Substituted imidazolidines, process for their preparation, and their use as a medicament or diagnostic

Abstract

The invention relates to novel compounds of the type of the imidazolidines of the formula I in which R1 to R7 are as defined herein. In one embodiment, these compounds are used for the treatment of the central nervous system, of lipid metabolism, of infection by ectoparasites, of disorders of gall function and for improving the respiratory drive such as for treating respiratory distress. In another embodiment, the compounds increase the muscle tone of the upper respiratory tract, thus suppressing snoring.

We claim:  
     
         1 . An imidazolidine of the formula  
       
         
           
           
               
               
           
         
       
       in which 
 R1 and R2 
 independently of one another are —CN, —(C 1 -C 5 )-alkyl, —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(C 3 -C 6 )-cycloalkyl or —(C 4 -C 6 )-cycloalkenyl 
 where the carbon chains and carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms or by up to two radicals selected from the group consisting of —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2  and —OCH 3 ;  
 or  
 
 
 R1 and R2 
 together with the two carbon atoms to which they are attached are a five- to eight-membered saturated or unsaturated carbon ring, where the ring is unsubstituted or substituted by 1-12 fluorine atoms or by up to two radicals selected from the group consisting of —CH 3  and —OCH 3 , 
 with the proviso that there is no double bond between the two carbon atoms to which R1 and R2 are attached;  
 
 
 R3 
 is F, Cl, Br, I, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-alkenyl, -(C 3 -C 6 )-cycloalkyl, —OH, —(C 1 -C 4 )-alkoxy, —O-phenyl, —CN, —NO 2  or —NH 2 ; 
 where the phenyl is unsubstituted or substituted by up to two radicals selected from the group consisting of —CH 3 , F, Cl, Br, I, —OH and —OCH 3 ; and  
 where the carbon chains or carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms;  
 
 
 R4 to R6 
 independently of one another are H, F, Cl, Br, I, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-alkenyl, —(C 3 -C 6 )-cycloalkyl, —OH, —(C 1 -C 4 )-alkoxy, —CN, —NO 2 , —NH 2 , —(C 1 -C 4 )-alkylamino or —(C 1 -C 4 )-dialkylamino; 
 where the carbon chains or carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms;  
 
 
 R7 
 is H, F, Cl, Br, I, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-alkenyl, -(C 3 -C 6 )-cycloalkyl, —OH, —(C 1 -C 4 )-alkoxy, —CN, —NO 2  or —NH 2 ; 
 where the carbon chains or carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms;  
 or a pharmaceutically acceptable salt thereof, or a trifluoroacetic acid salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.  
 
 
 
     
     
         2 . The compound as claimed in  claim 1 , in which 
 R1 and R2 
 independently of one another are —(C 1 -C 5 )-alkyl, —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(C 3 -C 6 )-cycloalkyl or —(C 4 -C 6 )-cycloalkenyl, 
 where the carbon chains and carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms or by up to two radicals selected from the group consisting of —NHCH 3 , —N(CH 3 ) 2  and —OCH 3 ;  
 or  
 
   R1 and R2 
 together with the two carbon atoms to which they are attached are a five- to eight-membered saturated or unsaturated carbon ring, where the ring is unsubstituted or substituted by 1-12 fluorine atoms or by up to two radicals selected from the group consisting of —CH 3  and —OCH 3 , 
 with the proviso that there is no double bond between the two carbon atoms to which R1 and R2 are attached;  
 
   R3 
 is F, Cl, Br, I, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-alkenyl, —(C 3 -C 6 )-cycloalkyl, —OH, —C 1 -C 4 )-alkoxy, —O-phenyl, —CN, —NO 2  or —NH 2 ; 
 where the phenyl is unsubstituted or substituted by up to two radicals selected from the group consisting of —CH 3 , F, Cl, Br, —OH and —OCH 3 ; and  
 where the carbon chains or carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms;  
 
   R4 to R6 
 independently of one another are H, F, Cl, Br, —CH 3 , —OH, —OCH 3 , —CN, —NO 2 , —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ; 
 where the methyl group, independently of one another, are unsubstituted or substituted by 1-3 fluorine atoms;  
 
   R7 
 is H, F, Cl, Br, I, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-alkenyl, —(C 3 -C 6 )-cycloalkyl, —OH, —(C 1 -C 4 )-alkoxy, —CN, —NO 2  or —NH 2 ; 
 where the carbon chains or carbon rings, independently of one another, are unsubstituted or substituted by 1-11 fluorine atoms;  
 or a pharmaceutically acceptable salt thereof, or a trifluoroacetic acid salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio  
 
   
     
     
         3 . The compound as claimed in  claim 1 , chosen from: 
 trans-(2-chloro-6-trifluoromethylphenyl)-(octahydrobenzimidazol-2-ylidene)amine hydrochloride,    (S,S)-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    cis-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    (R,R)-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    trans-(octahydrobenzimidazol-2-ylidene)-(2-phenoxyphenyl)amine hydrochloride,    trans-(2,6-dichlorophenyl)-(4,5-diisopropylimidazolidin-2-ylidene)amine hydrochloride,    trans-(2,6-dichlorophenyl)-(4,5-dicyclopropylimidazolidin-2-ylidene)amine trifluoracetic acid salt,    cis-(2,6-dichlorophenyl)-(4,5-dicyclopropylimidazolidin-2-ylidene)amine hydrochloride,    trans-(2,6-dichlorophenyl)-(4,5-diethylimidazolidin-2-ylidene)amine hydrochloride,    (2,6-dichlorophenyl)-(4,5-dimethylimidazolidin-2-ylidene)amine nitric acid salt, and    trans-(2,6-dichlorophenyl)-(hexahydrocyclopentaimidazol-2-ylidene)amine trifluoroacetic acid salt.    
     
     
         4 . The compound as claimed in  claim 1 , chosen from: 
 (S,S)-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    cis-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    (R,R)-(2,6-dichlorophenyl)-(octahydrobenzimidazol-2-ylidene)amine trifluoroacetic acid salt,    trans-(2,6-dichlorophenyl)-(4,5-diisopropylimidazolidin-2-ylidene)amine hydrochloride,    trans-(2,6-dichlorophenyl)-(4,5-dicyclopropylimidazolidin-2-ylidene)amine trifluoroacetic acid salt,    cis-(2,6-dichlorophenyl)-(4,5-dicyclopropylimidazolidin-2-ylidene)amine hydrochloride,    trans-(2,6-dichlorophenyl)-(4,5-diethylimidazolidin-2-ylidene)amine hydrochloride,    (2,6-dichlorophenyl)-(4,5-dimethylimidazolidin-2-ylidene)amine nitric acid salt, and    trans-(2,6-dichlorophenyl)-(hexahydrocyclopentaimidazol-2-ylidene)amine trifluoroacetic acid salt.    
     
     
         5 . A method for the treatment of disorders of the respiratory drive comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         6 . A method for the treatment of respiratory disorders associated with sleeping comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         7 . The method of  claim 6 , wherein the respiratory disorders associated with sleeping is sleep apnea.  
     
     
         8 . A method for the treatment of snoring comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt  
     
     
         9 . A method for the treatment of acute and chronic renal diseases comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         10 . The method of  claim 9 , wherein the acute and chronic renal diseases is chosen form acute kidney failure and chronic kidney failure.  
     
     
         11 . A method for the treatment of disorders of intestinal function comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         12 . A method for the treatment of disorders of gall function comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         13 . A method for the treatment of ischemic states of the peripheral and central nervous system and of stroke comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         14 . A method for the treatment of ischemic states of peripheral organs and limbs comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         15 . A method for the treatment of states of shock comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         16 . A method for preserving and storing transplants for surgical interventions comprising, contacting the transplant with at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         17 . A method for the treatment of diseases in which cell proliferation is a primary or secondary cause comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         18 . A method for the treatment of disorders of lipid metabolism comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         19 . A method for the treatment of infection by ectoparasites comprising, administering to a patient in need thereof at least one compound as claimed in  claim 1 , with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         20 . A pharmaceutical comprising at least one compound as claimed in  claim 1  and at least one pharmaceutical carrier, with the proviso that said compound is not a trifluoroacetic acid salt.  
     
     
         21 . A method of protecting a transplant organ in a host, comprising administering to the host in need thereof at least one compound as claimed in  claim 1 , 
 wherein the host is a transplant donor or a transplant recipient, with the proviso that said compound is not a trifluoroacetic acid salt.