4-Phenyltetrahydrochinoline utilized as an inhibitor of the cholesterol ester transfer protein
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. A compound selected from the group consisting of compounds of the formula (Ia):
the formula (VIII):
the formula (IX):
and the formula (X):
wherein in each formula:
A represents phenyl which is optionally substituted 1 to 2 times by identical or different substituents selected from the group consisting of halogen, trifluoromethyl and straight-chain or branched alkyl or alkoxy having in each case 1 to 3 carbon atoms;
R 5 represents hydrogen;
R 7 represents phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl, each of which are optionally substituted 1 to 4 times by identical or different substituents selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, and radicals 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 1 to 3 carbon atoms;
E represents cycloalkyl having 3 to 6 carbon atoms, or represents straight-chain or branched alkyl having 1 to 8 carbon atoms;
R 3 and R 4 are identical or different and represent straight-chain or branched alkyl having 1 to 3 carbon atoms; or
R 3 and R 4 together with the carbon atom to which they are attached form a spiro-linked alkyl chain having 2 to 4 carbon atoms;
or a salt or N-oxide thereof.
2. A process for preparing a tetrahydroquinoline of the formula (Ia) according to claim 1 :
in which
A represents phenyl which is optionally substituted 1 to 2 times by identical or different substituents selected from the group consisting of halogen, trifluoromethyl and straight-chain or branched alkyl or alkoxy having in each case 1 to 3 carbon atoms;
R 5 represents hydrogen;
R 7 represents phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl, each of which are optionally substituted 1 to 4 times by identical or different substituents selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, and radicals 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 1 to 3 carbon atoms;
E represents cycloalkyl having 3 to 6 carbon atoms, or represents straight-chain or branched alkyl having 1 to 8 carbon atoms;
R 3 and R 4 are identical or different and represent straight-chain or branched alkyl having 1 to 3 carbon atoms; or
R 3 and R 4 together with the carbon atom to which they are attached form a spiro-linked alkyl chain having 2 to 4 carbon atoms;
or a salt or N-oxide thereof;
said process comprising oxidizing a compound of the formula (VIII):
wherein A, E, R 3 , R 4 and R 7 are as defined above, to yield a compound of the formula (IX):
wherein A, E, R 3 , R 4 and R 7 are as defined above, and asymmetrically reducing the compound of the formula (IX) to yield the compound of the formula (X):
wherein A, E, R 3 , R 4 and R 7 are as defined above, and introducing a hydroxyl-protective group into the compound of the formula (X) to yield a compound of the formula (XI):
wherein A, E, R 3 , R 4 and R 7 are as defined above, and R 12 represents a hydroxyl-protective group, and subjecting the compound of the formula (XI) to diastereoselective reduction to yield a compound of the formula (XII):
wherein A, E, R 3 , R 4 , R 7 and R 12 are as defined above, and reacting the compound of the formula (XII) with a fluorinating agent to yield a compound of the formula (XIII):
wherein A, E, R 3 , R 4 , R 7 and R 12 are as defined above, and cleaving the hydroxyl-protective group.
3. The process according to claim 2 , wherein R 12 represents a radical of the formula —SiR 13 R 14 R 15 , wherein R 13 , R 14 and R 15 independently represent C 1-4 -alkyl.
4. The process according to claim 2 , wherein the fluorinating agent is selected from the group consisting of DAST and SF 4 .