CH622507A5 - Process for the preparation of 1,4-dihydropyridines - Google Patents

Abstract

Alkoxyalkyl dihydropyridine esters of the formula <IMAGE> are prepared in which the radicals R, R<3>, R<4> and X are defined in Claim 1. The abovementioned compounds are obtained by reaction of 2 parts of beta -ketocarboxylic acid ester of the formula R<4>-CO-CH2-COOR<3> (VI> with one part of amine of the formula H2N-R (III> or its salt and with one part of aldehyde of the formula X-CHO (IX) The novel compounds have a potent vasoactive action, in particular a potent coronary action.

Description

622507

2nd

PATENT CLAIMS 1. Process for the preparation of alkoxyalkyl dihydro-pyridine esters of the formula

R3OOC

COOR '

5. The method according to claim 1 for the preparation of 2,6- (diethoxymethyl) -4- (2'-nitrophenyl) -1, 4-dihydropyridine - 3,5-dicarboxylic acid diethyl ester and its salts.

6. The method according to claim 1 for the production of

5 2,6- (diethoxymethyl) -4-a-pyridyl-l, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salts.

(I)

in which

R represents hydrogen or a saturated or unsaturated aliphatic radical,

R3 is a straight-chain or branched, saturated or unsaturated or cyclic hydrocarbon radical which is optionally substituted by 1 or 2 hydroxyl groups and / or is optionally interrupted by 1 or 2 oxygen atoms in the chain,

R4 represents alkoxyalkyl, and

X is a phenyl radical which may be mono- to triple-nitro, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S (0) m-alkyl, where m is a number from 0 is 2, phenyl, trifluoromethyl and / or halogen is substituted, where the substituents on the phenyl radical may be the same or different, for benzyl, styryl, cycloalkyl, cycloalkenyl or for a naphthyl- optionally substituted by alkyl, alkoxy, dialkylamino, nitro or halogen , Quinolyl, isoquinolyl, pyridyl, pyrimidyl, furyl or pyrryl radical,

and their salts, characterized in that two parts of β-ketocarboxylic acid esters of the formula io. The present invention relates to the preparation of new 1,4-dihydropyridines which are valuable as medicaments, preferably as agents which affect the vessels, in particular as coronary agents.

It has already become known that certain 1,4-di-15 hydropyridines have interesting pharmacological properties (F. Bossert and W. Vater, Die Naturwissenschaften [1971], 58th volume, volume 11, page 578).

It has been found that the new dihydropyridine-dicarboxylic acid esters of the formula r5ooc

25th

30th

C00R-

(i)

R4-CO-CH., - COOR3

with a part of amine of the formula

(VI)

H.N-R (III)

or its salt and with a part of aldehyde of the formula

X-CHO (IX)

implements

and, if desired, preparing the salt with an acid from the compounds obtained.

2. The method according to claim 1, for the preparation of compounds of formula I, wherein

R represents hydrogen,

R3 represents alkyl having 1 to 4 carbon atoms,

R4 for alkoxyalkyl having 1 or 2 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part, and

X represents phenyl or phenyl which is substituted by alkoxy or methylthio with 1 or 2 carbon atoms, cyano, nitro, hydroxy, trifluoromethyl, fluorine, chlorine, iodine, carboalkoxy with 1 to 4 carbon atoms and / or alkylsulfonyl with 1 to 4 carbon atoms is substituted twice, and stands for pyridyl and 2-dimethylaminopyrimidyl.

3. The method according to claim 1 for the preparation of 2,6-dimethoxymethyl-4- (2'-chloropheny!) - 1, 4-dihydropyridine - 3,5-dicarboxylic acid ethyl ester and its salts.

4. The method according to claim 1 for the preparation of 2,6-dimethoxymethyl-4- (2'-trifluoromethylphenyl) -1,4-dihy-dropyridine-3,5-dicarboxylic acid diethyl ester and its salts.

in which

R represents hydrogen or a saturated or unsaturated aliphatic radical,

R3 represents a straight-chain or branched, saturated 35 or unsaturated or cyclic hydrocarbon radical which is optionally substituted by 1 or 2 hydroxyl groups and / or is optionally interrupted by 1 or 2 oxygen atoms in the chain,

R4 represents alkoxyalkyl, and 40 X represents a phenyl radical which may be mono- to triple by nitro, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S (0) m-alkyl , where m is a number from 0 to 2, phenyl, trifluoromethyl and / or halogen is substituted, it being possible for the substituents on the phenyl radical to be identical or different, for benzyl, styryl, cycloalkyl, cycloalkenyl or for one optionally substituted by alkyl, Alkoxy, dialkylamino, nitro or halogen-substituted naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, furyl-50 or pyrryl radical,

and their salts have a strong vasodilatory effect, in particular a strong coronary effect.

The process for the preparation of these new compounds consists in that two parts of β-ketocarboxylic acid 55 ester of the formula

R4-CO-CH., - COOR3 (VI)

in which

R3 and R 'have the meaning given above, with 60 part amine of the formula

H.N-R (III)

in which

65 R has the meaning given above,

or its salt and with a part of aldehyde of the formula

X-CHO (IX)

3rd

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in which

X has the meaning given above,

reacted and, if desired, the salt is prepared from the compounds obtained with an acid.

Surprisingly, the compounds obtained according to the invention have a very strong vasodilatory, in particular coronary, effect. The substances produced according to the invention thus represent an enrichment of the pharmaceutical industry.

If 3-nitro-benzaldehyde, 2 parts of diethyl y-methoxy-io-acetoacetate and ammonia are used as starting materials, the course of the reaction can be represented by the following formula:

H5C2OOC

CH50CH2

20th

COOC2H5

25th

0 0

CHgOCHj

H

H

s /

30th

35

40

45

50

In the formulas I and II, the saturated or unsaturated aliphatic radical R preferably denotes straight-chain or branched alkyl having 1 to 4, in particular 1 to 3 55

Carbon atoms, such as methyl, ethyl, n- and i-propyl,

n-, i- and t-butyl, or straight-chain or branched al-kenyl having 2 to 4, in particular 2 or 3, carbon atoms, such as ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3).

In the formulas, the alkoxyalkyl radicals R 'are preferably those of the formula -Y-O-Z, in which Y represents straight-chain or branched alkylene having 1 to 4, preferably 1 or 2, carbon atoms, such as methylene,

Ethylene and n- and i-propylene, and Z is alkyl having 1 to 4, preferably 1 or 2 carbon atoms, such as methylene, ethyl, n- and i-propyl, n-, i-, sec.- and t-butyl.

Straight-chain or branched, saturated or unsaturated or cyclic carbons. Hydrogen radicals R: 1, which are optionally substituted by 1 or 2 hydroxyl groups and / or are optionally interrupted by 1 or 2 oxygen atoms in the chain, are preferably alkyl, alkenyl, alkynyl and cycloalkyl.

The alkyl R3 is straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include methyl, n- and i-propyl, n-, i- and t-butyl.

Alkenyl R3 is straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4, carbon atoms. Examples include ethenyl, propynyl (1), propenyl (2) and butenyl (3).

The alkynyl R3 is straight-chain or branched alkynyl having preferably 2 to 6, in particular 2 to 4, carbon atoms. Examples include ethynyl, propionyl (1), propynyl (2) and butynyl (3).

The cycloalkyl R3 is mono-, bi- and tricyclic cycloalkyl having preferably 3 to 10, in particular 3, 5 or 6, carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2, 1] heptyl, bicyclo [2.2.2] octyl and adamantyl.

These alkyl, alkenyl, alkynyl and cycloalkyl radicals R3 can be substituted by 1 or 2, preferably 1, hydroxyl group and / or interrupted by 1 or 2, preferably 1, oxygen atom.

Alkyl R4 and RH means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.

The phenyl radical X can, as defined above, carry 1 to 3, in particular 1 or 2 identical or different substituents, namely phenyl; Alkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl; Alkoxy preferably having 1 to 4, in particular 1 or 2, carbon atoms; such as methoxy, ethoxy, n- and i-propyl and n-, i- and t-butyloxy; Trifluoromethyl; Hydroxy; Halogen, preferably fluorine, chlorine, bromine and iodine, especially chlorine and bromine; Cyano; Nitro; Azido; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methyl-ethylamino-no, n- and i-propylamino and methyl-n-butylamino; Carbalkoxy preferably having 2 to 4, in particular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; Acylamino preferably having 1 to 4, in particular 2 or 3, carbon atoms, such as acetylamino and propionylamino; Acyloxy preferably having 2 to 6, in particular 2 to 4, carbon atoms, such as acetyloxy and propionyloxy; S (0) m-alkyl, where m is a number from 0 to 2 and alkyl preferably contains 1 to 4, in particular 1 or 2, carbon atoms, such as methylthio, ethylthio. Methylsulfoxyl, ethylsulfoxyl, methylsulfonyl and ethylsulfonyl.

Cycloalkyl X preferably denotes mono-, bi- and tricyclic cycloalkyl with preferably 3 to 10, in particular 3.5 or 6, carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and adamantyl.

Cycloalkenyl X preferably denotes mono-, bi- and tricyclic cycloalkenyl with preferably 5 to 10, in particular 5, 6 or 7, carbon atoms. Examples include cyclopentenyl, cyclohexenyl and cycloheptenyl.

Alkyl and alkoxy as substituents in the naphthyl, quinyl, isoquinolyl, pyridyl, pyrimidyl, furyl or pyrryl radical X mean straight-chain or branched alkyl and alkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include methyl, ethyl, n- and i-propyl,

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called n-, i- and t-butyl and methoxy, ethoxy, n- and i-propoxy and n-, i- and t-butoxy.

Halogen as a substituent of the naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, furyl and pyrryl radical X means fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine.

Dialkylamino as a substituent of the naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, furyl or pyrryl radical X preferably contains 1 to 4, in particular 1 or 2, carbon atoms per alkyl group. Examples of alkyl groups are: methyl, ethyl, n- and i-propyl and n-, i- and t-butyl.

R is preferably hydrogen, R3 is alkyl having 1 to 4 carbon atoms, in particular methyl and ethyl, R4 is alkoxyalkyl having 1 or 2 carbon atoms in the alkyl part and 1 to 3, in particular 1 or 2 carbon atoms in the alkoxy part, and X is phenyl, or Phenyl which is alkoxy or alkylthio with 1 or 2, in particular 1 carbon atom, cyano, nitro, hydroxy, trifluoromethyl, fluorine, chlorine, iodine, carboalkoxy with 2 to 4, preferably 2 or 3 carbon atoms and / or alkylsulfonyl with 1 to 4, preferably 1 or 2 carbon atoms is mono- or disubstituted, preferably monosubstituted, and also for pyridyl or 2-dimethylaminopyrimidyl.

Salts of the compounds of the formula I are all non-toxic, physiologically tolerable acid addition salts. Examples of inorganic and organic acids which form such salts with the compounds of the formula I are: hydrogen halide acids, e.g. Hydrochloric and hydrobromic acids, especially hydrochloric acid, phosphoric acids, sulfuric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1,5-naphthalene carboxylic acid.

The salts are made according to generally accepted methods, e.g. prepared by dissolving the base in ether and adding the acid in question to the solution.

The amines of the formula III which can be used according to the invention are already known.

Examples include:

Ammonia, methylamine, ethylamine, propylamine, butylamine, isopropylamine, isobutylamine, allylamine.

The β-ketocarboxylic acid esters of the formula VI which can be used according to the invention are known or can be prepared by generally known processes (B. Johnson and H. Chesnoff, JACS 36, 1744 (1914); Pohl, Schmidt, US Pat. No. 2,351,366; AC Cope, JACS 67, 1017 119451).

Examples include:

ß-dicarbonyl compounds:

y-methoxyacetoacetic acid methyl ester, y-methoxyacetes-acetic acid ethyl ester, y-methoxyacetoacetic acid propyl ester, y-methoxyacetoacetic acid isopropyl ester, y-methoxyacetic acid ethyl acetate, y-ethoxyacetic acid ethyl acetate säureisopropylester, y-Propoxyacetessigsäure tert-butyl ester, y-Isopropoxyacetessigsäuremethylester, y-Isopropoxyacet-butyl acetate, y-Butoxyacetessigsäureäthylester, y-Butoxyacetessigsäureisobutylester, y-Isobutoxyacetessig-säurepropylester, y-Methoxypropionylessigsäuremethylester, y-Methoxypropionylessigsäureäthylester, y-Propoxypropio-nylessigsäurepropylester, S -Athoxypropionylacetate, 5-methoxy-y-ethylpropionylacetate.

The aldehydes of the formula IX which can be used according to the invention are already known or can be prepared according to known methods

Methods are produced (E. Mosettig, Org. Reactions, VIII, 218 ff, [1954]).

Examples include:

Aldehydes:

Benzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-iso-propoxybenzaldehyde, 3-butoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2-, 3- or 4-chloro / bromine / iodine / fluorobenzaldehyde, 2,4- or 2,6-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-diisopropyl-4-methoxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde hyd, 2-nitro-6-bromobenzaldehyde, 2-nitro-3-methoxy-6-chloro-benzaldehyde, 2-nitro-4-chlorobenzaldehyde, 2-nitro-4-methoxy-benzaldehyde, 2-, 3- or 4- Trifluoromethylbenzaldehyde, 2-, 3- or 4-dimethylaminobenzaldehyde, 4-dibutylamino-benzaldehyde, 4-acetaminobenzaldehyde, 2-, 3- or 4-cyano-benzaldehyde, 2-nitro-4-cyanobenzaldehyde, 3-chloro-4-cyano- benzaldehyde, 2-, 3- or 4-methyl mercaptobenzaldehyde,

2-methylmercapto-5-nitrobenzaldehyde, 2-butylmercapto-benzaldehyde, 2-, 3- or 4-methylsulfinylbenzaldehyde, 2-,

3- or 4-methylisulfonylbenzaldehyde, ethyl benzaldehyde-2-carboxylate, isopropyl benzaldehyde-3-carboxylate, butyl benzaldehyde-4-carboxylate, ethyl 3-nitrobenzaldehyde-4-carboxylate, cinnamaldehyde, formylcyclo-hexane, 1-formyl , l-formyl-cyclohexadiene-1,3, l-formylcyclopentene-3, a-, β- or y-pyridine aldehyde, 6-methyl-pyridine-2-aldehyde, furan-2-aldehyde and pyrrole-2-aldehyde, N Methylpyrrole-2-aldehyde, 2-, 3- or 4-azidobenzaldehyde, pyrimidine-4-aldehyde, 5-nitro-6-methylpyridine-2-aldehyde, 1-or 2-naphthaldehyde, 5-bromo-l-naphthaldehyde, Quinoline-2-aldehyde, 7-methoxy-quinoline-4-aldehyde, isoquinoline-1-al-dehyde.

The preferred diluents used are water and all inert organic solvents. These preferably include alcohols, e.g. lower alkyl alcohols preferably having 1 to 4 carbon atoms, such as ethanol, methanol, isopropanol, ether, e.g. lower dialkyl ethers, (preferably 3 to 5 carbon atoms), such as diethyl ether or ring ethers, such as tetrahydrofuran, dioxane, lower aliphatic carboxylic acids (preferably 2 to 5 carbon atoms), such as acetic acid, propionic acid, lower dialkylformamides (preferably 1 or 2 carbon atoms per alkyl group), such as dimethylformamide , lower alkyl nitriles (preferably 2 to 4 carbon atoms), such as aceto-nitrile, dimethyl sulfoxide, liquid heteroaromatic bases such as pyridine, and mixtures of these solvents, including water, with one another.

The reaction temperatures can be varied over a wide range. In general, between about 20 and about 150 ° C, preferably between 50 and 100 ° C, especially at the boiling point of the solvent used.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at normal pressure.

When carrying out the process according to the invention, the starting materials involved in the reaction are preferably each used in approximately molar amounts. The amine or its salt used is advantageously added in an excess of 1 to 2 mol. The molar ratios can be varied over a wide range without the result being adversely affected.

In addition to the compounds described in the examples, the following may be mentioned individually as new active ingredients:

l-methyl-2,6-dimethoxymethyl-4- (3 \ 5'-dioxy-4'-iodophe-ny 1) -1,4-dihydropyridine-3,5-dicarboxylic acid dipropyl ester,

1-isopropyl-2,6-dimethoxymethy l-4- (3-azidophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester,

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

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2,6-dimethoxymethyl-4- (3-carboxyphenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester,

2,6-dimethoxymethyl-4- (5'- [4,6-dimethoxy] pyrimidyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester,

2,6-Dibutoxymethyl-4- (2'-N-propylpyrryl) -1, 4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester.

The new compounds can be used as pharmaceuticals, in particular as active substances which affect the blood vessels and the circulatory system.

The compounds prepared according to the invention have a broad and varied spectrum of pharmacological activity.

In detail, the compounds produced according to the invention have the following main effects:

1) With parenteral, oral and perlingual administration, the new compounds result in a clear and long-lasting expansion of the coronary vessels.

This effect on the coronary vessels is reinforced by a simultaneous nitrite-like heart-relieving effect. They influence or change the heart's metabolism in the sense of saving energy.

2) The new compounds lower the blood pressure of normotonic and hypertensive animals and can thus be used as antihypertensive agents.

3) The excitability of the stimulation and conduction system within the heart is reduced, so that there is a detectable anti-inflammatory effect in therapeutic doses.

4) The smooth muscle tone of the vessels is greatly reduced under the action of the connections. This vasospasmolytic effect can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular areas (such as the central nervous system).

5) The compounds have strong muscular-spasmolytic effects, which are evident in the smooth muscles of the stomach, intestinal tract, urogenital tract and the respiratory system.

6) The compounds influence the cholesterol or lipid level of the blood.

The new compounds are therefore suitable for preventing, ameliorating or curing diseases in which the above-mentioned effects are desired in particular.

Pharmaceutical preparations can be obtained which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula I and / or their salts or which consist of one or more compounds of the formula I and / or their salts.

Pharmaceutical preparations can also be obtained in dosage units. This means that the preparations in the form of individual parts e.g. Tablets, dragées, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. Contain 1, 2, 3 or 4 single doses or Y2, Vi or Yi of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions may be mentioned as preferred pharmaceutical preparations. Oral preparations are particularly preferred.

The tablets, dragées, capsules, pills and granules can be coated with the usual opacifying agents, if

tel containing coatings and shells and also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, the embedding compounds being e.g. Polymer substances and waxes can be used.

In addition to compounds of the formula I and / or their salts, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.

The compounds of the formula I and / or their salts, and pharmaceutical preparations which contain one or more compounds of the formula I and / or their salts, can be used in human and veterinary medicine for the prevention, amelioration and / or healing of the abovementioned diseases Find.

The coronary action of some characteristic compounds produced according to the invention can be demonstrated by the test results contained in Table I.

TABLE I

v »linrliino Clearly recognizable increase in

"" "Oxygen saturation in the coronary sinus from the example of Dosj's duration of action"

(mg / kg - IV) (minutes)

1

10.0

30th

2nd

5.0

45

3rd

2.0

45

4th

3.0

20th

i. v. = intravenously

The coronary effect was determined in accordance with the generally known methods known from the literature on anesthetized cardiac-catered bastard dogs by measuring the increase in oxygen saturation in the coronary sinus.

The preparation of the new compounds will be explained using the following examples.

example 1

Cl

CH, 0-CH,

The solution of 14 g of 2-chlorobenzaldehyde, 32 g of Y-methoxyacetoacetic acid ethyl ester and 10 ml of aqueous ammonia in 60 ml of ethanol is boiled overnight and, after suction extraction, the 2,6-dimeth-oxymethyl-4- (2 '-chlorophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid ethyl ester in the form of light yellow crystals of mp. 133-134 ° C in a yield of 55% of theory.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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6

Example 2

H5C2OOC

H

COOC2H5

, 0 h5c2ooc

CH5-OCH2 H CH2-OCH3

8.7 g of 2-trifluoromethylbenzaldehyde, 16 g of ethyl Y-methoxyacetoacetate and 5 ml of aqueous concentrated ammonia in 30 ml of ethanol are boiled overnight, the mixture is cooled, and the 2,6-dimethoxymethyl-4- (2 '- trifluoromethylphenyl) is obtained. -l, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester in the form of light brown crystals of mp. 133-134 ° C in a yield of 60% of theory.

Example 3

IS

CHjOCHg cooc2h5

ch2-och3

h5c2ooc c2h5och2

Oil

NO,

COOC2H5

CH20C2H5

The solution of 15 g of 2-nitrobenzaldehyde, 35 g of ethyl y-ethoxyacetoacetate and 11 ml of aqueous concentrated ammonia in 80 ml of ethanol is heated to boiling overnight and then cooled. After suctioning off, the 2,6- (diethoxymethyl) -4- (2'-nitrophenyl) -l, 4 - dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of yellow crystals with an mp of 138-140 ° C. in a yield of 50% of theory.

Example 4

H5C2OOC>

H

, COOC2H5

H5C2OCH2

H CH2OC2H5

5.2 ml of pyridine-2-aldehyde, 17 g of ethyl y-ethoxyacetoacetate and 5 ml of aqueous concentrated ammonia in 40 ml of ethanol are heated to boiling overnight, the mixture is cooled, suction filtered, and the crystals obtained (mp. 110 ° C. ) in ether and drops the HCl salt with ethereal hydrochloric acid. The hydrochloride of 2,6- (diethoxymethyl) -4-a-py-ridyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester with a melting point of 168-170 ° C.

7.6 g of 4-methyl mercaptobenzaldehyde, 16 g of ethyl y-methoxyacetoacetate and 6 ml of aqueous concentrated ammonia in 30 ml of ethanol are heated to boiling for 6-8 hours and the 2,6-dimethoxymethyl-4- (4'-methyl-mercaptophenyI) is obtained ) -l, 4-dihydropyridine-3,5-dicarboxylic acid di-ethyl ester in the form of beige crystals of mp. 136-138 ° C.

Yield: 50% of theory.

25th

30th

35

40

Example 6

7.6 g of 3-methoxy-4-hydroxybenzaldehyde, 16 g of ethyl y-methoxymethylacetoacetate and 12 ml of aqueous concentrated ammonia in 30 ml of ethanol are boiled over 45 nights and, after cooling, the 2,6-di-methoxymethyl-4- is obtained. (3'-methoxy-4'-hydroxyphenyl) -l, 4-dihy-dropyridine-3,5-dicarboxylic acid diethyl ester in the form of light yellow crystals of mp 140-142 ° C in a yield of 40% of theory.

50

Example 7

55

H3 CaOOC CH3 OCHa /

COOCa H5 CHÄ 0CH3

65 7.5 g of 3-nitrobenzaldehyde, 16 g of y-methoxy-acetoacetic acid ethyl ester and 5 g of methylamine chlorohydrate are heated to 90-100 ° in 40 cc of pyridine for 5-6 hours. absorbs in ether, washes with dil. hydrochloric acid and

7

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water and evaporate the ether solution after drying. The 1-methyl-2,6-dimethoxymethyl-4- (3'-nitro-phenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained as a brown oil in 90% yield.

Example 8

H5C2OOC

Oîî OCH

? 2nd

The solution of 7.5 g of 2-nitrobenzaldehyde, 16 g of y-meth-oxyacetoacetic acid ethyl ester and 6 cc conc. Ammonia is heated to boiling in 50 cc of ethanol overnight and then cooled. After suction filtration and washing with ether, the 2,6-dimethoxymethyl-4- (2'-nitro-phenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in yellow crystals of mp 151-152 ° C ( Ethanol).

Yield: 55%.

10th

15