Methanocarba derivatives of pseudoribose that inhibit adenosine kinase

Abstract

where the moieties J and K, considered in combination, are —CH2—, or K and L, considered in combination, are —CH2—. The R1 moiety can be —NH2, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl. The R2 and R3 moieties are each independently C1-C6 alkyl. The R4 moiety is hydrogen or C1-C6 alkyl. The R5 and R6 moieties are each independently C6-C12 aryl, C3-C8 cycloalkyl, or C3-C8 heteroaryl, that is optionally further substituted.

What is claimed is: 
     
         1 . An adenosine kinase inhibitor having the formula: 
       
         
           
           
               
               
           
         
         wherein J and K, considered in combination, are —CH 2 —, or K and L, considered in combination, are —CH 2 —; 
         R 1  is —NH 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  hydroxyalkyl; 
         R 2  and R 3  are independently C 1 -C 6  alkyl; 
         R 4  is hydrogen, or C 1 -C 6  alkyl; and 
         R 5  and R 6  are independently C 6 -C 12  aryl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heteroaryl, that is optionally further substituted. 
       
     
     
         2 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The adenosine kinase inhibitor of  claim 1 , wherein R 1  is methyl or hydroxymethyl, R 2  and R 3  are independently hydrogen or methyl; R 4  is hydrogen; and each of R 5  and R 6  is phenyl or substituted phenyl. 
     
     
         5 . The adenosine kinase inhibitor of  claim 1 , wherein where R 5  or R 6  is an aryl substituent, the aryl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, sulfonyloxy, carboxyalkyl, nitro, C 1 -C 6  sulfonyloxyalkyl, or arylcarbonyl. 
     
     
         6 . The adenosine kinase inhibitor of  claim 1 , wherein where R 5  or R 6  is a cycloalkyl, the cycloalkyl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, sulfonyloxy, carboxyalkyl, C 1 -C 6  sulfonyloxyalkyl, or arylcarbonyl. 
     
     
         7 . The adenosine kinase inhibitor of  claim 1 , wherein where R 5  or R 6  is a heteroaryl substituent, the heteroaryl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, aryl, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, C 1 -C 6  sulfonyloxyalkyl, sulfonamide, C 1 -C 6  alkylcarbonyl, or arylcarbonyl. 
     
     
         8 . The adenosine kinase inhibitor of  claim 1 , wherein R 5  and R 6  are each independently aryl that is optionally further substituted by halogen, C 1 -C 6  alkyl, C 1 -C 6  perfluoroalkyl, hydroxy, C 1 -C 6  alkoxy, or NO 2 . 
     
     
         9 . The adenosine kinase inhibitor of  claim 1 , wherein each of R 5  and R 6  is phenyl or phenyl substituted by fluorine. 
     
     
         10 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The adenosine kinase inhibitor of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition, comprising an adenosine kinase inhibitor having the formula: 
       
         
           
           
               
               
           
         
         wherein J and K, considered in combination, are —CH 2 —, or K and L, considered in combination, are —CH 2 —; 
         R 1  is —NH 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  hydroxyalkyl; 
         R 2  and R 3  are independently C 1 -C 6  alkyl; 
         R 4  is hydrogen, or C 1 -C 6  alkyl; and 
         R 5  and R 6  moieties are independently C 6 -C 12  aryl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heteroaryl, that is optionally further substituted. 
       
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein R 1  is methyl or hydroxymethyl, R 2  and R 3  are independently hydrogen or methyl; R 4  is hydrogen; and each of R 5  and R 6  is independently aryl that is optionally further substituted by halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, or NO 2 . 
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein
 where R 5  or R 6  is an aryl substituent, the aryl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, sulfonyloxy, carboxyalkyl, nitro, C 1 -C 6  sulfonyloxyalkyl, or arylcarbonyl;   where R 5  or R 6  is a cycloalkyl, the cycloalkyl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, sulfonyloxy, carboxyalkyl, C 1 -C 6  sulfonyloxyalkyl, or arylcarbonyl; and   where R 5  or R 6  is a heteroaryl substituent, the heteroaryl substituent is optionally and independently further substituted one or more times by halogen, C 1 -C 6  haloalkyl, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, aryl, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, C 1 -C 6  sulfonyloxyalkyl, sulfonamide, C 1 -C 6  alkylcarbonyl, or arylcarbonyl.   
     
     
         18 . The pharmaceutical composition of  claim 15 , further comprising one or more pharmaceutically acceptable carriers, excipients, preservatives, and/or diluents. 
     
     
         19 . A method of preventing epilepsy and its progression in a patient, comprising: administering an effective amount of an adenosine kinase inhibitor having the formula 
       
         
           
           
               
               
           
         
         wherein J and K, considered in combination, are —CH 2 —, or K and L, considered in combination, are —CH 2 —; 
         R 1  is —NH 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  hydroxyalkyl; 
         R 2  and R 3  are independently C 1 -C 6  alkyl; 
         R 4  is hydrogen, or C 1 -C 6  alkyl; and 
         R 5  and R 6  are independently C 6 -C 12  aryl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heteroaryl, that is optionally further substituted. 
       
     
     
         20 . The method of  claim 19 , wherein administering the adenosine kinase inhibitor includes administering the adenosine kinase inhibitor intravenously, orally, transdermally, subcutaneously, mucosally, intramuscularly, intranasally, intrapulmonary, parenterally, intrarectally, or topically. 
     
     
         21 . The method of  claim 19 , wherein preventing epilepsy and its progression in a patient includes inhibiting seizures in the patient.