Methods for treating hyperactive gastric motility

Abstract

This invention provides methods and pharmaceutical compositions for treating, inhibiting or preventing hyperactive gastric motility in a mammal utilizing agonists of KCNQ potassium channels, including KCNQ2, KCNQ3, KCNQ4 and KCNQ5 potassium channels, alone or in combination. The hyperactive gastric motility may be associated with maladies including, colitis, irritable bowel syndrome and Crohn's disease. Compounds useful in these methods include the 1,2,4-triamino-benzene derivatives described in U.S. Pat. No. 5,384,330 (Dieter et al.) and the substituted 3-phenyl oxindole compounds described in U.S. Pat. No. 5,565,483 (Hewawasam et al.). Among the preferred compounds of this invention is N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester, also referred to as retigabine.

What is claimed:  
     
         1 . A method of treatment or inhibition of hyperactive gastric motility in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a KCNQ potassium channel agonist.  
     
     
         2 . The method of  claim 1  wherein the KCNQ potassium channel is a KCNQ4 potassium channel.  
     
     
         3 . The method of  claim 1  wherein the KCNQ potassium channel is a KCNQ⅔ potassium channel.  
     
     
         4 . The method of  claim 1  wherein the KCNQ potassium channel is a KCNQ⅗ potassium channel.  
     
     
         5 . The method of  claim 1  wherein the hyperactive gastric motility in a mammal is associated with inflammatory bowel disease.  
     
     
         6 . The method of  claim 1  wherein the hyperactive gastric motility in a mammal is associated with Crohn's disease.  
     
     
         7 . A method of treatment or inhibition of hyperactive gastric motility in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from hydrogen, C 1 —C 6 -alkyl, C 2 —C 6 -alkanoyl or the radical Ar;  
 R 2  is selected from hydrogen or C 1 —C 6 -alkyl;  
 R 3  is selected from C 1 —C 6 -alkoxy, NH 2 , C 1 —C 6 -alkylamino, C 1 —C 6 -dialkylamino, amino substituted by the radical Ar, C 1 —C 6 -alkyl, C 2 —C 6 -alkenyl, C 2 —C 6 -alkynyl, the radical Ar or the radical ArO—;  
 R 4  is selected from hydrogen, C 1 —C 6 -alkyl or the radical Ar;  
 R 5  is selected from hydrogen or C 1 —C 6 -alkyl or the radical Ar; Alk: a straight or branched alkylene group with 1-0 carbon atoms, which can also be substituted by the radical Ar;  
 Ar is a phenyl radical substituted by the radicals R 6 , R 7  and/or R 8  where these radicals R 6 , R 7  and R 8  are the same or different and represent C 1 —C 6 -alkyl, C 3 —C 7 -cycloalkyl, hydroxy, C 1 —C 6 -alkoxy, C 2 —C 6 -alkanoyloxy, halogen, hydroxy, C 1 —C 6 -halogenoalkyl, —CN, —NH 2 , —NH—C 1 —C 6 -alkyl, —N(C 1 —C 6 -alkyl) 2 , —CO 2 H, —CO—C 1 —C 6 -alkyl, —CO—O—C 1 —C 6 -alkyl, —COAr, —CO—OAr, —CONH 2 , —CONH—C 1 —C 6 -alkyl, —CON(C 1 —C 6 -alkyl) 2 , —CONHAr, —NH—CO—C 1 —C 6 -alkyl, —NHCO—Ar, —NHCO—C 1 —C 6 -alkoxy, —N—H—CO—Ar, —N HCO—NH 2 , —NHCO—N(—C 1 —C 6 -alkyl) 2 , —NHCO—NHAr, —NH—SO 2 —C—1—C 6 -alkyl, —NH—SO 2 Ar, —NH—SO 2 -nitrophenyl, —SO 2 —OH, —SO 2 —C 1 —C 6 -alkyl, —SO 2 —Ar, —SO 2 —C 1 —C 6 -alkoxy, —SO 2 —OAr, —SO 2 —NH 2 , —SO 2 —NH—C 1 —C 6 -alkyl, —SO 2 —N(C 1 —C 6 -alkyl) 2 , —SO 2 —NHAr, —SO 2 —C 1 —C 6 -alkoxy;  
 n is 0 or 1;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         8 . A method of  claim 7  in which the compound is selected from the group of: 
 2-Amino-4-(4-fluorobenzylamino)-1-ethoxycarbonylaminobenzene;  
 2-Amino-4-(4-trifluoromethylbenzylamino)-1-ethoxycarbonylamino-benzene;  
 2-Amino-4-benzylamino-1-ethoxycarbonylamino-benzene;  
 2-Amino-4-(3,5-dichlorobenzylamino)-1-ethoxycarbonylamino benzene;  
 2-Amino-4-(3,5-dichlorobenzylamino)-1-propyloxycarbonylamino benzene;  
 2-Amino-(2-chlorobenzylamino)-1-(diethylcarbamoylamino) benzene;  
 2-Amino-4-(2,4-dichlorobenzylamino)-1-(dimethylcarbamoylamino) benzene; or  
 1,2-Diacetylamino-4-(4-fluorobenzylamino) benzene;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         9 . The method of Claim of  claim 8  wherein the mammal is a human.  
     
     
         10 . The method of  claim 8  wherein the mammal is feline or canine.  
     
     
         11 . The method of  claim 8  wherein the hyperactive gastric motility in a mammal is associated with inflammatory bowel disease.  
     
     
         12 . The method of  claim 8  wherein the hyperactive gastric motility in a mammal is associated with Crohn's disease.  
     
     
         13 . A method of treatment or inhibition of hyperactive gastric motility in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid or a pharmaceutically acceptable salt or ester form thereof.  
     
     
         14 . The method of  claim 13  wherein the pharmaceutically acceptable ester form is N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester.  
     
     
         15 . The method of Claim of  claim 13  wherein the mammal is a human.  
     
     
         16 . The method of  claim 13  wherein the hyperactive gastric motility in a mammal is associated with inflammatory bowel disease.  
     
     
         17 . The method of  claim 13  wherein the hyperactive gastric motility in a mammal is associated with Crohn's disease.  
     
     
         18 . A method of treatment or inhibition of hyperactive gastric motility in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is hydrogen, hydroxy or fluoro;  
 R 1 , R 2 , R 3  and R 4  each are independently hydrogen, C 1-4  alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R 1  and R 2 , R 2  and R 3  or R 3  and R 4  are joined together to form a benzo fused ring;  
 R 5  is hydrogen or C 1-4  alkyl; and  
 R 6  is chlorine or trifluoromethyl;  
 or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof..  
 
     
     
         19 . The method of treatment or inhibition of hyperactive gastric motility in a mammal of  claim 18  wherein the compound is selected from the group of: 
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-2-H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-trifluoromethyl)2H-indol-2-one;  
 (±)-1,3-Dihydro-3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4,6-bis(trifluoromethyl)-2H-indol-2-one;  
 (−)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;  
 (−)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[g]indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-iodo-2H-indol-2one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(4-methylphenyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[e]indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-4,6-bis(trifluoromethyl)-2H-indol-2-one;  
 (±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-2H-indol-2one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-[4-(trifluoromethyl)phenyl]-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one;  
 (±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one;  
 (±)-3-(5-Chloro-hydroxyphenyl)-1,3-dihydro-6-iodo-2H-indol-2-one;  
 (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one;  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one; and  
 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[f]indol-2-one;  
 and the pharmaceutically acceptable salt forms thereof.  
 
     
     
         20 . The method of Claim of  claim 18  wherein the mammal is a human.  
     
     
         21 . The method of  claim 18  wherein the mammal is feline or canine.  
     
     
         22 . The method of  claim 18  wherein the hyperactive gastric motility in a mammal is associated with inflammatory bowel disease.  
     
     
         23 . The method of  claim 18  wherein the hyperactive gastric motility in a mammal is associated with Crohn's disease.