Novel substituted 2-aminoimidazoles, process for their preparation, their use as medicament or diagnostic aid

Abstract

The present invention comprises novel substituted 2-aminoimidazoles of formula I, processes for their preparation, pharmaceutical compositions thereof, and methods for their use in the treatment of disorders of the central nervous system, cardiovascular disorders, stroke and pulmonary disorders, urinary disorders such as acute or chronic renal failure, disorders of biliary function, respiratory disorders such as snoring or sleep apnea. wherein the substitutents R1-R8 are further defined herein.

1 . A compound of formula I, or a pharmaceutically acceptable salt or trifluoroacetic acid salt of said compound: 
       
         
           
           
               
               
           
         
       
       where:
 R1 and R2
 are independently selected from the group consisting of hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN and phenyl, provided that R1 and R2 are not both simultaneously hydrogen; 
 
 R3, R4, R5, R6 and R7
 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, and alkoxy with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, provided that R3 and R7 are not both simultaneously hydrogen; 
 
 R8
 is selected from the group consisting of H, alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, and cycloalkyl with 3, 4 or 5 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 
 
 
       provided, when R3 is C1 and R4, R5, R6, R7 and R8 are hydrogen, R1 and R2 are not both simultaneously methyl; and further provided that said compound is not (2,6-dichlorphenyl)-(4-methyl-1H-imidazol-2-yl)-amine. 
     
     
         2 . The compound or a salt thereof as recited in  claim 1 , wherein:
 R3 and R7 are independently selected from the group consisting of F, Cl, Br and alkyl has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms;   R4, R5 and R6 are H;   R8 is H or alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms;   
     
     
         3 . The compound or salt thereof as recited in  claim 1 , wherein:
 R1 and R2
 are independently selected from the group consisting of hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN and phenyl, provided that R1 and R2 are not both simultaneously hydrogen; and 
   R3, R4, R5, R6 and R7
 are independently selected from the group consisting of hydrogen, F, Cl, Br, and alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, provided that R3 and R7 are not both simultaneously hydrogen. 
   
     
     
         4 . The compound or salt thereof as recited in  claim 3 , wherein:
 R1 and R2
 are independently selected from the group consisting of either H or alkyl with 1, 2, 3 or 4 carbon atoms, provided that R1 and R2 are not both simultaneously hydrogen; 
   R3 and R7
 are independently selected from the group consisting of F, Cl, Br and alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 
   R4, R5 and R6
 are hydrogen; 
   R8 is selected from the group consisting of H or an alkyl which has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms.   
     
     
         5 . A pharmaceutical composition comprising the compound or a salt thereof as recited in  claim 1  in combination with one or more additional pharmaceutically acceptable carrier compounds. 
     
     
         6 . A pharmaceutical composition comprising the compound or a salt thereof as recited in  claim 1  in combination with one or more additional pharmaceutically acceptable carrier compounds . . . alone or in combination with one or more other drugs or active ingredients, in a pharmaceutically acceptable formulation for the treatment or prophylaxis of disorders of respiratory drive, of respiratory disorders, sleep-related respiratory disorders, of chronic renal failure, of disorders of intestinal function, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders which result from CNS overexcitability, epilepsy and centrally induced convulsions or of anxiety states, depressions and psychoses, of ischemic states of the peripheral or central nervous system or of stroke, of acute and chronic damage to and disorders of peripheral organs or limbs caused by ischemic or by reperfusion events, of atherosclerosis, of disorders of lipid metabolism, of thromboses, of disorders of biliary function, of infestation by ectoparasites, of disorders resulting from endothelial dysfunction, of protozoal disorders, of malaria, for preservation and storage of transplants for surgical procedures, for use in surgical operations and organ transplantations or for the treatment of states of shock or of diabetes and late damage from diabetes or of disorders in which cellular proliferation represents a primary or secondary cause, 
     
     
         7 . The composition of  claim 6 , wherein said drug is for the treatment or prophylaxis of disorders of respiratory drive and/or of sleep-related respiratory disorders and sleep apneas. 
     
     
         8 . The composition of  claim 7 , wherein said drug is for the treatment or prophylaxis of snoring. 
     
     
         9 . The composition of  claim 8 , wherein said drug is for the treatment or prophylaxis of acute and chronic renal disorders, of acute renal failure or of chronic renal failure. 
     
     
         10 . The composition of  claim 9  wherein said drug is for the treatment or prophylaxis of disorders of intestinal function. 
     
     
         11 . A method for the treatment of disorders of the central nervous system, cardiovascular disorders, respiratory disorders, sleep-related respiratory disorders, chronic renal failure, disorders of intestinal function, high blood pressure, of essential hypertension, and the like comprising the administration of a compound of formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       where:
 R1 and R2 are independently selected from the group consisting of hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN and phenyl, provided that R1 and R2 are not both simultaneously hydrogen; 
 R3, R4, R5, R6 or R7
 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms, (C 2 -C 4 )-alkenyl, cycloalkyl with 3, 4, 5 or 6 carbon atoms, OH, alkoxy with 1, 2, 3 or 4 carbon atoms, CN, NO 2 , NH 2 , alkylamino with 1, 2, 3 or 4 carbon atoms and dialkylamino with two alkyl parts each having 1, 2, 3 or 4 carbon atoms, said alkyl, alkenyl, cycloalkyl, alkoxy, alkylamino and dialkylamino being unsubstituted or substituted independently by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, provided that R3 and R7 are not simultaneously hydrogen; 
 
 R8
 is H, alkyl with 1, 2, 3 or 4 carbon atoms, or cycloalkyl with 3, 4 or 5 carbon atoms, said alkyl and cycloalkyl being independently unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms. 
 
 
     
     
         12 . The method of treatment as recited in  claim 11 , wherein said disorder is sleep apnea or another sleep-related respiratory disorder. 
     
     
         13 . The method of treatment as recited in  claim 12 , wherein said disorder is snoring. 
     
     
         14 . The method treatment as recited in  claim 11 , wherein said disorder is an acute and chronic renal disorder, acute renal failure, or chronic renal failure. 
     
     
         15 . The method of treatment as recited in  claim 11 , wherein said disorder is intestinal dysfunction. 
     
     
         16 . The method of treatment as recited in  claim 11 , wherein said disorder is high blood pressure or hypertension. 
     
     
         17 . The method of treatment as recited in  claim 11 , wherein said disorder is a disorder of the central nervous system, CNS over-excitability, epilepsy, or centrally induced convulsions. 
     
     
         18 . The method of treatment as recited in  claim 11 , wherein said disorder is selected from the group consisting of anxiety, depression or psychoses. 
     
     
         19 . The method as recited in  claim 11 , wherein said disorder is ischemia of the peripheral and central nervous system or stroke. 
     
     
         20 . The method of treatment of  claim 11 , wherein said disorder is diabetes. 
     
     
         21 . The method of treatment of  claim 11 , wherein said disorder is atherosclerosis. 
     
     
         22 . The method of treatment of  claim 11 , wherein said disorder is lipid metabolism. 
     
     
         23 . The method of treatment of  claim 11 , wherein said disorder is a disorder where cellular proliferation is a primary or secondary cause. 
     
     
         24 . The method of treatment of  claim 11 , wherein said disorder is thromboses. 
     
     
         25 . A method of treatment of  claim 11 , wherein said disorder is biliary dysfunction. 
     
     
         26 . A process for the preparation of α-amino ketals of the formula V 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 and R2
 are independently selected from the group consisting of hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN and phenyl, provided that R1 and R2 are not both simultaneously hydrogen; 
 
 E is alkyl with 1, 2, 3 or 4 carbon atoms, or forms a cyclic ketal with another E where E—
 E is (C 2 -C 4 )-alkylene; 
 
 Hal
 is Cl, Br, or I; 
 
 
       which comprises
 a) converting an α-halo ketone or aldehyde of the formula VI with an azide by azide-halogen exchange into a corresponding α-azide ketone or aldehyde of the formula VII 
 
       
         
           
           
               
               
           
         
         b) reacting said α-azide ketone or aldehyde with mono- or dihydric alcohols through ketalization or acetalization to give α-azide ketal or acetal of the formula VIII 
       
       
         
           
           
               
               
           
         
         c) reducing said α-azide ketal or acetal to a compound of the formula V.