Alkyl amino acid derivatives useful as pharmaceutical agents

Abstract

GABA-related pro-drugs of the formula (III) are provided that when administered to humans or other mammals provide an increased duration of active compound in the plasma compared to compounds of corresponding structure in which labile groups are not present. The compounds are of the formula (III) In the above formula: P represents hydrogen or methyl; Q represents a labile amine- or amide-forming organic group that becomes removed in the human or animal body; R 1 represents straight or branched C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl or phenyl; R 2 represents hydrogen or methyl; and R 3 represents hydrogen, methyl or carboxyl; and R 4 represents hydrogen or a labile ester-forming group selected from substituted and unsubstituted C 1 -C 6 alkyl, benzyl and phenyl groups that become removed in the human or animal body. In the above formula when R 1 is phenyl, R 2 , R 3 and R 4 are not simultaneously hydrogen. Pharmaceutically acceptable salts of any salt-forming compound within the above class are also included. The compounds may be used to treat a range of neurological conditions, e.g. epilepsy and pain.

1 . A compound of the formula (III)  
       
         
           
           
               
               
           
         
       
       in which: 
 P is hydrogen or methyl;  
 Q is a labile amine- or amide-forming organic group that becomes removed in the human or animal body;  
 R 1  is straight or branched C 2 -C 6  alkyl, C 3 -C 6  cycloalkyl or phenyl;  
 R 2  is hydrogen or methyl; and  
 R 3  is hydrogen, methyl or carboxyl; and  
 R 4  is hydrogen or a labile ester-forming group selected from substituted and unsubstituted C 1 -C 6  alkyl, benzyl and phenyl groups that become removed in the human or animal body,  
 or a pharmaceutically acceptable salt of any salt-forming compound within the above class,  
 but excluding compounds in which R 1  is phenyl and R 2 , R 3  and R 4  are each hydrogen.  
 
     
     
         2 . The compound of  claim 1 , in which R 4  is hydrogen.  
     
     
         3 . The compound of  claim 1 , in which R 4  is other than hydrogen and is more labile than Q.  
     
     
         4 . The compound of  claim 3 , in which R 4  is methyl or t-butyl.  
     
     
         5 . The compound of  claim 1 , wherein Q can be removed hydrolytically under physiological conditions.  
     
     
         6 . The compound of  claim 1 , wherein Q can be removed enzymatically under physiological conditions.  
     
     
         7 . The compound of  claim 1 , wherein Q is  
       
         
           
           
               
               
           
         
       
       in which: 
 R 5  is hydrogen, straight or branched chain C 1 -C 6  alkyl, phenyl or benzyl in which the benzene ring may be substituted or unsubstituted; and  
 Y is hydrogen, straight or branched chain C 1 -C 6  alkyl, or —CH 2 CO 2 R 6  in which R 6  represents straight or branched chain C 1 -C 6  alkyl.  
 
     
     
         8 . The compound of  claim 7 , wherein R 5  represents t-butyl, benzyl or phenyl.  
     
     
         9 . The compound of  claim 1 , wherein Q is selected from  
       
         
           
           
               
               
           
         
       
       in which: 
 R 7  is hydrogen, straight or branched chain C 1 -C 6  alkyl, phenyl or benzyl in which either or each benzene ring may be substituted or unsubstituted; and  
 X represents a phenyl group or any of the side chains of the 20 naturally encoded α-amino acids.  
 
     
     
         10 . The compound of  claim 1 , wherein Q is  
       
         
           
           
               
               
           
         
       
       wherein R 7  is methyl, t-butyl or phenyl.  
     
     
         11 . A compound of the formula (IV)  
       
         
           
           
               
               
           
         
         in which P, Q and R 4  have the meanings given in  claim 1 , or a pharmaceutically acceptable salt of any salt-forming compound within the above class.  
       
     
     
         12 . The compound of  claim 11 , in which R 4  is hydrogen.  
     
     
         13 . The compound of  claim 11 , in which R 4  is other than hydrogen and is more labile than Q.  
     
     
         14 . The compound of  claim 13 , in which R 4  is methyl or t-butyl.  
     
     
         15 . The compound of  claim 11 , wherein Q can be removed hydrolytically under physiological conditions.  
     
     
         16 . The compound of  claim 11 , wherein Q can be removed enzymatically under physiological conditions.  
     
     
         17 . The compound of  claim 11 , wherein Q is  
       
         
           
           
               
               
           
         
       
       in which: 
 R 5  is hydrogen, straight or branched chain C 1 -C 6  alkyl, phenyl or benzyl in which the benzene ring may be substituted or unsubstituted; and  
 Y is hydrogen, straight or branched chain C 1 -C 6  alkyl, or —CH 2 CO 2 R 6  in which R 6  represents straight or branched chain C 1 -C 6  alkyl.  
 
     
     
         18 . The compound of  claim 17 , wherein R 5  represents t-butyl, benzyl or phenyl.  
     
     
         19 . The compound of  claim 11 , wherein Q is selected from  
       
         
           
           
               
               
           
         
       
       in which: 
 R 7  is hydrogen, straight or branched chain C 1 -C 6  alkyl, phenyl or benzyl in which either or each benzene ring may be substituted or unsubstituted; and  
 X represents a phenyl group or any of the side chains of the 20 naturally encoded α-amino acids.  
 
     
     
         20 . The compound of  claim 11 , wherein Q is  
       
         
           
           
               
               
           
         
       
       wherein R 7  is methyl, t-butyl or phenyl.  
     
     
         21 . A compound selected from 
 (S)-3-(Benzoylaminomethyl)-5-methylhexanoic acid;    (S)-Benzyl 3-(acylaminomethyl)-5-methylhexanoate;    (S)-3-[N-(acetoxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoic acid;    (S)-3-[N-((2,2-dimethylpropionyloxy)methyleneoxycarbonyl)-amino-methyl]-5-methylhexanoic acid;    (S)-3-[N-(benzoyloxymethyleneoxycarbonyl)aminomethyl]-5-methyl-hexanoic acid; and    pharmaceutically acceptable salts of any of the above.    
     
     
         22 . A method for making a compound of the formula (III) or salt thereof, as defined in  claim 1 , above, which comprises: 
 coupling a compound of the formula:                          in which P and R 1 -R 4  have the meanings given in  claim 1  and in which said compound is in the form of a free base or an ammonium salt with a compound of the formula                          or QCl where Q has the meaning given in  claim 1 .    
     
     
         23 . The method of  claim 22 , in which the compound (V) is a carboxylic acid and comprising the further step of esterifying the carboxyl group with a substituted or unsubstituted C 1 -C 6  alkanol, benzyl alcohol or phenol.  
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula (III)  
       
         
           
           
               
               
           
         
       
       in which: 
 P is hydrogen or methyl;  
 Q is a labile amine- or amide-forming organic group that becomes removed in the human or animal body;  
 R 1  is straight or branched C 2 -C 6  alkyl, C 3 -C 6  cycloalkyl or phenyl;  
 R 2  is hydrogen or methyl; and  
 R 3  is hydrogen, methyl or carboxyl; and  
 R 4  is hydrogen or a labile ester-forming group selected from substituted and unsubstituted C 1 -C 6  alkyl, benzyl and phenyl groups that become removed in the human or animal body,  
 or a pharmaceutically acceptable salt of any salt-forming compound within the above class,  
 but excluding compounds in which R 1  is phenyl and R 2 , R 3  and R 4  are each hydrogen.  
 
     
     
         25 . A method for treating epilepsy comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         26 . A method for treating faintness attacks, hypokinesia and cranial disorders comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         27 . A method for treating a neurodegenerative disorder comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         28 . A method for treating depression comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         29 . A method for treating anxiety comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         30 . A method for treating panic comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         31 . A method for treating pain comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         32 . A method for treating a neuropathological disorder comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.  
     
     
         33 . A method for treating digestive disorder comprising administering a therapeutically effective amount of a compound according to  claim 1  to a human or animal in need of said treatment.