(S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, and Related Compounds as GABA Aminotransferase Inactivators for the Treatment of Epilepsy, Addiction and Hepatocellular Carcinoma

Abstract

Cyclopentene carboxylic acid-related compounds as GABA-AT inhibitors for treatment of various addictions, disorders and disease states.

We claim: 
     
         1 . A method of modulating GABA-AT activity, said method comprising:
 providing a compound of a formula   
       
         
           
           
               
               
           
         
       
       wherein each of R 1  and R 2  is independently selected from H, F, Cl, Br and I, providing at least one of R 1  and R 2  is not H, or a salt thereof; and
 contacting said compound with a medium comprising a γ-aminobutyric acid aminotransferase, said compound in an amount sufficient to modulate γ-aminobutyric acid aminotransferase activity. 
 
     
     
         2 . The method of  claim 1  wherein at least one of R 1  and R 2  is F. 
     
     
         3 . The method of  claim 1  wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof. 
     
     
         4 . The method of  claim 3  wherein the ammonio substituent is an ammonium salt which has a counter ion that is the conjugate base of a protic acid. 
     
     
         5 . The method of  claim 1  wherein said contact is in vivo. 
     
     
         6 . A method of modulating ornithine aminotransferase activity, said method comprising:
 providing a compound of a formula   
       
         
           
           
               
               
           
         
       
       wherein each of R 1  and R 2  is independently selected from H, F, Cl and Br, providing at least one of R 1  and R 2  is not H, or a salt thereof; and
 contacting said compound with a medium comprising an ornithine aminotransferase, said compound in an amount sufficient to modulate ornithine aminotransferase activity. 
 
     
     
         7 . The method of  claim 6  wherein at least one of R 1  and R 2  is F. 
     
     
         8 . The method of  claim 6  wherein said compound is a salt comprising a substituent selected from an ammonio substituent, a carboxylate substituent and a combination thereof. 
     
     
         9 . The method of  claim 8  wherein said the ammonio substituent is an ammonium salt which has a counter ion that is the conjugate base of a protic acid. 
     
     
         10 . The method of  claim 6  wherein said contact is in vivo. 
     
     
         11 . A method for treatment of psychological and neurological disorders, said method comprising administering to a mammalian subject in need thereof an effective amount of a compound of a formula 
       
         
           
           
               
               
           
         
       
       wherein each of R 1  and R 2  is independently selected from H, F, Cl, Br and I, providing at least one of R 1  and R 2  is not H, or a salt thereof. 
     
     
         12 . The method of  claim 11  wherein said neurological disorder is selected from epilepsy, infantile spasms, partial seizures, complex partial seizures, secondary generalized seizures, tonic-clonic seizures, succinic semialdehyde dehydrogenase deficiency (SSADHD), infantile spasms in West's syndrome, Lennox-Gastaut syndrome, tubulous sclerosis, Tourette's syndrome, movement disorders, fibromyalgia, neuropathic pain, migraine related to epilepsy, restless leg syndrome and post traumatic stress disorder, addiction, obesity, obsessive-compulsive disorder and Alzheimer's disease and combinations of the foregoing. 
     
     
         13 . The method of  claim 11  wherein said psychological disorder selected from general anxiety disorder, pathological or compulsive gambling disorder, compulsive eating, body dysmorphic disorder, hypochondriasis, pathologic grooming conditions, kleptomania, pyromania, attention deficit hyperactivity disorder and impulse control disorders and combinations thereof. 
     
     
         14 . The method of  claim 11  wherein each of R 1  and R 2  is F. 
     
     
         15 . The method of  claim 11  wherein said compound is provided in a pharmaceutical composition.