Use of thiazole derivatives for preparing a medicament intended to protect the mitochondria

Abstract

A method of treating Leber's syndrome in warm-blooded animals in need thereof an effective amount of a compound of the formula where the substituents are defined as in the specification.

1 . (canceled)  
   
   
       2 . The method of  claim 11 , wherein: 
 A is                          wherein R 5  is hydrogen or methyl, R 6  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy, R 7  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy and R 8  is selected from the group consisting of hydrogen, alkyl cycloalkyl, hydroxy and alkoxy, R 9  and R 10  are independently selected from the group consisting of hydrogen, hydroxy, alkyl and alkoxy, R 11  is hydrogen or methyl and R 12  is selected from the group consisting of hydrogen, hydroxy, alkyl and alkoxy;    B is selected from the group consisting of hydrogen, methyl and ethyl;    n is an integer from 0 to 3;    R 1  and R 2  are independenily hydrogen or alkyl;    R 3  and R 4  are independently hydrogen or alkyl, or R 3  and R 4  form together with the nitrogen atom which carries them a heterocycle containing in total 1 to 2 heteroatoms and 5 to 7 ring members, the missing members of which heterocycle are selected from the group consisting of —CHR 13 —, —NR 14 —, —O— and —S—, R 13  is selected from the group consisting of hydrogen, —OH, methyl and methoxy and R 14  is selected from the group consisting of hydrogen, alkyl, —COR 15 , —COOR 15  and    —CONR 16 R 17 , R 15  is alkyl and R 16  and R 17  are independently hydrogen or alkyl.    
   
   
       3 . The method of  claim 11 , wherein: 
 A is                          wherein R 5  is hydrogen, R 6  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy, R 7  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy and R 8  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy radical,    B is hydrogen or methyl;    n is an integer from 0 to 2;    one of R 1  and R 2  is hydrogen, the other is selected from the group consisting of hydrogen, alkyl and cycloalkyl;    R 3  and R 4  are independently hydrogen or alkyl, or R 3  and R 4  form together with the nitrogen atom which carries them a heterocycle of 6 members containing in total 1 to 2 heteroatoms, the missing members of which heterocycle are selected from the group consisting of  13  CHR 13 —, —NR 14 —, —O— and —S—, R 13  is hydrogen, —OH and methyl and R 14  is hydrogen or alkyl.    
   
   
       4 . The method of  claim 11 , wherein A is:  
     
       
         
         
             
             
         
       
     
     R 5  is hydrogen, R 6  is selected from the group consisting of hydrogen, alkyl, hydroxy and alkoxy, R 7  is selected from the group consisting of hydrogen, alkyl, hydroxy and alkoxy and RW is selected from the group consisting of hydrogen, alkyl, hydroxy and alkoxy.  
   
   
       5 . The method of  claim 11 , wherein n is 0.  
   
   
       6 . The method of  claim 11  wherein A is (A1).  
   
   
       7 . The method of  claim 11 , wherein the compound is selected from the group consisting of 
 4-[3 ,5-bis(1,1-dimethylethyl)4-hydroxyphenyl]-N-methyl-2-thiazolemethanamlne;    N-methyl[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]methanamine;    2,6-ditert-butyl4-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;    4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol;    2,6-ditert-butyl4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;    and a pharmaceutically acceptable salt thereof.    
   
   
       8 . (canceled)  
   
   
       9 . The method of  claim 11  wherein the condition is: amyopathies, ptosis, optical atrophy, pigmentary retinopathy, deafness, hepatic cytolysis, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, Leigh's syndrome, Leber's syndrome, NARP syndrome, MELAS syndromes, Pearson's syndrome, sepsis, cirrhosis of the liver, and cardiac, renal and hepatic toxicity induced by medicamentous agents.  
   
   
       10 . The method of  claim 9 , wherein the condition treated is cirrhosis of the liver.  
   
   
       11 . A method of treating Leber's syndrome cirrhosis of the liver in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula  
     
       
         
         
             
             
         
       
     
     in the form of a racemic mixture, of an enantiomer of any mixture thereof wherein:  
     A is  
     
       
         
         
             
             
         
       
       wherein R 5  is selected from the group consisting of hydrogen or alkyl, R 6  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy, R 7  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy and R 8  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy and alkoxy,  
       B is hydrogen or alkyl;  
       n is an integer from 0 to 5;  
       R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl;  
       R 3  and R 4  are independently hydrogen or alkyl, or R 3  and R 4  form together with the nitrogen atom which carries them a heterocycle containing in total 1 to 2 heteroatoms and 5 to 7 ring members, the missing members of which heterocycle are selected from the group consisting of —CH 13 —, —NR 14 —, —O— and —S—, R 13  is selected from the group consisting of hydrogen, —OH, alkyl and alkoxy and R 14  is selected from the group consisting of hydrogen, alkyl, —COR 15 , —COOR 15  and —CONR 16 R 17 , R 15  is alkyl and R 16  and R 17  are independently hydrogen or alkyl;  
       it being understood that alkoxy or alkyl, unless specified otherwise, has 1 to 6 carbon atoms and that cycloalkyl, unless specified otherwise, has 3 to 7 carbon atoms;  
       and a pharmaceutically acceptable salt thereof sufficient to treat Leber's syndrome.  
     
   
   
       12 . The method of  claim 4  wherein one of R 1  and R 2  is hydrogen and the other is methyl or ethyl.