Mono-and disubstituted 3-propyl gamma-aminobutyric acids

Abstract

The instant invention is a series of novel mono- and disubstituted 3-propyl gamma aminobutyric acids of Formula I The compounds are useful as therapeutic agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, arthritis, sleep disorders, IBS, and gastric damage. Methods of preparing the compounds and useful intermediates are also part of the invention.

1 . A method for treating restless leg syndrome comprising administering a therapeutically effective amount of a compound according to formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof to a mammal in need of said treatment wherein: 
 R 1  is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl;  
 R 2  is straight or branched alkyl of from 4 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, 
 alkylcycloalkyl,  
 alkylalkoxy,  
 alkyl OH,  
 alkylphenyl,  
 alkylphenoxy, and  
 substituted phenyl.  
 
 
     
     
         2 . The method according to  claim 1  wherein R 1  is hydrogen and R 2  is straight or branched alkyl of from 4 to 8 carbon atoms.  
     
     
         3 . The method according to  claim 1  wherein R 2  is substituted phenyl, or alkylphenyl.  
     
     
         4 . The method according to  claim 1  wherein R 2  is alkylphenoxy.  
     
     
         5 . The method according to  claim 1  wherein R 2  is cycloalkyl or alkylcycloalkyl.  
     
     
         6 . The method according to  claim 1  wherein R 2  is alkylhydroxy.  
     
     
         7 . The method according to  claim 1  wherein said compound is selected from: 
 3-Aminomethyl-5-methyl-nonanoic acid;  
 3-Aminomethyl-5-methyl-decanoic acid;  
 3-Aminomethyl-5-methyl-undecanoic acid;  
 3-Aminomethyl-5-methyl-dodecanoic acid;  
 3-Aminomethyl-5-methyl-tridecanoic acid;  
 3-Aminomethyl-5-cyclopropyl-hexanoic acid;  
 3-Aminomethyl-5-cyclobutyl-hexanoic acid;  
 3-Aminomethyl-5-trifluoromethyl-hexanoic acid;  
 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid;  
 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid;  
 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid;  
 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid;  
 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid;  
 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and  
 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid.  
 
     
     
         8 . A method for treating restless leg syndrome comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a mammal in need of said treatment wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid.    
     
     
         9 . A method for treating restless leg syndrome comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a mammal in need of said treatment wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid.    
     
     
         10 . The method according to  claim 1  wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid.  
 
     
     
         11 . The method according to  claim 1  wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid.  
 
     
     
         12 . The method according to  claim 1  wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid.  
 
     
     
         13 . The method according to  claim 1  wherein said compound is 
 (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid.  
 
     
     
         14 . The method according to  claim 1  wherein said compound is selected from: 
 (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;  
 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid;  
 (3S,5R)-3-Aminomethyl-5, 10-dimethyl-undecanoic acid;  
 (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;  
 (3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;  
 (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;  
 (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;  
 (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; and  
 (3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid.  
 
     
     
         15 . The method according to  claim 1  wherein said compound is selected from: 
 (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-hept-6-enoic acid;  
 (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;  
 (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid;  
 (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;  
 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;  
 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;  
 (E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;  
 (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;  
 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;  
 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid;  
 (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid;  
 (3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;  
 (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;  
 (3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid;  
 (3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;  
 (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and  
 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid.  
 
     
     
         16 . A method for treating restless leg syndrome comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a mammal in need of said treatment wherein said compound is selected from: 
 3-Aminomethyl-5-methylheptanoic acid;    3-Aminomethyl-5-methyl-octanoic acid;    3-Aminomethyl-4,5-dimethyl-hexanoic acid;    (3S,4S)3-Aminomethyl-4,5-dimethyl-hexanoic acid;    (3R,4R)3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;    3-Aminomethyl-4-isopropyl-hexanoic acid;    3-Aminomethyl-4-isopropyl-heptanoic acid;    (3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;    (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;    (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;    (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;    (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;    (3R,4R,5R)-3-Aminomethyl-4,5-dimethyl-heptanoic acid; and    (3R,4R,5R)-3-Aminomethyl-4,5-dimethyl-octanoic acid.