Use of benzoylalkyl-1,2,3,6-tetrahydropyridines

Abstract

The invention relates to the use of compounds of formula for the preparation of medicines designed for the treatment of neuronal and cerebral disorders. The invention also relates to the compounds of formula: a process for their preparation and the pharmaceutical compositions containing them.

1 . Use of the compounds of formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is halogen, a CF 3 , (C 1 —C 4 ) alkyl or (C 1 —C 4 ) alkoxy group;  
 n is 0 or 1  
 R 2  is hydrogen or a (C 1 —C 4 ) alkyl group;  
 R 3  is hydrogen, (C 1 —C 6 ) alkyl, (C 1 —C 6 ) alkoxy; halogen, a CF 3  group, hydroxy, a group selected from (C 3 —C 7 ) cycloalkyl, phenyl, phenoxy, phenylmethyl or phenylethyl, said group being optionally mono- or polysubstituted on the phenyl group by halogen, CF 3 , (C 1 —C 4 ) alkyl or (C 1 —C 4 ) alkoxy;  
 R 4  and R 5  is each independently hydrogen, (C 1 —C 6 ) alkyl, (C 1 —C 6 ) alkoxy, halogen, a CF 3  group or hydroxy;  
 as well as their salts and solvates and their quaternary ammonium salts, for the preparation of medicines designed for the treatment and/or the prophylaxis of the diseases which involve neuronal degeneration.  
 
     
     
         2 . Use according to  claim 1  of the compounds of formula (I) where n is zero.  
     
     
         3 . Use according to  claim 1  or  2  of the compounds of formula (I) where R 2  is hydrogen.  
     
     
         4 . Use according to one of the  claims 1  to  3  of the compounds of formula (I) where one of R 3 , R 4  and R 5  is hydrogen.  
     
     
         5 . Use according to one of the  claims 1  to  4  of the compounds of formula (I) where the group R 1  is a CF 3  group at position 3 of the phenyl group.  
     
     
         6 . Use according to one of the  claims 1  to  5  for the preparation of medicines indicated in the treatment and/or prophylaxis of memory disorders, vascular dementia, post-encephalitic disorders, post-apoplectic disorders, post-traumatic syndromes due to a cranial traumatism, Alzeheimer's disease, senile dementia, subcortical dementia, such as Huntington chorea and Parkinson's disease, dementia caused by AIDS, neuropathies resulting from morbidity or damage to sympathetic or sensory nerves, cerebral diseases such as cerebral oedema and spinocerebellar degenerations, degeneration of motoneurons like, for example, amyotrophic lateral sclerosis.  
     
     
         7 . Use according to  claim 6  where the compound of formula (I) is coadministered or combined with other active ingredients acting on the CNS, selected from selective M 1  cholinomimetics, NMDA antagonists and nootropic agents.  
     
     
         8 . Compound of formula (I′)  
       
         
           
           
               
               
           
         
       
       in which 
 R′ 1  is halogen, a CF 3 , (C 1 —C 4 ) alkyl or (C 1 —C 4 ) alkoxy group;  
 R′ 2  is (C 1 —C 6 ) alkyl, (C 1 —C 6 ) alkoxy; halogen, a CF 3  group, hydroxy, a group selected from (C 3 —C 7 ) cycloalkyl, phenyl, phenoxy, phenylmethyl or phenylethyl, said group being optionally mono- or polysubstituted on the phenyl group by 
 halogen, CF 3 , (C 1 —C 4 ) alkyl or (C 1 —C 4 ) alkoxy;  
 R′ 3  is hydrogen, (C 1 —C 6 ) alkyl, (C 1 —C 6 ) alkoxy, halogen, a CF 3  group or hydroxy;  
 
 as well as their salts and solvates and their quaternary ammonium salts.  
 
     
     
         9 . Compound according to  claim 8  of formula (I″)  
       
         
           
           
               
               
           
         
       
       where X— is a pharmaceutically acceptable anion, Alk is (C 1 —C 4 ) alkyl and R′ 1 , R′ 2  and R′ 3  are as defined for the compounds (I′) in  claim 8 .  
     
     
         10 . Compound according to  claim 8  selected from: 
 1-{2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4-isobutylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4-benzylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4-cyclohexylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4-n-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(biphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4-t-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(3,4-diethylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 1-{2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;  
 as well as their salts and solvates.  
 
     
     
         11 . Process for the preparation of the compounds of formula (I′) according to  claim 8 , their salts or solvates and their quaternary ammonium salts, characterized in that 
 (a) an aryl-1,2,3,6-tetrahydropyride of formula (II)  
                     
  in which R′ 1  is as defined for the compounds (I′) in  claim 8 , is reacted with a compound of formula (III)  
                     
 in which R′ 2  and R′ 3  are as defined for the compounds (I′) in  claim 8  and L is a leaving group; and  
 (b) the compound of formula (I′) thus obtained is isolated and optionally converted into one of its salts or solvates or one of its quaternary ammonium salts.  
 
     
     
         12 . Pharmaceutical composition containing as active ingredient a compound according to one of the  claims 8  to  10 .  
     
     
         13 . Pharmaceutical composition containing as active ingredient a compound of formula (I) such as defined in  claim 1  and a compound indicated in the symptomatic treatment of DAT, selected from the acetylcholinesterase inhibitors, the M1 muscarinic agonists, the nicotinic agonists, the NMDA receptor antagonists and the nootropic agents, and their pharmaceutically acceptable salts.