NO811424L - 1,4-DIHYDROPYRIDINES WITH DIFFERENT 2- AND 6-SUBSTANCES, PROCEDURE FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICALS - Google Patents

Abstract

1. Compound of the general formula I see diagramm : EP0039863,P18,F1 in which R represents a phenyl radical which optionally contains 1 or 2 identical or different substituents from the group comprising nitro, chlorine, cyano or trifluoromethyl, with the exception of a phenyl radical which is at the same time ortho- and metadichlorosubstituted, when R**2 denotes methyl and R**4 denotes alkyl with 2-3 carbon atoms, R**1 represents a saturated hydrocarbon radical with up to 6 carbon atons which is optionally interrupted by an oxygen atom, R**2 and R**4 are always different and each represents hydrogen, alkyl with 1 to 4 carbon atoms or cyclohexylmethyl, with the exception of the compound diethyl-2-methyl-6-propyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-carboxylate.

Description

The invention relates to new 1,4-dihydropyridines with different substituents in the 2- and 6-position, several methods for their preparation, as well as their use in pharmaceuticals, especially circulatory agents.

It is already known that 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3'5-dicarboxylic acid diethyl ester is obtained when benzylidene acetoacetic acid ethyl ester is reacted with 8-amino-crotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (E. Knoevenagel, Ber. dtsch, chem. Ges. 31, 743 (1898)).

Furthermore, certain 1, A-dihydropyridines are known to have interesting pharmacological properties (F. Bossert W. Vater, Naturwissenschaften 58, 578 (1971)).

Furthermore, there are known dihydropyridines which in 3-

and 5-position have different ester groups (DE-OS 2 117

571). 1, U-dihydropyridines with the same ester groups in the 3- and 5-position and different substituents in the 2- and 6-position have not yet been known.

The invention relates to new 1,4-dihydropyridines

with different substituents in the 2- and 6-position and with the general formula I

in which

R represents an aryl residue or a thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl , benzimidazolyl, quinazolyl or quinoxalyl residue, the aryl residue as well as heterocyclyl possibly containing 1 to 3 identical or different substituents from the group phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, monofluoroalkyloxy .

R means a linearly branched or cyclically saturated or unsaturated hydrocarbon residue which is optionally interrupted by 1 or 2 oxygen atoms in the chain and/or which is optionally substituted with a phenyl-phenoxy:->phenylthio-, or phenylsulfonyl group which in turn can be substituted with halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro,

R 2 and R^ L are always different, and each means hydrogen or a straight or branched, saturated or unsaturated hydrocarbon residue which in turn is optionally substituted with a saturated or unsaturated cyclic hydrocarbon residue and R^ means hydrogen or a straight or branched alkyl residue which is optionally interrupted by one or two oxygen atoms in the alkyl chain, or means an aryl or aralkyl residue.

It was found that the 1,4-dihydropyridine derivatives of formula I are obtained when

A) Ylidene-8-keto esters of the general formula II

in which

R, R 1 and R 2 have the above meaning, optionally reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula III

in which

R , R and R have the above meaning, or

B) Ylidene-8-ketoesters of the general formula II

in which

1 2

R, R and R have the above meaning

optionally reacted in the presence of inert organic solvents with amines of the general formula IV and B-ketocarboxylic acid esters. with the general formula V

in which

R 3 , R L and R 1 have the above meaning, or

C) Ylidene-3-ketoesters of the general formula VI

in which

R, R 1 and R L have the above meaning

optionally reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula VII

in which

R 2 , R 3 and R 1 have the above meaning, or D) Yyliden-3-ketoester with' formula VI

in which

R, R 1 and R L have the above-mentioned meaning, converted where appropriate

in the presence of inert organic solvents with amines of the general formula IV and 3-ketocarboxylic acid esters of the general formula VIII

in which

R 3 , R 2 and R<1> have the above meaning, or

E) Aldehydes of the general formula IX

if R has the above-mentioned meaning, it may be reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula III and 8-ketocarboxylic acid esters of the general formula VIII

in which

R\ / R 3 , R 1 and R 2 have the above meaning, or F) Aldehydes with the general formula IX

in which

R has the above meaning,

is reacted, optionally in the presence of inert organic solvents, with enaminocarboxylic acid esters of the general formula VII and B-ketocarboxylic acid esters of the general formula V

in which

R? , R 3 , R 1 and R L have the above meaning.

G) In the event that in formula I the residues R, R-) and R o have none under hydrogenating conditions for variable functional groups, and R 2 is different from. hydrogen, and R 3 and R L mean a hydrogen atom, the 1,4-dihydropyridines of formula XI according to the invention can also be obtained by catalytic hydrogenation of 2-dialkylamino-3,k-dihydropyridines of formula X in the presence of a noble metal

catalyst, with formula X R 5 and R 6 meaning lower alkyl residues which optionally form a heterocyclic ring with exocyclic nitrogen atoms.

The 1, 4-dihydropyridine derivatives according to the invention have valuable pharmacological properties. Due to their circulation-influencing effect, they can find use as antihypertensive agents, as vasodilators, as cerebral therapeutics, as well as coronary therapeutics and can thus be considered an enrichment of pharmacy.

Depending on the type of starting materials used, the preparation of the compound according to the invention can be reproduced with the following formula, 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrofenyl)-pyridine -3»5-dicarboxylic acid diethyl ester, as well as 1,4-dihydro-2-methyl(31-trifluoromethylphenyl)-pyridine-3»5-dicarboxylic acid diethyl ester can be chosen as examples:

Method variant A

According to method A, a ylidene-8-ketoester of formula II is brought

for reaction with enaminocarboxylic acid ester of formula III

In formula II means

R preferably a phenyl or naphthyl radical or a thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl. pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, quinolyl-, isoquinolyl-, indolyl-, benzimidazolyl quinazolyl- or ch inoxalylre st. The mentioned heterocycles and especially the phenyl residue can have 1 or 2 identical or different substituents, the substituents preferably being phenyl, straight or branched alkyl with 1 to 8, especially 1 to 4 carbon atoms, cycloalkyl with 3 to 7 carbon atoms , alkenyl or alkynyl with 2 to 6 carbon atoms, especially 2 to 3 carbon atoms, alkoxy with preferably 1 to 4»especially 1 to 2 carbon atoms, alkenoxy and alkynoxy with 2 to 6, especially 3 to 5 carbon atoms, tri-, tetra- and pentamethylene , dioxymethylene, halogen such as fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano, azido, hydroxy, amino,

mono- and dialkylamino with preferably 1 to 4, especially 1 or 2 carbon atoms per alkyl group, carboxy, caralkyloxy with preferably 2 to 4, especially 2 or 3 carbon atoms, carbonamido, sulfonamido or SOm-alkyl, in which m means a number from 1 to 2, dg alkyl contains preferably 1 to 4. especially 1 or 2 carbon atoms.

Further means in formula II

R -i preferably a straight-line, branched or cyclic saturated or unsaturated hydrocarbon residue with up to 8, especially with up to 6 carbon atoms which are optionally interrupted by 1 or 2 oxygen atoms in the chain and/or whose hydrogen atom can be substituted with an optionally halogen, especially fluorine , chlorine or bromine, cyano, dialkylamino with each time 1 to 2 carbon atoms per alkyl group, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, trifluoromethyl or nitro substituted phenyl, phenoxy, phenylthio or phenylsulfonyl group,

and

R 2 preferably means hydrogen or preferably a linear or branched alkyl radical with 1 to 8, especially 1

to 4 carbon atoms, in which a hydrogen atom may be substituted by a saturated or unsaturated cyclic hydrocarbon residue, with 3 to 7 carbon atoms, especially a phenyl residue.

The yl iden-3-keto esters of formula II used as starting materials are known from the literature or can be prepared according to methods known in the literature (cf. e.g. G.Jones "The Knoevenagel Condensation" in org. Reactions, Vol XV, 204 ff (1967)).

Examples include: Benzylideneformylacetic acid methyl ester, benzylidene-acetoacetic acid methyl ester, 2'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid-n-butyl ester, 2'-chloroacetbenzylideneacetic acid isopropyl ester, 2'-methoxybenzylideneacetoacetic acid isobutyl ester, 2'-trifluoromethyl benzylideneacetoacetic acid cyclopentyl ester . -nitrobenzylideneacetoacetic acid-(2-methoxy syl)-ester, 21-nitrobenzylideneacetoacetic acid isobutyl ester, 2'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid-(2-propoxye tyl)-ester, 3'-nitrobenzylidene-acetoacetic acid acetoacetic acid benzyl ester, 3<1->nitrobenzylidene-acetoacetic acid-(2-phenylethyl)-e ester, 3'-nitrobenzylideneacetoacetic acid-(2- phenoxyethyl)-ester, 31-nitrobenzylideneacetoacetic acid -.'(2-phenylthioethyl)-ester, 31-nitrobenzylideneacetoacetic acid-(2-phenylsulfonylethyl)-ester . -methylbenzyl)-ester, 3'-nitrobenzylideneacetoacetic acid-(2-(3-trifluoro,ethylphenoxy)-ethyl)-ester, 3<1->nitrobenzylideneacetoacetic acid(2-(3-chlorophenoxy)-ethyl)-ester, 2'- cyanobenzylideneacetate ethyl ester, 2'-cyanobenzylidenepropionylacetic acid ethyl ester, 2'-nitrobenzylidenepropionylacetic acid methyl ester, 3'-nitrobenzylidenepropionylacetic acid ethyl ester, 3'-nitrobenzylidene propionylacetic acid -(2-me to xyethyl)-ester, 3-nitro-benzylidenepropionylacetic acid isopropyl ester, 2'-nitrobenzylidenepropionylacetic acid isobutyl ester, 2 '-chlorobenzylidenepropionylacetic acid methyl ester, 2'-cyanobenzyl denisobutanoylacetic acid ethyl ester, 3'-nitrobenzylideneisobutanoylacetic acid ethyl ester, 2'-nitrobenzylideneisobutanoylacetic acid methyl ester 2<1->nitrobenzylideneisobutanoylacetic acid isobutyl ester, 3'-nitrobenzylideneisobutanoylacetic acid-(2-methoxyethyl)-ester, 3'-nitrobenzylidene - phenylacetoacetic acid ethyl ester, 2'-nitrobenzylidene - T^-phenylacetoacetic acid methyl ester . 3-(pyridy1-3)-acrylic acid methyl ester, a-propionyl-8 -(pyridyl-2)-acrylic acid ethyl ester, a-(n)-butanoyl-3 - (pyridyl-4)-acrylic acid isopropyl ester, a-isobutanoyl-8-( quinolinyl-$)-acrylic acid cyclopentyl ester, a-phenylacetyl-3-(thienyl-2)-acrylic acid (2-methoxyethyl)-ester, a-propionyl-8-(2-methyl-thiopyridyl-3)-acrylic acid ethyl ester, α-propionyl-8-(furyl-2)-acrylic acid isobutyl ester.

In formula III, R has the same meaning as i

formula II.

Further means in formula III

R 3 preferably a hydrogen atom or a linear or branched alkyl radical with 1 to 8 carbon atoms, especially 1 to 4 carbon atoms, the alkyl radical optionally being interrupted by an oxygen atom in the alkyl chain, or means a phenyl radical or aralkyl radical, especially a benzyl radical,

and

R^ preferably a hydrogen atom or preferably a linear or branched alkyl radical with 1 to 8, especially 1

to 4 carbon atoms in which a hydrogen atom may be substituted by a saturated or unsaturated cyclic hydrocarbon residue with up to 6 carbon atoms, especially a phenyl residue.

The enaminocarboxylic acid esters of formula III used as starting substances are known from the literature or can be prepared according to methods known in the literature, (cf. A.C.

Cope, J. Amer.chem. Soc. 67 1017 (1945)).

Examples should be mentioned: B.-amino-crotonic acid ethyl ester, 8-aminocrotonic acid ethyl ester, g-methylamino-crotonic acid ethyl ester, g-n-butyl-amino-crotonic acid isopropyl ester. B-isobutylamino-crotonic acid methyl ester, 8-(2-methoxyethylamino)-crotonic acid methyl ester, 3-aminocrotonic acid methyl ester, Q-benzylamino-crotonic acid-n - propyl ester, 3-amino-B-ethyl-acrylic acid methyl ester, B-amino-3 -e tyl-acrylic acid tyle ester, 8-amino-B-ethyl-acrylic acid isorpopyl ester, 8-amino-B-ethyl-acrylic acid neopentyl ester, B-amino-3-ethyl-acrylic acid allyl ester, B-amino-B-ethylacrylic acid propanyl ester, B-amino- B-ethyl-acrylic acid benzyl ester, B-amino-3-ethyl-acrylic acid-(2-phenylethyl)-ester, B-amino-3-ethyl.acrylic acid-(2-phenoxy-ethyl)- ester, B-amino-B-e tylacrylic acid -(2-phenylthioethyl)-ester, 8-amino-3-ethylacrylic acid -(2-phenylsulfonethyl ) -ester, 8-amino-8-ethylacrylic acid - (4-chlorobenzyl)-ester, 3-amino-B-ethyl-acrylic acid-(3,4-dichlorobenzyl)-ester, B-amino-B-ethyl-acrylic acid-(3, 4. 5-trime toxy benzyl ester )-3-amino -3-ethyl-acrylic acid-(4-trifluoromethylbenzyl)-ester, 3-amino-8-ethyl-acrylic acid-(4-nitrobenzyl)-ester, B-amino-B-ethyl-acrylic acid-(2-(3- trifluoromethylphenoxy)-ethyl)-ester, B-amino-3-ethyl-acrylic acid-(2-(3-methylphenoxy)-ethyl)-ester, 3-amino-8-propylacrylic acid methyl ester, B-amino-3-isopropyl- acrylic acid methyl ester, B-amino- B-n-butylacrylic acid methyl ester, 8-amino-B-isobutyl-acrylic acid - methyl ester, 8-amino-8-cyclohexylmethylacrylic acid methyl ester, 8-am 4-n 0-8-benzyl-acrylic acid - methyl ester, 8-amino-8-(2-phenylethyl)-acrylic acid ethyl ester.

Inert organic solvents are used as diluents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ester, tetrahydrofuran, glycol monomethyl ester, glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied within a

large area. Usually one works between 20 and 150°C, preferably between 20 and 100°C, especially at the boiling temperature of any solvent.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually you work under normal pressure.

When carrying out the method according to the invention, one mole of the ylidene-8-ketoesters of formula II is reacted with one mole of enaminocarboxylic acid ester of formula II in a suitable solvent. Isolation and purification of the substances according to the invention preferably takes place in such a way that the solvent is distilled off in a vacuum,

and optionally recrystallises the crystalline residue from a suitable solvent only after cooling.

Method variant B

According to method B, the ylidene-8-ketoester of formula II is brought

for reaction with an amine of formula IV and an 8-ketocarboxylic acid ester of formula V

In the formulas II, IV and V, the residues R, R 1 , R 2,

R and R preferably have the meaning given under method variant A.

For example, for the starting materials ylidene-B-ketoester with formula II, it is already listed under process variant A.

According to the invention usable amines of formula

IV is already known.

Examples include:

Ammonia, methylamine, n-propylamine, isopropylamine, n-butylamine, i sobutylamine, B-methoxyethylamine, benzylamine, aniline.

The 8-ketocarboxylic acid esters of formula V used as starting materials are known from the literature, and can be prepared according to methods known in the literature (e.g. D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen

und Mercaptanen", in Houben-Weyl, Methoden der Organischen Chemie, Vol. VII/4. 230 ff (1968) Y. Oikawa, K. Sugano and

0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).

Examples include: Acetoacetic acid methyl ester, Acetoacetic acid ethyl ester, acetoacetic acid n-butyl ester, acetoacetic acid isopropyl ester, acetoacetic acid cyclopentyl ester, acetoacetic acid allyl ester, acetoacetic acid propargyl ester, acetoacetic acid benzyl ester, acetoacetic acid -(2-phenyl ethyl)-ester, acetoacetic acid -(2-phenoxyethyl)-ester, acetoacetic acid -(2-phenylsulfonylethyl)-ester, propionyl-acetic acid methyl ester . Ionylacetic acid -(2-phenylethyl)-ester, Propionylacetic acid -(2-phenoxyethyl)-ester, Propionylacetic acid -(2-3-trifluoromethyl-phenoxy)-ethyl)-ester, Propionylacetic acid -(2-phenylthioethyl)-ester, Isobutanoylacetic acid methyl ester, " ^-Cyclohexylacetoacetic-

acid ethyl ester, Y"-phenylacetoacetic acid methyl ester.

Diluents include all inert organic solvents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ester, tetrahydrofuran, glycol monomethyl ester, glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied within a large range. Generally, one works between 20 and 150°C, preferably, however, at the boiling temperature of any solvent.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually you work under normal pressure.

When carrying out the method according to the invention, participating substances of formulas II and IV and V are used in the reaction each time in molar amounts. The amine used is suitably added in an excess of 1 to 2 Mol. The compounds according to the invention can be easily purified by recrystallization from a suitable solvent.

Method variant C

According to method variant C, a ylidene-B-ketoester of formula VI is reacted

with an enaminocarboxylic acid ester of formula VII

1L

In the formulas VI and VII, the residues R, R , R , R and R 2 preferably have the meaning indicated under process variant A.

The ylidene-8-keto esters of formula VI used as starting materials are known from the literature, and can be prepared according to methods known in the literature (cf. e.g. G. Jones "The Knoevenagel Condensations" in Org. Reactions, Vol. VX, 204 ff. (1977)).

As examples should be mentioned: Benzylideneformylacetic acid methyl ester, benzylidene acetacetic acid methyl ester, 2-nitrobenzylideneacetacetic acid ethyl ester, 3'-nitrobenzylideneacetacetic acid n-butyl ester, 2'-chloroacetbenzylideneacetic acid isopropyl ester, 2'-methoxy-benzylideneacetacetic acid isobutyl ester, 2'-trifluoromethyl benzyl - idenacetoacetic acid cyclopentyl ester, 2'-methylbenzylideneacetoacetic acid cyclohexyl ester, 2<!->cyanobenzylideneacetoacetic acid allyl ester, 3'-azidobenzylideneacetoacetic acid propargyl ester, 3'-dimethylaminobenzylideneacetoacetic acid tert-butyl ester, 3'-,ethylsulfonylbenzylideneacetoacetic acid benzyl ester, 3'-nitro-benzylideneacetoacetic acid isopropyl ester, 3' -nitrobenzylidene acetoacetic acid - (2-methyl) -ester , 2'-nitrobenzylidene acetoacetic acid isobutyl ester, 2'-nitrobenzylidene acetoacetic acid -.ethyl ester, 3'-nitrobenzylidene acetoacetic acid ethyl ester, 3'-nitrobenzylidene acetoacetic acid benzyl ester, 3'-nitrobenzylidene acetoacetic acid -. phenylethyl)-ester, 3'-nitrobenzylidene-acetacetic acid - (2-phenoxy tyl ) -ester , 3'-nitrobenzylidene-acetacetic acid-(2-phenylthioethyl)-ester, 3'-nitrobenzylideneacetacetic-acid-(2-phenylsulfonylethyl)-ester , 2'-cyano benzylidene-acetacetic-acid-(4.-chloro benzyl )-ester, 3'-nitrobenzylideneacetoacetic acid-(4-trifluoromethyl benzyl)-ester, 3<1->methoxybenzylidene-ace tedacetic acid - (4-n itro benzyl )-ester, 2 1 -trifluoro me tyl benzyl - ideneacetoacetic acid-(4-methylbenzyl)-ester, 3<1->nitrobenzylideneacetoacetic acid-(2-(3-trifluoromethylphenoxy)-ethyl)-ester, 31-nitrobenzylideneacetoacetic acid-(2-(3-chlorophenoxy)-ethyl) -

ester, 2'-cyanobenzylidene acetoacetic acid ethyl ester, 2'-cyano-benzylidenepropionylacetic acid ethyl ester, 2'-nitrobenzylidenepropionylacetic acid methyl ester, 3'-nitrobenzylidenepropionylacetic acid ethyl ester, 3'-nitrobenzylidenepropionylacetic acid-(2-methoxyethyl)-ester, 3'-riitrobenzylidenepropionylacetic acid isopropyl ester, 2'-nitrobenzylidenepropionylacetic acid iso -butyl ester, 2'-chlorobenzylidenepropionylacetic acid methyl ester, 2'-cyanobenzylideneisobutanoylacetic acid ethyl ester, 3'-nitro-

Benzylideneisobutanoylacetic acid ethyl ester, 2'-nitrobenzylidene - isobutanoylacetic acid methyl ester, 2'-nitrobenzylidene isobutanoylacetic acid ester, 3'-nitrobenzylideneisobutanoylacetic acid-(2-methoxyethyl)-ester, 3' -nitrobenzylidene - T-phenylacetacetic acid ethyl ester, 2'-nitrobenzylidene, T^-phenylacetate -acid methyl ester, 2' -nitrobenzylidene - f-phenylacetic acid iso-butyl ester, 3<1->nitrobenzylidene-T-phenylacetoacetic acid iso-propyl ester, 3' -nitrobenzylidene-^-f enylacetoacetic acid-(2-methoxyethyl) - ester, 2 1 -tr if luorme tyl benzyl iden - enyl - acetoacetic acid ethyl ester, a-acetyl-8-(pyridyl-3)-acrylic acid ethyl ester, a-propionyl-8 -(pyridy1-2)-acrylic acid ethyl ester, a-(n )-butanoyl- 8-(pyridyl-4-)-acrylic acid isopropyl ester, α-isobutanoyl-8-(quinolinyl-4)-acrylic acid cyclopentyl ester, α-phenylacetyl-8-(thienyl-2)-acrylic acid (2-methoxyethyl)-ester, ot-pr op ionyl-3-(2-methylthio-pyridyl-3)-acrylic acid ethyl ester, a-propionyl-8-(furyl-2)-acrylic acid isobutyl ester.

The enaminocarboxylic acid esters of formula VII used as starting materials are known from the literature, or can be prepared according to methods known from the literature (cf. A.C. Cope, J. Amer. Chem. Soc. 67, 1017 (1945)).

Examples include: 8-amirio-crotonic acid methyl ester, 8-aminocrotonic acid ethyl ester, 8-methylamino-crotonic acid ethyl ester, 8-n-butyl-amino-crotonic acid isopropyl ester, 8-isobutylamine-crotonic acid - methyl ester, 8-(2-me toxyethylamino)-crotonic acid methyl ester, 8-benzylamino-crotonic acid-n-propyl ester, 8-amino-B-ethyl - acrylic acid methyl ester, 8-amino-B-ethyl-acrylic acid ethyl ester, 8-amino- B-ethyl-acrylic acid isopropyl ester, 8 -amino-B-ethyl-acrylic acid cyclopentyl ester, 8-amino-B-ethyl-acrylic acid allyl ester, B-amino-B-ethyl-acrylic acid propargyl ester, 8-amino-8-ethyl-acrylic acid benzyl ester, B-amino-B-ethylacrylic acid-(2- phenylethyl)-ester, 8-amino-B-ethyl-acrylic acid-(2-phenoxyethyl)-ester, 3-amino-B-ethyl-acrylic acid-(2-phenylthioethyl)-ester, B-amino-B-ethyl-acrylic acid -(2-phenylsulfonylethyl)-ester, B-amino-B-ethyl-acrylic acid-(4-chlorobenzyl)-ester, B-amino-B-ethyl-acrylic acid -(3,4-dichloro-benzyl)-ester, 8-amino-B-ethyl-acrylic acid-(3,4»5-trimethoxy-benzyl)-ester, 8-amino-8-ethylacrylic acid-(4-trifluoromethyl-benzyl)-ester, 3-amino-3-ethyl- acrylics ure-(4-nitrobenzyl)-ester, 3-amino-3-ethyl-acrylic acid-(2-(3-trifluoromethylphenoxy)-ethyl)-ester, 3-amino-8-ethyl-acrylic acid-(2-chlorophenoxy )-ethyl)-ester, 3-amino-3-ethyl-acrylic acid-(2-(3.-methylphenoxy)-ethyl)-ester, 3-amino- 8-propyl-acrylic acid methyl ester, 8-amino-B- isopropyl-acrylic acid methyl ester, 8-amino- 8-n-butyl-acrylic acid methyl -

ester, 3-amino-3-isobutyl-acrylic acid methyl ester, 8-amino-3-cyclohexyl methyl -acrylic acid methyl ester, 3-amino - 3 -benzyl- -acrylic - acid methyl ester, 8-amino- 3-(2-phenylethyl)-acrylic acid ethyl ester

Diluents include all inert organic solvents• These preferably include alcohols such as ethanol, methanol, isopropanol, ethers,

such as dioxane, diethyl ether, tetrahydrofuran, glycol monoraethyl ether, glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid triamide.

The reaction temperatures can be varied within a large range. Usually, one works between 20 and 150°C, preferably between 20 and 100°C, especially at the boiling temperature of any solvent.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually you work under normal pressure.

When carrying out the method according to the invention, 1 mole of ylidene-8-ketoester with formula VI is reacted with one mole of enaminocarboxylic acid ester with formula VII

in a suitable solvent.

Procedure variant D

According to process variant D, a ylidene-8-ketoester of formula VI is reacted

with an amine of formula IV and an 8-keto carboxylic acid ester of formula

In formulas VI, IV and VIII, the residues R, R<1>, R^, R3 and

R 2 preferably has the meaning given under procedure variant<t>A.

Examples of the yl iden-6-ketoesters of formula VI used as starting compounds are already listed under process variant C.

According to the invention usable amines of formula

IV is already discussed under method variant B.

The S-ketocarboxylic acid esters of formula VIII used as starting materials are known from the literature, or can be prepared according to methods known in the literature (e.g.

D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen", in Houben-Weyl, Methoden der Organischen Chemie, Vol. VII/4-, 230 ff (1 968), Y. Oikawa, K Sugano and

0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).

Examples include: acetoacetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid n-butyl ester, acetoacetic acid isopropyl ester, acetoacetic acid cyclopentyl ester, acetoacetic acid allyl ester, acetoacetic acid propargyl ester, acetoacetic acid benzyl ester, acetoacetic acid-(2-phenyl syl)-ester, acetoacetic acid-(2-phenoxy) -ethyl)-ester, acetoacetic acid-(2-phenylthioethyl)-ester, acetoacetic acid-(2-phenylsulfonylethyl)-ester, propionylacetic acid - methyl ester, propionylacetic acid ethyl ester, propionylacetic acid isopropyl ester, propionylacetic acid cyclopentyl ester, propionylacetic acid allyl ester, propionylacetic acid propargyl ester, propionylacetic acid benzyl ester, propionyl acetic acid -(4-chloro - benzyl=-ester, propionyl acetic acid -(3,4-dichlorobenzyl)-ester, propionyl acetic acid -(4-trifluoromethylbenzyl )-ester, propionyl acetic acid -(2-phenylethyl)-ester, propionyl acetic acid -(2 -phenoxy-ethyl)-ester, propionylacetic acid-(2-(3-trifluoromethylphenoxy)-ethyl)-ester, propionylacetic acid-(2-phenylthioethyl)-ester, i sobutanoyl edd i ksy re methyl ester, "V"-cyclohexylacetoacetic acid - ethyl ester, V-phenylacetoacetic acid methyl ester.

Diluents include all inert organic solvents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid.

The reaction temperatures can be varied within a large range. Usually one works between 20 and 150°C, preferably, however, at the boiling temperature of any solvent.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually you work under normal pressure.

When carrying out the method according to the invention, the substances participating in the reaction with formulas VI, IV and VIII are used each time in molar amounts.

The amine used is suitably added in excess from

1 to 2- Mol.

Method variant E

According to method E, an aldehyde of formula IX is reacted

with an enaminocarboxylic acid ester of formula III

and a 3-ketocarboxylic acid ester of formula VIII.

- In the formulas IX, III and VIII, the residues R, R , R , R 1 and R preferably have the meaning indicated under process variant A.

They used aldehydes with the formula as starting materials

IX is known from the literature, or can be prepared according to methods known from the literature (cf. e.g. E.Mosettig, Org. Reactions VIII, 218 ff (1954)).

Examples include:

Benzaldehyde, 2-, 3-or 4-phenylbenzaldehyde, α-or 3-naphthylaldehyde, 2-, 3-or 4-methylbenzaldehyde, 2-or 4-n-butylbenzaldehyde, 2-, 3-or 4-isopropylbenzaldehyde, 2- or 4-cyclopropylbenzaldehyde, 2-vinyl - benzaldehyde, 2-ethynylbenzaldehyde, 2,3-tetramethylenebenzaldehyde, 3»4-dioxymethylenebenzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-cyclopropylmethyloxybenzaldehyde, 2-propargyloxybenzaldehyde, 2 -allyloxybenzaldehyde, 2-, 3-or 4-chloro/bromo/fluorobenzaldehyde, 2-, 3-or 4-trifluoro-ethylbenzaldehyde, 2-, 3- or 4-trifluoromethoxybenzaldehyde, 4-hydroxybenzaldehyde, 2-, 3 - or 4-nitrobenzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 3-carboethoxybenzaldehyde, 3- or 4-carbamoylbenzaldehyde, 2-, 3- or 4-methylthiobenzaldehyde, 2-, 3- or 4-methylsulfinylbenzaldehyde, 2 -, 3-or 4-niethylsulfonylbenzaldehyde, 3, 4, 5-trimoxybenzaldehyde, 2,3- or 2,6-dichlorobenzaldehyde, 2,4-dimethylbenz- aldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, 4-chloro-2-nitrobenzaldehyde, 2-nitro-4-methoxy-benzaldehyde, 2-nitro-4-cyanobenzaldehyde, 2-chloro -4-cyanobenzaldehyde, 4-cyano-2-methylbenzaldehyde, 3-methyl-4-trifluoromethyl - benzaldehyde, 3-chloro-4-trifluoromethylbenzaldehyde, 4-chloro-3-sulfamoxybenzaldehyde, thiophene-2-aldehyde, furan-2-aldehyde , pyrrole-2-aldehyde, pyrazole-4-aldehyde, imidazole-2-aldehyde, oxazole-2-aldehyde, isoxazole-3-aldehyde, thiazole-2-aldehyde, pyridine-2-aldehyde, pyridine-3-aldehyde , pyridine-4-aldehyde, 4-methyl-pyridine-2-aldehyde, 6-methylpyridine-2-aldehyde, pyridazine-4-aldehyde, pyrimidine-4-aldehyde, pyrazine-2-aldehyde, quinoline-4-aldehyde, isoquinoline -1-aldehyde, indole-3-aldehyde, benz-imidazole-2-aldehyde, quinazolin-2-aldehyde, quinoxaline-2-aldehyd.

The enaminocarboxylic acid esters of formula III that can be used according to the invention are already indicated under method variant A, the 8-keto carboxylic acid esters of formula VIII that can be used according to the invention are indicated under method variant D.

As diluents it comes into question

all inert organic solvents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether; tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or glacial acetic acid; ^ dime tylf ormamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethyl phosphoric acid triamide.

The reaction temperatures can be varied within a large range. Generally, one works between 20 and 150°C,

preferably, however, at the boiling temperature of the possible solvent.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually you work under

.normal pressure.

When carrying out the method according to the invention, the substances participating in the reaction with the formulas IX, III and VIII are used each time in molar amounts.

ProgressBmethod variant F

According to method F, an aldehyde of formula IX is reacted

with an enaminocarboxylic acid ester of formula VII and a 3-ketocarboxylic acid ester of formula V.

In the formulas IX, VII and V, R, R<1>, R , R and R^" preferably have the meaning indicated under process variant A.

The aldehydes of formula IX specified as starting materials are listed under process variant E, the enamino-carboxylic acid esters of formula VII under process variant C, and the 3-ketocarboxylic acid esters of formula V under process variant B.

Diluents include all inert organic solvents. These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or glacial acetic acid, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine and hexamethylphosphoric acid - triamide.

The reaction temperatures can be varied within a large range. Generally, one works between 20 and 150°C, preferably, however, at the boiling temperature of the possible solvent.

The turnover can be carried out at normal pressure, but also at excessively high pressure. Usually you work under normal pressure.

When carrying out the method according to the invention, the substances participating in the reaction with the formulas IX, VII and V are used each time in molar amounts.

Method variant G

In the event that in formula I the residues R, Ri

and R 2 does not have any functional groups changeable under hydrogenating conditions, and R 2 is different from hydrogen, and R 3 and R L mean a hydrogen atom, the 1,4-dihydropyridines of formula XI according to the invention can also be prepared by catalytic hydrogenation of 2- dialkylamino-3,4-dihydropyridines of formula X in an acidic environment in the presence of a noble metal catalyst.

1 2

In formulas X and XI, the residue has R, R and R

the meaning given under method variant A, as it applies to the above-mentioned limitation.

5 6

In formula X, R and R, which can be the same or different, preferably mean a lower alkyl radical with 1 to 4 carbon atoms, especially with 1 to 2 carbon atoms, as the radicals R 5 and R 6 together with exocyclic nitrogen atoms can preferably form a 5- to 7-membered heterocyclic ring.

The 2-dialkylamino-3,4-dihydropyridines of formula X used as starting materials are known from the literature, or can be prepared according to methods known in the literature,

(see H. Meyer, F. Bossert and H. Horstmann, Liebig's Ann. Chem. 1895 (1977)).

Examples include: 2-dimethylamino-3,4-dihydro-6-methyl-4-(3-chloro-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-dimethyl - amine o- 3, 4-dihydro - 6 -ethyl - 4 - (2 ' -chlorophenyl) -pyridine -3,5-dicarboxylic acid diethyl ester, 3-dimethylamino-3»4-dihydro-6 -propyl -4--(2 1 -methoxy phenyl )-pyridine-3,5-dicarboxylic acid diethenyl ester, 2-dimethylamino-3,4-dihydro-6-isopropyl-4-(21-methylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2 -

(1-Pyrrolidinyl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-(1-pyrr-olidinyl)-3,4 -dihydro-6-ethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester. 2-(1-piperidinyl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-(1-piperidinyl)-3,5-dihydro- 6-Methyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid die ty 1-ester.

As noble metal catalysts, platinum and platinum dioxide are preferably taken into account as solvents, preferably glacial acetic acid.

The reaction temperature can be varied over a large range, usually working between 10 and 100°C, preferably, however, at room temperature.

The turnover can be carried out at normal pressure or at elevated pressure. Particularly advantageous is the application of a weak overpressure.

When carrying out the method according to the invention, the 3-4-dihydropyridine derivative of formula X used as starting material is hydrogenated in the presence of a suitable noble metal catalyst in glacial acetic acid until the equimolar amount of hydrogen is absorbed.

The above-mentioned preparation method is only indicated for illustrative purposes, and the preparation of the compound of formula I is not limited to these methods,

but any modification of these methods is applicable in the same way for the preparation of the compounds according to the invention.

Depending on the choice of starting substances, the compounds according to the invention can exist in stereo in several forms,

which either relate as image and mirror image (enantiomers) or which do not relate as image and mirror image (dia-stereomers). Both antipodes as well as the race forms such as

the diastereomer mixtures are also the subject of the present invention. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomeric unitary components (cf. e.g. E.L. Eliel. Sterochemistry and Carbon Compounds, McGraw Hill, 1962).

For without the production examples listed below, • the following active substances according to the invention must be mentioned: 1,4-dihydro-2-ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 1 ,4-dihydro-2-ethyl - 6-methyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid di - n -butyl ester, 1,4-dihydro-2-ethyl-6-methyl-4 -(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisobutyl ester, 1,4-dihydro-2.ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid - dibenzyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid bis-(2-methoxyethyl)-ester, 1,4-dihydro- 2-Ethyl-6-methyl-4-(21-cyanophenyl)-pyridine-3,5-dicarboxylic acid in methyl ester, 1,4-dihydro-2-ethyl-6-methyl-4 - (2'•-cyano-phenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(21-cyanophenyl)-pyridine-3»5-dicarboxylic acid diisopropyl ester , 1, 4-dihydro-2-ethyl-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3»5-dicarboxylic acid dimethyl ester, 1, 4-dihydro-2-ethyl-6-methyl-4- -(2 1 -trifluoromethylphenyl)-pyridine-3»5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3»5-dicarboxylic acid - diethyl ester, 1 ,4-dihydro-2-ethyl-6-methyl-4-(3<1->nitrophenyl)-pyridine-3»5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4 - (31 -nitrophenyl)-pyridine-3,5-dicarboxylic acid - dicyclopentyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(3<1->nitrophenyl )-pyridine-3»5-dicarboxylic acid diallyl ester, 1,4 -dihydro-2-ethyl-6-methyl-4-(3'nitrophenyl)-pyridine-3»5-dicarboxylic acid - bis-(2-propoxyethyl)-ester, 1, 4-dihydro-2 -ethyl - 6- methyl -4-(31-nitrophenyl)-pyridine-3'' 5-dicarboxylic acid bis-(2-phenoxy-ethyl)-ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2' - me toxy-phenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(21-methoxyphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 1, 4-dihydro-2-ethyl-6-methyl-4-(2<1->chlorophenyl)-pyridine-3»5-dicarboxylic acid diethyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(pyridy1- 3)-pyridine-3,5-dicarboxylic acid dimethyl p ter, 1,4-dihydro-2-ethyl-6-methyl-4-(pyridyl-3)-pyridine -3,5-dicarboxylic acid diethyl ester, 1,4-dihydro-2 -ethyl-6-methyl-4-(pyr i dy 1-2)-pyridine-3»5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-propyl-6-methyl-4-(21-nitrophenyl)-pyridine-3»5-dicarboxylic acid dimethyl ester, 1,4-dihydro -2-isopropyl-6-methyl - 4-(2'-nitrophenyl)-pyridine-3»5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-benzyl-6-methyl-4-(2'-nitrophenyl) )-pyridine-3" 5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-peopyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3" 5-dicarboxylic acid diisopropyl ester, 1, 4-dihydro-2 -propyl-6-methyl-4-(3'-nitrophenyl)-pyri-din-3»5-dicarboxylic acid dicyclopentyl ester, 1,4-dihydro-2-propyl-6-methyl-4-(3'- nitrophenyl)-pyridine-3» 5-dicarboxylic acid bis-(2-propoxyethyl) residues, 1,4-dihydro-2-propyl-6-methyl-4-(pyridyl-3)-pyridine-3 » 5-dicarboxylic acid diethyl ester, 1,4-dihydro-2-propyl-6-methyl-4-(2-methylthiopyridyl-3)-pyridine-3»5-dicarboxylic acid diethyl ester.

As compounds according to the invention, mention should preferably be made of those with the general formula I in which R means a phenyl or naphthyl residue or a thienyl-, furyl-, pyrryl-, pyrazolyl-, imidazolyl-, oxazolyl-, isoxazolyl-, thiazolyl-, pyridyl- , pyridazinyl-, pyrimidyl-, pyrazinyl-, quinolyl-, isoquinolyl-, indolyl-, benzimidazolyl-, quinazolyl- or quinoxalyl residue, these aryl and heterocyclic residues possibly having one or two identical or different substituents from phenyl groups, alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, alkenyl or alkynyl with each time 2 to 6 carbon atoms, alkoxy with 1 to A carbon atoms, alkenoxy and alkynoxy with each time 2 to 6 carbon atoms, tri-, tetra- and pentamethylene , dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro. cyano. acido, hydroxy, amino, mono- and dialkylamino with each time 1 to A carbon atoms each per alkyl group, carboxy, caralkyloxy with each time 2 to A carbon atoms, carbonamido, sulfonamido or -SOm-alkyl, (m = 0, 1, 2) where alkyl contains 1 to A carbon atoms,

R -i means a linear, branched or cyclically saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms which may be interrupted with. 1 or 2 oxygen atoms in the chain,

and/or in which a hydrogen atom can be replaced by phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl residues being optionally substituted with 1 or 2 identical or different substituents from the group halogen, cyano, trifluoromethyl,

nitro, alkyl or dialkylamino with each time 1 to A carbon atoms in the alkyl residue,

R 2 and R A are always different from each other and each time means hydrogen or a straight or branched, saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms which in turn is optionally substituted with a saturated or unsaturated cyclic hydrocarbon residue with 3 to 7 carbon atoms,

R means hydrogen or a straight or branched alkyl residue with 1 to 8 carbon atoms, which is optionally interrupted by an oxygen atom in the chain, or means a phenyl, benzyl or

phenethylre st.

Of particular interest are compounds according to the invention with the general formula I in which R means a phenyl radical which optionally contains 1 or 2

the same or different substituents from the group nitro, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, azido, alkyl, alkyl oxy, alkyl mercapto , alkyl sulfonyl, alkylamino, the aforementioned alkyl-alkokoic acid residues containing 1 or 2 carbon atoms and optionally is substituted by fluorine or chlorine, or represents a thienyl, furyl, pyrryl or pyridyl residue,

R -i means a hydrocarbon residue with up to 6 carbon atoms which is optionally interrupted by an oxygen atom in the chain, and/or which is optionally substituted once by phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl group in turn being optionally substituted with fluorine, chlorine , bromine, cyano, trifluoromethyl, nitro, alkyl, alkoxy or dialkylamino with each time 1 to 2 carbon atoms in the alkyl and alkoxy group,

R 2 and R 4 are always different from each other and each time means hydrogen or an alkyl residue with 1 to 4 carbon atoms, the alkyl residue may be substituted with a saturated or unsaturated cyclic hydrogen carbon residue with 5 or 6 carbon atoms, and

R 3 means hydrogen or alkyl with 1 to 4 carbon atoms, the alkyl residue possibly being interrupted by an oxygen atom in the chain, or means a phenyl or benzyl residue.

The new compounds have a broad and versatile spectrum of pharmacological effects.

In detail, the following main effects could be demonstrated in animal experiments: 1. When administered parenterally, orally or perlingually, the compounds cause a clear and long-lasting dilation of the coronary vessels. This effect on the coronary vessels is enhanced by a simultaneous nitrite-like heart-relieving effect.

They influence, resp. alters cardiac metabolism

in the form of an energy saving.

2. The energisability of irritation formation - and the energization conduction system within the heart, is reduced so that in therapeutic doses a demonstrable

antif adhesive effects only.

3. The tone of the smooth muscles of the vessels decreases strongly under the action of the compounds. This carpasmolytic action takes place in the overall car-

system or manifests itself more or less in isolation

in the surrounding vascular areas (such as the central nervous system). The compound is therefore particularly suitable as a cerebral therapeutic. 4.. The compounds lower the blood pressure of normotonic and hypertonic animals and can thus be used as antihypertensive agents. 5. The compounds have strong muscular-spasmolytic effects, which are made clear on the smooth muscles of the stomach, the intestinal tract and the urogenital tract and the respiratory system.

The compound according to the invention is particularly suitable due to these properties for the prophylaxis and therapy of an acute and chronic ischemic heart disease in the broadest sense for the therapy of high blood pressure, as well as for the treatment of cerebral and peripheral blood circulation disorders.

The new active substances can be transferred in a known manner in the usual formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert non-toxic pharmaceutically suitable carriers or solvents. Hereby, the therapeutically active compound must each time be present in a concentration of from approx. 0.5 to 90% by weight of the overall mixture, i.e. in amounts sufficient to achieve the specified dosage margin.

The formulations are produced, for example, by

dredging of the active substances with solubilizers, and/or carriers possibly using emulsifiers and/or dispersants, as e.g. in

in the case of the use of water as a diluent, can

organic solvents are optionally used as auxiliary solvents.

As excipients, for example, the following must be stated:

Water, non-toxic organic solvents

agents such as paraffins (e.g. petroleum fractions), vegetable oil (e.g. groundnut/safflower oil), alcohols (e.g. ethyl alcohol, glycerol), glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as e.g. natural stone flour (e.g. kaolins, clay iodine, talc, chalk), synthetic stone flour (e.g. highly dispersed silica, silicates), sugar

(e.g. raw, milk and grape sugar), emulsifying agents (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulphonates and aryl sulphonates) - dispersing agents (e.g. e.g. equation, sulfite liquor, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenterally, especially perlingually or intravenously. In the case of oral use, tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with the various additives, such as starch, preferably potato starch, gelatin etc. without the aforementioned carriers. Furthermore, it can be used together with lubricants such as magnesium stearate, sodium lauryl sulfate and talc for tableting. In the case of aqueous suspensions and/or elixirs intended for oral use, the active substances can be mixed with various flavor enhancers or coloring substances in addition to the above-mentioned excipients.

For parenteral use, solutions of the active substances can be used using suitable liquid carrier materials.

Generally, it has been shown to be beneficial in intra-. venous application, to administer amounts of approx. 0.001 to 10 mg/kg, preferably approx. 0.05 to 5 mg/kg body weight/day to achieve effective results, because with oral application the dosage is approx. 0.05 to 20 mg/kg, preferably 0.5 to 5 mg/kg body weight/day.

Nevertheless, it may be necessary to deviate from the mentioned amounts, namely depending on the body weight of the experimental animal, resp. the type of of application mode, but also on

due to the type of animal and its individual relationship to drugs, resp. the type of its formulation and the time resp. the interval in which the administration takes place. So-

led, in some cases it may be sufficient to come out with less than the above-mentioned minimum amount, while in other cases the mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute these in several individual applications throughout the day. For application in human medicine, the same dosage range is prescribed. In the same way, the above-mentioned statements also apply here.

Manufacturing examples

1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester

Method variant A

A solution of 18.7 g (75 mmol) 2'-nitrobenzylideneacetoacetic acid methyl ester and 9.7 g (75 mmol) 6-amino-3-ethyl acrylic acid methyl ester in 100 ml methanol was heated to boiling under nitrogen for 14 hours. After cooling the reaction mixture, the solvent was distilled off in a vacuum, and the oily residue was expelled with a little ether, the crude product quickly solidifying. It was sucked off and recrystallized from methanol.

Melting point: 157°C, yield: 16.9g (62%).

Example 2

Analogous to example 1, 1, i-dihydro-2-propyl-6-methyl-U-(2-nitrophenyl)-pyridine-3,5 -dicarboxylic acid diethyl ester of sra.p.' 110 C (ethanol).

Yield: ^ 8% of the theoretical.

Example 3

Analogous to example 1, it was by turnover

of 2<1->nitrobenzylideneacetoacetic acid isopropyl ester with 8-amino-8-ethylacrylic acid propyl ester in isopropanol formed 1, i-dihydro-2-ethy 1' -6- methy 1-4-(2-nitrophenyl)-pyridine - 3- 5 - dicarboxylic acid diisopropyl ester of m.p. HO C (ethanol).

Yield: 28% of the theoretical./

Example 4

Analogously to example 1, 1,4-dihydro-2-benzyl-6-methyl-4-(2-nitrophenyl)-pyridine- 3 , 5-dicarboxylic acid dimethyl ester of m.p. 130°C (methanol).

Yield: 31% of the theoretical.

Example 5

Analogous to example 1, it was by turnover

of 3'-nitro benzyl idenace teddioxy-geme tylester with 8-amino-B-ethylacrylic acid methyl ester in me ta^fflfQ. formed 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3»5-dicarboxylic acid - dimethyl ester of m.p. 159 C (methanol).

Yield: 60% of the theoretical.

Example 6

Analogous to example 1, 1, 4-dihydro-2-propyl-6-methyl-4-(3- nitrophenyl)-pyridine- 3, 5-dicarboxylic acid - diethyl ester of m.p. 116UC (ethanol).

Yield: 70% of the theoretical.

Example 7

Analogous to example 1, 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine- 3. 5-dicarboxyl-acid diisopropyl ester of m.p.: 108°C (methanol).

Yield: 22% of the theoretical.

Example 8

Analogously to example 1, reaction of 31-nitro-benzylideneacetoacetic acid-(2-methoxyethyl)-ester with 3-amino-3-ethylacrylic acid-(2-methoxyethyl)-ester in ethanol formed 1,4-dihydro-2-ethyl- 6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid bis-(2-methoxyethyl)-ester of m.p. 86°C (methanol).

Yield: 55% of the theoretical.

Example 9

Analogously to example 1, 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)- pyridine-3,5-dicarboxylic acid dibenzyl ester of m.p. 102°C (ethanol).

Yield: 65% of the theoretical.

Example 10

Analogously to example 1, 1,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3 » 5-dicarboxylic acid diethyl ester of m.p. 153 o C (ethanol).<*>

Yield: 69% of the theoretical.

Example 11

Analogous to example 1, 1,4-dihydro-2-benzyl-6-methyl-4-(3-nitrophenyl)-pyridine was formed by reacting 3'-nitrobenzylideneacetate acetic acid methyl ester with 8-amino-8-benzylacrylic acid tylester in methanol -3,5-dicarboxylic acid dimethyl ester of m.p. 166 C (ethanol).

Yield: 63% of the theoretical.

Example 12

Analogously to example 1, 1,4-dihydro-2-ethyl-6.methyl-4-(2-chlorophenyl)-pyridine- 3.5-dicarboxylic acid dimethyl - ester of m.p. 14V°C (methanol).

Yield: 36% of the theoretical.

Example 13

Analogous to example 1, 1-4-dihydro-2-propyl-6-methyl-4-(2-chlorophenyl)-pyridine-3 » 5-dicarboxylic acid - diethyl ester of m.p. 100 C (ethanol).

Yield: 27% of the theoretical.

Example 14.

Analogous to example 1, 1,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(2-chlorophenyl)- pyridine -3.5-dicarboxylic acid diethyl ester of sm..p. 117UC (ethanol).

Yield: 29% of the theoretical.

Example 15

Analogously to example 1, 1,4-dihydro-2-ethyl-6-methyl-4-(2-cyanophenyl)- pyridine-3. 5-dicarboxylic acid diethyl ester of m.p. 123°C (ethanol).

Yield: 47% of the theoretical.

Example 16

Analogous to example 1, 1,4-dihydro-2-propyl-6-methyl-4-(2-trifluoromethylphenyl)-pyridine was formed by reaction of 2'-trifluoromethylbenzylideneacetate ethyl ester with 3-amino-g-propylacrylic acid ethyl ester in ethanol -3,5-dicarboxylic acid diethyl ester of m.p. 95°C (isopropanol).

Yield: 48% of the theoretical.

Example 1' 7

Analogously to example 1, 1,4-dihydro-2-ethyl-6-methyl-4-(2-trifluoromethylphenyl)-pyridine-3» 5-dicarboxylic acid diethyl ester of m.p. 81°C (isopropanol).

Yield: 62% of the theoretical.

Example 18

IN

Analogous to example 1, 1,4-dihydro-2-isopropyl'-6-methyl-4--(2 -nitrophenyl) -pyridine-3» 5 -dicarboxylic acid - diethyl ester of m.p. 117 C (ethanol).

Yield: 28% of the theoretical.

Example. 19

Analogously to example 1, 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)- pyridine-3.5-dicarboxylic acid - diethyl ester of m.p. 124 C (ethanol).

Yield: 35% of the theoretical.

Example 20

1, 4--dihydro-2-methyl-4--(2-trifluorotylphenyl)-pyridine-3»5-dicarboxylic acid diethyl ester

Method variant G

i, 5 g (10 mmol) 3'4-dihydro-6-methyl-2-(1-pyrro-1idinyl)-4-(2-trifluoromethylphenyl)-pyridine-3'5-dicarboxyl acid e - diethyl ester was hydrogenated in a shaker in 150 ml of glacial acetic acid over platinum (IV) oxide at 3.5 atu until uptake of the equimolar amount of hydrogen (approx. 2 hours). The catalyst was then filtered off, and the filtrate evaporated in vacuo. The residue was taken up in chloroform and chromatographed over a silica gel column (chloroform/acetic ester = 10:1), whereby after evaporation of the eluate an analytically pure product is obtained

product of sm.p. 95-96°C.

Yield: 28% of the .theoretical.

Claims (8)

1. Connection with the general formula .1 in which R means enaryl residue or a thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl, or chinaxalyl residue, the aryl residue and the heterocyclyls possibly containing 1 to 3 identical or different substituents from the group phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, monofluoroalkylene, polyfluoroalkylene, hydroxy, amino, alkylamino, nitro, cyano, azido, carboxy, caralkyloxy > carbonamido, sulfonamido or SO -alkyl (m= 0 to 2), R 1 means a straight, branched or cyclic saturated or unsaturated hydrocarbon residue which is optionally interrupted by 1 or 2 oxygen atoms in the chain and/or which is optionally substituted with a phenyl, phenoxy, phenylthio or phenylsulfonyl group, which in turn may be substituted with halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro. R 2 and R L are always different and each means hydrogen or a straight or branched, saturated or unsaturated hydrocarbon residue, which in turn is optionally substituted with a saturated or unsaturated cyclic hydrocarbon residue, and R <3> means hydrogen or a linear or branched alkyl residue which is optionally. interrupted by *1 or 2 oxygen atoms in the alkyl chain, or means an aryl or aralkyl residue. 2. Compound of the general formula I according to claim 1, wherein R means a phenyl or naphthyl residue or a thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl-, pyridazinyl-, pyriraidyl-, pyrazinyl-, quinolyl-, isoquinolyl-, indolyl-, benzimidazolylquinazolyl- or quinO'xalyl residues, where aryl and heterocyclic residues optionally have 1 or 2 identical or different substituents from the group phenyl, alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, alkenyl or alkynyl with each time 2 to 6 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenoxy and alkynoxy with each time 2 to 6 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano, acido, hydroxy, amino, mono- and dialkylamino with each time 1 to 4 carbon atoms per alkyl group, carboxy, caralkyloxy with each time 2 to 4 carbon atoms, carbonamido, sulfonamido or SO^ -alkyl, (m = 0, 1, 2) where alkyl contains 1 to 4 carbon atoms, R 1 means a linear, branched or cyclic saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms which is optionally interrupted by 1 or 2 oxygen atoms in the chain, and/or in which the hydrogen atom may be replaced by phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl residue being optionally substituted with 1 or 2 identical or different substituents from the group halogen, cyano, trifluoromethyl, nitro, alkyl or dialkylamino with each time 1 to 4 carbon atoms in the alkyl residue, R 2 and R 4 are always different and each means hydrogen or a straight or branched, saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms which in turn is optionally substituted with a saturated or unsaturated cyclic hydrocarbon residue with 3 to 7 carbon atoms, and R^ means hydrogen or a straight or branched alkyl residue with 1 to 8 carbon atoms which is optionally interrupted by an oxygen atom in the chain, or means a phenyl, benzyl or phenethyl residue. 3. Compound with the general formula I according to claim 1, in which R means a phenyl radical which is optionally substituted with 1 or 2, the same or different substituents from the group nitro, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, azido, alkyl, alkoxy, alkyl more capto , alkyl sulfonyl, alkylamino, in that the aforementioned alkyl and alkoxy acid residues contain 1 to 2 carbon atoms, and are optionally substituted with fluorine or chlorine, or means a thienyl, furyl, pyrryl or pyridyl residue, R means a hydrocarbon residue with up to 6 carbon atoms which is optionally interrupted in the chain by an oxygen atom and/or which is optionally substituted once with phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl groups in turn being optionally substituted with fluorine, chlorine, bromine, cyano , trifluoromethyl, nitro, alkyl, alkoxy or dialkylamino with each time 1 to 2 carbon atoms in the alkyl and alkoxy group, R^ and R^ are always different from each other, and each means a hydrogen or an alkyl residue with 1 to 4 carbon atoms, the alkyl residue may be substituted by one. saturated or unsaturated cyclic hydrocarbon residue with 5 or 6 carbon atoms, and R^ means hydrogen or alkyl with 1 to 4 carbon atoms, the alkyl residue possibly being interrupted by an oxygen atom in the chain, or means a phenyl or benzyl residue. 4. Process for the preparation of a compound of the general formula I according to claim 1, characterized in that A) Ylidene-3-ketoester of the general formula II in which R, R 1 and R 2 have the above meaning, optionally reacted in the presence of inert organic solvents with an aminocarboxylic acid ester of the general formula III in which 13/. R , R , and R 2 have the above-mentioned meaning, or B) Y1 iden-3-ketoesters of the general formula II in which R, R 1 ' and R 2 have the above meaning, reacted, possibly in the presence of inert solvents, with amines of the general formula IV and 3-ketocarboxylic acid esters of the general formula V in which R 3 , R 4 and R 1 have the above meaning, or C) Ylidene-3-keto esters of the general formula VI in which R, R 1 and R 4 have the above meaning, optionally reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula VII in which 2 3 1' R , R and R have the above meaning, or D) Yl iden - 3-ketoesters of formula VI in which 14 R, R and R have the above meaning, reacted, optionally in the presence of inert organic solvents, with amines of the general formula IV and 3-ketocarboxylic acid esters of the general formula VIII in which R o , R p and R 1 have the above meaning, or E) Aldehydes with the general formula IX in which R has the above meaning, optionally reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula III and 3-ketocarboxylic acid esters of the general formula VIII in which R L , R 3 , R 1 and R 2 have the above meaning, or F) Aldehydes with the general formula IX in which R has the above meaning, optionally reacted in the presence of inert organic solvents with enaminocarboxylic acid esters of the general formula VII and 3-ketocarboxylic acid esters of the general formula V in which R 2 , RJ3 , R 1 and R L have the above meaning. 5. Compound with the general formula I according to claim 1 for use in combating circulatory diseases. 6. Medicine containing at least one compound of the general formula I according to claim 1. 7. Process for the production of medicinal products characterized in that at least one compound of the general formula I according to claim 1 is optionally transferred using usual excipients and carriers into a suitable application form. 8. Uses of compounds with the general formula I according to claim 1 in combating diseases.