NL7907482A - 2-METHYL-DIHYDROPYRIDINE COMPOUNDS, METHODS FOR PREPARING THEREOF, AND CONTAINING PHARMACEUTICAL PREPARATIONS THEREOF. - Google Patents

Description

2-Methyl-dihydropyridine compounds, processes for their preparation as well as pharmaceutical preparations containing these compounds.

The invention relates to 2-methyl-dihydropyridine compounds and salts thereof *. More particularly, "the invention relates to novel 2-methyl-dihydropyridine compounds and pharmaceutically acceptable salts thereof having vasodilation and anti-hypertensive activity, methods of preparation thereof, as well as pharmaceutical compositions containing these components." for the therapeutic treatment of cardiovascular disorders and hypertension in humans * 10 Fat is known in the art in this field, b * v * are known the compounds of the formulas 4, 5 sa 6 of the formula sheet (known from U.S. Pat. * 485 * 847 * Hifedipine, formula 4 and German Qffenlegungsschrift 26.29.892, formulas 5 and 6).

15 It is one. main object of the invention to provide new and suitable 2-methyl-dihydropyridine compounds and pharmaceutically acceptable salts thereof, which are structurally characterized by the 3-position substituent of the dihydropyridine core and which are compared with known compounds, such as e.g. the aforementioned have a stronger activity.

It is another object of the invention to provide methods of preparing said 2-methyl-dihydropyridine compounds and their salts.

It is a further object of the invention to provide suitable pharmaceutical preparations containing as active ingredient said 2-methyl-dihydropyridine compound or a pharmaceutically acceptable salt thereof and which are suitable as vasodilating and anti-hypertensive agents.

It is a further object of the invention to provide 790 74 82 > - 2 - ♦ a therapeutic method · - for the treatment of cardiovascular disorders such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.

The 2-methyl-dihydropyridine compound of the invention can be represented by formula (1) of formula sheet f, wherein R 1 is phenyly. 3-anthrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl. 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2- thionyl.

2 · R propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (F-benzyl-IT-methylamino) -ethyl; alkyl} and 15 R 2 di (lower) alkoxymethyl, formyl, hydroxymethyl or cyanoia, provided that when 3-nitrophenylia, R 2 is 2-hydroxyethyl and R 2 is cyano or formyl, or 2 R propyl or isopropyl, is.

With regard to the title compound of formula (1), it is noted that optical isomers may occur due to the asymmetric carbon atom in the 4-position of. the dihydropyridine nucleus. This type of isomers. is considered to fall within the scope of the invention and is represented by the same formula (1).

In accordance with the invention, the title compound (1) can be prepared by a method as illustrated by the following schemes.

(i) Yorming of the basic structure: 30 (1) Method 1:

See reaction scheme JL from. the formula sheet, wherein R 1 and R 4 each have the aforementioned meanings, 2 R propyl, isopropyl, 2-chloroethyl, 2-ethoxyethyl, 2-phenoxy-3 »ethyl, 2-benzyloxyethyl, or 2- (R-benzyl-R- methylamino) ethyl 35 and 790 7 4 82 - 3 * d * R ^ di (lower) alkorymethyl, / provided that when R 1 is 3-nitrophenyl, 2 R is propyl or isopropyl.

5 (2) Method 2:

See reaction scheme B from. the formula sheet, where R1,

J T J

R, Br and: R ^ each have the aforementioned meanings, a a provided that when R is 5-nitrophenyl, £ 10 R is propyl isopropyl.

8 (U) Conversions of a functional group (3) Method 3 *

See reaction scheme CT of the formula sheet, wherein R, R 2, R 4 and R 4 each have the above meanings, provided that when R 1 is 5-nitrophenyl, 2 R is propyl, isopropyl, or 2-hydroryethyl.

(4) Method A '1 2

See reaction scheme B of the formula sheet, wherein R, R

And R 4 each have the aforementioned meanings, provided that when R ** is 3-nitrophenyl, 2 R is propyl or isopropyl.

(5) Method 5 * 25 See Reaction Scheme E of the formula sheet, wherein r * * and R ^ each have the aforementioned meanings, 2 R ^ propyl, isopropyl, 2-hydroryethyl, 2-ethoryethyl, 2-phenoryethyl, 2- benzyloryethyl or 2- (ST-benzyl-iT-methylamino) ethyl, provided that when R 1 is 3-nitrophenyl, 2 is R 1 propyl, isopropyl or 2-hydroryethyl.

(6) Method 6!

See reaction scheme F of the formula sheet, wherein R * 1 and 5 2 35 R each have the aforementioned meanings, and R is acyl.

6 d 790 7 4 82 «·> -4- (7) Method 7:

See reaction scheme G of the formula sheet, in which. R1, R ^ and R ^ "each have the aforementioned" meanings, provided that - | 5 'when R is 3-n-nitrophenyl, 2: R. propyl or isopropyl.

Lower alkyl for R 1 includes alkyl with 1-6 carbon atoms, L preferably alkyl with f-3 carbon atoms, and especially straight groups such as methyl, ethyl and propyl.

10 "Bi-lower" alkorymethyl for R 1 and R 3 "includes di (straight and branched lower alkory containing 1 to 6 carbon atoms) methyl, preferably groups with TJ carbon atoms, such as dimethozymethyl, diethoxymethyl and dipropoxymethyl .

2 .. "cyl" R includes conventional; groups, preferably alkanoylr, especially lower alkanoyl, such as alkanoyi. with. 1-6 carbon atoms (e.g. formyl, acetyl, propionyl, butyrryl, iso-butyryl and valeryl).

The starting compounds (2-1) and (2-2) used in the methods 1 and II include new and known compounds in which the new compounds can be prepared by reaction

in the usual manner of 4-substituted acetoacetate: (2 ^) or (2.1) and aldehyde (2 ^), as proposed in reaction scheme H

A, -E -j- y j "of the formula sheet, where R, R ^ and Rj" are the aforementioned

a 1 have niches and reaction scheme I of the formula sheet, in which R

2 25 and R have the aforementioned meanings.

The other starting compounds (3-1) and (3-2) used in methods 1 and 2 can be prepared from a 4-substituted acetoacetate compound (3 ^) - or (3 ^ ') and ammonia or a salt thereof as represented in reaction scheme J of the formula sheet, wherein R has the aforementioned meanings, and reaction scheme K. of the formula sheet, in which R1 and R1 each have the aforementioned meanings.

Furthermore, the starting compound (2 ^) used in method 6 can be prepared by the method as represented in reaction scheme L of the formula sheet, wherein R, R ^ and R ^ each have the 790 74 82 + + - 5 meanings mentioned above and the compound 1-8 according to / method 2 and method 3 »as described above,

The methods of preparing the 2-methyl dihydropyridine compound (t) will be described in more detail below 5 ", (1) Method 11

This process relates to a process for preparing a compound (1-I ') wherein, a compound (2-1) is reacted with an amino compound (3-1), 10 - each. of the starting compounds (2-1) and (3-1) includes symmetric cis and trans isomers due to the double bond in their molecules, and according to this method the compound (1-1 ') can be prepared by any reaction series of geometric isomereir of the compound (2-1) with that of the compound T5 (jl), whereby all isomers and optional mixtures of the isomers of these starting compounds (2-1) and (3-1) can be considered if they fall within the framework of the working method,

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

Regarding the reaction type of this method, it is noted that the reaction e.g. optionally can be carried out by the 4-substituted acetyl acetate compound (2 ^) 4 790 7 A 82 9% -6 - in the presence of. convert the amino compound (3-1) with the aldehyde / (2_) * (2) Method 2:

This process involves the preparation of a compound (5-2) by reaction of a compound (2-2) with an amino compound (3-2) *

This method is practically the same as method 1 and can thus be carried out by reacting the compound (2-2) with (5-2) according to method 1 * ie the same reaction conditions (eg reaction temperature, solvent, accelerator) and the same alternative reaction procedure as mentioned in method 1, - can be used in this method, provided that the compound (2-2) or alternative reagents (2 ^ 1), (2 ^) ,, and the compound (3-2) in this method 15 are used instead of compound (2-1) or alternative reactants (2 ^) and (2 ^) and the compound (3-1) in method 1 * (5) Method 5:

This process involves the "preparation of a compound: (T-3) by hydrolysing a compound (I-1). The compound (Ι-I") can be prepared as illustrated in Methods 1 and 2.

In this method, the di (lower) alkoxymethyl group of the compound (I-1) is converted into a formyl group.

€ L

Hydrolysis can be performed in a conventional manner such as from. application to the cleavage of a so-called acetal function into the corresponding carbonyl function, and preferably e.g. an acidic hydrolyser ie in the presence of an acid such as an inorganic acid (e.g. hydrochloric acid, sulfuric acid) or an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid) or an acidic ion exchange resin »

This hydrolysis can be carried out in a suitable known solvent, such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, HI-dimethylformamide or dimethyl sulfoxide, a mixture of its choice or a buffer solution thereof.

790 74 82 Λ ♦ - 7 -

The reaction temperature is not limited and the reaction is usually carried out under cooling, at room temperature or under a slightly elevated temperature. (4) Process 4 - 5 This process involves the preparation of a compound (1-4) by reduce the compound (1-3).

The reduction can be carried out in a manner customary for the reduction of a formyl group to a hydroxymethyl group, in particular by using a reducing agent such as an alkali borohydride (eg lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride) or by * catalytic reduction with a catalyst preferably consisting of palladium on carbon, palladium chloride or rhodium on carbon. The reduction is usually performed in a conventional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide or tetrahydrofuran. The reaction temperature is not limited and the reaction is usually carried out under cooling, at room temperature or. slightly elevated temperature. The reduction method can be used as desired. are selected according to the type of compounds (1-3) * - (5) Method 5?

This process involves the preparation of a compound (1-3) in which a compound (1-3 ') is converted with hydroxylamino or a salt thereof and the product obtained is then reacted with a dehydrating agent.

According to this method, the formyl group of the starting compound (1-3 ') can be converted into the hydroxyiminomethyl group (first stage) and then this group converted into the cyano group (second stage).

Preferred hydroxylamine salts can be a salt with an acid, such as an inorganic acid (eg, hydrochloric, sulfuric) or an organic (such as acetic).

(i) First stage;

The reaction of this step is usually carried out as a so-called oxidation reaction, e.g. in the presence of <790 74 82-8 ~ an acid (e.g. hydrochloric, hydrobromic, sulfuric, formic, acetic, p-toluenesulfonic, boron trifluoride, silicon tetrachloride or titanium tetrachloride); established in basic conditions by a base, e.g.

Free hydroxylamine or in a conventional acidic or basic buffer solution. The reaction is usually carried out in a suitably known solvent such as water, dioxane, ethanol, methanol, dimethylformamide, or a mixture of its choice, but in case the aforementioned acid is a liquid, it can also be used as a solvent .

The reaction temperature is not limited and the reaction is usually carried out under cooling at. room temperature or slightly elevated temperature.

(ii) Second stage? Suitable dehydrating agents used in this step include conventional organic or inorganic compounds, such as a. inorganic acid (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid) ,. a. organic acid (eg formic acid, ·····> {acetic acid, trifluoroacetic acid.,. ethanesulfonic acid, p-toluenesulfonic acid), an organic anhydride (eg, acetic anhydride, benzoic anhydride, phthalic anhydride), an inorganic, acid halide (hv acetyl chloride, benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenyl chloroformate); an inorganic halogen compound (eg * 25 thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannic chloride, titanium tetrachloride) 5 a carbodiimide (eg ff, P-dicyclohexylcarbodiimide, N-cyclohexyl-JP-πιοτίilino), -carbonyldiimidazole; pentamethylene-ketene-rr-cyclohexylimine ethoxyacetylene, 2-ethyl-7-hydroxyisoxazolium salt} other phosphorus compounds (e.g., phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenyl phosphate) or a mixture thereof. When an acid is used as the dehydrating agent, the reaction can also be carried out in the presence of its salt, such as an alkali metal salt (e.g., sodium salt, or potassium salt).

<790 7 4 82 - 9 -

This reaction is usually conducted in a known solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane, and usually at room temperature or under heating, although the reaction temperature is not is critical * (6) Method 6:

This method involves the preparation of compound (1-6) by hydrolysing compound (2c).

In this method, the R acyl group of compound (2c) is eliminated by hydrolysis to yield the 2-hydroxyethyl compound (1-6).

The hydrolysis is carried out in the usual manner, as usual, for the cleavage of a so-called ester bond in the hydroxy function, preferably e.g. by basic hydrolysis, ie in the presence of a base, such as an alkali metal hydroxide, carbonate or bicarbonate (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate) or by an acid hydrolysis 20 'in the presence of a organic or inorganic acid, suitable examples of which are mentioned in method 3

This hydrolysis is preferably performed in a conventional solvent, such as water, acetone, dioxane, methanol, ethanol, dimethylformamide, dimethyl sulfoxide or a mixture of its choice. The reaction temperature is not critical and the reaction is usually carried out at room temperature or under heating.

(7) Method 7:

This process involves the preparation of a compound 30 (1-7) by reacting compound (2 ^) with β-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 other conventional solvents or mixtures of your choice.

790 74 82 -10 -, '\

The reaction may also be carried out in the presence of a base, of which, as suitable examples, may be mentioned an inorganic base, such as an alkali metal hydroxide, carbonate, biarbonate, hydride or amide (eg sodium hydroxide, potassium hydroxide, sodium carbonate , potassium carbonate, sodium bicarbonate, sodium hydride, sodium amide) or an organic base such as an alkali metal oxide (eg sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide), a salt of an organic acid (eg sodium acetate, potassium acetate), a tertiary Amine or imine base (eg triethylamine, pyridine, picoline, F, IT-dimethylaniline, N-methylpyrrolidine, F-methylmorpholine).

Terder, this reaction is preferably carried out in the presence next to the base of. an alkali iodide, such as lithium iodide. . dide. or sodium iodide.

15 The reaction temperature is: not limited; the response becomes.

usually performed at room temperature or under heating or heating.

According to the. Invention, the title reaction product can be obtained from the reaction mixture. are separated and isolated and then purified by methods usually used for these purposes, e.g. extraction with a suitable solvent, chromatography ,. precipitation or recrystallization.

Suitable examples of salts of the 2-methyl-dihydro-pyridine compounds (1) include a pharmaceutically acceptable salt such as an inorganic acid salt (eg hydrochloride, hydrobromide, phosphate, sulfate) and an organic acid salt (eg formate, acetate, fumarate, maleate, aspartate, glutamate).

The compound (1) thus obtained often comprises at least one pair of optical isomers due to the presence of an asymmetric carbon atom in the 4-position of the 1,4-dihydropyridine nucleus and can exist as any optical isomer or a mixture thereof. A racemic compound can be cleaved in the optical isomer by a method customary for racemic cleavage, such as chemical cleavage of the diastereomer salts with a known optically active 790 7 4 82-11 -mic acid (eg tartaric acid or camphor sulfonic acid) .

• It is noted that the compound (1) and its pharmaceutically acceptable salts have strong vasodilatory and anti-hypertensive activity and are suitable for the therapeutic treatment of cardiovascular disorders and high blood pressure, such as coronary artery insufficiency, angina pectoris or myocardial infarction and high blood pressure.

The strong pharmacological action of the compounds (1) 2 according to the invention is structurally characterized by the R-10 group, specifically selected from propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl, and 2- (F-benzyl-methyl-thylamino) ethyl.

More specifically, the compound (1), wherein e.g.

t 3 Z

i) R is 5-aitrophenyl or 2-chlorophenyl, R isopropyl, R'7 methyl and R 4 is cyano, and ii) R is 2-trifluoromethylphenyl, R isopropyl or 2-phenoxyethyl, methyl and R 1 hydroxymethyl or cyano, compared to the compounds mentioned herein have a stronger therapeutic effect as described above.

. The compound (1), wherein e.g. iii) R 5-aitro- 2 5 4.

Phenyl or 2-chlorophenyl, R isopropyl, Έ / methyl and R is dimethoxy-1 2 methyl or formyl, and iv) R is 2-trifluoromethylphenyl, R isopropyl or 2-phenoxyethyl, R is methyl or ethyl and R is dimethoxy-methyl diethoxymethyl or formyl is not only suitable as a vasodilator and anti-hypertensive agent, but also as an intermediate for the preparation of the more preferred are the vasodilator and anti-hypertensive agents of the invention as previously illustrated.

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

The pharmaceutical preparations of the invention comprise as active component the 2-methyl-dihydropyridine compound (1) or pharmaceutically acceptable salts thereof in an amount of about 0.01-500, preferably 0.1-250 mg per dosage unit for oral and parenteral administration.

790 74 82 · 'Λ • - - -12-

As "the quantity of the active ingredient becomes known: · in the dosage unit form is determined by the activity of the ingredient as well as the weight of the patient · The active ingredient may be in a solid form, such as a tablet, granules, powder, capsule, pill, wafer or suppository, or a suspension. i or solution are like a syrup, - in your kt ie liquid, emulsion • [or lemonade.] A pharmaceutical carrier or "diluent includes solid or liquid." non-toxic pharmaceutically acceptable materials.

Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peptin, acacia, peanut oil, olive oil, or sesame oil, cocoa butter, ethylene glycol or other conventional agents.

15 similar mode can. carrier or the diluent include a release retarding material such as glyceryl mono-stearate, glyceryl distearate or a wax.

In order to demonstrate the suitability of the compound (1), the pharmacological test results of some of the following: suggested compounds are explained in more detail below.

Hypotensive effect: "

Test method

Five were placed per group. Wistar rats. Applied. Each animal was rigidly secured in a cage sized to its body. Blood pressure was measured in the femoral artery by. a pressure transducer and recorded as electrically integrated values of the mean arterial pressure, and the heart rate was determined with a pulse wave detector.

Catheterization was performed under light anesthesia with ether. The test compound was administered orally three hours after the completion of the operation.

Trial connection

Terbinding A-1: Hiphedipine (Reference Compound)

Compound B: Isopropyl ester of 6-cyano-5-nonhoxycarbonyl-2-35 methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3- 790 7 4 82 <-13-carboxylic acid

Yerbinding C: Isopropyl ester of. 4- (2-chlorophenyl) -6-cyano-5-methoxy carbonyl-2-thy1-1,4-dihydropyridine-3-carboxylic acid.

5 Yer bond D: Isopropyl ester of 6-cyano-4- (2-trifluoromethyl-phenyl) -5-methoxycarbonyl-2-methyl-1,4-dihydro-pyrldine-5-carboxylic acid

Yerbinding B t 2-Phenoxyethyl ester of 6-cyano-4- (2-trifluoro-methylphenyl) -5-ethoxycarbonyl-2-methyl-1,4-di-10-hydropyridine-3-carboxylic acid

Yerbinding F: Isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxymethyl-5-methoxycarb ony1-2-methyl-1t4-dihydropyridine-3-carboxylic acid

Yerbinding G! 2-Phenoxyethyl ester of 4- (2-trifluoromethyl-1-phenyl) -5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

Trial results

The mean values of the 4k maximum decrease of the. blood pressure (mmHg) are shown in Table A «

20. TABEI A

v- Dose

Yerbinding ^^^^^ 1 mg / kg 10 mg / kg A-1 -25.6 + 1.5 -44.6 + 1.2 B -44.6 +1.7 -50.0 + 1.3 25 C -29.2 + 3.0 -40.6 + 2.2 Γ -34.6 + 0.9 -47.4 + 1.3 E -22.8 + 2.1 -44.2 + 1 .5 P -18.0 + 1.9 -46.6 + 2.1 0 -13.2 + 3.3 -47.8 + 2.4 0 790 74 82 »\ - - u-

Effect of coronary blood flow:; Test method • Mixed-breed dogs weighing 8-15 kg were anesthetized with an intrapentoneal dose of sodium pentobarbital 5 35 mg / kg. After the chest was opened, under artificial respiration, a flow meter probe was attached to the left circumference. flex branch of the coronary artery. Blood pressure was measured in the IL, femoral artery and the compound of the invention injected intravenously. The values were measured during the peak blood-10 flow.

Trial results.

TABLE · B

Increase in coronary blood flow (%). The value indicates percentages compared to the blank.

15 Dose

Sample charges' ^^ - ^ / ^^^ ® 10 TOO

A-f 89 72; ; B. - lat 219

The invention is now further illustrated by the following examples.

Preparation of the starting compounds for Methods 1 and 2

Preparation 1 1) To a solution of J-nitrobenzaldehyde (7.56 g) and methyl-4,4-dimetho-cyacetoacetate (7.93 g) in dried benzene (30 ml), acetic acid (0.18 g) and piperidine ( 0.17 g) and the. The mixture was refluxed for 5 hours under azeotropic removal of water.

After adding benzene in the reaction mixture, the solution was washed successively with water, a dilute aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride and dried. After removal of the solvent under reduced pressure, an oily residue (15.74 g) was obtained, which was chromatographed on silica gel (470 g) <790 7482 - 15- with a mixture of benzene and ethyl acetate (25 5 l by volume). ) as an eluent to give a yellow oil (8.06 g) of methyl 4-4-dimethoxy-2- (3-nitrobenzilidene) acetoacetate (mixture of cis and trans isomers).

5 I.T.M.R. cTdpm (CDC13) r 3.45 (s)) 3 -48 (a) 5.88 (e) j 4.90 (a)} (1H) j 3.91 (s) 5.08 (s) 7.25 - 8.4 (5ΗΓ, m) »10 The following compounds were obtained in practically the same manner as in preparation 1.

2) Methyl-4,4-dimetho: ey-2- (2-methylbenzylidene) acetoacetate (a mixture of cis and trans isomers).

: M.S. / ppm (0DCl?) i 2.35 (3ΗΓ, a), 3.23 (s)) ^ 15 3 »42 (a) 3M («)) (31), 4.55 (s) (.) 5 > 04 (.)> (1H) '6.8-7.4 (4H, m), 7.97 (e)). (1E) 5r09 (ff) 20 3) Methyl-2- (2-chlorobenzylidene) -4,4-dimetho: ryacetoacetate (a mixture of cis and trans isomers), ΙΓ.Μ.Η. / ppm (CDCl ^) * 3.28 (s) ^ 3.41 (s) 3.71 (β)) (3Η) # 4.68 (s)} (1H) j 25 5.81 (s) 5 0.08 (s) 7-7.5 (4H, m), 8.02 (e) 8.12 (s) 4) Methyl-4,4-dimethoxy-2- (4-pyridylmethylene) -acetoacetate (a mixture of cis and trans isomers).

30 Ï.M.E. / ppm (CDC15): 3.41 (s) ^ 3.48 (s) 3.82 (s) j 4.82 (s) j 3.89 (a) 5.06 (s) 7.1-7.4 (2H, m), 7.73 (s)} (1H) 35 7.83 (s) 79074 82

* V

. ; ~ te-8.5-8.8 (2H-hl).

5) Methyl-2- (2-trifluoromethyl-benzylidene) -4,4-<RTI ID = 0.0> liaetlioxyacetoacetate (a mixture of cis and trans isomers).

M.R. ƒdpm (CDCl 3) r 5.28 (s) ^ 5 3 -42 (s). [3, 1 (β)} (3H), 4.62 (s). 1H), I - 3.84. (s) 5.06 (s). ... "i ·." 7.2.-7.8 (, 4Hr m), 8.0-8.14 (1H, m).

6) Ethyl-4,4-dimethoxy-2- (2-methoxybenzylidene) acetetoacetate (a mixture of cis and trans isomers).

JUr.E .. Jdpnt (ODClj) * 5.39 (a) j 5.47 (a) 5.78 (s) ^ 6h ^ 4, TT (a)), (1H) f>. 3.88 C «) 5.4 6 (a) 1f. 6, T-r, 2: (m.)) (4Η) Γ 8.7 5 W) (1H).

7.3-7.9%) 8.23 (e) 7) Methy 1-2- (2-allyloxybenzy lidine) -4,4-dimethornyacetoacetate (a mixture of cis and trans isomers).

V MR. C £ ppm (CI50I ^) r 5.3 (a) j (55) f 20 3.4 (s) 3.73 (s)} (3H) ï 4.54 (2H, m), 5 ^ 78 (s) 4.71 (a) j 5.1-5.5 (21, m), 5.07 Ce) 5.8-6.22 (1H, m), 6.7-7.0 (m)) 7.2-7.4 (a) 8.14 (s)} (1H) # 8.25 Cs) 8) Methyl-4,4-dimethoxy-2- (2-thenylidene) acetoacetate (a 50 mixture of cis and trans isomers), ICM ppm (CDC13): 3.45 (6H, s), 5.88 (s) ^ (you) f 3.95 (s) 5.11 (s)) (1H), 7 “7'8 (3H '' m) 5.17 (s) 35 7.93 (3), (1H) <8.08 (s) 790 74 82 -17 - * "9} Methyl 2- (2,4-dichlorobenzylidine) -4,4 -dimet] aoxyacetoacetate (a mixture of ranis and trans isomers).

/ ppm (CDCl ^ t 3.39 (s) ^ ^ 3.47 (s) 5 3.77 (·)) (yes) (4.77 (s)) (1Η) ^ 5.88 (s) 5.01 (s) 7.2-7.5 (3H, m), 7.97 (s)} (tE)> _ 8.08 (s) 10) 3-methyl-2- (5,4-dicilorobenzylidene) -4 4-dimetioxyaceto-10 acetate (cis and trans isomers), mp 86.5 - 87.5 ° C * 1t) Methyl-4,4-dimethoxy-2- (3,4-dimethyl-benzylidene) -acetoacetate (a mixture of cis and trans isomers).

1Γ.1Ι.Β, / ppm (CDCl ^ r 3.43 (ff)) ^ 5.49 (a) 15 J, 87 (s) * \ 4.87 (s)) (tff)> 5.92 ( s) l (9E) i 5.10 (s) 5.95 («) / 5.9T (s) o M - 7.4 (3E, a) r 7.80 (s)} ^ 1E ^ 20 'T, 89 (a) 12) 2-Phenoxyethyl ester of 2- (2-trifluoromethylbenzylidene) acetoacetic acid (a mixture of cis and trans isomers).

F.Ji.H. dppm (COCl 3) t 2.18 (s) ^ 2.47 (s) 3.9-4.9 (4H, m), 6.8-8.2 (10H, m).

13) 2-Ghloroethyl ester of 2- (2-trifluoromethyl "benzylidene) -acetoacetic acid (a mixture of cis and trans isomers).

2Γ.Μ.Η. / ppm (CDCI ^ ï 2.18 (s) j ^ 2.46 (s) 30 5.50 (t, J = 6Hz) ^ (2H), 3.78 (t, J = 6ffz) 4.34 ( t, J-6Hz) j (2E) i 7.5-7.9 (4H, m), 4.51 (t, J = 6Hz) 7.95 (q, J = 2.2Hz) j (-] 2) # 35 8.04 (q, J = 2.25z) 790 74 82 -18 - * * 14) 2-Ethoryethyl ester of 2- (2-trifluoromethylhenzylidene) - / acetoacetic acid (a mixture of cis and trans isomers).

M.R. Tdpa (CCl4) i 1.10 (t, J-7Ez) j t, 18 (t, J = 7Hz) 5, 2.11 (s) j 5.1-3.8 (4H, a). j. 2.38 (s) 4, -1-4.5 (2E, m), 7.3-β, Ο (5H, a), j. 15) Z-Benzyloryethyl ester of 2- (2-trifluoromethylhenzyl-) -44 $ a een een)) a a eet eet eet eet eet eet eet ± ± (((((((((((± ± ± ((((((((((((((((((»» »» »» »» (((((CC CC CC CC CC ^ ^ -3 -3 -3 -3 -3 -3 -3 -3 5. , a), 2.57 (?) 4r1-4.7 (a) λ 7.2-8.0 (10H, m) 4.37 (s) I (4E),

; 4.55 (s) J

15r Preparation of the compounds of the invention:

Yoorheeld S .v 1) Their mixture of methyl-4,4-dimethoxy-2- (3-nitrohenzilidene) acetoacetate (8.0-g) and, isopropyl-3-aminocrotonate (4.07 g) was added for 1 hour with stirring "he heated to 100 ° C", after which stirring was continued for 1 hour at 100 ° G and for a further 2.5 hours he continued at 120 ° C. Had the reaction mixture dissolved in ethyl acetate the solution was washed with water and an aqueous solution of sodium chloride, oven magnesium sulfate dried, and then evaporated to dryness under reduced pressure to give a yellow-orange oil (11.03 g) of the isopropyl ester of 5-ethoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid.

ÏT.M.R. £ ppm (CDCl3): 1.13 (d, J »7.0Hz) ^ 30 1.27 (d, J = 7.0Hz) 2.40 (5H, s), 3.47 (s)) 3, 50 (s) 3.69 (3H, s), 5.0 (1H, heptet, J = 7.0Hz), 5.17 (1H, s), 6.04 (IE, s), 35 6.92 (1H, hreed s), 7.2-8.2 (4H, m), 1 790 7482 -19-2) The isopropyl ester ran 5-methornycarbonyl-6-dinethoay-methyl-2-methyl-4-phenyl-1 4-dihydropyridine-3-carboxylic acid was prepared by reacting methyl-2-benzilidene-4,4-dimethylacetoacetate obtained from benzaldehyde and methyl 4,4-dimethoryoryoacetate 5 according to preparation t with isopropyl 5-aminocrotonate ten. in practically the same manner as in Example 1-1).

; HVi £ .IU cfipm (CDClj) j 1.11 (3E, d, J = 6.5Hz),: t, 2J (JE, d, J = 6.5Hz) ^ 2.57 * (3H, s), 3.42 (3Ξ, s), 3.46 (5I, s), 4.96 (1H, heptet, 4-6.5Hz), 10 5.03 (1E, s), 6.03 (1H, s ), 6.73 (H, s), 7.0-7.4 (5H, m).

The following examples were prepared in practically the same manner as in Example Γ-1).

3) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-T5 2-methyl-4- (2-tolyl) -1,4-dihydropyridine-3-carboxylic acid.

ÏT.H.R. / ppm (CDCI ^): 1.07 (31, d, 4-6.5Hz), t, 21 (3H, d, J = 6.5Hz), 2.32 (31, a), 2.55 ( 3S, s), 3.41 (31, s), 3.44 (31, s), 5.62 (3H, s) ,. 4.96 (1H, heptet, 4 * 6.51s), 5.20 (tl, s), 5.97 (11, s), 6.65 (1H, s), 6.9-7.4 (41, at).

4) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy thy1-2-methyl-4- (4-pyridyl) -1,4-dihydropyridine-5-carboxylic acid, mp 115-117 ° C-25) Isopropyl ester of 4- (2-chlorophenyl) -5-metho: cycarbonyl-6-dimethoxy thy1-2-thy1-1,4-dihydropyridine-3-carboxylic acid, mp 86-87.5 ° C.

6) Isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxy-carbonyl-6-dimethoryme thy1-2-me thy1-1,4-dihydropyridine-3-.

30-carboxylic acid, melting point 92-94 ° 07) Isopropyl ester of 5-methorycarbonyl-6-dimethoxyaethyl- 4- (2-methoryphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 110-111.5 ° C.

8) Isopropyl ester of 4- (2-allyloxyphenyl) -5-ethoxycarbonyl-35-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

790 7482 - 20-

Pk E.M.R. J ppm (CDCIj-Jj 1.01 (3E, d, J = 6.52z), 1.21 (32, d, J = 6.5Iz), 2.33 (32, β), 3.4β (6E , s), 3.63 (3E, s), 4.4-6.3 (SH, m), 6.60 (1E, broad s), 6.7-7.5 (4H, m).

9) Isopropyl ester of 5 "Ee7hoxycarbonyl-6-diethyl: cymethyl; 2-methy 1 -4- (2-thi-eny 1) -1,4-dihydropyridine - 3-carbonic acid.

? ÏT * li «R» </ ppm (CDCI ^) * 1.22 (32., 4, <7 = 6.5Hz),: 1 ►28 (3H, d, <7 = 6.52z), 2, 37 (32, s), 3.43 '(32, s),! 3.49 (32, s), 3.76 (32, s), 5.07 (12, heptet, 7 = 6.52z), 10 5.38 (1E, s), 6.04 (12, a ), 6.65-7.45 (4H, m).

10.) Isopropyl ester Tan 4- (2,4-dichlorophenyl) ~ 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carbonic acid, t / ppm (CBCl 3): · 1.07 (32d, J * 6.52z); 15! 7.2-1 (3H "d, 7 = 6.52z), 2.34 (32, s), 3", 42 (32, s) "5.46 (32, s), 3 * 64. 3E, 3), 4.97 '(12, heptet, 7 = 6.52z), 5.39 (1H, s), 5.96 (1E, s), 6.65 (1H, e), 7.0-7.4

* "”. (.32, m) · M

11) rsopropyl ester Tan 4- (3,4- <iichlorophenyl) -5-methoxycarbonyl-6-dimethorymethyl-2-methyl-1,4-dihydropyridine-3-carbonazmr.

E.M.H. / ppm (CECI ^.): 1.18 (d, 7 * 6.5Ez)) ^ 1.25 (d, 7 = 6.5Ez) 2.39 (3H, a), 5.46 (32, s ), 3.50 (32, e), 5.70 (32, s), 25 5.00 (1Ξ, s), 5.00 (1E, heptet, 7 = 6.52z), 6.03 (12 , s), 6.75 (1H, s), 7.0-7.5 (3H, m).

12) Isopropyl ester Tan 5-methoxycarbonyl-6-dimetho: xymethyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

30 IT.MR * / ppm (COCl 3) r 1.16 (32, d, 7 = 6.52z), 1.25 (32, d, 7 = 6.52z), 2.37 (32, s), 3.41 (s T \ '' Vt'U (6E), 3.45 (s) 35 3.49 (s) 790 7482 _ 21- 3.79 (JE, a), 3.84 (6H, a ), 4.99 (1E, s), 4.99 (1H, heptet, Ja6.5Hz), 6.03 (1H, a), 6.6-7.3 (4E, m).

13) Dipropyleter Taa 2-metliyl-4- (3-nitrophenyl-4-dipropoxymetliyl-1,4-dihydropyridine-3,5-dicarboxylic acid.

5 E. IUE. / ppm (CDCl 3 2.57 (3E, s), 5.02 (1E, s), 6.21 (1E, s), 6.88 (1E, step a).

14) 2- (iT-Benzyl-f-methylamino) ethylater of 5-ethorycartonyl-6-diethylmethyl-4- (2-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

10 Ï.M.E. cTdpm (CDCl 3): 1.1-1.3 (9E, m), 2.17 (3E, e), 2.35 (3H, a), 2.60 (2E, t, J »6Ez), 3.48 (2E, a), 3.4-4.4 (8H, m), 5.63 (m, s), 6.13 (1E, s), 6.71 (1E, a), 7 1-7.6 (9H, m) 15) 2-Fenoryethylester of. 5-Thorycartonyl-6-diethyl: -ethyl-4- (2-trifluoronietliylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

/ ppm (CDCl5) r 1.0-1.5 (9E, m), 2.37 (3E, a), 3.5-4.6 (10Ξ, ut), 5.67 (1H, s), 7.12 (1E, s), 6.7-7.8 (10E, a).

16) 2-Chloroethylate of 5-ethoxycartonyl-6-diethoxy-methyl-4- (2-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-5-carboxylic acid.

XH. <ƒ dpm (CC14): 1.0-1.5 (6E, m), 2.59 (3E, s), 3.4-4.5 (10E, m), 5.5-5.7 ( 1E, m), 6.10 (1Ξ, s), 6.55 (1E, s), 7-7.6 (4ï, m).

17) 2-Etho3: ethyl ester of 5-etho3ycarbonyl-6-diethoxy-thyme 1-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-gartonic acid.

E.Jt.R. J ppm (CCl4) i 1.0-1.4 (12E, tb), 2.38 (3E, s), 3.3-4.3 (12S, a), 5.5-5.7 (1E , m), 6.10 (1E, s), 6.47 (1E, s), 7.2-7.7 (4H, m).

18) 2-Benzylozyethyl ester of 5-ethoryoarbonyl-6-diethory-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

ΪΓ.Μ.Ε. <Tdpm (CDCl ^): 1.0-1.6 (9E, m), 2.32 (3H, a), 3.4-4.4, 10E, m), 4.47 (2E, s) , 5.6-5.7 (1E, m), 6.11 (1H, s), e 790 74 82 - 22— * * 6.6-6.8 (1H, wide 3), 7.2- 7.7 (9ff, m).

Example II

1) A mixture of the 2-phenoxyethyl ester of 2- (2-trifluoromethylbenzilidene) acetoacetate (19.62 g) and ethyl 2-amino-4.4-5 diethoxycrotonate (11.95 ff) was added for 20 hours at 100-110 ° C

and. heated at 120 ° -13 ° C for a further 12 hours. The resulting mixture was dissolved in ethyl acetate and washed with water. and dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give a crude oil 10 (27.7 ff) which was chromatographed on silica gel with a mixture of benzene and ethyl acetate (50: 1 in volume) as the eluent and the 2-phenoryethyl ester of 5-thoxycarbonyl-6-diethoxymethyl-4 - (2-trifluoromethyl-phenyl) -2-methyl-1,4-di-hydropyridine-3-carboxylic acid (19.54 ff ) yielded 1.15 M.iU <fdpm (CHO1.1) r 1.0-1.5 (9Hy m), 2.57 (3H, s), 3.5-5.4 (10Kr m), 5.67 (1H, s), 7.12 (1H, e) 6.7-7.8 (10H, m) The following compounds were obtained in substantially the same manner as in Example II-f). .

. 2): 2-Chloroethyl ester of 5-ethorycarbonyl-6-diethoxymeth-20'-yl-4- (2-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid. cfdpm (CCl4) r 1.0-1.5 (6l, m), 2.59 (3H, s), 3.4-4.5 (1OH, m), 5.5-5.7 (1H , m), 6.10 (1H, s), 6.55 (1H, s), 7-7.6 (4Ξ, m).

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

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

4) 2-Benzyloxyethyl ester of 5-thorycarbonyl-6-diethoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid »N.M.R. cf ppm (CDCl 3). 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), 790 74 82 -25- 6.6-6.8 (iff, treed s), 7.2-7 .7 (9H, m).

5) 2- (F-Benzy 1-F-nonhylamino) ethyl ester Tan 5-ethoxycarbonyl-6-diethoxymethyl-1- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-caronic acid.

5 F.M.R. <fdpm (CDC1?): 1.1-1.3 (9Ξ, m), 2.17 (31, a), 2.33 (3Ξ, s), - 260 (23, t, J-6ffz), 3.48 (23, s), 3.4-4.4 (8H, m). 5.63 (iff, a) ,. 6.13 (iff, a), 6.71 (1H, a), 7.1-7.6 '; (9H, m) -6) Isopropyl ester of 5-methozycartony1-6-dimethoxymethyl-10-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, 'F * 3i * R. ^ dpm (CDClj). ' 1.17 (d, J-7.0Hz) ^ 1.27 (d, J = 7.0Hz) 2.40 (3ff, a), 3.47 (a)) (6h ^ 3.50 (a ) 15 3.69 (3ff, a), 5.0 (15, heptet, J-7.0Hz), 5.17 (iff, s), 6.04 (iff, a), 6.92 (13, "broad s), 7.2-8.2 (43, m)" 7) Isopropyl ester Tan 5- "atho2ycarbonyl-6-dimethorymethyl-2-methyl-4-phenyl-1, 1, 4-dihydropyridine-3- carboxylic acid *! / ppm (CDCl 3) r 1.11 (3ff, dt. «Γ» 6.53ζ), 1.23 (3S, d, 20 J »6.5Sz), 2.37 (3H, a) , 3.42 (3H, a), 3.46 (3H, a), 4.96 (1H, heptet, J-6.5Hz), 5.03 (13, a), 6.03 (1H, s ), 6.73 (Iff, a), 7.0-7.4 (5ff, a).

8) Isopropyl ester Tan 5-ethoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (2-tolyl) -1,4-dihydropyridine-3-art.

25 F.M.ff. <£ ppm (CUClj): 1.07 (3H, d, «7 = 6.5Hz), 1.21 (3H, d, J * 6.5ffz), 2.32 (3H, a), 2.55 (5H, a), 3.41 (3H, a), 3.44 (3H, a), 5.62 (33, s), 4.96 (Iff, heptet, J = 6.5Hz), 5, 20 (Iff, a), 5.97 (1H, a), 6.65 (1H, a), 6.9-7.4 (43, m).

9) Isopropyl ester Tan 5-methozycarbonyl-6-dimethorymethyl-2-methyl-4- (4-pyiidyl) -1,4-dihydropyridine-3-amino acid.

I.ff. Y ® * l01: 3300, 3200, 3070, 171Ο (shoulder), 1700, 1650, 1603, 1518, 1278, 1269, 1190, 1090, 96Ο, 782 cm. 10) Isopropyl ester Tan 4- (2-chlorophenyl) -5-methorycarbonyl-35 6-dimethorymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, 79 0 7k 82 * * -24 - melting point 86 ^ 87.5 ° C.

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

5 ', R01: 3400, 1720, 1690, 1653, 1495, T319, 1310, 1278,. 1035, 951 x 788 cm -1. · 12; Isopropyl ester of S-methorycarhonyl-G-dimethoxymethyl-1,4-(2-methoryphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 110 ^ -111.5 ° ^.

10 tj) Isopropyl ester of 4- (2-allyloxyphenyl) -S-ethoxycarbonyl-6-dimethoxyme thy1-2-me thy 1-1,4-dihydropyridine-3-carboxylic acid. Jdpm (CICI ^): 1.01 (31, d, 1 = 6.5Hz), 1.21 (3E, d, J = 6.5Hz), 2.33 (3 ^, s), 3.46 (6h, s), 3.65 ( 3H, s).

«. 4.4-6.3 (8H, m), 6>, 60 (1E, broad s), 6.7-7.5 (4H, m).

T5 .14) Isapropyl 3 tervan 5-inethoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid.

ΪΓ.Μ..Ε *. é dpm (ClCl ^.) ·. 1.22 (3H, d, J = 6.5Hz), 1.28 (3ΒΓ, d, J- * 6.5ffz), 2.37 (5H-, s), 3.43 (3E,?) , 3.49 '(3ff, s); -j_ 3.76 (3Er a), 5.07 (lf „Septet, J * 6.5Hz), 5.38 (1H, s), 20 / 6.04 (1E, s), 6.63- 7.45 (4H, m).

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

IT.M.R. cTdpm (CDCl ^): 1.07 (3H, d, J = 6.5Hz), 1.21 (3H, d, 25 Je6.5Hz), 2.34 (3H, s), 3.42 (3E, s), 3.46 (3H, s), 3.64 (3H, s), 4.97 (1H, heptet, J = 6.5Hz), 5.39 (1Ht s), 5.96 (1H, s), 6.65 (1H, s), 7.0-7.4 (3H, m).

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

N.M.E. ^ ppm (CDCl ^): 1.18 (d, J = 6.5Hz) ^ 1.25 (d, J = 6.5Hz) 2.39 (3H, s), 3.46 <3H, s), 3.50 (3E, s), 3.70 (3H, s), 5.00 (1E, s), 5.00 (1H, heptet, J = 6.5Hz), 6.03 (1H, s) 6.75 (1H, s), 7.0-7.5 (3Ξ, m).

790 7 4 82 - 25-17) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl- ** 4- (5,4-dimethoxyphenyl) -2-methyl-1,4-ilihydropyridyl-5-carboxylic acid.

F.M.H. ƒ dpm (CDClj) * 1.16 (JH, d, J = 6.5Hz), 1.25 (31, d, 5 .J-6.5Sz), 2.37 (3H, s), Μη 5.451 ( 6H), 5.45 Γ

5.49 J

10 5.79 (3E, s), 3.84 (6H, s), 4.99 (1H, e), 4.99 (1H, heptet, «Γ = * 6.5Ηζ), 6.03 (1H s), 6.6-7.3 (4H, m).

18) Dipropyl ester -of. 2-methyl-4 - (? - nitrophenyl) -6-dipropoxy-methyl-1,4-dihydropyridine -5,5-dicarboxylic acid.

; F * / ppm (CDCl?) I 2.37 (5H, $), 5.02 (1H, s), 6.21 (1H, $), 15-6.88 (1E, broad 3).

Example III

1) To a solution of 2-phenoryethyl ester ran 5-ethoxy-carbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-T, 4-dihydropyridine-3-carboxylic acid (15.85 s) in acetone (159 ml) 20 hydrochloric acid (15.85 ml) was added at ambient temperature with stirring and stirring continued for 1 hour. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and the acetone removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and dried. Removal of the solvent gave an oil (13.58 g) of the 2-phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

F.M.R. / ppm (CDCl ^): 1.22 (3H, t, J = 7.5Hz), 2.40 (3H, s), 50 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 substantially the same manner as in Example III-1).

2) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid.

790 74 82 * * • - - 26 - 5) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl- / 4- (2-tolyl) -1,4-dihydropyridine ~ 3-carboxylic acid, mp 143-144 ° CT * 4) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-5- 4- (4-pyridyl) -1,4-dibydropyridine-3-carboxylic acid, melting point 143: H5 ° 2.

5: Isopropyl ester of 4- (2-chlorophenyl) -6-forinyl-5-inethoxy-carbanyl-2-methyl-1 t, 4-dibydropyridine-3-carboxylic acid, mp 102-103 ° C .

6) Isopropyl ester of 4- (2-trifluoromethylpheny1) -6-formyl-5-metboxyarbonyl-2-methyl-1,4-dihydropyridine -3-carbonic acid, mp 83-65 ° C.

7) Isopropyl ester of 6-formyl-5-methoxycarbonyl-4- (2-metboryphenyl) -2-methyl-1,4- <-hydropyridine-5-carboxylic acid melts! point 142-14J ° C.

8) Isopropyl ester of. 4- (2-ally loxyphenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid; mp 103-104.5 ° C *, 9 ') Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl ~ 20 4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid, melting point II4-116 ° Cf 1Ό) Isopropyl ester of 4 - (- 2,4- <iichlorophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N * M.R. <fdpm (CDC1?)! 1.07 (3E, d, J = 6.5Hz), 1.24 (3H, d, 25J * 6.5Hz). 2.39 (3H, s), 5.71 (31, s), 4.98 (1H, heptet, J-6.5Hz), 5.51 (1H, s), 6.93 (1H, s) 7.0-7.4 (3H, m), 10.54 (1H, a).

11) Isopropyl ester of 4- (3,4-4-chlorophenyl) -6-formyl-5r methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 95-9 ^ ° C, 12) Isopropyl ester of 6- formyl-5-methorycarbonyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

N.M.R. é ppm (CBCl 3): 1.14 (3H, d, J = 6.5Ez). 1.26 (3H, d, 1 = 6.5Hz), 2.40 (3H, s), 5.78 (3H, a), 3.84 (6H, s), 35 4.98 (1H, heptet , J = 6.5 Hz), 5.05 (1H, s), 6.5-7.3 790 7 4 82-27- (41, a), 10.44 (H, s).

13) Dipropyl ester of 6-formyl-2-methyl-1-4- (3-nitrophenyl) 1,4-dihydropyridine-3,5-dicarbonine.

IMMR / ppm (CDClj) * 0.87 (31, t, 7 = 7.51z), 0.90 (31, t, 5 7 * 7.5Hz), 1.55 (21, aixtet, 7 * 7.5Hz ), 1.61 (21, sixtet, '7 * 7.51z), 2.44 (31, a)., 4.02 (21, t, 7-7.5Hz), 4.13 (.21 , t, 7 * 7.5 Hz), 5.28 (11, a) ,. 7.11 (1H, broad s), 7.4-8.2 (4¾ a), 10.56 (11, a).

14) 2-hydroxyethyl ester of 5-ethoxycartonyl-6-formy 1-2-10 methyl-4- (3-aitrophenyl) -1,4-dihydropyridine-3-carboxylic acid.

3T.IC.Hr / ppm (CDGl / t 5.25 (1¾ a), 10.50 (1H, a).

15) 2-Ethoxyethyl ester of 5-ethoxycarhonyl-6-ormyl-4- (2-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid.

F.li.Er / dpm. (CDClj) * 1.14 (t, 7 = 71z) ^ I? 1.26 (t, J * 7Hz) 2.45 (31, s), 5.5-5.8 (4¾ a), 4.0-4.5 (4H, m), 5.7-5.8 (1H, m), 6.8-7.0 (11, a), 7.1-7.8 (4H, m), 10.27 (11, a).

16) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-formyl-4-20 (2-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carbonzunrv 3T.K.R. / ppm (CCl ^): 1.23 (3H, t, 7 = 7.51z), 2.40 (3¾ a), 3.4-4.5 (61, a), 4.41 (21, s), 5.7-5.8 (11, a), 6.8-6.9 (1H, m), 7.2-7.8 (91, a), 10.28 (1H, a).

17) 2- / 1-Benzyl-S'-methylamino / ethyl ester of 5-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydro-pyridine-3-carbonzunr .

H.M.H. / ppm (CDC1) * 1.23 (31, t, 7 * 7Hz), 2.19 (31, a), 2.41 (31, s), 2.63 (2H, t, 7 «7Hz), 3.51 (21, s), 50 4-4.4 (4H, m), 5.71 (11, broad s), 6.91 (11, broad s), 7.2-7.7 (91 , a), 10.28 (1H, s).

Example 17

A mixture of the isopropyl ester of 5-aethoxycarbonyl-6-dimethoxymethyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-35 3-carbonone number (11.0 g) and 61 hydrochloric acid (11 ml ) in 790 7482

* -V

28-acetone (110 ml) was stirred at ambient temperature * for 4 hours. After removing the acetone, water was added to the reaction mixture and the mixture 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. Removal of the solvent gave an oil-like residue which immediately solidified and gave crude yellow-orange crystals of the isopropyl ester of 6-formyl-5-methoxycar-10! honyl-2-methyl-4-C 1 -ntrophenyl.) 1,4-dihydropyridine-3-carboxylic acid.

1Γ.Μ.Η. cfdpm (CDCly) * 1.13. (3H, d, J = 7Hz), 1.28 (3E, d, J = 7Hz),; 1.79 '(3E, s), 3.80 (3ff, s), 3.02 (1E, heptet,. J-7Hz), • 5.2.7 (1E, s), 7.11 (1E, wide s), 7.4-8.2 (4ΗΓ, m), 10.60 Oh, s).

; Example V "1) To a solution of the isopropyl ester of 6-formyl-5-m & thOxycarbonyl-2-methyl-4- (3-ntrophenyl) -1,4-dihydropyridine: 3-carboxylate (4.2 g) in Ethanol (85 ml) was gradually added in 20 portions over a period of 35 min with cooling below 0 ° C with stirring, sodium borohydride (0.409 g).

After the reaction mixture was acidified with a 50% aqueous solution of acetic acid, the ethanol was removed under reduced pressure. The resulting aqueous suspension was diluted with water and the precipitated pale yellowish powder was collected by filtration, washed with water and dried. This powder (3.89 g) was recrystallized with ethanol to give a yellow powder (3.05 S) of the isopropyl ester of 6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) - 1,4-dihydro-30-pyridine-3-carboxylic acid, melting point 164-166 ° C,

The following compounds were prepared in substantially the same manner as in Example V-1).

2) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, mp 132-333 ° C.

790 7 4 02 -29- 3) Isopropyl ester of 6-hydroxymethyl-1-5-methoxycarbony1-2-methyl-4- (2-tolyl) -1,4-dihydropyridine-3-carboxylic acid, melting point 134-155.5 ° C.

4) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2- 5 methyl-4- (4-pyridyl) -1,4-dihydropyridine-5-carboxylic acid, mp 182-183 ° C (decomposition).

5) Isopropyl ester of 4- (2-chlorophenyl) -6-hydroxymethyl 1-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-5-cart2 hours, mp 122-123 ° C.

10 6) Isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydroxy-methyl-5-methoxycarbonyl-2-methyl-t, 4-dihydropyridine-3-carboxylic acid, melting point 123-125 ° C «7) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (2-methoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 142-143 ° --8) Isopropyl ester of 4- (2-allyloxyphenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 124-125 ° C.

9) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2- 20 methyl-4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid, melting point 124.5-126 ° C ^ 10) Isopropyl ester of 4 - (2,4-dichlorophenyl) -6-hydroxymeth-yl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 150-151 ° C.

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

12) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4- (5,4-dime thoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, 30, mp 125-124 ° C.

1j) Dipropyl ester of 6-hydrorymethyl-2-methyl-4- (3-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, mp 118-120 ° C.

14) 2-Phenoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxyethyl-2-methyl-1,4-dihydro pyridine -3-35 carboxylic acid, mp 148-149 ° C.

7907482 * * - '-30-' 15) 2-Ethoxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 65- 66.5 ° C.

16) 2-Benzyloxyethyl ester of 5- (thoxycarbonyl-4- (2-tri-5-fluoromethylphenyl) -6-hydroxy thy1-2-thy1-1,4-dihydropyridine | 3-Carbonic acid mp 104-106 ° C.

i j Yoorbeeld 7Γ:.,. | f) To a solution of the isopropyl ester of 6-formyl-5-: methoxycarbonyl-2-methyl-4- (3-aitrophenyl) -1,4-dihydropyridine-10 5-carbonur (4.5 s) in . acetic acid (35 ml) became hydroxylamine

hydrochloride (0.97 g) and sodium acetate (ΐ, 45 g) are added and the mixture is stirred for 2 hrs. the ambient temperature was stirred, Fadat was added to this reaction mixture acetic anhydride I (4 ^ 4 ^ g), whereupon the mixture was stirred at 15 for 1 hour. ambient temperature and for a further 4 hours at 95-100 ° C

stirred. The acetic acid and excess acetic anhydride were mixed in. vacuum, followed by addition of water to the residue, which is treated with a saturated aqueous solution of. sodium bicarbonate was neutralized, this aqueous suspension was.

Extracted twice with ethyl acetate, then the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a reddish brown oil (4.88 g) which was over silica gel (150 g) was chromatographed on a mixture of benzene and ethyl acetate (10: 1 by volume) as eluent to afford crude crystals (2.99 U). These were recrystallized from ethanol, and yellow prisms (1.89 g) of the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid were obtained mp 148-150 ° C.

The following compounds were prepared in substantially the same manner as in Example YI-1).

2) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, mp 130-131 ° C.

35 5) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-790 74 82 ... 31 _ 4- (2-tolyL) -1,4-dxhydropyridine-3-carboxylic acid, mp 147-149 ° C * 4) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (4-pyridyl) -1,4-dihydropyridine-3-carboxylic acid, mp 192-595 ° C (decomposition).

5) Isopropyl ester ran 4- (2-chlorophenyl) -6-cyano-5-methoxy-carbonyl-2-methyl-1,4-dihydropyridine-3-arbic acid, melting point 1-6-177σσ. - 6) Isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-10 methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 172-173 ° C.

7) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4- (2-methoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point t39-T4Q ° C »13 8). Isopropyl ester of 4- ( 2-allyloryphenyl) -6-cyano-5-metho3ycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 115-116 ° C * 9} Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl - 4- (2-thiCnyl) -1,4-dihydric opyridine-3-earborboric acid melting point 129-20 13TCTfc 10) Isopropyl ester of 4- (2,4-dichlorophenyl) -6-cyano-5-methoxycarbonyl-2- methyl 1,4-dihydr o pyridine - 3 - arbic acid, mp 141-142 ° C.

11) Isopropyl ester of 4- (3'-4-dichlorophenyl) -6-cyano-5-25-thoxycarbonyne-2-methyl-1,4-dihydropyridine-5-carboxylic acid, mp 159-110 ° C.

12) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4- (3 »4-dimethoryphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, melting point 124» 5-125 »5 ° C · 30 13) Dipropyl ester of 6-cyano-2-methyl-4- (3-itrophenyl) 1,4-dihydropyridine-3,5-dicarboxylic acid, mp 138-140 ° C.

Η) 2-Penoxyethyl ester of 6-cyano-5-ethorycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 118-119 ° C.

35 15) 2-Hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2- 7 9 0 7 4 β2 / * - 52-methyl-4- (5-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, melting point 150.5-152 ° C.

16) 2-Ethoxyethyl ester of 6-cyano-5-ethoxycarbonyi-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 104-105 ° C.

1:17) 2-Benzyloxyethyl ester of 6-cyano-5-ethoxycarbonyl-4-; (2-trifluoromethylphenyl) -2-methy 1-1,4-dihydropyridine-3-carbon- | acid, melting point 1'46-147 r5 ° C., 18) 2- (N-Benzyl-lir-methylamino) ethyl ester of 6-cyano-5-10 'ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl- 1,4-dihydro-; pyridine-5-carboxylic acid hydrochloride, melting point 203-204 ° C (decomposition) *

Example VII

; -. On. a solution of the 2-acetoxyethyl ester of 6-cyano- »15-ethoxy-carbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (1» 119 g Ethanol (20 ml) was added dropwise with an aqueous solution (5 ml) of potassium carbonate (0.346 g) to reflux the mixture. boiling and stirring for 2 hours »20 Bau cooling- the ethanol was removed from the reaction mixture in vacuo, then neutralized with acetic acid and. extracted twice with ethyl acetate. The combined extract was washed with a dilute aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried.

The solvent was removed in vacuo to give an oil which crystallized spontaneously to form crystals (0.94 g) of the 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4- (3-ai Phrophenyl) -1,4-dehydropyridine-3-carboxylic acid, mp 150.5-152 ° C.

Preview beeld

A mixture of. the 2-chloroethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-1- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydro-pyridine-3-carboxylic acid (5.20 g), H-methylbenzylamine (3.63 g) and sodium iodide (0.2 g) in propyl alcohol (100 ml) was heated at reflux for 790 74 82 -33- 4f5 hours. After the solvent / in vacuum. water was removed from the reaction mixture and water and ethyl acetate were added to the residue. The ethyl acetate layer was separated, washed with water and dried. Removal of the solvent gave a residual oil (6.95 g), which was chromatographed on silica gel (210 g) with a mixture of henzene and ethyl acetate (5: 1 by volume) as eluent and oil (3.67 g) Ieverde = of the 2- (F-henzyl-ir-methylamino) ethyl ester of 5 * ethorycarhonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -10 2-methyl-1,4-dihydropyridine-3-caronic acid .

1.Jf.E * <fdpm (CDCX3) i 1.1-1.3 (91 ,. *), 2.1T (3H, s), 2.33 (31 s), 2.6Q (21, t , J »6Ez), 3» -48 (2E, s), 3.4-4.4 (81, m), • 5.63 (1ï, s) 6.13 (11, s), 6.71 (1E, s), 7.1-7.6 (91, m).

i '' ** y790 7482

Claims (3)

R 1 - di (lower) alkoxymethyl 1. formyl, hydroxymethyl or cyano is f. "Provided that. * when * R 1 is J-nitr or enyl; * - -. I Rd Rd is 2-hydroxy ethyl and ΕΓ cyano or formyl, or 2 is 15. propyl or isopropyl, as well as pharmaceutically acceptable salts thereof. 2 Rl Rl R oocvJx ^ coor3 reduction ^ oocI ^^ coor3 ch3AnXcho ^ C ^ lC 3. CH ^ U CH2OH JL (1-31 [1-5] r1 (i) hydroxylamine r1 Rboocv '^ V''COOR3 or a salt thereof r3ooc i coor3 «Ar» "llisrrt"! "· = ΛΚ, F ( 2c) - 11-6) R1 r1 ReOCH2CH2OOC l ^ COOR3 HOCH ^ OOclrOOR3 CH, CH ^ N ^ N 3 H ώ H _G_ (2d), (1-7) R1 R1 α ^ Β, αχAxcor3 JLcoor3 CH / li ^ R4 CH- / NH 3 Oi. N ^ R4 3. a -J H a 7907482 Fujieava Pharmaceutical Co., Ltd. -r '· * JL (2b) (2a) (2-1) © R1 * CHO + R? -COCH-COOR3-> R1-CH = C-CO-Rf a * LI a I 3 GOOR ° χ (2g ) (2a.) (2-2) © RX-CHO + CH.COCH-COOR? - »R1-CH = C-COCH, w 3 L a | -3 coor: a X (3A) (3-1) © CH - C-CH-COOR? + NH- - »CH - OCH-COOR2 - '3 || Z a 3 3i a 0 nh2 JL C3A.) (3-2) © + ^ 3 —5 * R * -C = CH-COOR3 0. X (1-8) (2c) pl (1) Hydroxylamine R ^ HOG ^ O ^ OOC'VOXR3 hydrochloride ^ j ^ x ^ q ^ qoC J ^ J-OOR3 TT CÜ) 0 0? 0 XX CH ANXcHO ^ 2 CH ^ N ^ CN 2. A compound according to claim 1, characterized in that. - * "r" 'phenyl ,, J-nitrophenyl r 2-chlorophenyl · ,, 2-trif luor thy 1-phenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlorophenyl, 3> 4 -20 dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyliyl or 2-thienyl, 2R propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2- (1T-benzyl-yr-me thy1amino) e thy1, R 1 is methyl, ethyl or propyl, and R 1 is dimethoxymethyl, diethoxymethyl, dipropoxymethyl, formyl, hydroxymethyl or cyano. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-30 methyl-4- (3-aitrophenyl) -1,4- <ihydropyridine-3-carboxylic acid. Compound according to claim 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid. Compound according to claim 2, characterized in that 790 7 4 82 - 35- it is the isopropyl ester of 6-hydro3ymethyl-5-metho: xycarbonyl-2-methyl-4- (2-tolyl) -1,4-dihydropy ridin-3-carboxylic acid. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-hydro: xymethyl-5-beetho: xycarbonyl-2-5 methyl-4- (4-pyridyl) -1,4-dihydropyridine-3 -carboxylic acid. . A compound according to claim 2, characterized in that it is the isopropyl ester of. 4- (2-chlorophenyl) -6-hydro: xymethyl-5- methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. 8 ». A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2-trifluoromethylphenyl) -6-hydrorymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. Compound according to claim 2, characterized in that it is the isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4-15 (Z-methoxyphenyl) ~ 2-methyl-1,4-dihydropyridine-3-carboxylic acid »10 * A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2-allyloxyphenyl) -6-hydroxymethyl-5-methorycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. 1t * Compound 1 according to claim 2, characterized in that it is the isopropyl ester of. 6-hydroxymethyl-5-methorycarbonyl-2-methyl-4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid. Compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2,4-dichlorophenyl) -6-hydrory-methyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carbonarbon 25 is acidic. Compound according to claim 2, characterized in that it is the isopropyl ester of 4- (3,4 ** 4ichlorophenyl) -6-hydroxy-methyl-5-methozycarbonyl-2-methyl-1,4-dihydropyridine-3-carbon -acid. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-hydro3cymethyl-5-methoxycarbonyl-4- (3,4-dimethoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid. Compound according to claim 2, characterized in that it contains the dipropyl ester of 6-hydrorymethyl-2-methyl-4- (3-nitro-790 74 82 - 56- * f01171) -1,4-dihydropyridine-3 5- <iicarboxylic acid is ..; A compound according to claim 2, characterized in that it contains the 2-phenoxyethyl esters & 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydro: cymethyl-2-methyl-1,4-dihydropyridine-3 -5 i is carboxylic acid. A compound according to claim 2, characterized in that it contains the 2-ethoxyethyl ester of 5-etho 3 -cycarbonyl-4- (2-trifluoro-methylphenyl) -6-hydraxymethyl-2-methyl-1,4-dihydropyridine-3 -carboxylic acid. RF A bond according to claim 2. characterized in that it is the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -6-hydroxymethyl-2-methyl-1,4-dihydropyridine-J-carbonic acid. 19-. Bonding according to claim 2. characterized in that it is the isopropyl ester of 6-cyano-5-etho: xycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. 20. » A compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-5-methozycarbonyl-2-methyltet. 4-phenyl-1,4-dihydropyridine-3-carboxylic acid. 20 "s. A compound according to claim 7, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4- (2-tolyl) -1,4-dihydropyridine-3-carboxylic acid. 22. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-5-nonhorycarbonyl-2-methyl-4- (4-pyidyl) -1,4-dihydropyridine-3-carboxylic acid. A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2-chlorophenyl) -6-cyano-5-methoxy-carbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. 24. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-4- (2-trifluoromethylphenyl) -5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-5-carboxylic acid. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-5-methoxycarbonyl-4- (2-methoxyphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid. 26. A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2-allyloryphenyl) -6-cyano-5-methorycarbonyl-methyl-1,4-dihydropyridine. -3-carboxylic acid. A compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-5-methorycarbonyl-2-methyl-5- 4- (2-thienyl) -1,4-dihydropyridine-3-carboxylic acid. 28 * A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2,4- <iichlorophenyl) -6-cyano-5- • metho-3-cycarhonyl-2-methyl.-1,4- <lihydropyridine -3-carboxylic acid. 29 A compound according to claim 2, characterized in that it is the isopropyl ester of 4- (3,4-dichlorophenyl) -6-cyano-5-methorycarbonyl-2-methyl-1,4-dihydropyridine-5-carboxylic acid. 3Q * Compound according to claim 2, characterized in that it is the isopropyl ester of 6-cyano-5-methorycarbonyl-4- (J, 4-dimethoryphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid . 15 31.. A compound according to claim 2, characterized in that it is the dipropyl ester of 6-cyano-2-methyl-1-4- (3-aitrophenyl) -1,4-dihydropyridine-3,5-cyclic acetic acid. A compound according to claim 2, characterized in that it is the Z-phenoryethyl ester of 6-cyano-5-ethorycarbonyl-4- (2- '2Q-trifluoromethyl-phenyl) -2-methyl-1,4-dihydropyridine-3 -carboxylic acid. A compound according to claim 2, characterized in that it is the 2-hydroryethyl ester of 6-cyano-5-ethorycarbonyl-2-methyl-4- (3-aitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. 34. A compound according to claim 2, characterized in that it is the 2-ethoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid » A compound according to claim 2, characterized in that 30 'it is the 2-benzylozyethyl ester of 6-cyano-5-ethoxycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carbon- is acidic. 36. A compound according to claim 2, characterized in that it contains the 2- (H-benzyl-1-methylamino) ethyl ester of 6-cyano-5-35 ethorycarbonyl-4- (2-trifluoromethylphenyl) -2-methyl- 1,4-dihydro-c 790 74 82 ί * -38.-pyridine- 3 - carboxylic acid hydrochloride is * 37 * A compound according to claim 2, characterized in that it is the isopropyl ester of 5-metho: cycarbonyl-6-dimethoxymethyl - 2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. 38. The binding according to claim. 2, characterized in that this. the. isopropyl ester of 4- (2-chlorophenyl) -5-methaxycarbonyl-; · 6-dimethoxyme thy 1-2-me thy 1-ΐ, 4-dihydro pyridine -3-carbonic acid. [39] Terbinding according to claim 2, characterized in that .... . This is the isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxy-10-carbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. 40. The compound according to claim 2, characterized in that it is the dipropyl ester of 2-methyl-4- (5-nitrophenyl) -6-diproporymethyl-t-1,4-dihydropyridine-5,5-dicarboxylic acid. 41. Compound according to claim 2, characterized in that it comprises the 2- (F-benzyl-N-methylamino) ethyl ester of. 5-ethoxycarbonyl-6-diethoxymethyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid. 42. A compound according to claim 2, characterized in that it contains the 2-phenoryl ethyl ester of 5-ethoxycarbonyl-6-diithoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1, 1,4-dihydr opyridine-3-carboxylic acid. 43 * A compound according to claim 2, characterized in that it contains the 2-ethoxyethyl ester of 5-ethoxycarbonyl-6-diethory-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-3 - is carboxylic acid. 44. The compound according to claim 2, characterized in that it contains the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxy-methyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine-30 3 "carboxylic acid is. 45. The compound according to claim 2, characterized in that it is the isopropyl ester of 5-methoxycarbonyl-6-formyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid. 46. The compound according to claim 2, characterized in that it is the isopropyl ester of 4- (2-chlorophenyl) -5-methoxycarbonyl 790 74 82. * Is 6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. The linkage according to claim 2, characterized in that it is the isopropyl ester of 4- (2-trifluoromethylphenyl) -5-methoxy-carbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. The compound according to claim 2, characterized in that it is the dipropyl ester of 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4- <liyl> iropyridine-5,5-dicarlic acid. Yerhinding according to claim 2, characterized in that it contains the 2- (ΪΓ -he nzy Ι-ίΓ-methylamino) ethyl ester of 5-ethoxycar-10 bonyl-6-formyl-4- (2-trifluoromethylphenyl) - 2-methyl-1,4-dihydropyridine-J-carboxylic acid is * Yerhinding according to claim 2, characterized in that it contains the 2-enoryethyl ester of. 5-ethoryarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-hydroxyhydropyridine-3-carboxylic acid T5 ie. 51. The compound according to claim 2, characterized in that it contains the 2-ethoryethyl ester of 5-ethyl-xycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridin e -3 - carb acid is -is. 52. Yerhinding according to claim 2, characterized in that it contains the 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6-formyl-4- (2-trifluoromethylphenyl) -2-methyl-1,4-dihydropyridine. 3-carboxylic acid. 53 * Pharmaceutical composition, characterized in that it comprises as active component a compound according to claims 1-52 together with a pharmaceutically acceptable carrier or diluent. / 790 74 82 R1 R2OOC coor3 d T ch, ^ n «" "R4 3 h - n- - ^ v ^ ° 2 - y ^ Cr Qr ™ 300Ctr C00CH3 ^ 5OOC \ X-COOC, Hc = 2H5OOC ^ X ^ OOC2HS ^ ΙΓ TT ^ 3. H CHj'yJ ch2oh REACT1 SCHEME A (2-1] (3-1] (3-η, R1 R1-CH = C-CO-Rf + CH.-C'CH-COOR ^ R ^ OOC ^ J ^ TOOR3 I 3 IT if COOR3 NH2 Λ \ 4 ^ 3 H Ka (2-2) (3-2) (1-2}, R R1-CH = C-COCH_ + R4-C * CH-C00R3- ^ R200C ^ Jv ^ C00R3 ^ * "! ..XX · ο H a (1-1) - (1-3) R1 R1 r2 ° occoor3 hydrolysis r2oocsJv, coor3 XT - * xx ®3ΛΗ Ri ®3 H ® ° Fujisawa Pharmaceutical Co., Ltd 790 7 4 82 11-3) - 11-41 3 H 5 H 7907482 Pujiaava Pharmaceutical Co. , Ltd.