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-propylsulfonyloxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isopropylsulfonyloxy-2-methoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-methylsulfonyloxyphenyl)-8-(2-methoxy-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(2-methoxy-5-nitrophenoxymethyl)-7-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isobutylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxy-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxy-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxy-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxy-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(2-methoxy-5-nitrophenoxymethyl)-7-(2-methoxy-4-propylsulfonyloxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isobutylsulfonyloxy-2-methoxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-methylsulfonyloxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-propylsulfonyloxyphenyl)-8-(2-methyl-5-nitrophenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-propylsulfonyloxyphenyl)-8-(4-methylbenzoyloxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[4-(3-chloropropylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-chloromethylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenylaminomethyl)-7-(2-methoxy-4-propylsulfonyloxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(2-methoxy-4-methylsulfonyloxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(2-methoxyphenylaminomethyl)-7-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isobutylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-isopropylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(2-methoxyphenylaminomethyl)-7-(2-methoxy-4-propylsulfonyloxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   7-[4-(3-benzylaminopropylsulfonyloxy)-2-methoxy-phenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(3-propylaminopropylsulfonyloxy)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-[3-(morpholin-4-yl)propylsulfonyloxy]phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-[3-(piperidin-1-yl)propylsulfonyloxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, and   8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-[3-[N-(2-methylaminoethyl)-N-methylamino]propylsulfonyloxy]phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, or a salt thereof.   
     
     
         5 . The method according to  claim 1 , wherein the inflammatory disease is an inflammatory bone-joint disorder. 
     
     
         6 . The method according to  claim 5 , wherein the inflammatory bone-joint disorder is rheumatoid arthritis or osteoarthritis. 
     
     
         7 . The method according to  claim 4 , wherein the inflammatory disease is an inflammatory bone-joint disorder. 
     
     
         8 . The method according to  claim 7 , wherein the inflammatory bond-joint disorder is rheumatoid arthritis or osteoarthritis.