Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-12
2003-10-07
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06630494
ABSTRACT:
The invention relates to novel phenyl-substituted 1,4-dihydropyridines, processes for their preparation and their use in medicaments, in particular as cerebrally active agents.
It has been disclosed that some dihydropyridines, such as e.g. nimodipine, have cerebral activity [cf. German Offenlegungsschrift 28 15 578]. Dihydropyridines having circulatory activity have also been disclosed which in the 4-position carry a phenyl ring which is substituted by halogen, CN or CF
3
[cf. German Offenlegungsschrift 1 963 188, German Offenlegungsschrift 2 117 572, German Offenlegungsschrift 2 117 573 and EP 007 293).
The present invention relates to selected new 4-phenyl-substituted 1,4-dihydropyridines of the general formula (I):
in which
R
1
and R
3
are identical or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by straight-chain or branched alkoxy having up to 6 carbon atoms or hydroxyl, or
represent cycloalkyl having 3 to 7 carbon atoms, and R
2
represents the radical
in which
R
4
and R
5
are identical or different and represent halogen, cyano, ethinyl, trifluoromethoxy, methyl, methylthio, trifluoromethyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or
R
4
or R
5
represents hydrogen
and their salts, in particular the new compounds of exemplary embodiments 1-124 coming under the formula (I).
Physiologically acceptable salts are salts of the compounds according to the invention with inorganic or organic acids. Preferred salts are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
The compounds according to the invention exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can also be separated in a known manner into the stereoisomerically uniform constituents.
Preferred compounds are those of the general formula (I)
in which
R
1
and R
3
are identical or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by straight-chain or branched alkoxy having up to 5 carbon atoms or hydroxyl, or
represent cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,
and R
2
represents the radical
in which
R
4
and R
5
are identical or different and represent fluorine, bromine, chlorine, cyano, ethinyl, trifluoromethoxy, methyl, methylthio, trifluoromethyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
R
4
or R
5
represents hydrogen
and their salts.
Particularly to be emphasized are new compounds of the general formula I, in which R
3
represents the radical —(CH
2
)
n
—OR
6
, in which n represents a number from 2 to 4 and R
6
represents hydrogen or alkyl having 1 to 4 C atoms, in particular compounds of the formula I in which R
3
represents the radical —CH
2
—CH
2
—OCH
3
, and R
1
is identical to or different from R
3
and represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl or alkoxy having 1 to 4 C atoms, or represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
Of particular interest are compounds of the general formula I in which R
2
represents a cyanophenyl radical which as a second phenyl substituent carries fluorine, chlorine or CF
3
. Of particular interest are also those compounds of the general formula I which in the 2- and 3-position of the phenyl radical R
2
are substituted by substituents from the group consisting of chlorine, fluorine, cyano and CF
3
, the 2,3-dichlorophenyl radical being excluded.
Very particularly preferred compounds of the general formula (I) are the following:
(±) isopropyl 2-methoxyethyl 4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2,5-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2,6-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2,5-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2-fluoro-3-trifluoromethylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(3-chloro-2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) isopropyl 2-methoxyethyl 4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) isopropyl 2-methoxyethyl 4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) isopropyl 2-methoxyethyl 4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) tert-butyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) tert-butyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) tert-butyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) cycloheptyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) cycloheptyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−) cycloheptyl 2-methoxyethyl 4-(3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(±) cyclopentyl 2-methoxyethyl 4-(2-chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(+) cyclopentyl 2-methoxyethyl 4-(2-chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(−)-cyclopentyl 2-methoxyethyl 4-
de Jonge Maarten
Gao Zhan
Hartwig Wolfgang
Junge Bodo
Meier Heinrich
Bayer Aktiengesellschaft
Goldberg Jerome D.
Norris McLLaughlin & Marcus
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