Tetrahydrobenzo[d]azepin-2-one derivatives and the use thereof for treating cardiovascular diseases
The present application relates to novel tetrahydrobenzo[d]azepin-2-one derivatives, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders, especially of dyslipidaemias, arteriosclerosis, restenosis and ischaemias.
1. A compound of the formula (I)
in which
A is (C 6 -C 10 )-aryl or 5- to 10-membered heteroaryl, each of which may be substituted up to three times, identically or differently, by substituents selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkynyl and (C 1 -C 6 )-alkoxy,
or
is a group of the formula
n is the number 1, 2 or 3,
R 1 and R 2 are identical or different and are independently of one another hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy,
R 3 is (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl or (C 2 -C 8 )-alkynyl, each of which may be substituted by phenyl, (C 3 -C 8 )-cycloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-acyloxy or amino,
and
R 4 is a group of the formula —OR 7 or —NR 8 R 9 , in which
R 7 is hydrogen or (C 1 -C 6 )-alkyl,
R 8 and R 9 are identical or different and are independently of one another hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 8 )-cycloalkyl, each of which may be substituted by substituents selected from the group consisting of carboxyl, (C 1 -C 6 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 6 )-alkylaminocarbonyl,
or
R 8 and R 9 form together with the nitrogen atom to which they are bonded a 4- to 8-membered heterocycle which may comprise a further ring member selected from the series N—R 10 , O, S, SO and SO 2 and may be substituted by substituents selected from the group consisting of hydroxy, oxo, amino, (C 1 -C 6 )-alkyl, carboxyl, (C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 6 )-alkylaminocarbonyl, in which
(C 1 -C 6 )-alkyl in turn may be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C 1 -C 6 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 6 )-alkylaminocarbonyl,
and
R 10 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-acyl or (C 1 -C 4 )-alkoxycarbonyl,
or a salt thereof.
2. The compound of the formula (I) according to claim 1 , in which
A is phenyl, naphthyl or pyridyl, each of which may be substituted up to twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkynyl and (C 1 -C 4 )-alkoxy,
or
is a group of the formula
n is the number 1, 2 or 3,
R 1 is hydrogen, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R2 is hydrogen,
R3 is (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl, each of which may be substituted by phenyl, (C 3 -C 6 )-cycloalkyl or hydroxy,
and
R 4 is a group of the formula —OR 7 or —NR 8 R 9 in which
R 7 is hydrogen,
R 8 and R 9 are identical or different and are independently of one another hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl, each of which may be substituted by substituents selected from the group consisting of carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylaminocarbonyl,
or
R 8 and R 9 form together with the nitrogen atom to which they are bonded a 5- to 7-membered heterocycle which may comprise a further ring member selected from the series N—R 10 and O and may be substituted by substituents selected from the group consisting of hydroxy, oxo, amino, (C 1 -C 4 )-alkyl, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylaminocarbonyl, in which
(C 1 -C 4 )-alkyl in turn may be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 -alkylaminocarbonyl,
and
R 10 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-acyl or (C 1 -C 4 )-alkoxycarbonyl, or a salt thereof.
3. The compound of the formula (I) according to claim 1 or 2 , in which
A is phenyl which may be substituted once or twice, identically or differently, by fluorine, chlorine, bromine, methyl, ethyl, ethynyl or methoxy, or is naphthyl or is a group of the formula
n is the number 1,
R 1 is hydrogen, chlorine, methyl or trifluoromethyl,
R 2 is hydrogen,
R 3 is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or is benzyl,
and
R 4 is a group of the formula —OR 7 or —NR 8 R 9 in which
R 7 is hydrogen,
R 8 and R 9 are identical or different and are independently of one another hydrogen or (C 1 -C 6 )-alkyl which may be substituted by carboxyl or (C 1 -C 4 )-alkoxycarbonyl,
or
R 8 and R 9 form together with the nitrogen atom to which they are bonded a 5- to 6-membered heterocycle which may comprise a further ring member selected from the series N—R 10 and O and may be substituted by substituents selected from the group consisting of hydroxy, oxo, amino, (C 1 -C 4 )-alkyl, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylarninocarbonyl, in which
(C 1 -C 4 )-alkyl in turn may be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylaminocarbonyl,
R 10 is hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-acyl,
or a salt thereof.
4. A compound of the formula (I-A)
in which
A is phenyl which may be substituted once or twice, identically or differently, by fluorine, chlorine, bromine, methyl, ethynyl or methoxy, or is a group of the formula
R 1 is chlorine, methyl or trifluoromethyl,
R 3 is (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl,
and
R 4 is a group of the formula —OR 7 or —NR 8 R 9 in which
R 7 is hydrogen,
R 8 and R 9 are identical or different and are independently of one another hydrogen or (C 1 -C 6 )-alkyl which may be substituted by carboxyl or (C 1 -C 4 )-alkoxycarbonyl,
or
R 8 and R 9 form together with the nitrogen atom to which they are bonded a 5- to 6-membered heterocycle which may comprise a further ring member selected from the series N—R 10 and O and may be substituted by substituents selected from the group consisting of hydroxy, oxo, amino, (C 1 -C 4 )-alkyl, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylaminocarbonyl, in which
(C 1 -C 4 )-alkyl in turn may be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, and mono- and di-(C 1 -C 4 )-alkylaminocarbonyl,
and
R 10 is hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-acyl,
or a salt thereof.
5. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with a further active ingredient selected from the group consisting of cholesterol-lowering statins, cholesterol absorption inhibitors, HDL-elevating or triglyceride-lowering and/or apolipoprotein B-lowering substances, oxidation inhibitors and compounds having antiinflammatory activity.
6. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.