Anticonvulsant and central nervous system-depressing bis (fluorophenyl) alkylamides and their uses

Abstract

Bis(Fluorophenyl)alkylamides have been chemically synthesized which possess beneficial pharmacological properties (e.g., anticonvulsant activity) useful for the treatment of neurological diseases or disorders, such as, for example, epilepsy, convulsions, and seizure disorders. The preferred compounds of the invention also cause little sedation and have high therapeutic and protective indices in animal models of epilepsy. These compounds further possess long pharmacologic half-lives, which, in practical clinical therapeutic application, should translate into once-a-day dosing, of great benefit to patients suffering from these diseases and/or disorders. These compounds may also be of further clinical utility in the treatment of other diseases and disorders of the central and peripheral nervous systems, or diseases or disorders affected by them, including, but not limited to, spasticity, skeletal muscle spasms and pain, restless leg syndrome, anxiety and stress, and bipolar disorder.

1 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 Y is independently selected from the group consisting of —H, —F, and —Cl;  
 X is either —NR 1 R 2  or —OR 1 ;  
 R 1  is selected from the group consisting,of —H, alkyl, and hydroxyalkyl;  
 R 2  is selected from the group consisting of —H, methyl, and ethyl;  
 and n is either 0, 1, 2, 3, or 4, except for 3,3-bis(3-fluorophenyl)propanamide, N-methyl-3,3-bis(3-fluorophenyl) propanamide, N-ethyl-3,3-bis(3-fluorophenyl)propanamide, N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, and N,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.  
 
     
     
         2 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 each F is independently in either the meta- or para-position;  
 R 1  is selected from the group consisting of —H, alkyl, and hydroxyalkyl;  
 R 2  is selected from the group consisting of —H, methyl, and ethyl;  
 and n is 0, 1, 2, 3, or 4, except for 3,3-bis(3-fluorophenyl)propanamide, N-methyl-3,3-bis(3-fluorophenyl)propanamide, N-ethyl-3,3-bis(3-fluorophenyl)propanamide, N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, and N,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.  
 
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of —H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl, and R 2  is —H.  
     
     
         4 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 0, 1, or 2;  
 both F are either in the meta- or para-position;  
 R 1  is selected-from the group consisting of —H, alkyl, and hydroxyalkyl; and  
 R 2 is selected from the group consisting of —H, methyl, and ethyl, except for 3,3-bis(3-fluorophenyl)propanamide, N-methyl-3,3-bis(3-fluorophenyl)propanamide, N-ethyl-3,3-bis(3-fluorophenyl)propanamide, N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, and N,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.  
 
     
     
         5 . The compound of  claim 1 , wherein said compound is selected from the group consisting of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.  
     
     
         6 . The compound of  claim 1 , wherein said compound is selected from the group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15.  
     
     
         7 . The compound of  claim 1 , wherein said compound is Compound 1.  
     
     
         8 . A method for treating a patient having a neurological disease or disorder comprising administering a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 Y is independently selected from the group consisting of —H, —F, and —Cl;  
 X is either —NR 1 R 2  or —OR 1 ;  
 R 1  is selected from the group consisting of —H, alkyl, and hydroxyalkyl;  
 R 2  is selected from the group consisting of —H, methyl, and ethyl;  
 and n is either 0, 1, 2, 3, or 4  
 
     
     
         9 . The method of  claim 8 , wherein R 1  is selected from the group consisting of —H, methyl, ethyl, isopropyl, isobutyl, hydroxyisopropyl, and hydroxyethyl, and R 2  is —H.  
     
     
         10 . The method of  claim 8 , wherein said compound is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.  
     
     
         11 . The method of  claim 8 , wherein said compound is selected from the group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15.  
     
     
         12 . The method of  claim 8  wherein said compound is compound 1.  
     
     
         13 . A method for treating a patient having a neurological disease or disorder comprising administering a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 each F is independently in either the meta- or para-position;  
 R 1  is selected from the group consisting of —H, alkyl, and hydroxyalkyl;  
 R 2  is selected from the group consisting of —H, methyl, and ethyl;  
 and n is 0, 1, 2, 3, or 4.  
 
     
     
         14 . A method for treating a patient having a neurological disease or disorder comprising administering a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 0, 1, or 2;  
 both F are either in the meta- or para-position;  
 R 1  is selected from the group consisting of —H, alkyl, and hydroxyalkyl; and  
 R 2  is selected from the group consisting of —H, methyl, and ethyl.  
 
     
     
         15 . The method of  claim 8 , wherein said neurological disease or disorder is selected from the group consisting of epilepsy, convulsions, and seizure disorders.  
     
     
         16 . The method of  claim 8 , wherein said treating of said patient alleviates or prevents convulsions in said patient.  
     
     
         17 . The method of  claim 8 , wherein said neurological disease or disorder is associated with spasticity.  
     
     
         18 . The method of  claim 15 , wherein said neurological disease or disorder is a neurodegenerative disease or disorder.  
     
     
         19 . The method of  claim 8 , wherein said neurological disease or disorder is selected from the group consisting of spasticity, skeletal muscle spasms, restless leg syndrome, anxiety, stress, multiple sclerosis, stroke, head trauma, spinal cord injury, Parkinson's disease, Huntington's disease, Alzheimers disease, amyotrophic lateral sclerosis, migraine headaches, and bipolar disorder.  
     
     
         20 . A method of alleviating or preventing a symptom of spasticity, or one or more side effects of spasticity, in a patient comprising administering a compound of any of claims  1 - 4 , or  7 .  
     
     
         21 . A pharmaceutical composition, comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         22 . A pharmaceutical composition, comprising a compound of  claim 2 , and a pharmaceutically acceptable carrier.  
     
     
         23 . A pharmaceutical composition, comprising a compound of  claim 3 , and a pharmaceutically acceptable carrier.  
     
     
         24 . A pharmaceutical composition, comprising a compound of  claim 4 , and a pharmaceutically acceptable carrier.  
     
     
         25 . A pharmaceutical composition, comprising a compound of  claim 5 , and a pharmaceutically acceptable carrier.  
     
     
         26 . A pharmaceutical composition, comprising a compound of  claim 7 , and a pharmaceutically acceptable carrier.  
     
     
         27 . A method for making a therapeutic agent comprising the steps of screening for said agent by determining whether said agent alleviates a symptom of spasticity, and synthesizing said therapeutic agent in an amount sufficient to provide said agent in a therapeutically effective amount to a patient.  
     
     
         28 . The method of  claim 18 , wherein said therapeutic agent comprises a compound of  claim 1 .  
     
     
         29 . A method for modulating CNS activity comprising administering to a patient a compound of  claim 1 .  
     
     
         30 . The method of  claim 29 , wherein said modulation of CNS activity alleviates a symptom associated with convulsions, spasticity, an affective mood disorder, a neuropathic pain syndrome, a headache, a restlessness syndrome, or a movement disorder.