4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein

Abstract

Hetero-tetrahydroquinolines can be prepared either by condensing correspondingly substituted hetero-tetrahydroquinoline aldehydes with the desired substituent or by reducing the corresponding keto-substituted hetero-tetrahydroquinolines, followed by introduction of the desired substituent by customary methods. The hetero-tetrahydroquinolines are suitable for use as active compounds in medicaments, in particular in medicaments for treating artheriosclerosis and dyslipidaemias.

1 . A hetero-tetrahydroquinoline compound of the formula (I),  
     
       
         
         
             
             
         
       
     
     in which 
 A represents cycloalkyl having 3 to 8 carbon atoms or 
 represents a 5- to 7-membered saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and O which, in the case of a saturated heterocycle with a nitrogen function, is optionally also attached via this function, and where the abovementioned ring systems are optionally substituted up to 5 times by identical or different substituents from the group consisting of halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy having in each case up to 7 carbon atoms, or by a group of the formula —NR 3 R 4 ,  
 in which  
 R 3  and R 4  are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,  
 
 A represents a radical of the formula  
                     
 D represents aryl having 6 to 10 carbon atoms which is optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or 
 represents a radical of the formula  
                     
 which  
 R 5  and R 9  independently of one another represent cycloalkyl having 3 to 6 carbon atoms, or 
 represent aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered optionally benzo-fused saturated or unsaturated mono-, bi- or tricyclic hetreocycle having up to 4 heteroatoms from the group consisting of S, N and O,  
 where the cycles are optionally substituted, in the case of the nitrogen-containing rings also via the N function, up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, and straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or by an optionally benzo-fused aromatic 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O,  
 and/or by a group of the formula —OR 10 , —SR 11 , —SO 2 R 12  or —NR 13 R 14 ,  
 in which  
 R 10 , R 11  and R 12  independently of one another represent aryl having 6 to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen and straight-chain or branched alkyl having up to 6 carbon atoms,  
 R 13  and R 14  are identical or different and have the meaning of R 3  and R 4  given above,  
 
 or  
 R 5  and/or R 6  represent(s) a radical of the formula  
                     
 R 7  represents hydrogen or halogen,  
 and  
 R 8  represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula —NR 15 R 16 , 
 in which  
 R 15  and R 16  are identical or different and have the meaning of R 3  and R 4  given above,  
 or  
 R 7  and R 8  together form a radical of the formula ═O or ═NR 17 , 
 in which  
 R 17  represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms,  
 
 L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl,  
 T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms,  
 or  
 T or X represents a bond,  
 V represents an oxygen or sulphur atom or represents an —NR 18  group, 
 in which  
 R 18  represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,  
 
 
 E represents cycloalkyl having 3 to 8 carbon atoms, or 
 represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluoromethyl,  
 
 R 1  and R 2  together form a straight-chain or branched alkylene chain having up to 7 carbon atoms which has to be substituted by a carbonyl group and/or by a radical of the formula  
                     in which    a and b are identical or different and represent a number 1, 2 or 3,    R 19  represents hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or by phenyl which for its part may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazolesubstituted phenyl, and alkyl is optionally substituted by a group of the formula —OR 22      in which    R 22  represents straight-chain or branched acyl having up to 4 carbon atoms or benzyl,    
 or  
 R 19  represents straight-chain or branched acyl having up to 20 carbon atoms or benzoyl which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or 
 represents straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms,  
 
 R 20  and R 21  are identical or different, represent hydrogen, phenyl or straight-chain or branched all having up to 6 carbon atoms,  
 or  
 R 20  and R 21  together form a 3 to 6-membered carbocycle 
 and, if appropriate also geminally, the carbocycles formed are optionally substituted up to 6 times by identical or different substituents from the group consisting of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon atoms, straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to 6 carbon atoms and straight-chain or branched all having up to 6 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl having in each case up to 4 carbon atoms and phenyl which for its part may be substituted by halogen, trifluoromethyl or trifluoromethoxy,  
 and/or the carbocycles formed are optionally substituted, also seminally, up to 5 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,  
 and/or are optionally substituted by a radical of the formula  
                     
 in which  
 c represents a number 1, 2, 3 or 4,  
 d represents a number 0 or I,  
 R 23  and R 24  are identical or different and represent hydrogen, 30 cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, cyan, phenyl and nitro, 
 and/or the carbocycles formed are optionally substituted by a Spiro-linked radical of the formula  
                     
 
 in which  
 w represents either an oxygen or a sulphur atom,  
 Y and Y′ together form a 2- to 6-membered straight-chain or branched alkylene chain,  
 e represents a number 1, 2, 3, 4, 5, 6 or 7,  
 f represents a number 1 or 2,  
 R 25 , R 26 , R 27 , R 28 , R 29 , R 30  and R 31  are identical or different and represent hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,  
 R 25  and R 26  or R 27  and R 28  in each case together form a straight-chain or branched alkyl chain having up to 6 carbon atoms,  
 or  
 R 25  and R 26  or R 27  and R 28  in each case together form a radical of the formula  
                     in which    W is as defined above,    g represents a number 1, 2, 3, 4, 5, 6 or 7,    
 R 32  and R 33  together form a 3- to 7-membered heterocycle which contains an oxygen or sulphur atom or a group of the formula SO, SO 2  or —NR 34 , 
 in which  
 R 34  represents hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,  
 
 
 or a salt of said compound or an N-oxide of said compound or said salt.  
 
 
   
   
       2 . The hetero-tetrahydroquinoline compound of the formula (1) according to  claim 1 , 
 in which    A represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, or 
 represents thienyl, imidazolyl, pyrrole, furryl, pyridyl, morpholine, pyrimidyl or pyridazinyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, and alkoxy having in each case up to 6 carbon atoms,  
   or    A represents a radical of the formula                          D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or 
 represents a radical of the formula  
                     
   in which    R 5 , R 6  and R 9  independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or 
 represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,  
 where the cycles are optionally substituted up to 3 times, in the case of the nitrogen-containing rings also via the N function, by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, trifluoromethyl-substituted phenyl and phenyl,  
   or    R 7  represents hydrogen, fluorine, chlorine or bromine,    and    R 8  represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula —NR 15 R 16 , 
 in which  
 R 15  and R 16  are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,  
   or    R 7  and R 8  together form a radical of the formula ═O or ═NR 17 ,    in which    R 17  represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms,    L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms which are optionally substituted up to 2 times by hydroxyl,    T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 6 carbon atoms,    or    T or X represents a bond,    V represents an oxygen or sulphur atom or represents a group of the formula —NR 18 —, 
 in which  
 R 18  represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,  
   E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or 
 represents straight-chain or branched all having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,  
   R 1  and R 2  together form a straight-chain or branched alkylene chain having up to 6 carbon atoms which has to be substituted by a carboxyl group and/or by a radical of the formula                        in which    a and b are identical or different and represent a number 1, 2 or 3,    R 19  represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl which for its part may be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl, 
 and alkyl is optionally substituted by a group of the formula —OR 22 ,  
 in which  
 R 22  represents straight-chain or branched acyl having up to 3 carbon atoms or benzyl,  
   or    R 19  represents straight-chain or branched acyl having up to 18 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or 
 represents straight-chain or branched fluoroacyl having up to 6 carbon atoms,  
   R 20  and R 21  are identical or different, represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,    or    R 20  and R 21  together form a cyclpropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring, 
 and the carbocycles formed are optionally substituted, if appropriate, also geminally, up to 5 times by identical or different substituents from the group consisting of trifluoromethyl, hydroxyl, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to about 5 carbon atoms and straight-chain or branched alkyl having up to 5 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benryloxy, benzoyl, straight-chain or branched alkoxy or oxyacyl having in each case up to 3 carbon atoms, trifluoromethyl and phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,  
 and/or the carbocycles formed are optionally substituted, also geminally, up to 4 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,  
 and/or are optionally substituted by a radical of the formula  
                     
 in which  
 c represents a number 1, 2, 3 or 4,  
 d represents a number 0 or 1,  
 R 23  and R 24  are identical or different and represent hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl,  
 and/or the carbocycles formed are optionally substituted by a spiro-linked radical of the formula  
                     
   in which    w represents either an oxygen or a sulphur atom,    Y and Y′ together form a 2- to 5-membered straight-chain or branched all chain,    e represents a number 1, 2, 3, 4, 5 or 6,    f represents a number 1 or 2,    R 25 , R 26 , R 27  and R 28  are identical or different and represent hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms,    or    R 25  and R 26  or R 27  and R 28  in each case together form a straight-chain or branched alkyl chain having up to 5 carbon atoms    or    R 25  and R 26  or R 27  and R 28  in each case together form a radical of the formula                        in which    W is as defined above,    g represents a number 1, 2, 3, 4, 5 or 6,        or a salt of said compound or an N-oxide of said compound or said salt.    
   
   
       3 . The hetero-tetrahydroquinoline compound of the formula (I) according to  claim 1 , 
 in which    A represents cyclopropyl, cyclopentyl or cyclohexyl, or 
 represents thienyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched all or alkoxy having in each case up to 5 carbon atoms,  
   or    A represents a radical of the formula                          D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or 
 represents a radical of the formula  
                     
 in which  
 R 5 , R 6  and R 9  independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or 
 represent phenyl, naphthyl or pyridyl,  
 where the cycles optionally up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy and straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,  
 
 or  
 R 7  represents hydrogen or fluorine,  
 and  
 R 8  represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula —NR 15 R 16 , 
 in which  
 R 15  and R 16  are identical or different and represent hydrogen or straight-chain or branched all having up to 3 carbon atoms, or  
 
 R 7  and R 8  together represent a radical of the formula ═O,  
 L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl,  
 T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms,  
 or  
 T or X represents a bond,  
 V represents an oxygen or sulphur atom or a group of the formula —NR 18 ,  
 in which  
 R 18  represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,  
   E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or 
 represents straight chain or branched alkyl having up to 4 carbon atoms  
   which is optionally substituted by hydroxyl, R 1  and R 2  together form a straight-chain or branched alkylene chain having up to 5 carbon atoms which has to be substituted by a carbonyl group and/or a radical of the formula —OR 19 , 
 in which  
 R 19  represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl,  
 or  
 R 19  represents straight-chain or branched acyl having up to 15 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or 
 represents a radical of the formula —Si(CH 3 ) 2 C(CH 3 ) 3 ,  
 and the carbocycles formed are optionally substituted, if appropriate also geminally, up to 4 times by identical or different substituents from the group consisting of fluorine, hydroxyl, trifluoromethyl, carboxyl, azido, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, straight-chain or branched  
                   
alkoxycarbonyl, alkoxy or alkylthio having in each case up to 4 carbon atoms and straight-chain or branched alkyl having up to 4 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,  
 and/or the carbocycles formed are optionally substituted, also geminally, up to 4 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro,  
 and/or are optionally substituted by a radical of the formula  
                     
 in which  
 c represents a number 1, 2, 3 or 4,  
 and/or the carbocycles formed are optionally substituted by a spiro-linked radical of the formula  
 in which  
 e represents a number 1,2,3,4 or 5,  
 R 25 , R 26 , R 27 , and R 28  are identical or different and represent hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched all or alkoxy having in each case up to 4 carbon atoms,  
 or  
 R 25  and R 26  or R 27  and R 28  together form a straight-chain or branched alkyl chain having up to 4 carbon atoms,  
 
   or a salt of said compound or an N-oxide of said compound or said salt.    
   
   
       4 . The hetero-tetrahydroquinoline compound of the formula (I) according to  claim 1 , 
 in which    A represents cyclopropyl, cyclopentyl or cyclohexyl, or 
 represents thienyl or pyndyl, or A represents a radical of the formula  
                     
   D represents phenyl which is optionally substituted by trifluoromethyl, fluorine, or 
 represents a radical of the formula  
                     
 in which  
 R 6  represents phenyl which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl having in each case up to 4 carbon atoms,  
 or  
 R 7  represents hydrogen or fluorine,  
 and  
 R 8  represents hydrogen, fluorine, chlorine, hydroxyl, methoxy or  
 R 7  and R 8  together represent a radical of the formula ═O,  
   E represents cyclopropyl, cyclopentyl or cyclohexyl 
 represents straight-chain or branched all having up to 4 carbon atoms,  
   R 1  and R 2  together form a straight-chain or branched alkylene chain having up to 5 carbon atoms which has to be substituted by a carbonyl group and/or a radical of the formula —OR 19 , 
 in which  
 R 19  represents hydrogen  
 or represents a radical of the formula —Si(CH 3 ) 2 C(CH 3 ) 3 ,  
   or a salt of said compound or an N-oxide of said compound or said salt.    
   
   
       5 . (canceled)  
   
   
       6 . Process for preparing hetero-tetrahydroquinolines according to  claim 1 , characterized in that 
 [A] in the case where D≠aryl, compounds of the general formula (II)                          in which    A, E, R 1  and R 2  are as defined above,    with organometallic reagents in a Grignard or Wittig reaction or in a reaction with organolithium compounds, the substituent D is synthesized in inert solvents,    or in the case where D represents the radical of the formula R 9 -T-V-X in which V is an oxygen atom,    [B] either compounds of the general formula (III)                          in which    A, E, X, R 1  and R 2  are as defined above,    are reacted with compounds of the general formula (IV)     R 9 -T-Z  (IV),   in which    R 9  and T are 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 initially, by reaction with compounds general formula (V)                          in which    R 35  represents straight-chain alkyl having up to 4 carbon atoms,    to the compounds of the general formula (VI)                          in which    A, E, X, R 1 , R 2  and R 35  are as defined above,    and subsequently reacted with compounds of the general formula (VII)     R 9 -T-V-H  (VII),   in which    R 9 , T and V are as defined above,    and, if appropriate, protective groups are removed,    or    [D] in the case of the compounds of the general formula (Ia)                          in which    A and R 6  are as defined above,    R 36  and R 37  are identical or different and 
 represent cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon atoms, or  
 represent straight-chain or branched alkyl having up to 6 carbon atoms, or  
 represent phenyl which for its part are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, or  
 R 16  and R 37  represent one of the abovementioned spiro-linked radicals of the formula  
                     
 which  
 W, Y, Y′, R 25 , R 26 , R 27 , R 28 , e, R 29 , R 30 , R 31 , R 32  and R 33  are as defined above, pounds of the general formula (VIII)  
                     
 which  
 R 6 , R 36 , R 37 , A and E are as defined above,  
 initially oxidized to the compounds of the general formula (IX)  
                     
 which  
 R 6 , R 36 , R 37 , A and E are as defined above,  
 these are, in a subsequent step, converted by asymmetric reduction into the compounds of the general formula (X)  
                     
 which  
 R 6 , R 36 , R 37 , A and E are as defined above,  
 these are then converted, by the introduction of a hydroxyl protective group, into compounds of the general formula (XI)  
                     
 which  
 R 6 , R 36 , R 37 , A and E are as defined above  
 and  
 R 38  represents a hydroxyl protective group, preferably a radical of the formula —SiR 39 R 40 R 41    
 which  
 R and R are identical or different and represent C 1 -C 4 -alkyl,  
 which is used to prepare in a subsequent step, by diastereoselective reduction, the pounds of the general formula (XII)  
                     
 which  
 R 6 , R 36 , R 37 , R 38 , A and E areas defined above,  
 the compounds of the general formula (XIII)  
                     
 which  
 R 6 , R 36 , R 37 , R 38 , A and E are as defined above,  
 are subsequently prepared by introducing the fluorine substituent with fluorinating agents, such as, for example, DAST and SF 4  derivatives,  
 and the hydroxyl protective group is then removed 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.  
   
   
   
       7 .- 11 . (canceled)  
   
   
       12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the hetero-tetrahydroquinoline compound of the formula (I) according to  claim 1 , or a salt or an N-oxide of said compound or said salt.  
   
   
       13 . A method of treating hyperlipoproteinanaemia comprising administering to a patient in need thereof an effective amount therefor of the composition according to  claim 12 .  
   
   
       14 . A method of treating arteriosclerosis comprising administering to a patient in need thereof an effective amount therefor of the composition according to  claim 12 .  
   
   
       15 . A method of treating dislipidaemia comprising administering to a patient in need thereof an effective amount therefor of the composition according to  claim 12.