CA1175438A - 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position, their production, and their medicinal use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to 1,4-dihydro-pyridines having different substituents in the 2- and 6- positions and described herein as being of the formula:

Description

~ 175~3~

The present invention relates to certain new 1,4-dihydro-pyridine compounds having different substituents in the 2-position and 6-position, to several processes for their production and to their use in agents which influence the circulation.
It has already been disclosed that 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylic acid diethyl esters are obtained when benzylidene-acetoacetic acid ethyl ester is reacted with ~-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (see E. Knoevenagel, Ber. dtsch. chem.
Ges. 31, 743 (1898)).
Further, it is known that certain 1,4-dihydropyridines possess interesting pharmacological properties (see F. Bossert and W. Vater, Naturwis-senschaften 58, 578 (1971)).
Further, dihydropyridines which carry different ester groups in the 3-position and 5-position are known (see DE-OS (German Published Specification)

2,117,571). 1,4-Dihydropyridines with identical ester groups in the 3-position and 5-position and different substituents in the 2-position and 6-position have hitherto not been disclosed.
According to the present invention we provide compounds which are 1,4-dihydro-pyridines of the general formula R O2C ~ CO2R

~ ~ 4 in which R represents a phenyl radical optionally containing 1 or 2 identical or different substituents selected from methoxy, halogen, trifluoromethyl, nitro and cyano; R represents a straight-chain or branched alkyl radical with up to 8 carbon atoms which is optionally interrupted by 1 or 2 oxygen atoms in the C ' - 1 -~ :~75~38 chain, and/or which is optionally substituted by a phenyl radicali R and R
are also different and each represents a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, benzyl or cyclohexylmethyl; with the exception of the com-pound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
The compound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate is disclosed as an intermediate in United States Patent No. 4,021,434. The United S-tates patent contains no suggestion of any medicinal utility for the compound. The compound displays circulation influenc-ing properties simi]ar to the compounds of formula I and pharmaceutical composi-tions containing diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-

3,5 dicarboxylate as active ingredient are the subject of our Patent Application D Serial No.~y~ o60, which is divided out of this application.
According to the present invention we further provide a process for the production of compounds of the present invention, in which (A) an ylidene-~-keto-ester of the general formula coR2 R-CH=C II
\ COOR
in which R, R and R have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R4-C=CH-CooR
¦ III
in which R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (~) an ylidene-~-keto-ester of the general formula II, as defined above, is reacted with ammonia and a 3-ketocarboxylic acid ester of the general formula V

, ~ - 2 -~ ~7543~

in which R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (C) an ylidene-~-keto-ester of the general formula CoR4 R-CH=C/ VI
COOR
in which R, R and R have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R2-C=CH-COOR
¦ VII

in which R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (D) an ylidene-~-keto-ester of the general formula VI, as defined above, is reacted with ammonia and a 3-ketocarboxylic acid ester of the general formula VIII 2 in which R and R have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (E) an aldehyde of the general formula R-C IX
~0 in which R has the abovementioned meaning, is reacted with an enaminocarboxylic acid ester of the general formula III, as defined above, and a ~-ketocarboxylic acid ester of the general formula VIII, as defined above, optionally in the presence of an inert organic solvent, or ~' ~ - 3 -~ ~543~

(F) an aldehyde of the general formula IX, as defined above, is reacted with an enaminocarboxylic acid ester of the general formula VII, as defined above, and a ~-ketocarboxylic acid ester of the general formula V, as defined above, optionally in the presence of an inert organic solvent, or (G) when a compound of formula I is required, in which the radicals R, R and R do not c,~rry any functional groups which can undergo modification under hydrogenating conditions, and R is different from hydrogen, and R repre-sents a hydrogen atom, a 2-dialkylamino-3,4-dihydro-pyridine of the general formula R

R 02C ~ C02R
R N / ~ X

\R6_~ J

~ I - 4 -~ 17$~3~3 in which R, Rl and p~2 have the abovementioned meanings and do not carry any functional groups which urdergo modification under hydrogenating conditions, and ~5 and R6 represent Cl to C6 alkyl groups or together complete a heterocyclic ring with the exocyclic nitrogen atom, is : catalytically hydrogenated in the presence of a noble metal catalyst.
The new compounds of the present invention possess valuable pharmacological properties. By virtue of their circulation-influencing action they can be used as anti-hypertensive agents, as vasodilators, as cerebral therap-eutic agents and as coronary therapeutic agents, and they are thus to be regarded as an enrichment of pharmacy.
The process variants (A~ (B), (C), (D~, (E), (F) and (G) for the production of the compounds accordin~ to the invention are illustrated by the following equations, in which in each case, the end-product offormula (I) is 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester and 1,4-dihydro-2-methyl-

4-(3'-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester:

A) ~ N0z ~ N02 H5 C2 2 C ~ H H ~ C02C2Hs Hs C2 2 C ~ C2 C2 Hs H3C ~ 0 H2N C2H5 -H20 H3C H C2Hs ~, NO2 ~ NO2 ~j/ ,CO2 C2 H5 H5 C2 02 C ~ CO2 C2 H5 H5C202C ~ ~ H H2C D ~ ~
H3 C ~ NH3 C2Hs -2H20 H3C NH C2H5 Le A 20 322 ~ ~5~38 C) ~ NO2 ~ NO2 H5C202C~H HJ~Co2C2H5 H,C202C~ co2C2H5 H3 C NHz C2 H5 -H2 o H3 C N C2 H5 D ) ~ N2 [~ NO2 Hs C2 2 C~TH HJ~ C2 C2 H5 H C2 2 C ~ CO2 C2 H5 ,C~, C8 H5 -2 H2 0 H3 C H C2 H5 E ) (~J N2 NO2 H5 Cz Oz C~ H~6 COz C2 Hs ~ C

H C ' C~ H2 N C2 H5 -2 H2 0 H3 C NH C2 Hs ~, NO2 F ) l~, ~NO2 H5 C2 2 C H H H2 C ~ Hs C2 2 C ~C2 C2 Hs H~C ~ NH2 C2H5 -2 H20 H3C H c~H5 Le A 20 322 ~75~3a CF CF

5 2 2 ~ H2/PtO2 ~ 2 2 5 Specific details of the various process variants are as follows:
Process variant A
The ylidene-~-keto-esters of the formula II used as the starting material are known from the literature or can be prepared according to methods known from the literature (see, for example, G. Jones "The Knoevenagel Condensa-tion" in Org. Reactions, Vol. XV, 204 et seq. (1967)).
As examples of esters of formula II there may be mentioned: benzyli-dene-formylacetic acid methyl ester, benzylideneacetoacetic acid methyl ester, 2'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid n-butyl ester, 2'-methoxybenzylideneacetoacetic acid isobutyl ester, 3'-nitrobenzylideneacetoacetic acid isopropyl ester, 3'-nitrobenzylideneacetoacetic acid 2-methoxyethyl ester, 2'-nitrobenzylideneacetoacetic acid isobutyl ester, 2'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-propoxy-ethyl ester, 3'-nitrobenzylideneacetoacetic acid benzyl ester, 3'-nitrobenzylideneacetoacetic acid 2-phenyl-ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-phenoxy-ethyl ester, 2'-cyanobenzylideneacetoacetic acid ethyl ester, 2'-cyanobenzylidene-propionylacetic acid ethyl ester, 2'-nitrobenzylidenepropionylacetic acid methyl ester, 3'-nitrobenzylidenepropionylacetic acid ethyl ester, 3'-nitrobenzylidene-propionylacetic acid 2-methoxyethyl ester, 3'-nitrobenzylidenepropionylacetic acid isopropyl ester, 2'-nitrobenzylidenepropionylacetic acid isobutyl ester, ( ~ 7 _ ~ 1 ~543~

2'-chlorobenzylidenepropionyl acetic acid methyl ester, 2'-cyanobenzylidene-isobutanoylacetic acid ethyl ester, 3'-nitrobenzylideneisobutanoylacetic acid ethyl ester, 2'-nitrobenzylideneisobutanoylacetic acid methyl ester, 2'-nitro-benzylideneisobutanoylacetic acid isobutyl ester, 3'-nitrobenzylideneisobutanoyl-acetic acid 2-methoxy-ethyl ester, 3'-nitrobenzylidene-y-phenylace-toacetic acidethyl ester, 2'-nitrobenzylidene-y-phenylacetoacetic acid methyl ester, 2'-nitrobenzylidene-y-phenylacetoacetic acid isobutyl ester, 3'-nitrobenzylidene-y-phenylacetoacetic acid isopropyl ester, 3'-nitrobenzylidene-y-phenylaceto-acetic acid 2-methoxy-ethyl ester and 2'-trifluoromethylbenzylidene-y-phenyl-acetoacetic acid ethyl ester.
Preferred starting compounds of formula III are those in which R has the same meaning as in the preferred compounds of formula II and R represents a hydrogen atom or represents a straight-chain or branched alkyl radical with 1 to 8, especially 1 to 4 carbon atoms, in which a hydrogen atom can be replaced by a saturated or unsaturated cyclic hydrocarbon radical with up to 6 carbon atoms, especially a phenyl radical.
The enaminocarboxylic acid esters of the formula III used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J.Amer. chem. Soc. 67, 1017 (1945)).
As examples of compounds of formula III there may be mentioned:
~-amino-crotonic acid methyl ester, ~-amino-crotonic acid ethyl ester, ~-amino-3-ethyl-acrylic acid methyl ester, ~-amino-~-ethyl-acrylic acid ethyl ester, 3-amino-3-ethyl-acrylic acid isopropyl ester, 3-amino-3-ethyl-acrylic acid neopentyl ester "3-amino-~-ethyl-acrylic acid benzyl ester, ~-amino-3-ethyl-acrylic acid 2-phenylethyl ester, 3-amino-~-ethyl-acrylic acid 2-phenoxyethyl ester, 3-amino-3-propyl-acrylic acid methyl ester, 3-amino-3-isopropyl-acrylic acid methyl ester, 3-amino-3-n-butyl-acrylic acid methyl ester, ~-amino-3-~ ~754~

isobutyl-acrylic acid methyl ester, ~-amino-~-cyclohexylmethyl-acrylic acid methyl ester, ~-amino-~-benzyl-acrylic acid methyl ester and 3-amino-3-(2-phenylethyl)-acrylic acid ethyl ester.
Suitable diluents are any of the inert organic solvents. These include as preferences alcohols (such as ethanol, methanol and isopropanol), ethers (such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether and glycol dimethyl ether), glacial acetic acid, dimethylformamide, dimethyl-sulphoxide, acetonitrile, pyridine and hexamethylphosphorotriamide.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, preferably between 20 and 100 C, especially at the boiling point of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, one mole of an ylidene-g-keto-ester of the formula II is reacted with one mole of an enamino-carboxylic acid ester of the formula II in a suitable solvent. The substances according to the invention are preferably isolated and purified by distilling off the solven-t in vacuo and recrystallizing the residue, which may only be obtained in a crystalline form after cooling with ice, from a suitable solvent.
Process variant B
Preferred ylidene-~-keto-ester starting compounds of the formula II
are those mentioned as preferred for reaction variant A.
Preferred starting compounds of formula V are those in which the radicals R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formula III.
Examples of the ylidene-~-keto-esters of the formula II, used as starting materials, have already been listed under process variant A.
The ~-ketocarboxylic acid esters of the formula V used as starting .~ _ g_ 117543~3 materials are known from the literature and can be prepared in accordance with methods known from the literature (see example, D. Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("Reaction of Diketene with Alcohols, Phenols and Mercaptans"), in Houben-Weyl, Methoden der Organischen chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y. Oikawa, K. Sugano and O. Yonemitsu, J. org. Chem. 43, 2087 (1978)).
As examples of esters of formula V there may be mentioned: aceto-acetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid n-butyl ester, acetoacetic acid isopropyl ester, acetoacetic acid benzyl ester, aceto-acetic acid 2-phenyl-ethyl ester, acetoacetic acid 2-phenoxyethyl ester, propionylacetic acid methyl ester, propionylacetic acid ethyl ester, propionyl-acetic acid isopropyl ester, propionylacetic acid benzyl ester, propionylacetic acid 2-phenyl-ethyl ester, propionylacetic acid 2-phenoxyethyl ester, isobutano-ylacetic acid methyl ester, y-cyclohexylacetoacetic acid ethyl ester and ~-phenylacetoacetic acid methyl ester.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, but preferably at the boiling point of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae II and V, are each employed in molar amounts. The amine used is advantageously added in an excess of 1 to 2 moles. The compounds according to the invention can easily be purified by recrystallization from a suitable solvent.

' ' -- 10 --~ 1~543~

Process variant C
Preferred starting materials of formuiae VI and VII, are those in which the radicals R, R , R and R have the meanings mentioned for the preferred starting materials of formulae II and III under process variant A.
The ylidene-~-keto-esters of the formula VI, used as starting materials, are known from the literature or can be prepared in accordance with methods known from the literature (see, for example, G. Jones (The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204 et seq. (1967)).
As examples of esters of formula VI there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula II.
The enaminocarboxylic acid esters of the formula VII used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J. Amer. Chem. Soc. 67, 1017 (1945)).
As examples of esters of formula VII there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula III.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, preferably between 20 and 100 C, especially at the boiling point of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out th`e process according to the invention, one mole of the ylidene-~-keto-ester of the formula VI is reacted with one mole of enamino-carboxylic acid ester of the formula VII in a suitable solvent.

~,,, - 11 -1 1~543~

Process variant D
Preferred ylidene-~-keto-ester starting compounds of the formula VI
are those mentioned as preferred for reaction variant C.
Preferred starting compounds of formula VIII, are those in which the radicals R and R have the meaning mentioned under process variant A in respect of preferred compounds of formula II.
Examples of the ylidene-~-keto-esters of the formula VI used as starting compounds have already been listed under process variant C.
The ~-ketocarboxylic acid esters of the formula VIII used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see for example, D. Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("Reaction of Diketene with Alcohols, Phenols and Mercaptans"), in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y.
Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).
As examples of esters of formula VIII there may be mentioned those esters specifically mentioned under process variant B as examples of esters of formula V.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, but preferably at the boiling point of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae VI and VIII, are each employed in molar amounts. The amine used is advantageously added in an excess of 1 to 1 1~5438 2 moles.
Process variant E
Preferred ester starting compounds of the formula III are those mentioned as preferred for reaction variant A. Preferred ester starting com-pounds of the formula VIII are those mentioned as preferred for reaction variant D.
Preferred starting compounds of formula IX are those in which the radicals R, R , R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formulae II and III.
The aldehydes of the formula IX, used as starting materials, are known from the literature or can be prepared in accordance with methods known from the literature (see, for example, E. Mosettig, Org. Reactions VIII, 218 et seq.
(1954)).
As examples of aldehydes of formula IX there may be mentioned:
benzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-, 3- or 4-chloro-, bromo- or fluoro-benzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde, 2-, 3- or 4-nitro-benzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2,3- or 2,6-dichlorobenzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, 4-chloro-2-nitrobenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2-nitro-4-cyanobenzaldehyde, 2-chloro-4-cyanobenzaldehyde and 3-chloro-4-trifluoromethylbenzaldehyde.
Examples of the enaminocarboxylic acid esters of the formula III, used as starting compounds have already been listed under process variant A, and examples of the 3-ketocarboxylic acid esters of the formula VIII, used as starting compounds have already been listed under process variant D.
Suitable dlluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, but preferably ~ ~ - 13 -~ .1 ._ .

~ ~5~3~

at the boiling point of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae IX, III and VIII, are each employed in molar amounts.
Process variant F
Preferred aldehyde starting compounds of the formula IX are those mentioned as preferred for reaction variant E.
Preferred ester starting compounds of the formula V are those men-tioned as preferred for reaction variant B, preferred ester starting compounds of formula VII are those mentioned as preferred for reaction variant C.
Examples of the aldehydes of the formula IX used as starting compounds are listed under prorcess variant E, examples of the enaminocarboxylic acid esters of the formula VII are listed under process variant C and examples of the ~-ketocarboxylic acid esters of the formula V are listed under process variant B.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out atbetween 20 and 150 C, but preferably at the boiling point of the particular solvent.
The reaction can be carried out under noraml pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulae IX, VII and V, are each employed in molar amounts.
Process variant G
Preferred starting compounds of formula X are those in which the ~ 175~3~

radicals R, R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formula II with the restriction that the radicals R, R and R do not contain any functional groups which can undergo change under hydrogenating conditions, and provided R is different from hydro-gen and R represents a hydrogen atom, and in which, R and R , which can be identical or different, represent an alkyl radical with 1 to 4 carbon atoms, especially with 1 or 2 carbon atoms, or the radicals R and R together with the exocyclic nitrogen atom form a 5-membered to 7-membered heterocyclic ring.
The 2-dialkylamino-3,4-dihydropyridines of the formula X, used as starting materials, are known from the literature or can be prepared according to methods known from the literature (see H. Meyer, F. Bossert and H. Horstmann, Liebigs Ann. Chem. 1895 (1977)).
As examples of starting compounds of formula X there may be mentioned:
2-dimethyl-amino-3,4-dihydro-6-methyl-4-(3-chlorophenyl)-pyridine-3,5-dicarboxyl-ic acid diethyl ester, 2-dimethylamino-3,4-dihydro-6-ethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-dimethylamino-3,4-dihydro-6-propyl-4-(2'-methoxyphenyl)-pyridine-3,5-disarboxylic acid diethyl ester, 2-(pyrrolidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-(pyrrolidin-1-yl)-3,4-dihydro-6-ethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 2-(piperidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester and 2-(piperidin-1-yl)-3,4-dihydro-6-methyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester.
Preferred noble metal catalysts are platinum and platinum dioxide and a preferred solvent is glacial acetic acid.
The reaction temperature can be varied within a substantial range.
In general, the reaction is carried out at between 10 and 100 C, but preferably at room temperature.

~ - 15 -.~

~ 17 543~

The reaction can be carried out under normal pressure but also under elevated pressure. The use of slightly superatmospheric pressure is particular-ly advantageous.
In carrying out the process according to the invention, the 3,4-dihydropyridine derivative of the formula X, used as starting substance, is hydrogenated in the presence of a suitable noble metal catalyst, in glacial acetic acid until the equimolar amount of hydrogen has been taken up.
Compounds according to the invention which are of particular interest are those of the general formula I, in which R represents a phenyl radical which optionally contains 1 or 2 identical or different substituents selected from nitro, fluorine, chlorine, bromine, cyano, trifluoromethyl and methoxy, R
represents an alkyl radical with up to 6 carbon atoms, which is optionally interrupted by an oxygen atom in the chain and/or which is optionally monosub-stituted by phenyl.
Depending on the choice of the starting substances, the compounds according to the invention may exist in stereoisomeric forms, which either are related to one another like an image and its mirror image (enantiomers) or are not related to one another like an image and its mirror image (diastereomers).
Both the antipodes and the racemic forms, and also thediastereomer mixtures, form a subject of the present invention. The racemic forms, like the diastereo-mers, can be separated in a known manner into the individual stereoisomer components (see for example, E.L. Eliel, Stereo-chemistry of Carbon Compounds, McGraw Hill, 1962).
In addition to those mentioned in the preparative examples, the follow-ing active compounds according to the invention may 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-1 ~75~3~

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-(2'-cyanophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2'-cyanophenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2'-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'-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'-nitrophenyl)-pyridine-3,5-dicarboxylic acid dipropyl ester, l,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-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid bis-(2-phenoxyethyl) ester, 1,4-dihydro-2-ethyl-6-methy]-4-(2'-methoxyphenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2'-methoxyphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 1,4-dihydro-2-ethyl-6-methyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester, 1,4-dihydro-2-propyl-6-methyl-4-(2'-nitro-phenyl)-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-propyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester, 1,4-dihydro-2-propyl-6-methyl-4-(3'-nitro-phenyl)-pyridine-3,5-dicarboxylic acid dicyclopentyl ester and 1,4-dihydro-2-propyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid bis-(2-propoxyethyl) ester.
The new compounds have a broad and diverse pharmacological action ., . ;, ~ ~7~38 spectrum.
In detail, the following main actions can be demonstrated in animal experiments:
(1) On parenteral, oral and perlingual administration the compounds produce a distinct and long-lasting dilation of the coronary vessels. This action on the coronary vessels is intensified by a simultaneous nitrite-like effect of reducing the load on the heart. They influence or modify the heart metabolism in the sense of an energy saving.
(2) The excitability of the stimulus formation and excitation con-duction system within the heart is lowered, so that an anti-fibrillation action demonstrable at therapeutic doses results.
(3) The tone of the smooth muscle of the vessels is greatly reduced under the action of the compounds. This vascular-spasmolytic action can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular regions (such as, for example, the central nervous system). The compounds are therefore particularly suitable as cerebral thera-peutic agents.
(4) The compounds lower the blood pressure of normotonic and hyper-tonic animals and can thus be used as anti-hypertensive agents.
(5) The compounds have strongly muscular-spasmolytic actions which manifest themselves on the smooth muscle of the stomach, the intestinal tract, the urogenital tract and the respiratory system.
On the basis of these properties, the compounds according to the inven-tion are particularly suitable for the prophylaxis and therapy of acute and chronic ischaemic heart disease in the broadest sense, for the therapy of hypertension and for the treatment of cerebral and peripheral circulation disorders.

, - 18 -~ 75~3 i9 As stated above~ the invention also relates tc the use in human and veterinary medicine of the compounds of the inventior..
The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent~ or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides a pharmaceutical composition ~ontaining as active ingredient a compound of the lnvention in the form of a sterile and/or physiologically isotcnic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical composition according to the invention may, fGr example, take the form of ointments, gels, pastes, creams, sprays (including .. .. . .... ....
Le A 2~ 322 ... ....

~ ~75~

,~
aerosols), lotions, suspensions, solutions and emulsions of the active in~redient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, ar.d silicic acid; (b) binding agents, e,g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone;
(c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) ager.ts for retarding dissolution e.g, paraffin; (f) resorption accelerators, e.g.
quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorptive carriers, e.g. kaolin and bentonite;
(i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
. The tablets, dragees~ capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencap-sulated form together with one or several of theabove-~entioned diluents.
The diluents to be used in pharmaceutical compositlons adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g. C14-alcohol with C16~fatty acid)) or mixtures of these diluents.

. .
Le A 20 322 s43a The pharmaceutical compositions whi'ch are ointments, pastes, creams ar.d gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch3 tragacanth, cellulose derivatives 9 polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances~ Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydro-carbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers;
specific examples of such diluents are water, ethyl alcohol, isopropyl alco~ol~ ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyler.e glycol, 1,3-butylene glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydro-furfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usu21 diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium meta-hydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
.... .... ....
' Le A~ 2'0' 322 " ~ ~75~3~

All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compos.itions according to . t.he invention generally contain from 0.5 to 90%
of the active ingredient by weight of the total composition.
In addition to a co~ ~nd of the invention, the pharmaceutical compositions and medicaments according to.the invention can also contain other pharmaceutically active compounds. ~hey may also contain a plurality of ccmpounds of the invention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmace.uti.cal compositions of the present invention. Such medicaments may include so:lvents of molecular weight .less. than 200 as sole diluent.
~he discrete coherent portions constituting . the medicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, .25 any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient.
Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
~ he preferred daily dose for administratior Gf the medicaments of the invention is 2.5mg to 250mg of active ingredient in the case of intravenous administration .35 and 25mg to 250mg of active ingredient in the case of oral administration.

Le~ A 20 322 ~ 175438 o~3 The production of the abové-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition ~e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering tothe animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneallyS sub-cutaneously and intravenously), rectally or locally, preferably orally or parenterally, especially perlingually or intravenously. Preferred pharmaceutical compositions and medicaments are therefore those adapted for administration such as oral or parenteral administration.
Administration in the method of the invention is preferably oral or parenteral administration.
In general it has proved advantageous to administer amounts of from O.OOlmg to lOmg/kg, preferably 0.05mg to 5mg/kg, of body weight per day in the case of intravenous administration, and 0.05mg to 20mg/kg, preferably 0.5mg to 5mg/kg of body weight per day, in the case of oral administration, to achieve effective results.
Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of .
Le A 2~ 322 ~ ~ ~7S438 ~J, the disease or interval at which it is to be administered.
~hus lt may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
The following Examples illustrate processes for the production of compounds of the present invention.
Example 1.
1,4-Dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester.

~ N02 H3C02C ~ C02CH3 ~rocess variant A
-A solution of 18.7 g (75 mmoles) of 2'-nitro-benzylideneacetoacetic acid methyl ester and 9;7 g (75 mmoles) of ~-amino-~-ethyl-acrylic acid methyl ester in 100 ml of methanol was heated to the boil, under nitrogen, for 14 hours. After the reaction mixture had cooled, the solvent was distilled off in vacuo and ~e A 2~ 322 .

~1~75438 g ,~
the oily re,sidue was triturated with a small amount of ether, whereupon the crude product soon solidified, It was filtered off and recrystallised from methanol, Melting point: 157C; yield: 16,9 g (62%), Exa~le 2 ~ N0~
H5C202C ~ co2C2H5 H3~ N C~ H-? ( ~) Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 110C (ethanol).
Yield: 48% of theory.
Example 3 ~ 2 (CH3)2~C0zC ~ C02-CH(C~)2 H,C ~2~5 Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid isopropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 140C (ethanol).
Yield: 28% of theory.

Le A 20 322 l 175438 ~(~
. ~
~ ' Example 4 ~ .'JO~
H3COzC ~ COzCH3 ~ 1~
H3C ~ CH2 ~

Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid methyl ester with ~-amino-~-benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180C (methanol).
Yield: 31% of theory.
Example 5 ~,, NO2 ~ .
H~.C02C ~ ~ C02CH3 H3C N C2Hs rl , .
Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid methyl ester with ~-amino-~-ethyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl ester of melting point 159C
(methanol).
Yield: 60% of theory.
Example 6 N02 H5C202C co2C2H5 ~ ~
H~C ~ C,H~(n?

Le A 20 322 .

~ ~7543~

Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetlc acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-methyl-4-~3-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 116C (ethanol), Yield: 70% of -theory, Example 7 ,~ NO2 ~ .
(CH3)2HCO2C ~ ~ CO2CH(CH3)z H~C N ~2Hs Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid isopropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropan-ol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of 5 melting point 108C (methanol), Yield: 22% of theory, Example 8 ,~ N2 HjCO-H2C-H2CO2C ~ C~z-CH2-CH2-OCH3 Il il X3C ~`N ~ C2~5 H
Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid 2-methoxyethyl ester with ~-amino-~-ethyl-acrylic acid 2-methoxyethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid bis-(2-methoxy-ethyl) ester of melting point 86C (methanol), Yield: 55% of theory, Le A 20 322 ~ ~ ~S~3~
_ ~ _ --a.
Example 9 ~ IJ
<~2 C2 C ~ C2 -CH2 ~>

H3 C N ~ ~5 Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid benzyl ester with ~-amino-3-ethyl-acrylic acid benzyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxy-lic acid dibenzyl ester of melting point 102C (ethanol).
Yield: 65% of theory.
Example_10 ~,, N2 H~C202C ~, CC2C2~
Il 11 H~C ~ CH2 ~

Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-cyclohexylmethyl-acrylic acid ethyl ester in ethanol ga~e 1,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 153C (ethanol).
Yield: 69% of theory.
Example 11 ,~,, NO2 .. ~
H3 C02 C ~J~,co2 CH.

H~C ~ y 1 CH2 ~

Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid methyl ester with ~-amino-~-Le A 20 322 -~ 17~438 2~

benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-methyl-4~(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 166C
(ethanol).
Yield: 63% of theory.
Example 12 ~

~ Cl H3C02C ~ C02CH3 ~3 C N C2~g Analogously to Example 1, reaction of 2'-chloro-benzylideneacetoacetic acid methyl ester with ~-amino-~-10 ethyl-acrylic acid methyl ester in methanol gave 1,4-dihy-dro-2-ethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-di-carboxylic acid dimethyl ester of melting point 147C
(methanol).
Yield: 36% of theory.
15 Example 13 ~
~1 H5 C2 2 C jJ~, C2 C2 U~

H3C N C3H~n) Analogously to Example 1, reaction of 2'-chloro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave l,4-dihydro-20 2-propyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-dicar-boxylic acid diethyl ester of melting point 100C (ethanol).
Yield: 27% of theory.
Example 14 ~ ~ Cl HgC202C ~ ~ 52C2r-s H3C l~ CH
Le A 20 322 S~38 ~o Analogously to Example 1, reaction of 2'-chloro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-cyclohexylmethyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 117C (ethanol).
Yield: 29% of theory.
Example 15 ~~~ '' ' ~ CN
H5C202C ~CO2C2H5 H3C ~ C2Hs Analogously to Example 1, reaction of 2'-cyano-benzylideneacetoacetic acid ethyl ester with ~-amino-~-ethyl-acrylic acid ethyl ester in ethanol gave 1,4-di-hydro-2-ethyl-6-methyl-4-(2-cyanophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 123C
(ethanol).
Yield: 47% of theory.
Example 16 ~ CF3 H5C2 2C ~ CO~C2~5 I
H3C ~NH C~H7(n) Analogously to Example 1, reaction of 2~-tri-fluoromethylbenzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-methyl-4-(2-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 95C (isopropanol).
Yield: 48% of theory.

Le A 20 322 - ` ~17543~

_ ~ _ Example 17 [~C~3 H5C202C ~ ~ C0cC2H~
H3C ri C2 ~5 Analogously to Example 1, reaction of 2'-tri-fluoromethylbenzylideneacetoacetic acid ethyl ester with 3-amino-~-ethyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(2-tri~luoromethylphenyl)-pyridine-~,5-dicarboxylic acid diethyl ester o~ melting point 81C (isopropanol).
Yield: 62% of theory.
ExamPle 18 ~ N0~
H5C202C ~ C0OC2~s tl ~1~
H~`C ~ CH."U-~ )2 Analogously to Example l, reaction of 2'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-isopropyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-isopropyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester o~ melting point 117C (ethanol).
Yield: 28% of theory.
Example 19 ~ .
~ ~02 H5C202C ~ C02C2Hs H C ~--N~ C2Hs Le A 20 322 7s43a s~

~, 7~ Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-ethyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 124C
(ethanol).
Yield: 35% of theory.
Example 20 1,4-Dihydro-2-methyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester ~_C~3 HsC202C 1 Co2c2Hs X~

Process variant G
4.5 g (10 mmols) of 3,4-dihydro-6-methyl-2-(pyrrolidin-l-yl)-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester were hydrogenated in 150 ml of glacial acetic acid over platinum-(IV) oxide, in a shaking apparatus, at 3.5 atmospheres gauge, until the equivalent amount of hydrogen had been taken up (about 2 hours~. The catalyst was then filtered off and the filtrate was concentrated in vacuo. The residue was taken up in chloroform and chromatographed over a silica gel column (chloroform/ethyl acetate =
10:1), an analytically pure product, of melting point 95-96C, being obtained after concentrating the eluate.
Yield: 28% of theory.

Le A 20 322 ` - 1 17~43~

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. ~ a~

o o o o ~ ~ U U U

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~,1 bD
o o a I ~ .

Le A 20 322 ., ~ ~7543 ~, ~ 00 ;0 ,~

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h o O ~ Z

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-Le A 20 322 --` 1 t75k3 3~' ~:~ J
,,, The present invention also comprises pharmaceutically acceptable bioprecursors of the active compounds of the present invention.
For the purposes of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.

Le ~: 2~ 322

Claims (25)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a 1,4-dihydropyridine of the formula I

in which R represents a phenyl radical optionally containing 1 or 2 identical or different substituents selected from methoxy, halogen, trifluoromethyl, nitro and cyano; R1 represents a straight-chain or branched alkyl radical with up to 8 carbon atoms which is optionally interrupted by 1 or 2 oxygen atoms in the chain, and/or which is optionally substituted by a phenyl radical; R2 and R4 are always different and each represents a hydrogen atom, an alkyl radical with l to 4 carbon atoms, benzyl or cyclohexylmethyl; with the exception of the com-pound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; which process comprises (A) reacting an ylidene-.beta.-keto-ester of the formula II

in which R, R1 and R2 are as defined above with an enaminocarboxylic acid ester of the formula III

in which R1 and R4 are as defined above;
(B) reacting an ylidene-.beta.-keto-ester of the formula II, as defined above, with ammonia and a .beta.-ketocarboxylic acid ester of the formula V

in which R4 and R1 are as defined above;
(C) reacting an ylidene-.beta.-keto-ester of the formula VI

in which R, R1 and R4 are as defined above with an enaminocarboxylic acid ester of the formula VII

in which R2 and R1 are as defined above;
(D) reacting an ylidene-.beta.-keto-ester of the formula VI, as defined above, with ammonia and a .beta.-ketocarboxylic acid ester of the formula R2-CO-CH2-COOR1 (VIII) in which R2 and R1 are as defined above;
E) reacting an aldehyde of the formula (IX) in which R is as defined above, with an enaminocarboxylic acid ester of the formula (III), as defined above, and a .beta.-keto-carboxylic acid ester of the formula (VIII), as defined above;
F) reacting an aldehyde of the formula (IX), as defined above, with an enaminocarboxylic acid ester of the formula (VII), as defined above, and a .beta.-keto-carboxylic acid ester of the formula (V), as defined above; or G) when a compound of formula (I) is required, in which the radicals, R, R1 and R2 do not carry any functional groups which can undergo modification under hydrogenating conditions, and R2 is different from hydrogen, and R4 represents a hydrogen atom, catalytically hydrogenating in the presence of a noble metal catalyst, a 2-dialkylamino-3,4-dihydropyridine of the formula (X) in which R, R1 and R2 have the above-mentioned meanings and do not carry any functional groups which undergo modification under hydro-genating conditions, and R5 and R6 represent C1 to C6 alkyl groups or together complete a heterocyclic ring with the exocyclic nitrogen atoms.

2. A process according to claim 1, in which the reaction is carried out in the presence of an inert organic solvent.

3. A process according to claim 1, in which the reaction is carried out at a temperature between 10 and 100°C.

4. A process according to claim 1, in which process A) or C) is used and the reaction is carried out at a temperature between 20 and 100°C.

5. A process according to claim 1 in which process G) is used and the reaction is carried out at a temperature between 10 and 100°C in the presence of platinum or platinum dioxide as catalyst.

6. A process according to claim 1 in which process G) is used and the reaction is carried out at a temperature between 10 and 100°C in the presence of platinum or platinum dioxide as catalyst and in the presence of glacial acetic acid as solvent.

7. A compound of formula I as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

8. A process according to claim 1 wherein R is 2-nitrophenyl, R1 is methyl, R2 is ethyl and R4 is methyl.

9. A process for preparing 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester which comprises reacting 2'-nitro-benzylideneacetoacetic acid methyl ester with .beta.-amino-.beta.-ethyl-acrylic acid methyl ester.

10. The compound 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester when prepared by a process according to claim 9 or an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein R is 2-nitrophenyl, R1 is ethyl, R2 is propyl and R4 is methyl.

12. A process for preparing 1,4-dihydro-2-propyl-6-methyl-4-(2-nitrophenyl)-pyridine dicarboxylic acid diethyl ester which comprises reacting 2'-nitrobenzyl-ideneacetoacetic acid ethyl ester with .beta.-amino-.beta.-propyl-acrylic acid ethyl ester.

13. The compound 1,4-dihydro-2-propyl-6-methyl-4-(2-nitrophenyl)-pyridine dicarboxylic acid diethyl ester when prepared by a process according to claim 12 or an obvious chemical equivalent thereof.

14. A process according to claim 1 wherein R is 3-nitrophenyl, R1 is methyl, R2 is ethyl and R4 is methyl.

15. A process for preparing 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester which comprises reacting 3'-nitro-benzylideneacetoacetic acid methylester with .beta.-amino-.beta.-ethyl-acrylic acid methyl ester.

16. The compound 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester when prepared by a process according to claim 15 or an obvious chemical equivalent thereof.

17. A process according to claim 1 wherein R is 2-chlorophenyl, R1 is methyl, R2 is ethyl and R4 is methyl.

18. A process for preparing 1,4-dihydro-2-ethyl-6-methyl-4-(2-chloro-phenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester which comprises reacting 2'-chlorobenzylideneacetoacetic acid methyl ester with .beta.-amino-.beta.-ethyl-acrylic acid methyl ester.

19. The compound 1,4-dihydro-2-ethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester when prepared by a process according to claim 18 or an obvious chemlcal equivalent thereof.

20. A process according to claim 1 wherein R is 2-cyanophenyl, R1 is ethyl, R2 is ethyl and R4 is methyl.

21. A process for preparing 1,4-dihydro-2-ethyl-6-methyl-4-(2-cyanophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester which comprises reacting 2'-cyano-benzylideneacetoacetic acid ethyl ester with .beta.-amino-.beta.-ethyl-acrylic acid ethyl ester.

22. The compound 1,4-dihydro-2-ethyl-6-methyl-4-(2-cyanophenyl)pyridine-3,5-dicarboxylic acid diethyl ester when prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

23. A process according to claim 1 wherein R is 2-trifluoromethylphenyl, R1 is ethyl, R2 is ethyl and R4 is methyl.

24. A process for preparing 1,4-dihydro-2-ethyl-6-methyl-4-(2-trifluoro-methylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester which comprises reacting 2'-trifluoromethylbenzylideneacetoacetic acid ethyl ester with .beta.-amino-.beta.-ethyl-acrylic acid ethyl ester.

25. The compound 1,4-dihydro-2-ethyl-6-methyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester when prepared by a process accord-ing to claim 24 or an obvious chemical equivalent thereof.