Substituted 4-aryl-1,4-dihydro-1,6-naphthyridines and use thereof

1. A compound of the formula (I)

in which

Ar is a group of the formula

in which

* is the linkage point,

R 8 is hydrogen or fluorine,

R 9 is halogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy,

R 10 is cyano or nitro,

D is CH, C—R 9 or N,

and

n is the number 0, 1 or 2,

it being possible in the case where the substituent R 9 occurs more than once for its meanings to be identical or different,

R 1 is cyano, nitro or a group of the formula —C(═O)—R 13 in which

R 13 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl or once to three times by fluorine, or phenyl which may be substituted by halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy, or (C 3 -C 7 )-cycloalkyl,

R 2 is (C 1 -C 4 )-alkyl, trifluoromethyl, cyclopropyl, cyclobutyl, (C 1 -C 4 )-alkoxy or (C 1 -C 4 )-alkylthio,

R 3 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, (C 1 -C 6 )-alkylthio, amino, mono-(C 1 -C 6 )-alkylamino or a group of the formula —O—SO 2 —R 14 ,

where said (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy and (C 1 -C 6 )-alkylthio radicals may in each case be substituted by (C 3 -C 7 )-cycloalkyl,

and

R 14 is (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, phenyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the series N, O and/or S,

it being possible for phenyl and heteroaryl in turn each to be substituted once or twice, identically or differently, by halogen, cyano, nitro, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and/or trifluoromethoxy,

and

R 4 is hydrogen, fluorine, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, (C 1 -C 4 )-alkylthio, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,

and the salts thereof.

2. A compound of claim 1 , in which

Ar is a group of the formula

in which

* is the linkage point,

R 9 is fluorine, chlorine, methyl or ethyl,

R 10 is cyano or nitro,

and

n is the number 0 or 1,

R 1 is cyano, acetyl or trifluoroacetyl,

R 2 is methyl or trifluoromethyl,

R 3 is (C 1 -C 4 )-alkoxy, trifluoromethoxy or a group of the formula —O—SO 2 —R 14 in

which

R 14 is (C 1 -C 4 )-alkyl, trifluoromethyl, (C 3 -C 6 )-cyaloalkyl, phenyl or thienyl, where phenyl and thienyl in turn may each be substituted once or twice, identically or differently by fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and/or trifluoromethoxy,

and

R 4 is hydrogen, fluorine or methyl.

3. A process for preparing compounds of the formula (I) as defined in claim 1 , in which R 3 is optionally (C 3 -C 7 )-cycloalkyl-substituted (C 1 -C 6 )-alkoxy, trifluoromethoxy or a group of the formula —O—SO 2 —R 14 in which R 14 has the meaning indicated in claim 1 , characterized in that a compound of the formula (II)

in which Ar has the meaning indicated in claim 1 ,

either

[A] is reacted in a one-stage (one-pot reaction) or two-stage process with a compound of the formula (III)

in which

T is methyl or ethyl,

and a compound of the formula (IV)

in which R 1 and R 2 have the meanings indicated in claim 1 ,

to give a compound of the formula (V)

in which Ar, R 1 , R 2 and T each have the meanings indicated above, and the latter is then reacted in an inert solvent with s-triazine in the presence of a base to give a compound of the formula (VIa)

in which Ar, R I and R 2 each have the meanings indicated above,

Or

[B] is reacted in a one-stage (one-pot reaction) or two-stage process with a compound of the formula (VII)

in which R I and R 2 have the meanings indicated in claim 1 ,

and a compound of the formula (VIII)

in which R 4 has the meaning indicated in claim 1 ,

to give a compound of the formula (VI)

in which Ar, R 1 , R 2 and R 4 each have the meanings indicated above,

and then the compounds of the formula (VIa) or (VI) are alkylated in an inert solvent, where appropriate in the presence of a base, with a compound of the formula (IX) or a trialkyloxonium salt of the formula (X)

in which

R 15 is (C 1 -C 6 )-alkyl which may be substituted by (C 3 -C 7 )-cycloalkyl or is trifluoromethyl,

R 15A is methyl or ethyl,

X is a leaving group such as, for example, halogen, mesylate, tosylate or triflate,

and

Y − is a non-nucleophilic anion such as, for example, tetrafluoroborate,

or in the presence of an acid with an orthoformic ester of the formula (XI)

in which R 15A has the meaning indicated above,

to give compounds of the formula (I-A)

in which Ar, R 1 , R 2 , R 4 and R 15 each have the meanings indicated above,

or the compounds of the formula (VIa) or (VI) are reacted in an inert solvent in the presence of a base with a compound of the formula (XII)

in which R 14 has the meaning indicated in claim 1 ,

to give compounds of the formula (I-B)

in which Ar, R 1 , R 2 , R 4 and R 14 each have the meanings indicated in claim 1 ,

and where appropriate the resulting compounds of the formula (I-A) or (I-B) are separated by methods known to the skilled worker into their enantiomers and/or diastereomers, and/or converted with the appropriate (i) solvents and/or (ii) bases or acids into salts thereof.

4. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

5. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with one or more further active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-blockers, acetylsalicylic acid, diuretics, potassium supplements, calcium antagonists, statins, digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics.