Methods of making 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile and its preferred salt form

Abstract

6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile substantially free of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile, and the anhydrous monoacetate salt thereof, are useful in the treatment of alpha-2 mediated disorders such as ocular hypertension.

What is claimed is:  
     
         1 . A composition comprising 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H -benzimidazole-4-carbonitrile anhydrous monoacetate salt or tautomer thereof.  
     
     
         2 . A composition comprising 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H -benzimidazole-4-carbonitrile substantially free of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile or tautomer thereof.  
     
     
         3 . The composition of  claim 2 , wherein the 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile is less than 70 parts per billion.  
     
     
         4 . The composition of  claim 3 , wherein the 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile is less than 5 parts per billion.  
     
     
         5 . A method of making a compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein: 
 (a) Q 1 , and Q 3  are each independently selected from the group consisting of hydrogen, hydrogen functional group equivalent and nil;  
 (b) Q 2  is selected from the group consisting of hydrogen, and hydrogen functional group equivalent;  
 (c) R 4  is selected from the group consisting of amide, carboxylic acid, cyano, carboxylic acid functional group equivalent and cyano functional group equivalent;  
 (d) Q 5  is selected from hydrogen or hydrogen functional group equivalent;  
 (e) R 6  is selected from the group consisting of amino, nitro, formylamino, and amino functional group equivalent; and  
 (f) R 7  is either methyl or methyl functional group equivalent;  
 (g) or tautomer thereof;  
 comprising:  
 a) providing a compound of formula (I):  
                     
 wherein: 
 (a) X and Y are each independently selected from the group consisting of nitro, amino, formylamino and nitrogen/one carbon equivalent conjugate, and amino functional group equivalent;  
 (b) R 4  is selected from the group consisting of carboxylic acid, cyano, carboxylic acid functional group equivalent, and cyano functional group equivalent;  
 (c) Q 5  is selected from hydrogen or hydrogen functional group equivalent;  
 (d) R 6  is selected from the group consisting of hydrogen, amino, nitro, and amino functional group equivalent;  
 (e) R 7  is selected from methyl or methyl functional group equivalent;  
 (f) provided X and Y are not both amino; and  
 (g) provided X and Y are not both nitrogen/one carbon equivalent conjugate.  
 
 b) cyclizing the formula (I) compound in a single pot by using a non ferrous metal hydrogenation catalyst, in the presence of hydrogen or a hydrogen donor, and optionally a cyclization agent, yielding the compound of formula (II).  
 
     
     
         6 . The method of  claim 5 , wherein the hydrogen donor is formic acid.  
     
     
         7 . The method of  claim 6 , wherein the hydrogen donor and cyclization agent are both formic acid.  
     
     
         8 . The method of  claim 5 , wherein the non-ferrous metal hydrogenation catalyst is selected from the group consisting of platinum, palladium, rhodium, ruthenium, and nickel.  
     
     
         9 . The method of  claim 8 , wherein the non-ferrous metal hydrogenation catalyst is sulfided platinum on carbon.  
     
     
         10 . The method of  claim 9 , wherein the hydrogen donor is formic acid.  
     
     
         11 . The method of  claim 10 , wherein the formula (II) compound is selected from the group consisting of 6-Formylamino-7-methyl-1H-benzimidazole-4-carboxylic acid; 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile; 6-Formylamino-7-methyl-1H-benzimidazole-4-carbonitrile; 6-Formylamino-7-methyl-1H-benzimidazole-4-carboxamide; and 7-Methyl-1H-benzimidazole-4-carboxylic acid.  
     
     
         12 . The method of  claim 10 , wherein the formula (II) compound is substantially free of a compound of formula (III):  
       
         
           
           
               
               
           
         
       
       wherein: 
 (a) Q 11 , Q 12  and Q 13  are each independently selected from the group consisting of nitro, amino, formylamino, and amino functional group equivalent;  
 (b) R 11  and R 12  are each independently selected from methyl or methyl functional group equivalent;  
 (c) R 13  and R 14  are each independently selected from the group consisting of amide, carboxylic acid, cyano, and cyano functional group equivalent.  
 
     
     
         13 . The method of  claim 12 , wherein the formula (III) compound is selected from the group consisting of: 2,3,7-tri(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 7-amino-2,3-di(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 3-amino-2,7-di(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 2-amino-3,7-di(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 2,3-diamino-7-(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 2,7-diamino-3-(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; 3,7-diamino-2-(formylamino)-4,6-dimethyl-1,9-phenazinedicarbonitrile; and 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile.  
     
     
         14 . The method of  claim 13 , wherein the formula (III) compound is less than two parts per million.  
     
     
         15 . The method of  claim 10 , wherein the formula (I) compound is selected from the group consisting of N′-(6-Cyano-3-methyl-2,4-dinitro-phenyl)-N,N-dimethyl-methanimidamide; 2-Amino-4-methyl-3,5-dinitro-benzonitrile; 2-Amino-4-methyl-3,5-dinitro-benzamide; 6-Bromo-3-formyamino-4-methyl-2-nitro-benzoic acid; 3-Amino-4-methyl-2-nitro-benzoic acid; and 3-Formyamino-4-methyl-2-nitro-benzoic acid.  
     
     
         16 . A composition comprising 7-Cyano-4-methyl-1H-benzimidazol-5-amine substantially free of a compound of formula III comprising:  
       
         
           
           
               
               
           
         
       
       wherein: 
 (a) Q 11 , Q 12  and Q 13  are each independently selected from the group consisting of nitro, amino, formylamino and amino functional group equivalent;  
 (b) R 11  and R 12  are each independently selected from methyl or methyl functional group equivalent; and  
 (c) R 13  and R 14  are each independently selected from the group consisting of amide, carboxylic acid, cyano, and cyano functional group equivalent.  
 
     
     
         17 . The composition of  claim 16 , wherein the formula (III) compound is less than 2 parts per million.  
     
     
         18 . The composition of  claim 17 , wherein the formula (III) compound is 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile.  
     
     
         19 . A method of treating an alpha-2 mediated disorder comprising administering a safe and effective amount of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl -1H-benzimidazole-4-carbonitrile substantially free of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile to a subject in need thereof.  
     
     
         20 . The method of  claim 19 , wherein the alpha-2 mediated disorder is selected from the group consisting of irritable bowel syndrome, migraine, chronic tension type headache, ocular hypertension, muscle spasm, muscle hypertonia, attention deficit hyperactivity disorder, sedation, adjunct for anesthesia, anxiety, and Tourette's Syndrome.  
     
     
         21 . A method of treating an alpha-2 mediated disorder comprising administering a safe and effective amount of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile anhydrous monoacetate salt to a subject in need thereof.  
     
     
         22 . The method of  claim 21 , wherein the alpha-2 mediated disorder is selected from the group consisting of irritable bowel syndrome, migraine, chronic tension type headache, ocular hypertension, muscle spasm, muscle hypertonia, attention deficit hyperactivity disorder, sedation, adjunct for anesthesia, anxiety, and Tourette's Syndrome.  
     
     
         23 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile substantially free of 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile; and    (b) a pharmaceutically-acceptable carrier.    
     
     
         24 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile anhydrous monoacetate salt; and    (b) a pharmaceutically-acceptable carrier.