CH642353A5 - 2-METHYL-DIHYDROPYRIDINE COMPOUND, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENT CONTAINING IT. - Google Patents

Description

The invention relates to a new 2-methyl-dihydropyridine compound and its pharmaceutically acceptable salts which have vasodilatory and antihypertensive activities, processes for their preparation and a pharmaceutical composition containing them for the therapeutic treatment of cardiovascular disorders and hypertension in humans.

In the field in question here, for example, the dihydropyridine compounds given below are already known:

A-1 CH3OOC

(U.S. Patent 3,485,847)

A-2 C2H5OOCN ^ A ^ COOC2H5

(German Offenlegungsschrift CN 26 29 892)

A-3 C2HSOOC _X ^ ß00C2ES

Jy II disclosure

X ^ N QH 26 29 892)

CH.

H

The invention relates to new, valuable 2-methyl-dihydropyridine compounds and their pharmaceutically acceptable salts, which are structurally characterized by a substituent in the 3-position of the dihydropyridine ring and which have a higher activity than the known compounds, such as for example, they are given above.

I) Synthesis of the basic structure:

The invention further relates to processes for the preparation of this 2-methyl-dihydropyridine compound and its pharmaceutically acceptable salts.

The invention also relates to a valuable pharmaceutical agent which contains, as active ingredient, a 2-methyl-dihydropyridine compound or a pharmaceutically acceptable salt thereof, optionally in combination with at least one pharmaceutically acceptable carrier and / or diluent, which need-lo bar is a vasodilatory and antihypertensive agent.

The pharmaceutical composition according to the invention can be used for the treatment of cardiovascular disorders, e.g. coronary insufficiency, angina pectoris or myocardial infarction and hypertension. 15 The 2-methyl-dihydropyridine compound according to the invention can be represented by the general formula

R200C C00R *

 ¥

CD

in which mean:

R1 phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-di-30 chlorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl,

R2 propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl-N-methylamino) ethyl,

35 R3 lower alkyl and

R4 di (lower) alkoxymethyl, formyl, hydroxymethyl or cyano, with the proviso that when Rl is 3-nitrophenyl, R2 is 2-hydroxyethyl and R4 is cyano or formyl or R2 is propyl or isopropyl. 40 The connections excluded from the scope of protection are already known.

Regarding the compound of formula (I) given above according to the invention, it should be noted that this can be a pair of two optical isomers 45 as a result of the asymmetric carbon atom in position 4 of the dihydropyridine ring and that this type of isomers is therefore also within is within the scope of the present invention and is also encompassed by the same formula (I).

The compound of the formula (I) according to the invention can be prepared by a process which forms a further object of the invention and is explained by the reaction schemes below and defined in claims 40 to 46:

55

1) Procedure 1

R.

R1-CH = C-CO-Rf + CH - C = CH-COOR ^ R2OOCvJssroOR3

1 ■> t. XX-

CH3 N D

COOR * (II-l)

2nd

Cnr-D

R4 H a

7

642353

in which mean:

R1 and R3 each have the groups given above, Ra2 propyl, isopropyl, 2-chloroethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl-N-methylamino) ethyl and

Ra4 di (low) alkoxymethyl,

with the proviso that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl.

2) Procedure 2

R

R1-CH = C-COCH, + R4-C = CH-C00R3- ^ R200C.J \ £ 00R *

i. s i A rr i

00R

(n -2)

AH2

(331-2)

in which mean:

R \ Ra2, R3 and Ra4 each the groups given above,

with the proviso that when R1 is 3-nitrophenyl, Ra2 is propyl or isopropyl.

II) Transformations of a functional group

20th

3) Procedure 3

R

CH.

COOR "4

R

R00CvV

XX

'3 H (1-1)

in which mean:

R1, R2, R3 and Ra4 each the groups given above,

with the proviso that when R1 is 3-nitrophenyl, R2 is propyl, isopropyl or 2-hydroxyethyl

Hydrolysis indicates.

4) Procedure 4

R

R 00C

CH.

XjC

.COOR reduction cho

"H (1-3)

in which mean:

R1, R2 and R3 each have the groups indicated above, with the proviso that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl.

5) Procedure 5

CH

AK

H

(1-2)

R

* °: xx

CH.

H

(1-3)

COOR * CHO

R

RoocvV

XX

• CH.

H

(1-4)

COOR *

ch2oh

R ^ OOci ^ TOOR3

R

CH

XK

3 H CH0

(i) hydroxylamine •

or a salt L thereof R ^ OOC COOR *

(ii) Dehydrating agent

CH

A ^ cn

H

tl-3 ')

(1-5)

642353

in which mean:

R1 and R3 each have the groups indicated above and Rb2 propyl, isopropyl, 2-hydroxyethyl, 2-ethoxyethyl,

2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl-N-methylamino) ethyl, with the proviso that when R1

Represents 3-nitrophenyl, Rb2 means propyl, isopropyl or 2-hydroxyethyl.

6) Procedure 6

à

3 H (He)

in which mean:

R1 and R3 each have the groups indicated above and Re2 acyl.

r ^ och-ch-ooc e 2 2

ch coor-

cn

Hydrolysis hoch2ch2ooc.

.coor *

7) Procedure 7

R

ClŒ7Œ9OOC ^ A ^ œOR "-

XX?

h a

CH,

C6H5CH2

R

C6H5ffl2

«V

■ nh

CH.

NNŒ2CH200C J ^ COOR-

CH.

H

(Ild)

(1-7)

in which mean:

Rl, R3 and Ra4 each have the groups indicated above, with the proviso that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl.

The term “lower alkyl” or “lower alkyl” used here for R3 includes C 1 -C 6 -alkyl, preferably C 1 -C 3 -alkyl, in particular normal straight-chain (unbranched) alkyl, such as methyl, ethyl, propyl or the like.

The term “di (lower) alkoxymethyl” used for R4 and Ra4 includes di-CCj-Q straight-chain and branched chain lower alkoxy) methyl, preferably CrC3-

Alkoxymethyl, such as dimethoxymethyl, diethoxymethyl, di-propoxymethyl or the like.

40 The term "acyl" used for Re2 includes a conventional acyl, preferably alkanoyl, especially lower alkanoyl such as Q-Q-alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and the like) or the like.

45 The starting compounds (II -1) and (II - 2) used in processes 1 and 2 include new and known compounds and the new compounds can be prepared by reacting 4-substituted acetoacetate (IIA) or (IIA>) with a Aldehyde (IIB) in such a conventional manner according to the reaction schemes given below:

(d r1-ch0 + r4-coch2coor3

(IIB)

(Ha)

r1-ch = c-c0-rf i 3 coor

(II-l)

so wherein R1, R3 and Ra4 each have the meanings given above.

(2) r1-ch0 + ch_c0ch7c00r2> r1-ch = c-c0ch

* ì00r?

'3W 2 a

(IIB) (IIA,)

(II-2)

9

642353

wherein R1 and Ra2 each have the meanings given above.

The other starting compounds (III -1) and (III - 2) used in processes 1 and 2 can be prepared from a 4-substituted acetoacetate compound (IIIA) or (IIIA.) And ammonia or a salt thereof, as in the following reaction schemes:

® CH - C-CH9COOR2 + NH- - * CH - C = CH-C00R2 v- / onZa 3 3 I a

ö m2

tmA) (iii-i)

where Ra2 has the meanings given above.

© R ^ -C-CH2COOR3 + NHj - ^ R £ -C = CH-C00R3 0 NH2

CIIIA ') (III-2)

wherein R3 and Ra4 each have the meanings given above.

In addition, the starting compound (IIC) used in Process 6 can be prepared by a process according to the reaction scheme given below, and the compound (I-8) can be prepared in a similar manner to that in Process 2,

which is followed by the method 3 mentioned above:

pl (i) hydroxylarain- R *

HOCH0CH0OOC JL COOR3 hydrochlond R20CH CH 00C COOR3

2 2 XjT Ci «(R |) 2O 'XT

(H-AN- ^ CHO Z CN

H H

(1-8) (Ile)

wherein R1, R3 and Re2 each have the meanings given above.

The processes for producing the 2-methyl-dihydropyridine compound (I) are explained in more detail below.

1) Procedure 1

This process relates to the preparation of a compound (I -1 ') by reacting a compound (II -1) with an amino compound (III -1).

Each of the starting compounds (II -1) and (III -1) includes the geometric eis and trans isomers as a result of the double bond in their molecules, and therefore, the compound (I -1 ') can be prepared by this method by any reaction sequence , in which one of the geometric isomers of the compound (II -1) is reacted with one of the geometric isomers of the compound (III -1) and therefore this process comprises all isomers and optical mixtures of the isomers of these starting compounds (II -1) and (III -1).

The reaction can be carried out at ambient temperature or with heating or with heating.

The reaction may preferably be carried out in the absence of a solvent, but may also be carried out in a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride or other conventional solvents. The reaction may preferably be carried out in the presence of an agent , such as an acid (such as acetic acid), a base (such as pyridine or picoline) or in a conventional buffer solution. These agents act as reaction accelerators and can also be used as solvents if they are liquid. The reaction can also be accelerated by heating 60 or heating. The reaction conditions may vary depending on the type of reactants, solvent and / or other agent mentioned above that are used.

Regarding the nature of the reaction of this process, it should be noted that it can alternatively be carried out, for example by reacting the 4-substituted acetoacetate compound (IIA) with the aldehyde (IIB) in the presence of the amino compound (III - 1).

642353

10th

2) Procedure 2

This process relates to the preparation of a compound (1-2) by reacting a compound (II - 2) with an amino compound (III - 2).

This process is essentially the same as Process 1, and therefore it can be carried out by reacting Compound (II-2) with Compound (III-2) in the same manner as that for Process 1. That is, the same reaction conditions (e.g., the same reaction temperature, the same solvent, the same accelerator, and the like) and the same alternative reaction method as that specified in Method 1 can also be applied to this method, provided that the compound (II - 2) or the alternative reactants (IIA0 and (IIB) and the compound (III - 2) in this process instead of the compound (II -1) or the alternative reactants (IIA) and (IIB) or Compound (III -1) can be used as in Method 1.

3) Procedure 3

This method relates to the preparation of a compound (I-3) by hydrolysis of a compound (I-1).

The compound (I -1) can be prepared by the method explained above (methods 1 and 2). In this process, the di (lower) alkoxymethyl group for Ra4 of the compound (I -1) is converted into a formyl group.

The hydrolysis can be carried out in a conventional manner, as is applicable to the cleavage (saponification) of a so-called acetal function into the corresponding carbonyl function, preferably e.g. by acid hydrolysis, i.e. in the presence of an acid, e.g. an inorganic acid (such as hydrochloric acid, sulfuric acid and the like) or an organic acid (such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like), or an acidic ion exchange resin.

This hydrolysis can be carried out in a suitable conventional solvent, e.g. in water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N, N-dimethylformamide or dimethyl sulfoxide, any mixture thereof or a buffer solution thereof. The reaction temperature is not restricted, and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature.

4) Procedure 4

This process relates to the preparation of a compound (1-4) by reduction of the compound (I - 3).

The reduction can be carried out in a conventional manner applicable to the reduction of a formyl group to a hydroxymethyl group, and the reduction is preferably carried out using a reducing agent such as an alkali metal borohydride (e.g. lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride and the like) or by catalytic reduction, for which a preferred catalyst may be palladium on carbon, palladium chloride or rhodium on carbon, and the like. The reduction is usually carried out in a conventional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran and the like, and the like. The reaction temperature is not subject to any restrictions and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature. The reduction process can depend on the

Type of connection (I - 3) can be selected in any way.

5) Method 5 s This method relates to the preparation of a compound (1-5) by reacting a compound (1-3) with hydroxylamine or a salt thereof and the subsequent reaction of the product obtained in this way with a dehydrating agent.

In this process, the formyl group of the starting compound (I - 3 ') can be converted into the hydroxyiminomethyl group (first stage) and then this group is converted into the cyano group (second stage). A preferred hydroxylamine salt can be a salt with an i5 acid, e.g. an inorganic acid (such as hydrochloric acid, sulfuric acid and the like) or an organic acid (such as acetic acid and the like).

i) First stage

The reaction of this step is carried out in the usual way as a so-called oximation reaction, for example in the presence of an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride); under basic conditions generated by a base, for example free hydroxylamine; or in an acidic or basic conventional buffer solution. The reaction is usually carried out in a suitable conventional solvent such as water, dioxane, ethanol, methanol, dimethylformamide or in any mixture thereof and if the above acid is a liquid, it can also be used as a solvent. The reaction temperature is not subject to any restrictions and the reaction 35 is generally carried out under cooling, at room temperature or at a slightly elevated temperature. The reaction product of the first stage is subjected to the subsequent second stage with or without isolation and / or purification.

40

ii) Second stage

The suitable dehydrating agent used in this step includes conventional organic or inorganic dehydrating agents such as e.g. an inorganic acid (such as sulfuric acid, phosphoric acid, polyphosphoric acid and the like), an organic acid (such as formic acid, acetic acid, trifluoroacetic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like), an organic acid anhydride (such as acetic acid anhydride, benzoic anhydride, Phthalic acid anhydride-50 drid and the like), an organic acid halide (such as acetyl chloride, benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenyl chloroformate and the like); an inorganic halogen compound (such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, 55 phosphorus tribromide, tin (IV) chloride, titanium tetrachloride and the like); a carbodiimide (such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide and the like), N, N'-carbonyldiimidazole; Pentamethylene ketene-N-cyclohexyl-imine; Ethoxyacetylene; 2-ethyl-7-hydroxyisoxazolium salt, 60 another phosphorus compound (such as phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenylphosphate) and the like, or any mixture thereof. If an acid is used as the dehydrating agent, the reaction can also be carried out in the presence of its salt, 65 e.g. an alkali metal salt (such as a sodium or potassium salt) or the like.

This reaction is usually carried out in a conventional solvent, such as diethyl ether, dimethylformamide,

11

642353

Pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane and the like., And it is usually carried out at room temperature or with heating, but the reaction temperature is not limited to the ranges given above.

6) Procedure 6

This process relates to the preparation of a compound (I-6) by hydrolysis of a compound (Ile).

In this method, the acyl group represented by Re2 in the compound (Ile) is eliminated by hydrolysis to form the 2-hydroxyethyl compound a-6).

The hydrolysis is carried out in a conventional manner, as is usually applied to cleavage (saponification) of a so-called ester bond to the hydroxy function, and it is preferably carried out, for example, using basic hydrolysis, i.e. in the presence of a base such as an alkali metal hydroxide, carbonate or bicarbonate (such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like), or using acidic hydrolysis in the presence of an organic or inorganic acid for which suitable examples are those as given in Process 3 described above.

This hydrolysis can preferably be carried out in a conventional solvent such as water, acetone, dioxane, methanol, ethanol, dimethylformamide, dimethyl sulfoxide or in any mixture thereof. The reaction temperature is not restricted and the reaction is usually carried out at room temperature or with heating.

7) Procedure 7

This process relates to the preparation of a compound (I-7) by reacting a compound (Ild) with N-methylbenzylamine.

The reaction is usually carried out in a suitable solvent such as chloroform, methylene chloride, benzene, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanol, propanol, isopropanol, water and another conventional solvent or any mixture thereof.

The reaction can also be carried out in the presence of a base, for which suitable examples include an inorganic base, e.g. an alkali metal hydroxide, carbonate, bicarbonate, hydride or amide (such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, potassium amide and the like), or an organic base such as e.g. an alkali metal alkylate (such as sodium methylate, sodium ethylate, potassium ethylate, lithium methylate and the like), an organic acid salt (such as sodium acetate, potassium acetate and the like), a tertiary amine or an imine base (such as triethylamine, pyridine, picoline, N , N-dimethylaniline, N-methylpyrrolidine, N-methylmorpholine and the like.) And the like.

In addition, this reaction is preferably carried out in the presence of an alkali metal iodide such as lithium iodide, sodium iodide or the like in addition to the base. The reaction temperature is not restricted, and the reaction is usually carried out at room temperature or under heating or under heating.

According to the invention, the desired reaction product can be separated from the reaction mixture and isolated and purified using the methods commonly used for this purpose, e.g.

by extraction with a suitable solvent, by chromatography, by precipitation, by recrystallization and the like.

Suitable examples of a salt of the 2-methyl-dihy-dropyridine compound (I) include a salt, especially a pharmaceutically acceptable salt such as e.g. inorganic acid salt (such as a hydrochloride, hydrobromide, phosphate, sulfate and the like) and an organic acid salt (such as formate, acetate, fumarate, maleate, aspartate, glutamate and the like).

The compound (I) thus obtained often comprises at least one pair of optical isomers due to the presence of an asymmetric carbon atom in the fourth position of the 1,4-dihydropyridine ring or nucleus, and it can be in the form of any optical isomer or in the form of a mixture of which are available. A racemic compound can be separated into the optical isomers using a conventional method for separating a racemic compound into the optical isomers, such as e.g. by chemical separation of the salts of the diastereoisomer with a conventional optically active acid (such as tartaric acid or camphor sulfonic acid and the like).

It should be noted that the compound (I) and its salts, especially its pharmaceutically acceptable salts, have strong vasodilatory and antihypertensive activities (efficacies) and are suitable for the therapeutic treatment of cardiovascular disorders and hypertension, such as e.g. coronary insufficiency, angina or myocardial infarction and hypertension.

Strong pharmacological activities (activities) of the compound (I) according to the invention occur in particular if they are structurally characterized by the radical R2, which is selected in particular from the group propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl and 2- (N-benzyl-N - methylamino) ethyl.

In particular, the compound (I) in which, for example, (i) R1 is 3-nitrophenyl or 2-chlorophenyl, R2 is isopropyl, R3 is methyl and R4 is cyano, and (ii) R1 is 2-tri-fluoromethylphenyl, R2 isopropyl or 2-phenoxyethyl, R3 methyl and R4 hydroxymethyl or cyano mean stronger therapeutic effects, as mentioned above, than the known compound mentioned above.

Also suitable is the compound (I) in which, for example, (iii) R1 is 3-nitrophenyl or 2-chlorophenyl, R2 isopropyl, R3 is methyl and R4 is dimethoxymethyl or formyl and (iv) R1 is 2-trifluoromethylphenyl, R2 isopropyl or 2- Phenoxyethyl, R3 methyl or ethyl and R4 dimethoxymethyl, diethoxymethyl or formyl mean not only as a vasodilatory and antihypertensive agent, but also as an intermediate for the preparation of the more preferred vasodilatory and antihypertensive agents according to the invention, as explained above.

For therapeutic purposes, the 2-methyl-dihydro-pyridine compound (I) is administered in a daily dose of 0.1 to 500 mg, preferably 1 to 50 mg.

The pharmaceutical compositions or medicaments according to the invention contain at least one 2-methyldihydropyridine compound (I) and / or at least one pharmaceutically acceptable salt thereof in an amount of about 0.01 to about 500 mg, preferably of, as an active ingredient about 0.1 to about 250 mg per dosage unit for oral and parenteral use.

It is readily apparent to those skilled in the art that the amount of active ingredient (active5

io

15

20th

25th

30th

35

40

45

50

55

60

65

642353

12

substance) is determined in the unitary dosage form taking into account the activity of the active ingredient (active ingredient) and the size of the human patient. The active ingredient (active ingredient) can usually be in a solid form, e.g. in the form of tablets, granules, in the form of a powder, in the form of capsules, troches, pills or suppositories or in the form of a suspension or solution, such as e.g. in the form of a syrup, an injection, an emulsion, a lemonade and the like.

Examples of pharmaceutical carriers or diluents include solid or liquid non-toxic, pharmaceutically acceptable substances. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, kaolin, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia gum, peanut oil, olive oil or sesame oil, cocoa butter, ethylene glycol or other conventional substances. The carrier or diluent may also include a time delay material such as glyceryl monostearate, glyceryl distarate, a wax and the like.

In order to demonstrate the utility of compound (I), some pharmacological test results from some representative compounds are given below.

Hypotensive effect

Test procedure:

Five Wistar rats were used per group. Each animal was locked in (immobilized) in a cage tailored to its body size. Blood pressure was measured by a pressure transducer on the femoral artery and recorded in the form of electrically integrated values of the mean arterial pressure, and the heart rate or heart rate was determined using a pulse wave detector. The catheterization was carried out under weak anesthesia with ether. The test compound was administered orally 3 hours after the end of the operation,

Test connection connection A-l:

Nifedipine (reference compound)

Compound B:

Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid. Compound C:

Isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-meth-oxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. Compound D:

Isopropyl ester of 6-'cyano-4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-car-bonic acid.

Connection E:

2-phenoxyethyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine - 3-carboxylic acid.

Connection F:

Isopropyl ester of 4- (2'-trifluoromethylphenyl) -6-hydroxymethyl I-5-methoxycarbonyl-2-methyl-l, 4-dihy-dropyridine-3-carboxylic acid,

Connection G:

2-phenoxyethyl ester of 4- (2-trifluoromethylphenyl) -5-

-thoxycarbonyl-6-hydroxymethyl-2-methyl-l, 4-dihy-

d'ropyridine-3-carboxylic acid.

Test results

The mean values of the maximum decrease in blood pressure (in mm Hg) are given in Table I below.

TABLE I

A-l

-25.6 ± 1.5

-44.6 ± 1.2

io B

-44.6 ± 1.7

-50.0 ± 1.3

C.

-29.2 ± 3.0

-40.6 = h 2.2

D

-34.6 ± 0.9

-47.4 = t 1.3

.5 E

-22.8 ± 2.1

-44.2 ± 1.5

F

-18.0 ± 1.9

-46.6 ± 2.1

G

-13.2 ± 3.3

-47.8 ± 2.4

20th

Effect on coronary blood flow test procedure

Bastard dogs weighing 8 to 15 kg were anesthetized with an intraperitoneal dose of Pentobarbitalna-25 trium of 35 mg / kg. After the thorax was opened under artificial ventilation, a flow measuring probe was attached to the left branch of the coronary artery. Blood pressure was measured in the Fe moral artery and the compound of the invention was injected intravenously. Peak blood flow values were measured.

Test results

TABLE II Increase in Coronary Blood Flow (%)

The values are given in%, based on the control

^ \ Dose

40

10th

100

[ig / kg

Test connections \ ^

45 A-l

89

72

B

181

219

The invention is explained in more detail by the following examples 50, without however being limited thereto.

Preparation of the starting compounds for carrying out processes 1 and 2

55

Production Example 1 1) To a solution of 7.56 g of 3-nitrobenzaldehyde and 7.93 g of methyl 4,4-dimethoxyacetoacetate in 30 ml of dried benzene, 0.18 g of acetic acid and 0.17 g of piperidine 60 were added and the mixture was Heated under reflux for 3.5 hours, the water formed being removed azeotropically therefrom. After adding benzene to the reaction mixture, the solution was washed successively with water, with a dilute aqueous sodium bicarbonate solution, with water and with a saturated aqueous sodium chloride solution, and then dried. After removal of the solvent under reduced pressure, 15.74 g of an oily residue was obtained

13

642353

Chromatographed on 470 g of silica gel and eluted with a mixture of benzene and ethyl acetate (volume ratio 25: 1) as the eluent, 8.06 g of a yellow oil of methyl 4,4-dimethoxy-2- (3-nitrobenzylidene) Acetoacetate (mixture of the ice and trans isomers) was obtained.

N.M.R. 6ppm (CDClj): 3.45 (s)

3.48 (s)

} (6H),

(1H),

5.8-6.22 (1H, m),

6.7 - 7.0 7.2-7.4

(m) (m)

} (4H),

8.14 8.23

(s) "I

(s) '

(1H).

3.88 (s) ì (3yy \ 4.90 (s) \

3.91 (s) '5.08 (s) 1

7.25 - 8.4 (5H, m).

The following compounds were obtained in the same manner as in Production Example 1:

8) Methyl 4,4-dimethoxy-2- (2-thenylidene) acetoacetate (mixture of the ice and 'trans isomers).

N.M.R. Sppm (CDC13): 3.45 (6H, s), I

3.95

(s)} (1H) 7 "7-8 (3H> m)>

(s) \ (s) /

(3H),

5.11 5.17 7.93 8.06

(s) (s) (s)

} (1H).

2) Methyl-4,4-dimethoxy-2- (2-methylbenzylidene) acetoacetate (mixture of the ice and trans isomers).

N.M.R. 5ppm (CDClj): 2.33 (3H, s),

3.23 3.42

3.64 (s)

3.79 (s) 6.8 - 7.4 (4H, m),

} (3H),

4.53 (s) 5.04 (s) 7.97 (s) 8.09 (s)

(s) \ (s) '

(6H),

} (1H),> (1H).

3) Methyl 2- (2-chlorobenzylidene) -4,4-dimethoxyacetoacetate (mixture of the ice and trans isomers).

N.M.R. 5ppm (CDCI3):

3.71 (s) 3.81 (s) 7-7.5 (4H,

} (3H), m),

3.28 (s) 3.41 (s) 4.68 (s) 5.08 (s) 8.02 (s) 8.12 (s) /

} (6H),} (1H),

(1H).

4) Methyl 4,4-dimethoxy-2- (4-pyridylmethylene) acetoacetate (mixture of the ice and trans isomers).

N.M.R. 5ppm (CDClg):

(3H),

3.82 (sK 3.89 (s) 7.1-7.4 (2H, m),

3.41 (s) 3.48 (s)

4.82 (s) 5.06 (s) 7.73 (s)

7.83 (s)

} (6H),

(1H), (1H),

8.5 - 8.8 (2H, m).

15 9) Methyl 2- (2,4-dichlorobenzylidene) -4,4-dimethoxy-acetoacetate (mixture of the ice and trans isomers). N.M.R. Sppm (CDCI3): 3.39 (s)

3.47 (s)

4.77 (s)

3.77 (s) 3.88 (s) 7.2 - 7.5

} (3H), (3H, m),

5.01 (s) 7.97 (s) 8.08 (s)

} (6H),} (1H),} (1H).

10) Methyl 2- (3,4-dichlorobenzylidene) -4,4-dimethoxy-25 acetoacetate (one of the ice and trans isomers).

F. 86.5 - 87.5 ° C.

11) Methyl-4,4-dimethoxy-2- (3,4-dimethoxybenzylidene) acetoacetaf (mixture of the ice and trans isomers).

N.M.R. Sppm (CDCI3):

30th

3.87

3.92

3.93 3.97

(s)] (») l

(S) I (S) l

(9H),

3.43 (s) 3.49 (s) 4.87 (s) 5.10 (s)

6.6 - 7.4 (3H, m),

7.80 7.89

(s) (s)

} (6H),} ÜH),

} (1H).

12) 2-phenoxyethyl ester of 2- (2-trifluoromethylbenz-ylidene) acetoacetic acid (mixture of the ice and trans isomers). N.M.R. Sppm (CDCI3): 2.18 (s) 1 (3H)

2.47 (s) /

3.9-4.9 (4H, m), 6.8-8.2 (10H, m).

5) Methyl 2- (2-trifluoromethylbenzylidene) -4,4-dimeth-oxyaeetoacetate (mixture of the ice and 'trans isomers).

N.M.R. Sppm (CDCI3): 3.28 (s) -1

3.42 (s) *

3.61 (s) cTtr \ 4.62 (s) -, / itt \

3.84 (s) '(3H)' 5.06 (s)> (1H)> 7.2-7.8 (4H, m), 8.0-8.14 (1H, m).

6) Methyl 4,4-dimethoxy-2- (2-methoxybenzylidene) acetoacetate (mixture of the ice and trans isomers).

N.M.R. Sppm (CDCI3): 3.39 (s) i (6H)

3.47 (s) 5

3.78 (s) 1 (6H) 4.77 (s)} (iH); 3.88 (s) 1 5.16 (s)

13) 2-chloroethyl ester of 2- (2-trifluoromethylbenzyliden) acetoacetic acid (mixture of the ice and trans isomers). N.M.R. Sppm (CDC13): 2.18 (s) j (3H)

3.50 (t, J = 6Hz) 3.76 (t, J = 6Hz)

2.48 (s)> (2H),

} (2H),

4.34 (t, J = 6Hz)

4.51 (t, J = 6Hz)

7.95 (q, J = 2.2Hz -, (m) 8.04 (q, J = 2.2Hz /

7.3 - 7.9 (4H, m),

6.7-7.2 (m) 7.3-7.9 (m)

} (4H),

8-15 G)} (1H). 8.23 s) '

14) 2-Ethoxyethyl ester of 2- (2-trifluoromethylbenzyli-den) acetoacetic acid (mixture of the ice and trans isomers). N.M.R. Sppm (CC14): 1.10 (t, J = 7Hz) y (3H))

7) Methyl 2- (2-allyloxybenzylidene) -4,4-dimethoxyacetoacetate (mixture of the ice and trans isomers).

N.M.R. Sppm (CDCI3): 3.3 (s) j (6H),

2. n (s) 1 (3H) 2.38 (s) '4.1-4.5 (2H, m), 7.3

1.18 (t, J = 7Hz) 3.1-3.8 (4H, m),

8.0 (5H, m).

3.73 3.78 4.71 5.07

(s) (s) (s) (s)

} (3H),} (1H),

3.4 (s) 4.54 (2H,

m),

5.1-5.5 (2H, m),

15) 2-Benzyloxyethyl ester of 2- (2-trifluoromethyl-benzylidene) acetoacetic acid (mixture of the ice and trans isomers).

642353

14

N.M.R. Sppm (CCI4): 2 10 (s) i (3H)

2.37 (s) 1 3.4-3.9 (2H, m), 4.1-4.7 (m) j 7.2 - 8.0 (10H, m)

4.37 (s) t (4H),

4.53 (s) j

Preparation of the Compounds According to the Invention Example 1

1) A mixture of 8.0 g of methyl 4,4-dimethoxy-2 - (3-nitrobenzylidene) acetoacetate and 4.07 g of isopropyl 3-aminocrotonate was heated to 70 ° C. with stirring for 1 hour and stirring was continued at 100 ° C for 1 hour and at 120 ° C for a further 2.5 hours. After dissolving the reaction mixture in ethyl acetate, the solution was washed with water and with an aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness under reduced pressure, whereby 11.03 g of the isopropyl ester of 5-methoxycarbonyl-6-d ' imthoxymethyl-2-methyl I-4- (3-nitrophenyl) -1,4-dihy-dropyridine-3-carboxylic acid was obtained in the form of a yellow-orange oil.

N.M.R. Sppm (CDCI3): 1.13 (d, J = 7.0Hz) i (6H)

1.27 (d, J = 7.0Hz) / 2.40 (3H, s), 3.47 (s), f6H)

3.50 (s) '(

3.69 (3H, s), 5.0 (1H, heptett, J = 7.0Hz), 5.17 (1H, s), 6.04 (1H, s),

6.92 (1H, broad s), 7.2 - 8.2 (4H, m).

2) The isopropyl ester of 5-methoxycarbonyl-6-dimeth-oxymethyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid was prepared by reacting methyl-2-benzylidene-4,4- dimethoxyacetoacetate obtained from benzaldehyde 'and methyl-4,4-dimethoxyaeetoacetate in the same manner as indicated in Preparation 1 with isopropyl 3-aminocrotonate in practically the same manner as in Example 1-1.

N.M.R. Sppm (CDClj): 1.11 (3H, d, J = 6.5Hz),

1.23 (3H, d, J = 6.5Hz), 2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 4.96 (1H, Heptett, J = 6.5Hz), 5.03 (1H, s ), 6.03 (1H, s), 6.73 (1H, s), 7.0-7.4 (5H, m).

The examples below were made in practically the same manner as given in Example 1-1:

3) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDC13): 1.07 (3H, d, J = 6.5Hz),

1.21 (3H, d, J = 6.5Hz), 2.32 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, s), 4.96 (1H , Heptett, J = 6.5Hz), 5.20 (1H, s), 5.97 (1H, s), 6.65 (1H, s), 6.9-7.4 (4H, m).

4) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4- (4-pyridyl) -l, 4-dihyd'ropyridine-3-carboxylic acid, mp 115 ^ -117 ° C .

5) Isopropyl ester of 4- (2-chlorophenyl) -5-methoxy-carbonyl-6-dimethoxymethyl-2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, mp 86-87.5 ° C.

6) Isopropyl ester of 4- (2-trifluoromethylphenyl) -5 - methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 92-94 ° C.

7) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-4- (2-methoxyphenyl) -2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, mp 110-111.5 ° C.

8) Isopropyl ester of 4- (2-allyloxyphenyl) -5-methoxy-

carbonyl-6-d'imethoxymethyl-2-methyl-1,4-dihydropyridine - 3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.01 (3H, d, J = 6.5Hz),

1.21 (3H, d, J = 6.5Hz), 2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4-6.3 (8H, m), 6.60 (1H,

broad s), 6.7-7.5 (4'H, m).

9) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.22 (3H, d, J = 6.5Hz),

1.28 (3H, d, J = 6.5Hz), 2.37 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.76 (3H, s), 5.07 (1H, Heptett, J = 6.5Hz ), 5.38 (1H, s), 6.04 (1H, s), 6.65-7.45 (4H, m).

10) Isopropyl ester of 4- (2,4-dichlorophenyl) -5-meth-oxycarbonyl-6-dimethoxymethyl-2-methyl-l, 4-dihydropyri-din-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.07 (3H, d, J = 6.5Hz),

1.21 (3H, d, J = 6.5Hz), 2.34 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 4.97 (1H, Heptett, J = 6.5Hz ), 5.39 (1H, s), 5.96 (1H, s), 6.65 (1H, s), 7.0-7.4 (3H, m).

11) Isopropyl ester of (3,4-dichlorophenyl) -5-methoxy-carbonyl-6-dimethoxymethyl 1-2-methyl-1,4-dihydropyridine - 3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.18 (d, J = 6.5Hz) \ (6fj)

1.25 (d, J = 6.5Hz) 2.39 (3H, s), 3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1H, s), 5.00 (1H, Heptett, J = 6.5Hz), 6.03 (1H, s), 6.75 (1H, s), 7.0-7.5 (3H, m).

12) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-4- (3,4-d'imethoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.16 (3H, d, J = 6.5Hz), 1.25 (3H, d, J = 6.5Hz), 2.37 (3H, s),

3.41 (s)

3.49 (s)

3.79 (3H), s), 3.84- (6H, s), 4.99 (1H, s), 4.99 (1H, Heptett, J = 6.5Hz), 6.03 (IH, s), 6.6-7.3 (4H, m) .

13) Dipropyl ester of 2-methyl-4- (3-nitrophenyl) -6-di-propoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid.

N.M.R. Sppm (CDCI3): 2.37 (3H, s), 5.02 (1H, s), 6.21 (1H, s), 6.88 (1H, broad s).

14) 2- (N-Benzyl-N-methylamino) ethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.1-1.3 (9H, m), 2.17 (3H, s), 2.33 (3H, s), 2.60 (2H, t, J = 6Hz), 3.48 (2H, s), 3.4-4.4 ( 8H, m), 5.63 (1H, s), 6.13 (1H, s), 6.71 (1H, s), 7.1-7.6 (9H, m).

15) 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-di-ethoxymethyI-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-di-hydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI ;,): 1.0-1.5 (9H, m), 2.37 (3H, s), 3.5-4.6 (1ÒH, m), 5.67 (1H, s), 7.12 (1H, s), 6.7-7.8 ( 10H, m).

16) 2-Chloroethyl-ester of 5-ethoxycarbonyl-6-diet-oxymethyl-4- (2-trifluoromethyl) -2-methyl-l, 4-dihydropyri-din-3-carboxylic acid.

N.M.R. Sppm (CCI4): 1.0-1.5 (6H, m), 2.39 (3H, s), 3.4-4.5 (10H, m), 5.5-5.7 (1H, m), 6.10 (1H, s), 6.55 (lH, s), 7-7.6 (4H, m).

17) 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-diet

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

642353

oxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihy-dropyridine-3-carboxylic acid.

N.M.R. Sppm (CC14): 1.0-1.4 (12H, m), 2.38 (3H, s), 3.3-4.3 (12H, m), 5.5-5.7 (1H, m), 6.10 (1H, s), 6.47 (1H, s), 7.2-7.7 (4H, m).

18) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-di-ethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-di-hydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDC1S): 1.0-1.6 (9H, m), 2.32 (3H, s), 3.4-4.4 (10, m), 4.47 (2H, s), 5.6-5.7 (1H, m), 6.11 (1H, s), 6.6-6.8 (1H, broad s), 7.2-7.7 (9H, m).

Example 2

1) A mixture of 19.62 g of the 2-phenoxyethyl ester of 2- (2-trifluoromethylbenzylidene) acetoacetate and 11.95 g of ethyl 2-amino-4,4-diethoxycrotonate was at 100 to 110 ° C for 20 hours heated at 120 to 130 ° C for a further 12 hours. The resulting mixture was dissolved in ethyl acetate and washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 27.7 g of a crude oil which was chromatographed on silica gel and eluted with a mixture of benzene and ethyl acetate (50: 1 by volume) as the eluent.

19.34 g of the 2-phenoxyethyl ester of 5-ethoxy-carbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid were obtained.

N.M.R. Sppm (CDC13): 1.0-1.5 (9H, m), 2.37 (3H, s), 3.5-4.6 (10H, m), 5.67 (1H, s), 7.12 (1H, s), 6.7-7.8 (10H, m).

The following compounds were obtained in the same manner as in Example 2-1:

2) 2-chloroethyl ester of 5-ethoxycarbonyl-6-diethoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CCI4): 1.0-1.5 (6H, m), 2.39 (3H, s), 3.4-4.5 (10H, m), 5.5-5.7 (1H, m), 6.10 (1H, s), 6.55 (1H, s), 7-7.6 (4H, m).

3) 2-Ethoxyethyl ester of 5-ethoxycarbonyl-6-diethoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CC14): 1.0-1.4 (12H, m), 2.38 (3H, s), 3.3-4.3 (12H, m), 5.5-5.7 (1H, m), 6.10 (1H, s), 6.47 (IH, s), 7.2-7.7 (4H, m).

4) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydro-pyridine-3-carboxylic acid.

N.M.R. Sppm (CDClj): 1.0-1.6 (9H, m), 2.32 (3H, s), 3.4-4.4 (10H, m), 4.47 (2H, s), 5.6-5.7 (1H, m), 6.11 (1H, s), 6.6-6.8 (1H, broad s), 7.2-7.7 (9H, m).

5) 2- (N-Benzyl-N-methylamino) ethyl ester of 5-ethoxy-carbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.1-1.3 (9H, m), 2.17 (3H, s), 2.33 (3H, s), 2.60 (2H, t, J = 6Hz), 3.48 (2H, s), 3.4-4.4 ( 8H, m), 5.63 (IH, s), 6.13 (1H, s), 6.71 (1H, s), 7.1-7.6 (9H, m).

6) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridin-3-car-bonic acid.

N.M.R. Sppm (CDClj): 1.13 (d, J = 7.0Hz) •> (6H)

1.27 (d, J = 7.0Hz) / 2.40 (3H, s), 3.47 (s) 1 (6H)

3.50 (s) *

3.69 (3H, s), 5.0 (1H, heptet, J = 7.0Hz), 5.17 (1H, s), 6.04 (1H, s), 6.92 (1H, broad s), 7.2-8.2 (4H, m).

7) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4-phenyl-l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.11 (3H, d, J = 6.5Hz), 1.23 (3H, d, J = 6.5Hz), 2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 4.96 (1H, heptet, J = 6.5Hz), 5.03 (1H, s), 6.03 (1H, s), 6.73 (1H, s), 7.0-7.4 (5H, m).

8) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDClj): 1.07 (3H, d, J = 6.5Hz),

1.21 (3H, d, J = 6.5Hz), 2.32 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, s), 4.96 (1H , Heptett, J = 6.5Hz), 5.20 (1H, s), 5.97 (1H, s), 6.65 (1H, s), 6.9-7.4 (4H, m).

9) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (4-pyridyl) -l, 4-dihyd'ropyridine-3-carboxylic acid.

I.R. v Nujoi: 3300, 3200, 3070, 1710 (shoulder), 1700, max 1650, 1603, 1518, 1278, 1269, 1190, 1090, 960, 782 cm-1.

10) Isopropyl ester of 4- (2-chlorophenyl) -5-methoxy-carbonyl-6-dimethoxybethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 86-87.5 ° C.

11) Isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

LR. v ^ x01: 3400, 1720, 1690, 1653, 1493, 1319, 1310, 1278, 1206, 1095, 1035, 951, 768 cmJ.

12) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-4- (2-methoxyphenyl) -2-methyl-1,4-dihydropyridine - 3-carboxylic acid, mp 110-111.5 ° C.

13) Isopropyl ester of 4- (2-allyloxyphenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.01 (3H, d, J = 6.5Hz), 1.21 (3H, d, J = 6.5Hz), 2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4-6.3 (8H, m), 6.60 (1H, broad s), 6.7-7.5 (4H, m).

14) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.22 (3H, d, J = 6.5Hz), 1.28 (3H, d, J = 6.5Hz), 2.37 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.76 (3H, s), 5.07 (1H, heptett, J = 6.5Hz), 5.38 (1H, s), 6.04 (1H, s), 6.65-7.45 (4H, m).

15) Isopropyl ester of 4 '- (2,4-dichlorophenyl) -5-meth-oxycarbonyl-6-dimethoxymethyl-2-methyl-l, 4-dihydropyri-din-3-carboxylic acid.

N.M.R. Sppm (CDClg): 1.07 (3H, d, J = 6.5Hz),

1.21 (3H, d, J = 6.5Hz), 2.34 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 4.97 (1H, Heptett, J = 6.5Hz ), 5.39 (1H, s), 5.96 (1H, s), 6.65 (1H, s), 7.0-7.4 (3H, m).

16) Isopropyl ester of 4- (3,4-dichlorophenyl) -5-meth-oxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.18 (d, J = 6.5Hz) \ (gH)

1.25 (d, J = 6.5Hz) S 2.39 (3H, s), 3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1H, s), 5.00 (1H, heptet , J = 6.5Hz), 6.03 (1H, s), 6.75 (1H, s), 7.0-7.5 (3H, m) ..

17) Isopropyl ester of 5-methoxycarbonyl-6-dimeth-oxymethyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.16 (3H, d, J = 6.5Hz),

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

642353

16

1.25 (3H, d, J = 6.5Hz), 2.37 (3H, s), 3.41 s)

3.49 (s)

3.79 (3H, s), 3.84 (6H, s), 4.99 (1H, s), 4.99 (1H, Heptett, J = 6.5Hz), 6.03 (1H, s), 6 6-7.3 (4H, m).

18) Dipropyl ester of 2-methyl-4- (3-nitrophenyl) -6-di-propoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid. N.M.R. Sppm (CDC13): 2.37 (3H, s), 5.02 (1H, s), 6.21 (1H, s), 6.88 (1H, broad s).

Example 3

1) To a solution of 15.85 g of the 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid in 159 ml of acetone 15.85 ml of 6N hydrochloric acid was added at ambient temperature with stirring and stirring was continued for 1.5 hours. The reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution and the acetone was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and then dried. After removal of the solvent, 13.56 g of the 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-formyl-2-methyl-l, 4-dihydropyridin-3-car-bonic acid in Form of an oil.

N.M.R. Sppm (CDClg): 1.22 (3H, t, J = 7.5Hz), 2.40 (3H, s), 4.0-4.6 (6H, m), 5.71 (1H, s), 6.7-7.7 (10H, m), 10.26 (1H, s).

The following compounds were prepared in the same manner as in Example 3-1:

2) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-phenyl-l, 4-dihydropyridine-3-carboxylic acid.

3) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridine-3-carboxylic acid.

Mp 143-144 ° C.

4) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -l, 4-dihydropyridine-3-carboxylic acid.

Mp 143-145 ° C.

5) Isopropyl ester of 4- (2-chlorophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 102-103 ° C.

6) Isopropyl ester of 4- (2-trifluoromethylphenyl) -6-formyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 83-85 ° C.

7) Isopropyl ester of 6-formyl-5-methoxycarbonyl-4 - (2-methoxyphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 142-143 ° C.

8) Isopropyl ester of 4- (2-allyloxyphenyl) -6-formyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 103-104.5 ° C.

9) isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid,

M. 114-116 ° C.

10) Isopropyl ester of 4- (2,4-dichlorophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDCI3): 1.07 (3H, d, J = 6.5Hz),

1.24 (3H, d, J = 6.5Hz), 2.39 (3H, s), 3.71 (3H, s), 4.98 (1H, Heptett, J = 6.5Hz), 5.51 (1H, s), 6.93 (1H, s ), 7.0-7.4 (3H, m), 10.34 (1H, s).

11) Isopropyl ester of 4- (3,4-dichlorophenyl) -6-formyl - 5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 95-96 ° C.

12) isopropyl ester of 6 formyl-5-methoxycarbonyl-4-

- (3,4-dimethoxyphenyl) -2-methyl-l, 4-dihydropyridine-3-car-bonic acid.

N.M.R. Sppm (CDClj): 1.14 (3H, d, J = 6.5Hz),

1.26 (3H, d, J = 6.5Hz), 2.40 (3H, s), 3.78 (3H, 5 s), 3.84 (6H, s), 4.98 (1H, Heptett, J = 6.5Hz),

5.05 (1H, s), 6.5-7.3 (4H, m), 10.44 (1H, s).

13) Dipropyl ester of 6-formyl-2-methyl-4- (3-nitro-phenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid.

N.M.R. Sppm (CDCI3): 0.87 (3H, t, J = 7 5Hz), 10 0.90 (3H, t, J = 7.5Hz), 1.55 (2H, sextet,

J = 7.5Hz), 1.61 (2H, sextet, J = 7.5Hz), 2.44 (3H, s), 4.02 (2H, t, J = 7.5Hz), 4.13 (2H, t, J = 7.5Hz), 5.28 (1H, s), 7.11 (1H, broad s), 7.4-8.2 (4H, m), 10.56 (1H, s). 15 14) 2-Hydroxyethyl ester of 5-ethoxycarbonyl-6-formyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDClg): 5.25 (1H, s), 10.50 (1H, s).

15) 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-formyl-20 -4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3 -

-carboxylic acid.

N.M.R. Sppm (CDClg): 1.14 (t, J = 7Hz) \ (gjj)

1.26 (t, J = 7Hz)

2.43 (3H, s), 3.3-3.8 (4H, m), 4.0-4.5 (4H, m), 25 5.7-5.8 (1H, m), 6.8-7.0 (1H, m), 7.1-7.8 (4H,

m), 10.27 (1H, s).

16) 2-Benzyloxyethyl ester of 51-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid.

30 N.M.R. Sppm (CC14): 1.23 (3H, t, J = 7.5Hz), 2.40 (3H, s), 3.4-4.5 (6H, m), 4.41 (2H, s), 5.7-5.8 (1H, m), 6.8 -6.9 (1H, m), 7.2-7.8 (9H, m), 10.28 (1H, s).

17) 2- [N ~ benzyl-N-methylamino] ethyl ester of 5-eth-35 oxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-

-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. Sppm (CDClg): 1.23 (3H, t, J = 7Hz),

2.19 (3H, s), 2.41 (3H, s), 2.63 (2H, t, J = 7Hz), 3.51 (2H, s), 4-4.4 (4H, m), 5.71 (1H, broad s), 40 6.91 (1H, broad s), 7.2-7.7 (9H, m), 10.28

(1H, s).

Example 4

A mixture of 11.0 g of the isopropyl ester of 45 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (3-nitro-phenyl) -l, 4-dihydropyridine-3-carboxylic acid and 11 ml of 6N hydrochloric acid in 110 ml of acetone was stirred at ambient temperature for 4 hours. After removal of the acetone, water was added to the reaction mixture 50 and it was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution. The resulting aqueous solution was extracted with ethyl acetate and the extract was washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, an oily residue was obtained, which immediately solidified to form crude yellow-orange crystals of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1, 4-dihydro -pyridine-3-carboxylic acid.

60 N.M.R. Sppm (CDCI3): 1.13 (3H, d, J = 7Hz),

1.28 (3H, d, J = 7Hz), 1.79 (3H, s), 3.80 (3H, s), 5.02 (1H, Heptett, J = 7Hz), 5.27 (1H, s), 7.11 (1H, broad s) , 7.4-8.2 (4H, h), 10.60 (1H, s).

65 Example 5

1) To a solution of 4.2 g of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4 - dihydtopyridine-S-carboxylate in 85 ml of ethanol were long

17th

642353

sam added in portions over a period of 35 minutes with cooling below 0 ° C with stirring 0.409 g of sodium borohydride. After the reaction mixture was acidified with a 50% aqueous acetic acid solution, the ethanol was removed under reduced pressure. Water was added to the resulting aqueous suspension, and the pale yellowish powder precipitated was collected by filtration and washed with water and dried. This powder (3.89 g) was recrystallized from ethanol, giving 3.05 g of the isopropyl ester of 6-hydromethyl-5-mthoxycarbonyl-2-methyI - 4- (3-nitrophenyI) -l, 4-d'ihydropyridine -3-carboxylic acid, mp 164 to 166 ° C, was obtained in the form of a yellow powder.

The following compounds were prepared in the same manner as in Example 5-1:

2) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-phenyl-l, 4-dihydropyridine-3-carboxylic acid, mp 132-133 ° C.

3) Isopropyl ester of 6-hydroxymethyl-5-methoxycarb-onyl-2-methyl-4- (2-toIyl) -l, 4-dihydropyridine-3-carboxylic acid, mp 134-135.5 ° C.

4) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4- (4-pyridyl) -l, 4-dihydropyridine-3-carbon acid, mp 182-183 ° C.

5) Isopropyl ester of 4- (2-chlorophenyl) -6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 122-123 ° C.

6) Isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyri-din-3-carboxylic acid, mp 123-125 ° C.

7) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-4- (2-methoxyphenyI) -2-methyl-1, 4-dihydropyridine - 3-carboxylic acid, mp 142-143 ° C.

8) Isopropyl ester of 4- (2-allyloxyphenyl) -6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-l, 4-d'ihydropyridine-3-carboxylic acid, mp 124-125 ° C.

9) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid, mp 124.5-126 ° C.

10) Isopropyl ester of 4- (2,4-dichlorophenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 150-151 ° C.

11) Isopropyl ester of 4- (3,4-dichlorophenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyri-din-3-carboxylic acid, mp 122-123 ° C.

12) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine - 3-carboxylic acid, mp 123-124 ° C.

13) dipropyl ester of 6-hydroxymethyl-2-methyl-4 - (3-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid,

Mp 118-120 ° C.

14) 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-tri-f luoromethylphenyI) -6-hydroxymethyl-2-methyl-1,4-dihy dro-pyridine-3-carboxylic acid, F. 148-149aC.

15) 2-Ethoxyethyl ester of 5-ethoxycarbonyl-4- (2-tri-fluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihy-dropyridine-3-carboxylic acid, mp 65-66.5 ° C

16) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethyIphenyl) -6-hydroxymethyI-2-methyl-1,4-dihy-dropyridine-3-carboxylic acid, mp 104-106 ° C.

Example 6

1) To a solution of 4.5 g of the isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid in 35 ml of acetic acid, 97 g of hydroxylamine hydrochloride and 1.43 g of sodium acetate were added and the mixture was stirred at ambient temperature for 2.5 hours. After 4.14 g of acetic anhydride was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and then at 95 to 100 ° C for a further 4 hours. The acetic acid and excess acetic anhydride were removed in vacuo, then water was added to the residue and neutralized with a saturated aqueous sodium bicarbonate solution. This aqueous suspension was extracted twice with ethyl acetate and the combined extract was washed with io water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give 4.88 g of a reddish brown oil which was chromatographed on 150 g of silica gel and washed with a Mixture of benzene and ethyl acetate (volume ratio 15 10: 1) as the eluent was eluted to obtain 2.99 g of crude crystals. These were recrystallized from ethanol, 1.89 g of the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydro-pyridine-3-carboxylic acid, F. 148-150 ° C, in the form of yellow 20o prisms.

The following compounds were prepared in the same manner as in Example 6-1:

2) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-25-methyl-4-phenyl-l, 4-dihydropyridine-3-carboxylic acid, F. 130

up to 131 ° C.

3) isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridine-3-carboxylic acid,

Mp 147-149 ° C.

30 4) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -l, 4-dihydropyrid'in-3-carboxylic acid, mp 192-195 ° C (dec. ).

5) Isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carbon

35 acid, mp 176-177 ° C.

6) Isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, mp 172-173 ° C.

7) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-40 - (2-methoxyphenyl) -2-methyl-l, 4-d'ihydropyridine-3-carbon-

acid, mp 139-140 ° C.

8) Isopropyl ester of 4- (2-allyloxyphenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 115-116 ° C.

45 9) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid, mp 129-131 ° C.

10) Isopropyl ester of 4- (2,4-dichlorophenyl) -6-cyano - 5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carbon-

50 acid, mp 141-142 ° C.

11) Isopropyl ester of 4- (3,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp 159-160 ° C .

12) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-55 - (3,4-dimethoxyphenyl) -2-methyl-l, 4-dihydropyridin-3-car-

bonic acid, mp 124.5-125.5 ° C.

13) Dipropyl ester of 6-cyano-2-methyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3,5-d'icarboxylic acid, mp 138-140 ° C.

14) 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbo-

60 nyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine - 3-carboxylic acid, mp 118-119 ° C.

15) 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridin-3-car-bonic acid, mp 150.5-152 ° C.

65 16) 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl - 4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3 - carboxylic acid, mp 104-105 ° C.

17) 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbo-

642353

18th

nyl-4- (2-trifhioromethylphenyl) -2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, mp 146-147.5 ° C.

18) 2- (N-Benzyl-N-methylamino) ethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid hydrochloride! s, mp 203 to 204 ° C (dec.).

Example 7

5 ml of an aqueous solution were added to a solution of 1.119 g of the 2-acetoxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid in 20 ml of ethanol Solution of 0.346 g of potassium carbonate was added dropwise under reflux and with stirring for 2 hours. After cooling, the ethanol was removed from the reaction mixture in vacuo, after which it was neutralized with acetic acid and extracted twice with ethyl acetate. The combined extract was washed with a dilute aqueous sodium bicarbonate solution and with an aqueous sodium chloride solution, and then dried. The solvent was removed in vacuo to give an oil which spontaneously crystallized to give 0.94 g of crystals of the 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-nitrophenyI) -l, 4-dihydropyridine-3-carboxylic acid, mp 150.5-152 ° C.

Example 8

A mixture of 5.20 g of the 2Jchloroethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphe- 'nyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid, 3.63 gs N-methylbenzylamine and 0.2 g sodium iodide in 10 ml propyl alcohol was refluxed for 4.5 hours. After the solvent was removed from the reaction mixture in vacuo, water and ethyl acetate were added to the residue. The ethyl acetate layer 10 was separated, washed with water and then dried. After removal of the solvent, 6.98 g of a residue oil were obtained, which was chromatographed on 210 g of silica gel and eluted with a mixture of benzene and ethyl acetate (volume ratio 5: 1) as the eluent 15, giving 3.67 g of an oil of the 2nd - (N-Benzyl - N-methylamino) ethyl ester of 5-ethoxycarbonyl-6-di-ethoxymethyI-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihy-dropyridine-3-carboxylic acid.

N.M.R. Sppm (CDClj): 1.1-1.3 (9H, m), 2.17 (3'H, s), 20 2.33 (3H, s), 2.60 (2H, t, J = 6Hz), 3.48 (2H, s),

3.4-4.4 (8H, m), 5.63 (1H, s), 6.13 (1H, s), 6.71 (1H, s), 7.1-7.6 (9H, m).

Claims (6)

642353 CLAIMS 1. 2-methyl-dihydropyridine compound, characterized by the general formula in which: R1 is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-di -chlorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl, R2 propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2- Benzyloxyethyl or 2- (N-benzyl-N-methylamino) ethyl, R3 lower alkyl and R4 di (lower) alkoxymethyl, formyl, hydroxymethyl or cyano, with the proviso that when R13 means Ni-trophenyl, R2 2- Hydroxyethyl and R4 cyano or formyl or R2 propyl or isopropyl, and the pharmaceutically acceptable salts thereof. (1-7) H 45 characterized in that a compound of the general formula R ClŒ2ffl2OOCvA ^ œOR3 CH , W4 H (iid) reacted with N-methylbenzylamine, wherein in the above formulas R1, R3 and Ra4 each have the meanings given in claim 40, with the proviso that when Rl is 3-nitrophenyl, R2 is propyl or isopropyl. 47. Pharmaceutical composition which contains as an active ingredient a 2-methyldihydropyridine compound of the formula I according to claim 65 or a pharmaceutically acceptable salt thereof. 642353 (1-3) reduced, wherein in the above formulas R1, R2 and R3 have the meanings given in claim 40, with the proviso that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl. 44. Process for the preparation of a compound of the general formula C00R * CH3 '"JJ" CN a-5) characterized in that a compound of the general formula R R ^ OOC CH .COOR " CHO • N-H (I - 3 ') with hydroxylamine or a salt thereof and then reacting the product obtained with a dehydrating agent, wherein in the above formulas R1 and R3 each have the meanings given in claim 40 and Rb2 is propyl, isopropyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl - N-methylamino) ethyl, with the proviso that that 5 when R1 is 3-nitrophenyl, Rb2 is propyl, isopropyl or 2-hydroxyethyl. 45. Process for the preparation of a compound of the general formula HIGH2CH2OOC. characterized in that a compound of the general formula R1 R ^ OCH2CH200CJ ^ COOR3 CH J 1 (1-4) characterized in that a compound of the general formula - R1 r2 ° 0C \ ^ k / C00R3 CH- AN ^ CHO 5 H (1-1) hydrolyzed, wherein in the above formulas R1, R2, R3 and Ra4 each have the meanings given in claim 40, with the proviso that when R1 is 3-nitrophenyl, R2 is propyl, isopropyl or 2-hydroxyethyl. 43. Process for the preparation of a compound of the general formula R1 R200C1, C00R3 CH3 H i2OH '(1-3) characterized in that a compound of the general formula (1-2) characterized in that a compound of the general formula r1-chs = c-c0ch " i00R? (II-2) with an amino compound of the general formula R * -c = ch ~ coor3 -1,4-dihydropyridine-3-carboxylic acid. 22. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-tolyl) -1,4-dihydropyridine-3- carboxylic acid. 23. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -1,4-dihydropyridine-3- carboxylic acid. 24. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3- carboxylic acid. 25. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-4- (2-tri-luormethylphenylj-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine- 3-carboxylic acid. 26. A compound according to claim 1 or 2, characterized in that it is the isopropyl 2nd 50 (III - 2) implements wherein in the above formulas R1, Ra2, R3 and Ra4 each have the meanings given in claim 40, with the proviso that when R1 is 3-nitrophenyl, 55 Ra2 is propyl or isopropyl. 42. Process for the preparation of a compound of the general formula R ^ coor * (i-i '> 60 r200c i ^ / coor3 TT ch / ^ i ^ ch0 2. Compound according to claim 1, characterized in that in the general formula (I) mean: R1 phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-di-chlorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4 -Pyridyl or 2-thienyl, R2 propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl-N-methylamino) ethyl, R3 is methyl, ethyl or propyl and R4 is dimethoxymethyl, diethoxymethyl, dipropoxymethyl, formyl, hydroxymethyl or cyano. 3 H (Ile) CN 30 hydrolyzed, wherein in the above formulas R1 and R3 each have the meanings given in claim 40 and Re2 means acyl. 46. Process for the preparation of a compound of the general formula 35 ^ ^^ nNCH ^ OOC J ^ COOR3 CH. CH. 3rd 642353 methyl-2-methyl-4- (3-nitrophenyl) -I, 4-dihydropyridin-3-car-bonic acid, the isopropyl ester of 4- (2-chlorophenyl) -5-methoxy-carbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine - 3-carboxylic acid, the isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid, the dipropyl ester of 2-methyl-4- (3-nitrophenyl) -6-di-propoxymethyl-l, 4-dihydropyridine-3,5-dicarboxylic acid, the 2- (N-benzyl-N-methylamino) ethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-di-ethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihy-dropyridine-3-carboxylic acid, the 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-diethoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6-di-ethoxymethyI-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihy-dropyridine-3-carboxylic acid, the isopropyl ester of 5-methoxycarbonyl-6-formyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-chlorophenyl) -5-methoxycarbonyl-6-formyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-6-formyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the dipropyl ester of 2-methyl-4- (3-nitrophenyl) -6-formyl-l, 4-dihydropyridine-3,5-dicarboxylic acid, the 2- (N-benzyl-N-methylamino) ethyl ester of 5-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, the 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-formyl - 4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, the 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-formyl - 4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid or the benzyloxyethyl ester of 5-ethoxycarbonyl-6-formyl - 4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid. 3. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3- -carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-chlorophenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridin-3-car-bonic acid, the isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (2-methoxyphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-allyloxyphenyl) -6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2,4-dichlorophenyl) -6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (3,4-dichlorophenyl) -6-hydroxy-5 methyl-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (3,4-dimethoxyphenyl) -2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, io the dipropyl ester of 6-hydroxymethyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid, the 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-tri-fluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydro-pyidin-3-carboxylic acid, 15 the 2-ethoxyethyl ester of 5-ethoxycarbonyl-4- (2-tri-fluoromethylphenyl) -6-hydroxymethyl-2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid, the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-tri-fluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydro-20 pyridine-3-carboxylic acid, the isopropyl ester of 6-cyano-5-methylcarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl-l, 4-dihydropyridine-3-carboxylic acid, 25 the isopropyl ester of 6-cyano-5-methoxycarbonyl-2 - methyl-4- ( 2-tolyl) -1, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl- (4-pyridyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-meth-30oxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) ) -5-methoxycarbonyl-2-methyl-l, 4-dihydropyridin-3-car-bonic acid, the isopropyl ester of 6-cyano-5-methoxycarbonyl-4-35 - (2-methoxyphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2-allyloxyphenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, 4o the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-thienyl) -l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 4- (2,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, 45 the isopropyl ester of 4- (3,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, the isopropyl ester of 6-cyano-5-methoxycarbonyl-4 - (3,4-dimethoxyphenyl) -2-methyl-l, 4-dihydropyridin-3-car-50 bonic acid, the dipropyl ester of 6-cyano-2-methyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid, the 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl - 4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine-3-55 carboxylic acid, the 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylic acid, the 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4-60 - (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridin-3-car-bonic acid, the 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine - 3-carboxylic acid, 65 den 2- (N-benzyl-N-methylamino ) ethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid hydrochloride, the isopropyl ester of 5-methoxycarbonyl-6-dimethoxy 4th ester of 6-cyano-5-methoxycarbonyl-4- (2-methoxyphenyl) -2-methyl-l, 4-dihydropyridine-3-carboxylic acid. 27. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2-allyloxyphenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine-3- carboxylic acid. 28. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-thie-nyl) -l, 4-dihydropyridin-3 -carboxylic acid. 29. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl-2-methyl-l, 4-dihydropyridine. 3-carboxylic acid. 30. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (3,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl - 2-methyl-l, 4-dihydropyridine- 3-carboxylic acid. 31. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine -3-carboxylic acid. 32. Compound according to claim 1 or 2, characterized in that it is the dipropyl ester of 6-cyano-2-methyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid . 33. Compound according to claim 1 or 2, characterized in that it is the 2-phenoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-l, 4-dihydropyridine -3-carboxylic acid. 34. Compound according to claim 1 or 2, characterized in that it is the 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-ni-trophenyl) -l, 4th -dihydropyridine-3-carboxylic acid. 35. Compound according to claim 1 or 2, characterized in that it is the 2-ethoxy-ethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4 -dihydropyridine-3-carboxylic acid 36. Compound according to claim 1 or 2, characterized in that it is the 2-benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydroxypiridine. 3-carboxylic acid. 37. Compound according to claim 1 or 2, characterized in that it is the 2- (N-benzyl-N-methylamino) ethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2- trif luormethylphenyl) -2-methyl-1,4-dihydropyridine - 3-carboxylic acid hydrochloride. 38. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl - 4- (3-nitrophenyl) -l, 4-dihydropyridin-3- carboxylic acid. 39. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 5-methoxycarbonyl-6-formyl-2-methyl-4- (3-ni-trophenyl) -l, 4-dihydropyridin-3 -carboxylic acid. 40. Process for the preparation of a compound of the general formula, characterized in that a compound of the general formula r1-ch = c-c0-rf | a c00r3 (ii-D io with an amino compound of the general formula ch? -c = ch-c00r? 4. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4 - (3-nitrophenyl) -l, 4-dihydropyridine-3- carboxylic acid. 5 642353 R2ooc 5 | a nh0 15 2 to -1) is implemented, wherein in the formulas R1 and R3 above have the meanings given in Claims 1 and 2, 20 Ra2 is propyl, isopropyl, 2-chloroethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (N-benzyl-N-methylamino-no) ethyl and Ra4 is di (lower) alkoxymethyl, with the proviso that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl. 25 41. Process for the preparation of a compound of the general formula R1 R ^ OOC ^ JvXOOR * CH A A " H 5 io 15 20th 25th 30th 35 40 45 50 55 60 65 642353 5. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4 - phenyl-l, 4-dihydropyridine-3-carboxylic acid. 6. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (2-tolyl) -l, 4-dihydropyridin-3 -carboxylic acid. 7. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -1,4-dihydropyridine-3 -carboxylic acid. 8. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2-chlorophenyl) -6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-1,4-dihydropyridine-3 -carboxylic acid. 9. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxy-2-methyl-l, 4-dihydropyridine-3- carboxylic acid. 10. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (2-meth-oxyphenyl) -2-methyl-1,4-dihydropyridine-3 -carboxylic acid. 11. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2-allyloxyphenyl) -6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-l, 4-dihydropyridine-3 -carboxylic acid. 12. Compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4 - '(2-thienyl) -1,4-dihydropyridine-3- carboxylic acid. 13. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (2,4-dichlorophenyl) -6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-1,4-dihydropyridine -3-carboxylic acid. 14. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 4- (3,4-dichlorophenyl) -6-hydroxymethyl-5-meth-oxycarbonyl-2-methyl-1,4-dihydropyridine -3-carboxylic acid. 15. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (3,4-di-methoxyphenyl) -2-methyl-1,4-dihydropyridine -3-carboxylic acid. 16. A compound according to claim 1 or 2, characterized in that it is the dipropyl ester of 6-hydroxymethyl-2-methyl-4- (3-nitrophenyl) -l, 4 - dihydropyridine-3,5-dicarboxylic acid. 17. A compound according to claim 1 or 2, characterized in that it is the 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) - 6-hydroxymethyl-2-methyl-l, 4-dihydropyridine- 3-carbon acid. 18. A compound according to claim 1 or 2, characterized in that it is the 2-ethoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) - 6-hydroxymethyl-2-methyl-1,4-dihydropyridm- 3-carbon acid. 19. A compound according to claim 1 or 2, characterized in that it is the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethyl) -6 - hydroxymethyl-2-methyl-1,4-dihydropyridine 3-carboxylic acid. 20. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitro-phenyl) -1, 4-dihydropyridine-3 -carboxylic acid. 21. A compound according to claim 1 or 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl- 6