Tetrahydroquinolines

Abstract

The tetrahydroquinolines can be prepared by condensing appropriately substituted tetrahydroquinoline aldehydes with suitable substances and subsequently varying the substituents present by customary methods. The tetrahydroquinolines are suitable as active compounds in medicaments, in particular in medicaments for the treatment of arteriosclerosis and dyslipidaemias.

1 . Tetrahydroquinolines of the general formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 A represents phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, trifluoromethyl and straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,  
 D represents a radical of the formula  
                     
 or  
 R 8 —CH 2 —O—CH 2 —,  
 in which  
 R 5  and R 6  together form a carbonyl group (═O),  
 or  
 R 5  represents hydrogen  
 and  
 R 6  represents halogen or hydroxyl,  
 or  
 R 5  and R 6  represent hydrogen,  
 R 7  and R 8  are identical or different and represent phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl which are optionally substituted up to 4 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, or by a radical of the formula —SO 2 —CH 3  or —NR 9 R 10 ,  
 in which  
 R 9  and R 10  are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,  
 E represents cycloalkyl having 3 to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms,  
 R 1  represents hydroxyl,  
 and  
 R 2  represents hydrogen or represents methyl,  
 R 3  and R 4  are identical or different and represent straight-chain or branched alkyl having up to 3 carbon atoms,  
 or  
 R 3  and R 4  together form a spiro-linked alkyl chain having 2 to 4 carbon atoms,  
 and their salts and N-oxides.  
 
     
     
         2 . Tetrahydroquinolines of the formula according to  claim 1   
       in which 
 A represents phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy and ethoxy,  
 D represents a radical of the formula  
                     
 or  
 R 8 —CH 2 —O—CH 2 —,  
 in which  
 R 5  and R 6  together form a carbonyl group (═O),  
 or  
 R 5  represents hydrogen  
 and  
 R 6  represents fluorine or hydroxyl,  
 or  
 R 5  and R 6  represent hydrogen,  
 R 7  and R 8  are identical or different and represent phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl, which are optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoromethoxy, amino or dimethylamino,  
 E represents cyclopropyl, cyclobutyl, cyclopentyl or represents straight-chain or branched alkyl having up to 6 carbon atoms,  
 R 1  represents hydroxyl,  
 and  
 R 2  represents hydrogen or represents methyl,  
 R 3  and R 4  are identical or different and represent methyl,  
 or  
 R 3  and R 4  together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,  
 and their salts and N-oxides.  
 
     
     
         3 . Tetrahydroquinolines of the formula according to  claim 1   
       in which 
 A represents phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and ethoxy,  
 D represents a radical of the formula  
                     
 or  
 R 8 —CH 2 —O—CH 2 —,  
 in which  
 R 5  and R 6  together form a carbonyl group (═O),  
 or  
 R 5  represents hydrogen  
 and  
 R 6  represents fluorine or hydroxyl,  
 or  
 R 5  and R 6  represent hydrogen,  
 R 7  and R 8  are identical or different and represent phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl which are optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoromethoxy, amino and dimethylamino,  
 E represents cyclopropyl or cyclopentyl, or represents straight-chain or branched alkyl having up to 3 carbon atoms,  
 R 1  represents hydroxyl,  
 and  
 R 2  represents hydrogen or represents methyl,  
 R 3  and R 4  are identical or different and represent methyl,  
 or  
 R 3  and R 4  together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,  
 and their salts and N-oxides.  
 
     
     
         4 . Tetrahydroquinolines according to  claims 1  to  3  as medicaments.  
     
     
         5 . Process for preparing tetrahydroquinolines according to  claims 1  to  3 , characterized in that 
 [A] in the case D represents the radical  
                     
 in compounds of the general formula (II)  
                     
 in which  
 A, E, R 1,  R 2 , R 3  and R 4  are as defined above,  
 the substituent D is synthesized in inert solvents using organometallic reagents in a Grignard, Wittig or organolithium reaction,  
 or, in the case that D represents the radical of the formula R 8 —CH 2 —O—CH 2 , in which R 8  is as defined above,  
 [B] either compounds of the general formula (III)  
                     
 in which  
 A, E, R 1,  R 2 , R 3  and R 4  are as defined above  
 are reacted with compounds of the general formula (IV)  
 R 8 —CH 2 —Z   (IV),  
 in which  
 R 5  is as defined above,  
 and  
 Z represents halogen, preferably chlorine or bromine,  
 in inert solvents, if appropriate in the presence of a base and/or auxiliary,  
 or  
 [C] compounds of the general formula (III) are first converted, by reaction with compounds of the general formula (V)  
                     
 in which  
 R 11  represents straight-chain alkyl having up to 4 carbon atoms,  
 into the compounds of the general formula (VI)  
                     
 in which  
 A, E, R 1 , R 2,  R 3 , R 4  and R 11  are as defined above,  
 and subsequently reacted with compounds of the general formula (VII)  
 R 8 —CH 2 —OH   (VII),  
 in which  
 R 8  is as defined above  
 and, if appropriate, protective groups are cleaved off,  
 or  
 [D] in the case of the compounds of the general formula (Ia)  
                     
 in which  
 A, E, R 3 , R 4 , R 5  and R 6  are as defined above, compounds of the general formula (VIII)  
                     
 in which  
 A, E, R 3,  R 4  and R 7  are as defined above,  
 are first oxidized to the compounds of the general formula (I)  
                     
 in which  
 R 3 , R 4 , R 7 , A and E are as defined above,  
 these are, in a next step, converted by asymmetric reduction into the compounds of the general formula (X)  
                     
 in which  
 R 3 , R 4 , R 7 , A and E are as defined above,  
 these are then converted, by introduction of a hydroxyl-protective group, into the compounds of the general formula (XI)  
                     
 in which  
 R 3 , R 4 , R 7 , A and E are as defined above  
 and  
 R 12  represents a hydroxyl-protective group, preferably a radical of the formula —SiR 13 R 14 R 15 ,  
 in which  
 R 13 , R 14  and R 15  are identical or different and represent C 1 -C 4 -alkyl,  
 from which compound, in a subsequent step, the compounds of the general formula (XII)  
                     
 in which  
 R 3 , R 4 , R 7 , R 12 , A and E are as defined above  
 are prepared by diastereoselective reduction,  
 and subsequently, by introducing the fluorine substituent with fluorinating agents, such as, for example, DAST and SF 4  derivatives, the compounds of the general formula (XIII)  
                     
 in which  
 R 3 , R 4 , R 7 , R 12 , A and E are as defined above,  
 are prepared,  
 and the hydroxyl-protective group is subsequently cleaved off by customary methods,  
 and, if appropriate, the substituents listed under D, E and/or R 1  and R 2  are varied or introduced by customary methods.  
 
     
     
         6 . Medicaments, comprising at least one tetrahydroquinoline according to  claim 1  and pharmacologically acceptable formulation auxiliaries.  
     
     
         7 . Medicament according to  claim 6  for treating hyperlipoproteinaemia.  
     
     
         8 . Medicament according to  claim 6  or  7  for treating arteriosclerosis.  
     
     
         9 . Use of tetrahydroquinolines according to  claim 1  for preparing medicaments.  
     
     
         10 . Use according to  claim 9  for preparing medicaments for the treatment of arteriosclerosis, in particular dyslipidaemias.