3-cyano 5-thiazaheteroaryl-dihydropyridine and the use thereof for the treatment of cardiovascular diseases
View Patent ↗The present application relates to novel aryl-substituted 3-cyano-5-thiazolyl- and 3-cyano-5-thiadiazolyl-1,4-dihydropyridines, a process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders.
1. A compound of the formula (I)
in which
Ar is (C 6 -C 10 )-aryl which may be substituted once to three times, identically or differently, by substituents selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylthio,
where said alkyl, alkoxy and alkylthio radicals may in turn be substituted by cyano or up to three times by fluorine,
R 1 is (C 1 -C 6 )-alkyl which may be substituted by phenyl, or is (C 1 -C 6 )-alkylthio,
where said alkyl and alkylthio radicals may in turn be substituted up to three times by fluorine,
R 2 is (C 1 -C 6 )-alkyl which may be substituted by cyano, hydroxy, (C 1 -C 4 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, (C 3 -C 6 )-cycloalkyl, phenyl or up to three times by fluorine, or is (C 3 -C 6 )-cycloalkyl,
X is C—R 4 ,
and
R 3 and R 4 are identical or different and independently of one another are hydrogen, halogen, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, are (C 1 -C 4 )-alkyl which may be substituted by hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino or up to three times by fluorine, or are phenyl which may be substituted by halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy or trifluoromethoxy,
or a salt thereof.
2. A compound of the formula (I) as claimed in claim 1 , in which
Ar is a group of the formula
in which
* is the point of linkage to the dihydropyridine ring,
R 7 is hydrogen or fluorine,
R 8 is fluorine, chlorine, bromine, cyano or (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy or (C 1 -C 4 )-alkylthio, each of which may be substituted up to three times by fluorine,
R 9 is hydrogen, fluorine, chlorine or methyl, and
R 10 is hydrogen, cyano, fluorine, chlorine or bromine,
R 1 is (C 1 -C 4 )-alkyl which may be substituted up to three times by fluorine,
R 2 is (C 1 -C 4 )-alkyl which may be substituted by (C 1 -C 4 )-alkoxy or up to three times by fluorine,
X is C—R 4 ,
and
R 3 and R 4 are identical or different and independently of one another are hydrogen, fluorine, chlorine, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino or (C 1 -C 4 )-alkyl,
or a salt thereof.
3. A compound of the formula (I) as claimed in claim 1 , in which
Ar is a group of the formula
in which
* is the point of linkage to the dihydropyridine ring,
R 8 is fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, methoxy or trifluoromethoxy,
and
R 10 is fluorine, chlorine or cyano,
R 1 is methyl or trifluoromethyl,
R 2 is methyl, ethyl, n-propyl or methoxymethyl,
X is C—R 4 ,
R 3 is hydrogen, methyl or ethyl,
R 4 is hydrogen, methyl, ethyl or n-propyl,
or a salt thereof.
4. A process for preparing a compound of the formula (I) as defined in claim 1 , comprising:
reacting a compound of the formula (II)
in which Ar has the meaning indicated in claim 1 ,
[A] in a one-stage process (one-pot reaction) with a compound of the formula (III)
in which R 1 has the meaning indicated in claim 1
and
M + is an alkali metal ion such as Li + , Na + or K + ,
and a compound of the formula (IV)
in which R 2 , R 3 and X each have the meanings indicated in claim 1 ,
or
[B] in a one-stage process (one-pot reaction) with a compound of the formula (V)
in which R 1 has the meanings indicated in claim 1 ,
and a compound of the formula (VI)
in which R 2 , R 3 and X each have the meanings indicated in claim 1 ,
or
[C] in a two-stage process comprising reacting the compound of formula (II) with a compound of the formula (VI) thereby producing a compound of the formula (VII)
in which Ar, R 2 , R 3 and X each have the meanings indicated in claim 1 ,
and reacting the compound of formula (VII) in a second step with a compound of the formula (V),
and optionally reacting the resulting compound of formula (I) with the appropriate (i) solvents and/or (ii) bases or acids thereby producing a salt thereof.
5. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.