DD269381A5 - PROCESS FOR PREPARING ARALKYL-1,4-DIHYDROPYRIDES - Google Patents

Abstract

The invention relates to a process for the preparation of aralkyl-1,4-dihydropyridines of the formula (I) in which X, R, R2, R3, R4 and Y have the meaning given in the description. The preparation is carried out in such a way that the cyclopropane ring of a compound of the general formula (II) in which R, R4, X and Y have the meaning given in the description, by a molar excess of monobasic mineral acid or organic acid in an inert solvent is split. The compounds according to the invention are suitable agents for lowering hypertension, against ulcers and for the protection of living cells. Formula (I) and (II)

Description

Field of application of the invention

The present invention relates to a process for the preparation of aralkyl-1,4-dihydropyridines which find use in the pharmaceutical industry.

Characteristic of the known state of the art

Derivatives of M-dihydropyridine-S-B-dicarboxylic acids having a (2-phenyl-2-hydroxy) ethyl chain in the 2-position are claimed in Japanese Patent Application No. 856492. Derivatives of i -dihydropyridine-S-dicarboxylic acids which are substituted at the 2-position by a 3-oxo-1-propenyl chain are claimed in German Patent Application No. 2935772. In both cases, there are obvious structural differences between the compounds mentioned and the compounds according to the invention.

Object of the invention

The compounds prepared by the process according to the invention are suitable agents for lowering hypertension, against ulcers as well as for protecting the iobenden cells.

-5- 269 381 Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of aralkyl-1,4-dihydropyridines available

put.

The compounds of the invention have the following general formula I.

R ^(l) '

-C- R ₄ ^R 3

wherein X represents a -CO ₂ Rr. Cyano, nitro or COCHj group, R and R ₁ , which may be the same or different, primary, secondary or tertiary, saturated or unsaturated, linear or branched d-Cg-alkyl groups by one or more

Hydroxyl groups, monoalkylamino ·, Diaikylamino-, C ₁ -C ₈ -alkoxy, phenoxy or optionally substituted aryl groups

R _{2 is} hydrogen, or R _{3 is} hydrogen or a hydroxy, -OCOR ₆ , - OSOjR ₄ , azide, amino, -NHPO (OR ₇ J ₂ -, -NHCOR ₅ - Grupep, a C _t -C ₄ alkoxy group or a fluorine, chlorine, bromine or

Iodine atom, an SH group, a SCOR ₄ - or a Ci-CvAlkylthio-, phenylthio or benzylthio group, R _{4 is} a

gep ^"h 9nenfalls substituted aromatic or optionally substituted 5- or Bgliedrige heteroaromatic Gruppedarstellt, Y is one or more substituents which may be the same or different from each other and to a

Group C ₁ -C ₄ alkoxy groups, halogens, nitro, cyano, Ct-Cj-alkoxycarbonyl, Ci-C ^ alkylthio, halo-Ci-C ^ AIkyl- and Halo-Ci-Ce-alkoxy groups, R _{5 is} hydrogen or a Ci-C-alkyl, Trihalopenmethyl-, Ci-C ₄ -Aikoxy- or a

unsubstituted or substituted phenyl group, R _{4 is} hydrogen or a CHVAikyl-, trihalomethyl, phenyl or p-methylphenyl group and R _{7 represents} a C, -C ₄ alkyl group or a phenyl group.

Included within the scope of this invention are pharmaceutically acceptable salts, optical antipodes, i. the single r Enantiomers, their mixtures, the individual diastereoisomers of formula I and their mixtures. Pharmaceutically acceptable salts of the compounds of formula I are those of pharmaceutically acceptable acids and

Bases.

The alkyl, alkoxy, alkylthio, acyloxy and acylamino groups according to the invention may contain both a linear and an internal

have branched structure; an unsaturated C ₁ -C ₈ -KeMe can be either an cis or trans alkenyl radical or an alkynyl radical

According to the invention, a halogeno-C 1 -C 4 -alkyl group is preferably a trichloromethyl or trifluoromethyl group; a Halo-C 1 -C 4 alkoxy group is preferably a difluoromethoxy group; a Ct-Co-alkyl group is preferably one Methyl, ethyl, isopropyl or tert-butyl group; a monoalkylamino group is preferably a methyl, ethyl, isopropyl

or benzylamino group; a dialkylamino group is preferably a dimethyl, diethyl or N-methyl-N-benzylamino group.

Examples of preferred compounds of the invention are the following:

2- (3-Forniyloxy-3-phonylpropyl) -3-carbethoxy-5'Carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-formyloxy-3-phenylpropyl) - 3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-formyloxy-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m -trifluoromethylphenyl) -6-methyl-1,4-dihydropyridine; 2- (3-trifluoroacetoxy ^/ 3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m -nitrophenyl) -6-methyl-1,4 -dihydropyridin; 2- (3-azido-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3- hydroxypropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; (2- (3-phenyl-3-hydroxypropyl) -3,5-dicarbethoxy-4- m-methylthiophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-hydroxypropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluormethvlphenyl) -6-methyl-1,4 -dihydropyridin; 2- (3-phenyl-3-hydroxypropyl) -3,5-dicarbethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-cyano-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-nitro-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- ( 3-fluoro-3-phenylpropyl) -3-carbethoxy-5-cyano-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; -2- (3-azido-phenylpropyl) -3-carbethoxy-5 -nitro-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; -2- (3-azido-3-phenylpropyl) -3-narbethoxy-5-carbisopropoxy) -4- (m-nitrophenyl) - 6-methyl-1,4-dihydropyridine; -2- (3-azido-3-phenylpropyl) -3-carbethoxy-5 <arbethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-azido-3-phenylpropyl) -3-carbethoxy-5-carbethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-aminopropyl) -3- carbethoxy5 <arbmethoxy-4- (m-nitrophenyl) -e-methyM, 4-dihydropyridine; 2- (3-phenyl-3-aminopropyl) -3-carbethoxy5-carbmethoxy-4- (m-chlorophenyl) -6- methyl-1,4-dihydropyridine; 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-methyl-thiophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluoromethylphenyl) -6-met hyl-1,4-dihydropyridine; 2- [3-phenyl-3- (N-ethoxycarbonyl) aminopropyl-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-formylaminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine;

2- (3-phenyl-3-formylaminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -e-methyl-1,4-dihydropyrldin; 2- (3-phenyl-3-formylnminopropyl) - 3-Carbethoxy-5-carbmethoxy-4- (m-methylthiophenyl) -e-methyl-1,4-dihydropyridine; 2- (3-Ethoxy-3-phenyl- _1- ropyl) -3-carbethoxy-5-carbmethoxy-4 - (m-nitrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-Phenylpropy)) - 3 ^: arbetjoxy-5 <arbmethoxy4- (m-nitrophenyl) -6-methyM, 4-dihydropyridine, 2 - {3-phenylpropyl) -3- <arbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -e-metnyl-1,4-dlnydropyridln; 2- (3-phenylpropyl) -3-t; arbethoxy-5- carbmethoxy-4- (m-methylthlobhenyl) -6-methyl-1,4-dlhydropyridin; 2- (3-Methylsulfonylo: cy-3-phenyl) propyl-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridine; -2- (3-azido-3 ^ henylpropyl) 4 <arbethoxy-5 <yan4- (m-nitrophenyl) -6-methyM, 4-dihydropyrid: n; 2- (3 -Chloro-3-phenyl (ropyl) -3,5-dicarbetlioxy-4- (m -nitrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-chloro-3-phenylpropyl) -3-carbethoxy 5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridln; 2- (3-Chlo r-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluorethylphenyl 6-methyl-1,4-dlhydropyridln) '; 2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5 -carbmethoxy-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridine; 2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5-carbisopropoxy-6-methyl-4- (m- nitrophenyl) -1,4-dihydropyridln; 2- (3-bromo-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nltrophenyl) -6-methyl-1,4-dihydropyrldin; (2- 3-Bron-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dlhydropyridin; 2- (3-Fli.or-3-phenylpropyl) -3 -carbethoxy-5-carbmethoxy-4- (m-nltrophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-nuor-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m- methylthiophenyl) -6-methyl-1,4-dihydropyridine; 2- [3-formyloxy-3- (pyrid-3-yl) propyl] -3, S-dicarbethoxy-4- (m-methylthiophenyl) _-e-methyM> 4-dihydropyridine; 2- [3-Formyloxy-3- (4-methoxyphenyl) propyl] 3,5-dicarbethoxy-4- (m-ir-hylthiophenyl) -6-methyl-1,4-dlhydropyridine; 2- (3 -hydroxy-3- (4-nitrophenyl) propyl] -3,5Hdicarbethoxy-4- (m-methylthiophenyl) - 6-methyl-1,4-dihydropyrldin; 2- [3-hydroxy-3- (3-thienyl) -propyH-3-carbethoxy-5-carbmethoxy-4- (m-nltrophenyl) -6-methyl-1,4 -dihydropyridin; 2- (3-chloro-3- (3-thienyl) propyl] -3,5-dicarboethoxy-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridln; 2- [3-Ghlor -3- (4-niethoxyphenyl) propyl) -3,5-dicarboethoxy-4- (m-mothylthiophenyl) -6-metnyl-1,4-dihydropyridine; 2- [3- (4-methoxyphenyl) -3-aminopropyl] -3 _/ 5-dicarbethoxy-6-methyl-4- (m-methylthiophenyl) -1,4-dihydropyridine; 2- [3- (pyrid-3-yl) -3-aminopropyll-3,5-dicarbethoxy-6- Methyl 4- (m-methylthi (1enyl) -1,4-dihydropyridine; 2- [3-Acetamido-3 - (- thienyl) -propyl-3-carbethoxy-5-carbomethoxy-4- (m-nitro. <nyl) -6-methyl-1,4-dihydropyridine; 2- (3-Acetamido-3- (4-methoxyphenyl) propyl] -3,5-dicarbethoxy-4- (m-methylth -> henyu-6-methyl 2- (3-phenyl · 3-phβnylthiopropyl) -3,5 · dicarbβthoxy-4- (m-nitrophθnyl ^ β-mβthyl·l, 4 · dihydropyridine;; 2- (3-phenyl-3 -1,4-dihydropyridine -methylthiopropyl) -3-carbmethoxy-5-carbethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-acetylthlopropyl) -3,5-dicarbmethoxy- (m -trlfluormethylphenyl) -e-methyl-1,4-dihydropyridine;

The compounds according to the invention are prepared by a process which comprises the cleavage of a cyclopropane ring of a Compound of formula II

(ID.

wherein R, R ₄ , X and Y are as defined above, with a mineral acid or a monobasic organic acid, e.g. Example, with nitric acid (HN ₃ ), hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (Hl), monobasic carboxylic acids, eg. For example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, or sulfonic acids, eg. For example, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, to give a compound of the formula Ia:

(Ia) ₁

wherein X, Y, R and R _{4 are} as defined above, while R ' _{3 is} an azide group, halogen, an -OCORf or a -OSO ₂ R ₆ group, wherein Re and Fi ₄ WJe are defined above, the then converted to another compound of formula I by hydrolysis of an ester group to give an alcohol, which in turn is etherified or esterified; or by substitution of a halogen or OSOjRj group in the compound of formula Ia by an azide group; or by reducing an azide group to a primary amino group which can then be alkylated or acylated, if desired; or by reductive substitution of a sulfonate or halogen derivative into an alkane and, if desired, a compound of formula I can be further resolved or resolved into the optical or diastereoisomers. The reaction to cleave the cyclopropane ring in a compound of formula Ia is obtained with a molar excess of monobasic mineral acid or organic acid, preferably in the presence of another solvent such as alcohols (e.g., methanol, ethanol, isopropanol), ethers (e.g. B. Tetrhydrofuran, Uioxan, 1,2-Dlmethoxyethane), halogenated solvents (eg., Dichlormethan, chloroform, 1,2-dichloroethane), water or mixtures thereof. The reaction temperature is in the range of -3O ⁰ C to the reflux temperature of the solvent. The reaction times are a few minutes to 48 hours, but the reaction is preferably carried out at temperatures between O ⁰ C and room temperature within a time of 10 minutes to a few hours.

The compounds of the formula Ia can, if desired, be further converted into other compounds of the formula I by using methods known in the art:

a) Selective hydrolysis of the ester groups FV ₃ in aqueous alcohols in the presence of alkali metal carbonates or bicarbonates (eg lithium hydroxide, sodium hydroxide, sodium or potassium bicarbonate) at room temperature in a few hours. The alcohols of general formula I (R ₃ = OH) thus obtained can then be etherified or esterified using conventional methods.

b) reduction of an azide group to an amino group, e.g. By reaction with a trialkyl phosphite in benzene or toluene followed by hydrolysis with aqueous mineral acid to hydrolyze the intermediate nitrogen ylide or, alternatively, reduction with sodium or lithium borohydrides in the equivalent of an alcohol such as methanol or ethanol followed by if desired, the resulting primary amine of general formula I is alkylated or acylated by known methods.

c) Reductive substitution of a halogen or sulfonated RV group to an alkane by reaction with tributyltin hydrides in inert solvents, eg benzene or toluene, most preferably in the presence of a free radical generator, eg azobisisobutyronitrile, or alternatively, reaction with LiAlH ₄ in ethers.

The compounds of formula II are described in E.P. Application No. 86110517.9. The preferred compounds of formula II are the individual icy- or trans-cyclopropyl-diastereoisomers. The cis or trans configuration of the cyclopropane ring in compounds of formula II is indicated by the cis or trans. Configuration of the β-ketoesters of general formula III predetermined:

00-.CH ₂ -CO ₂ R

(III)

wherein R ₄ and R are as defined above, which are used in the preparation of the compounds of formula II in accordance with the preferred method of preparation in the above cited patent application.

The compounds of the formula II which are used in this invention can be used both for the cis- and the trans- Cyclopropyl diastereoisomers. It has now been found that the cleavage of the cyclopropane ring (of both the ice and the trans isomer) in Compounds of formula II by monobasic mineral or organic acids on directional and stereospecific The route is such that, assuming a single diastereoisomer of formula II, a single diastereoisomer

of the formula Ia is obtained and the subsequent, if appropriate, conversion takes place stereospecifically.

In addition, when using optically pure diastereoisomers of the formula II, pure enantiomers of the formula I a

receive. Thus, compounds of formula I are prepared when starting from pure cis or pure trans-cyclopropyl

Diastereoisomers of the formula II starting and the pure diastereoisomers of the general formula Ia is obtained. The use of mixtures of diastereoisomers of the icy and trans-cyclopropanes of the formula II leads to the same Mixtures of D> astereoisnmeren of compounds of general formula I a, which, if desired, in the individual Diastereoisomers can be separated. Cis and trans cyclopropanes of the formula III can be prepared by known methods, wherein one of the

corresponding cis- or trans-cyclopropanecarboxylic acids of formula IV:

(IV) ₍

COOH

wherein R _{4 is} as defined above.

The most suitable methods for preparing compounds of formula III from the compounds of formula IV are

known in the art and consist in the reaction of the acyl chloride of compounds of formula IV, either with malonic acid monoethyl ester in the presence of magnesium or with Meldrum's acid in the presence of pyridine.

Compounds of formula IV are known both as racemates and as individual optical antipodes. So z. B. In a recent publication (J.Aaral et al., J. Amor., Chom. Soc., 107, 8254-8256, 1985), there is an improvement in the synthesis of chiral cyclopropanoic acids which involves the preparation of ketals of α, β-unsaturated aldehydes goes out, described.

If optically pure γ, δ-cyclopropane-β-ketoejter of the formula II is used in the ring closure reaction according to Hantzech for the synthesis of dihydropyridines of the formula II, a mixture of optically active diastereol isomers of the formula II is obtained, The individual chiral diastereoisomers by fractional crystallization or separated by chromatography

When a racemic mixture of γ, δ-cyclopropane-β-ketoesters of the formula III is used, a mixture of racemic diastereol isomers of the formula II is obtained, which can be separated into the individual racemic diastereoisomers by fractional crystallization or by chromatography.

When the compounds of the invention are administered orally to conscious spontaneously hypertensive rats (SHR) or hypertensive rats induced hypoxia by administration of deoxycorticosterone acetate (DOCA rats), they produce a significant, long-lasting, dose-dependent Lowering the mean blood pressure.

The lowering of the blood pressure occurs gradually, with the greatest effect being reached after 6 to 8 hours after the administration and this effect lasting for another 8 to 10 hours. In some compounds of the invention, this antihypertensive effect is evident even at small doses, z. At 0.2 to 0.4 mg / kg per os; z. B. 4- (R, S) -3 '- (R, S) -2- (3'-chlorophenyl) -4- (m-nitrophenyl) -e-methyl-5-carbmethoxy-3-carbethoxy-1, 4-dihydropyridine a decrease in mean blood pressure by 40 mm Hg (18%) when administered at a dose of 0.2 mg / kg per os SHR rats, and this effect then persists for 12 hours.

It is surprising that the compounds of formula I behave moderately to active when tested in the classical Godfraind test (Arch. Int Pharmacol 172, 235, 1968) and compared with nifedipine (from 10 to 10,000 times less active).

When tested in vitro, these compounds are effective in inhibiting spontaneous lipid peroxidation in homogenized rat brain.

The compounds of the present invention are therefore useful as antihypertensive agents for the treatment of circulatory disorders of varying severity and etiology and for the treatment of thromboembolic disorders in ischaemia of the heart, kidney and brain.

The compounds according to the invention can furthermore be used as cytoprotective and antiulcer agents.

The compounds of the invention are characterized by high LD _U values ranging from 400 mg / kg to more than 1000 mg / kg (in mice, both orally and intraperitoneally).

According to the above-described pharmacotoxicological results, the compounds of the present invention are considered to be particularly useful in the treatment of various hypertensive conditions wherein progressive hypertension reduction is achieved by administration of low dose compounds of formula I (preferably one administration within each 12 to 24 hours) becomes.

The compounds can be administered in a variety of ways to achieve the desired effect. The compounds can be administered to the patient, alone or in the form of pharmaceutical compositions, with oral or parenteral administration, e.g. As an intravenous or intramuscular, is possible. The formulation of suitable pharmaceutical compositions may be made by those skilled in the art according to the well-known art and by reference to corresponding reference works, e.g. Remington's Pharmaceutical Sciences, Handbook, Mack Publishing Company, USA.

The amount of compound administered depends on the severity of hypertension and the mode of administration. When administered orally, the effective antihypertensive effect amount of the compound is about 0.01 mg / kg (milligrams per kilogram of body weight) per day to about 10 mg / kg per day, and preferably about 0.05 mg / kg per day to 5 mg / kg and day. For parenteral administration, the antihypertensive effective amount of the compound is about 0.001 mg / kg per day up to 5 mg / kg per day, and preferably 0.01 mg / kg per day up to about 2 mg / kg and day.

For oral administration, a unit dose, e.g. B. between 0.50 and 70mg of the active ingredient. Since the compounds of the present invention generally have long-lasting efficacy, they may best be administered once or twice a day, but in some cases the administration repeated several times a day may be desirable, which ultimately depends on the condition of the patient and the mode of administration. The term "patient" as used herein is intended to have the meaning of a warm-blooded animal, including humans.

For oral administration, the compounds of the invention may be formulated into solid or liquid compositions, e.g. As capsules, pills, tablets, Trochiscen, powders, solutions, suspension or emulsions. The shape of the solid unit dosage may, for. Example, be a capsule, which is of the type of ordinary gelatin, either hard or soft, the z. B.

Contains lubricants and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the compounds of the invention may be tabletted with conventional tabletting agents such as lactose, sucrose and corn starch, together with excipients such as acacia, corn starch or gelatin, comminuting excipients such as potato starch or alginic acid and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration, the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically suitable diluent, together with a pharmaceutical carrier, e.g.

a sterile liquid such as water or oils, with or without the addition of a surfactant and others

be administered pharmaceutically suitable adjuvant. Examples of oils which may be used herein are those derived from petroleum, animal or vegetable or synthetic sources, e.g. Peanut oil, soybean oil and mineral oil. In general, water, physiological saline, dextrose solutions and other sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol may be used as liquid carriers for injectable solutions.

For rectal administration, the compounds are in the form of suppositories with the addition of usual HHfstoffen such. As cocoa butter, wax, spermaceti, polyvinylpyrrolidone, polyethylene glycols or their derivatives

administered.

The preferred form of processing of the compounds according to the invention is the oral one. The following examples illustrate the invention, but do not limit it. Ausfflhrungsbelsplele Composition 1

A solution of 5 g of trans-3- (2-phenyl-1-cyclopropyl) -2- (m-nitrophenyl-methylene) -3-oxo-propanoic acid ethyl ester and 1.5 g of methyl 3-amino-crotonic acid in ethanol becomes 4 hours boiled under reflux, then evaporated under vacuum and the residue dissolved in 60 ml of ethyl acetate. This solution is washed 3 times with 10 ml of water, dried over sodium sulfate and purified over 300 g of silica gel with isopropyl ether as eluent. Thereby, 4 g of a mixture of the diastereoisomers of trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridine, F = 123-12S ⁰ C. received.

The diperasteroisoisomeric mixture, which on thin layer chromatography (Merck Kieselgel 60 F-254, eluent isopropylothermal) shows two spots at Rf bets 0.37 and 0.42 mm intensity, is purified by chromatography on silica gel (240g, eluent: dichloroethane / isopropyl ether / hexane = 15/15/70) to give the two pure diastereoisomers trans-2- (2-phenyl-1-cyclopropyl) -carbethoxy-5-carbmethoxy-4- (m -nitrophenyl) -6-methyl-1,4 -dihydropyridin; the less polar diastereoisomers (thin layer chromatography on Merck silica gel 60, eluent isopropyl ether, R ₁ = 0.42), recrystallized from methanol (1 g / 12ml) had a F = 135-137 ⁰ C, the polar diastereoisomers (Dünnichichtchromatographie on Merck Kieselgel 60, Eluent isopropyl ether, R ₁ * = 0.37), recrystallized from methanol (1 g / 20 ml) had a F = 144-145 ⁰ C.

Composition 2 Using the same protocol and conditions as in Preparation 1, the following compounds were used

prepared (as mixtures of diastereoisomers):

Trans-2- (2-i-phenyl-1-cyclopropyl) -3-carbethoxy-5-cyano-4- (m-nitrophenyl) -e-methyl-1,4-dihydropyridine, trans-2- (2-phenyl -1-cyclopropyl) -3-carbethoxy-5-nitro-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy 5-methylcarbonyl-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, cis-2- (2-phenyl-1-cyclopropyl) -3,5-dicarboethoxy-4- (m-nitrophenyl) - 6-methyl-1,4-dihydropyridine, cis -2- (2-phenyl-1-cyclopropyl) -3 _/ 5-dicarbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine, trans -U-lpyrid-S-yD-i-cyclopropyll-SB-dicarbethoxy ^ -lm-methylthiophenyD-e-methyl-IAdihydropyridin, trans -2- | 2- (4-methoxyphenyl) -1-cyclopropyll-3,5-dicarbethoxy -4- (m-methylthlophenyl) -6-methyl-1,4-dihydropyridine, trans -2- | 2- (4-nitrophenyl) -1 - <; yclopropyl | -3,5-dicarbethoxy-4- (m- methylthlophenyl) -6-methyl-1,4-dihydropyridine.

example 1

A solution of the less polar diastereoisomer of trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (mnitrophenyl) -6-methyl-1,4-dihydropyridine (2.5 g) in 50 ml of 97% formic acid is stirred for 30 minutes at 25 ⁰ C under a nitrogen atmosphere, then poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The organic phase is washed 3 times with 50 ml of 5% NaHCO ₃ solution and twice with 50 ml of water each time. The organic phase is dried over Na ₃ SO ₄ , filtered and evaporated. 2.68 g of the most polar diastereoisomer of 2- (3-phenylformyloxypropyl) -3-carbethoxy-5-carbomethoxy-4- (m-nitrophenyl) -1,4-dlhydropyridine are obtained as a yellow, glassy foam

NMR (δ CDCl ₃ ): 8.2 (s, 1H); 7.2-7.9 (m, 9H); 6.5 (sb, 1H); 5.4 (t 1 H); 5.1 (s, 1H); 4.1 (q, 2H); 3.6 (s, 3H); 1.9-2.9 (m, 4H); 2,3 (s, 3H); 1,2 (t, 3H).

Using the conditions described above, the most polar diasterecisomer of trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine , the less polar diastereoisomers of 2- (3-phenyl-3-formyloxypropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine

NMR (δ CDCl ₃ J: 8.2 (s, 1H); 7.2-7.8 (m, 9H); 6.6 (sb, 1H); 5.5 (t, 1H); 5.2 (s, 1H), 4.2 (q, 2H), 3.6 (s, 3H), 1.9-2.9 (m, 4H), 2.2 (s, 3H); 1,1 (t, 3H).

When operating under the same conditions, however, a mixture of the diastereoisomers trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4 -dihydropyridine, trans -2- 2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluoromethylphenyl) -6-methyl-1,4-dihydropyridine and trans-2- (H Phenyl-1-cyclopropoxy-3-carbethoxy-5-carbmethoxy-4- (m-n'-phenyl-6-yl) -6-methyl-1,4-dihydropyridine, the following mixtures of diastereoisomers are obtained:

2- (3-phenyl-3-formyloxypropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-r ^ rmyloxypropyl) -3-caibethoxy-5-carbmethoxy-4- (m-trifluürmethylphenyl) -6-methyl-1,4-dihydropyridine; 2- (3-phenyl-3-formyloxypropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine.

Example 2 A solution of 10 g of trans ^ -thenyl-i-cyclopropyl-carboxylic acid (prepared according to J.W.McFarlan, J.Org.Chem.30 | 196bj, 3298) In 10 ml of thionyl chloride is stirred for 24 hours at room temperature; after the usual workup, the thus obtained Acyl chloride (7.6 g) was added dropwise at ⁰ ° C. to a solution of 5.8 g of Meldrum's Sture and 8.0 g of pyridine in toluene of dichloromethane. After 4 hours at room temperature to 20 ml of water are added, the two phases separated and the organic Phase 3 times with 10 ml NaHCOy solution and washed 3 times with 20 ml of water, dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in 100 ml of ethanol and this solution is refluxed for 2 hours; after that it will Evaporated reaction mixture and the resulting crude 2- (2-ThienyM-cyclopropyl) -3-oxo-propansä jre ethyl ester (6g)

this form used in the following reactions. It is reacted with 3.8 g of m-nitrobenzaldehyde in 70 ml of benzene in the presence of 2.0 g of piperidine acetate as catalyst. This reaction mixture is refluxed for 8 hours, on

Cooled to room temperature, washed 3 times with 15 ml of water, dried and e'ng ^ evaporated. The resulting mixture of 7.0 g of the ice and trans isomers of 3- [2- (2-thienyl) -1-cyclopropyl) -3-oxo-2- (m-nitrophenyl).

Methylene propanesic acid ethyl ester is dissolved in 70 ml of ethanol in the presence of 2.2 g of methyl 3-amino-crotonate. This solution is refluxed for 6 hours, then evaporated in vacuo, and the residue is purified by chromatography on 200 g

Silica gel with diisopropyl ether as eluant to give 4.8 g of trans-2- [2- (2-thlenyl) cyclic) propyl) -3-carbethoxy-5.

carbmethoxy-4- (m -nitrophenyl) -e-melhyl-1,4-dihydropyrldin (mixture of diastereoisomers).

A solution of 2.0 g of this dihydropyridine in 40 ml of 99% formic acid is stirred for 45 minutes at 25 ⁰ C. The Finally, the mixture is poured into 300 ml of water and extracted with 100 ml of diethyl ether. After the usual work-up, 1.5 g of 2- [3- (2-thlenyl) -3-formyloxypropyl-3-carbethoxy-5-carbmethoxy-4- (m) are added.

nitrophenyl) -6-methyl-1,4-dihydropyridine.

NMR (OCDCI ₃ ): 8.1 (s, 1H), 7.9-6.5 (m, 8H), 5.3 (t, 1H), 5.1 (s, 1H), 4.1 (q, 2H) 0.6 (s, 3H), 2.9 to 1.9 (m, 4H), 2.3 (s, 3H); 1.2 (t, 3H). Example 3 Applying the experimental conditions of Examples 1 and 2, the following 6-methyl-1,4-

dihydropyridines obtained as mixtures of diastereoisomers:

2- (3-formyloxy-3-phenylpropyl) -3-carbethoxy-5-cyano-4- (nvnitrophenyl);

2- (3-formyloxy-3-phenyl-p, opyl) -3-carbethoxy-5-nitro-4- (m-nitrophenyl);

2- (3-formyloxy-3-phenylpropyl) -3-carbethoxy-5-methyl-carbonyl-4- (m-nitrophenyl); 2- (3-formyloxy-3-phenylpropyl) -3,5-dicarbethoxy-4- (m-nitrophenyl);

2- (3-formyloxy-3-phenylpropyl) -3,5-dicarbethoxy-4- (m-chlorophenyl);

2-i3- (pyrid-3-yl) -3-formyloxypropyl] -3,5-dicarbethoxy-4- {ITI methylthiophenyl), 2- [3-formyloxy-3- (4-methoxyphenyl) propyl) -3, 5-dicarbethoxy-4- (m-methylthiophenyl); 2- [3-formyloxy-3- (4-nitrophenyl) propyl] -3,5-dicarboethoxy-4- (m-methylthiophenyl).

Example 3 a

1 ml of trifluoroacetic acid under inert gas atmosphere (N ₁ ) at room temperature in a solution of 0.1 g of the mixture

Diastereoisomers of trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-

dihydropyridine is added dropwise. After 3 hours, the reaction mixture is worked up as described in Example 1 and the crude residue is purified by chromatography on 6 g silica gel with isopropyl ether: hexane as 60:40 as eluent. 20mg of the mixture of stereoisomers of 2- (3-phenyl-2-trifluoroacetoxypropyl) -3-caroethoxy-5-carbmethoxy-4- (m -nitrophenyl) -6-methyl-1,4-dihydropyridine thus becomes as glassy, yellow Obtained foam.

NMR (OCDCI ₃ ): 8.0-7.2 (m, 9H), 6.5 (sb, 1H), 5.7 (t, 1H), 5.2 (s, 1H), 4.2 ( q, 2H), 3.5 (s, 3H), 1.9-2.7 (m, 4H), 2.2 (s, 3H), 1.1 (t, 3H). When, under the conditions described above, the mixture of diastereoisomers of trans-2- (2-phenyl-1-cyclopropyl) -3-

carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine and trans-2- (2-phenyl-1-cyclopropyD-S-carbethoxy-5-carbmethoxy-4- (m- methylthiophenyl) -6-methyl-1,4-dihydropyridine, the following mixtures are used

Diastereoisomers obtained:

2- (3-phenyl-3-trifluoiacetoxypropyl) -3-carbethoxy-5-carbomethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyiidin; 2- (3-phenyl-3-trifluoracetoxypropyl) - 3-carbethoxy-5-carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine.

Example 4

0.45 ml of methanesulfonic acid at 25 ° C under inert gas atmosphere to a solution of 50 mg of the mixture

Stereoisomers of trans-2- (2-Phanyl-1-cyclopropyl-S-carbethoxy-S-carbmethoxy) -1-nitrophenyl O-e-methylm, 4-

dihydropyridine in 5 ml of chloroform; After 1.5 hours, the reaction mixture is poured into ice-water and washed with 20 ml

Extracted diethyl ether. The organic phase is washed 3 times with 20 ml of a 5% aqueous NaHCO ₃ solution and twice with 30 ml of water,

dried over sodium sulfate, filtered and evaporated.

The crude compound is purified by chromatography on 5 g silica gel with isopropyl ether: hexane 60:40 as eluent. There are 25 g of 2- (3-phenyl-3-methylsulfonyloxypropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenvD-1,4-

dihydropyridine obtained as a mixture of diastereoisomers in the form of an amorphous yellow solid.

NMR (δCDCI ₃ ): 8.0-7.2 (m, 9H); 6.5 (sb, 1H); 5.7 (t, 1H), 5.2 (s, 1H), 4.2 (q, 2H); 3.5 (s, 3H); 3.0 (s, 3H); 1.9-2.7 (m, 4H); 2.2 (s,

3H); 1.0 (t, 3H).

Using the same conditions and mixtures of diastereoisomers of trans-2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine and of trans -2- (2-phenyl-1-cyclopropyl) -3-carbethoxy-ö-carbmethoxy-e-methyl-1-trifluoromethyl-phenyi-1-dihydropyridine are the following mixtures

Diastereoisomers obtained:

2 (3-phenyl-3-methylsulphonyloxypropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-chlorophenyl) -1,4-dihydropyridine; 2- (3-phenyl-3-methylsulphonyloxypropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (o-trifluoromethylphenyl) -1,4-dihydropyridine.

Example B A solution of 600 mg of the mixture of the diastereol isomers of Irane ^ -tfPhenyM-cyclopfopyO-S-cerbethoxy-i

carbmethoxy-4- (n-nitrophenyl) -e-methyl, 4-dihydropyridine in 6 ml of chloroform and SmI of a 6% solution of

Hydrezojlure In chloroform, under N | in the sealed tube iwel heated to 80'C. The mixture is then cooled to 0 ° C., the tube is opened and poured into 26 ml of water / ice and 20 ml of diethyl ether. The Phases are separated and the organic phase is washed with PBmI of a SHIgen, aqueous NaHCO 3 solution and water

washed, dried over sodium sulfate and eingedam '. 0.6 g of a red, glassy oil is obtained by

Column chromatography on 20 g of silica gel with isopropyl ether is purified to give 26 mg of 2 × 1 ×

aiidopropyl-S-carbethoxy-B-carbomethoxy-6-methyl-4- (m-iiltroplunyl) -1,4-diphohydro-pyrrole as a yellow, glassy oil

Mixtures of diastereolsomers are obtained. NMR (OCDCI,): 7.9-7.2 (m, 9H); 6, e (ib, 1H); B, 3 (1, 1H); 6.2 (s, 1H); 4.1 (q, 2H); 3, e (i, 3H); 2.9 to 1.9 (m, 4H), 3 | i, 3 H).?; 1,20.3H). Using the reaction conditions described above, only one Dlattereolsomeres vr η trans-2- (2-phenyl-1 ·

cyclopropyl) -3-carbethoxy-5-carbmethoxy * & methylH * (n-vinyl-phenyl) * 1,4-dihydropyridine, and only one diastereol isomer of / (S-phenyl-S-amidopropyD-carbethoxy-B-carbmethoxy-e-methyl-1'-m -nitrophenyD-i ^ -dihydropyridine.

Thus, for example, starting from the less polar diastereol isomer (F-135-137 * C), the less polar image of the ivate

(F - 128-131 · Ο received.

Example β

0.3 ml of a 5% aqueous NeHCOy solution is added to 2.5 g of the polar-sound diastereoisomer of 2- | 3-formyloxy-3-phenyl-i-propyl-a-carboihoxy-S-carbmethoxy-tm-n-urophenyl-e-methyl -i ^ -dlhydropyrldln, dissolved in 20ml methanol, added.

The mixture is refluxed for 30 minutes, then cooled to 25'C and reduced to a small volume (about 2 ml)

The sticky mass is diluted with 70 ml of ethyl ether and 30 ml of water and the phases are separated. The organic phase is washed twice with 30 ml of water each time and dried over sodium sulfate. The solvent is distilled off under reduced pressure to give 2.3 g of the polarest diestoreol isomer of 2- (3-phenyl-3-hydroxv-propyl) .3 <arbmethoxy-6-carbethoxy-e-methyl-4- (m-nitrophenyl) * 1 , 4-dihydropyridine be obtained as a yellow foam m.

NMR (SCDCI ₁ ): 7.9-7 _l 2 (m, 9H); e ₍ B (eb, 1H); 6 _l 2 <e, 1H); 5.1 (t, 1H); 4.1 (1H); ς, 2Η), 3, β (ι ₍ 3Η), 2,9-1,9Ν, 5Η, 2,3 (s, 3H), 1,2 (t, 3H). In the same way the following compounds were prepared:

2 × (3 × phylnyl-3 × hydroxypropyl) × 3 × carbethoxy-5 × carbomethoxy 4 × (methylmethylthio) · β · methyl · 1.4 × (tihydropyridine; 2 × (3-phenyl-3 × hydroxypropyl) · 3.5 x dicarbethoxγ × 4 × (m · methylthiophenyl) · 6 · methyl · 1,4 · dihydropyrldin; 2- (3-phenyl-4-hydroxypropyl)> 3,5-dicarbethoxv4 * (o-methylthiophenyl) 4-methyM, 4 2- (3-phenyl-3-hydroxypropyl) -3-carbethoxy-5-carb-2-propanopropoxy-4- (p -fluorophenyl) -e-methyl-1,4-diphhydropyridine; 2 x (3-phenyl-3 · Hydroxypropyl) -3 · carbethoxy · 5 · cyβn · 4 · (m-nitrophenyl) · β · methyl · 1.4 · dihydropyridine · n · 2 · (3 · phenyl-3-hydroxypropyl) -3'-rbβthoxy · · nitrophenyl) · β-mβ ^ hyl · 1,4 · dlhydropyridln 5 · n tro x 4 x {m!;

Z-O-phenyl-S-S, S-hydroxypropyD dlcarbethoxy ^ -lo-nltrophenyD-e-mathylO ^ -dihydropyrldln;

2- {3-phenyl-3-hydroxypropyl) -3,5-dicarbethoxy-4- (2-nltro-5-methylthlophenyl) -e-methyl'1,4-dihydropyrldln; 2- [3-hydroxy-3- ( pyrid-3-yl) propyl) -3,5-dicarboethoxy-4- (m-methylthiophenyl) dihydropyrldin -e-methyl'1,4 *; 2 x [3-hydroxy · 3 · (4 · methoxyphenyl) propyl] · 3.5 x dicarbθthoxγ × 4 × (m · mβthylthiophenyl ^ β · methyl · 1,4 · dihydropyridine; 2- (3-hydroxy-3- (4-nltrophenyl) propyl | -3,5-dicarbothoxy-4- (m -methylthlophenyl) -e-methyl-1,4-dihydropyrldin; 2 * (3-hydroxy · 3- (2 x thienyl) propyl | -3 · carbethoxγ x 5 x carbmθthoxy × 4 × (m · nitrophθnyl) · β · methyl · 1.4 · dihydropyridine; 2 * (3-Hydroxγ-3 · (3 · thienyl) propyl) -3-carbβthoxy x 5 x carbmethoxy × 4 × (m · nitrophenyl) · 6 · methyl · 1,4 · dihydropyridine; 2- (3-Phθnyl · 3 · hydroxypropyl) x 3 x 5 x carbθthoxy carbmθ ^ hoxy · β · mβthyl × 4 × (m · chloΓphβnyl) · 1,4 · dihydropyrldln; 2- (3-phenyl-3-hydroxypropyl ) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (m-trifluoromethylphenyl) -1 ₍ 4-dihydropyridine; 2- (3-phenyl-3-hydroxypropyl! -3-carbethoxy-5-carbmethoxy-e- melhyl-4- (m-methylthiophene yl) -1,4-dihydropyridine,

Example 7 An 8N solution of hydrogen chloride gas in absolute ethanol (10ml) is added to a suspension of 4g of the less at O'C

polar diastereoisomers of trans-2- (2-phenyl-1-cyclopropyl-S-carbethoxy-S-carbmethoxy) -im-nilrophenyD-e-methyl-1H-dihydropyridine (F135-137'C) in 20 ml of ethanol dripped.

After stirring at room temperature for 20 minutes, the clear solution is concentrated in vacuo. The residue

is dissolved in 200 ml of ethyl ether, washed 3 times with 20 ml of water, 2 times with 10 ml of a 5% solution of

Sodium bicarbonate, washed twice with 20 ml of water and dried over sodium sulfate. The organic phase is in the Vacuum evaporated, the residue is slurried with 30 ml of ethyl ether and stirred at O'C for 12 hours. They are doing this

forming crystals are filtered off and washed with ether cooled by ice. It became 2.97g of the polarest

Diastereoisomers of 2- (3-phthyl-3-chloropropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4 ·

dihydropyridine, F = 119-120 "C.

Using the reaction conditions described above, the polarest diastereoisomer of trans-2- (2- Phenyl-1-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m - • rophenyl) -e-methyl-1,4-dihydropyridine, the less polar one Diastereoisomerovon2- (3-phenyl-3-chloropropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophep.yl) -e-methyl-1,4-dihydropyridine, F = 137-139'C. Using the reaction conditions described above, the mixture of diastereoisomers of

Trans-2- (2-phenyl-cyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, as well as the like

Mixture of diastereoisomers of 2- (3-phenyl-3-chloropropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1 _< 4 ·

= 110-114 ⁰ C obtained dihydropyridine, F.

Using the mixtures of the diastereoisomers of. Using the reaction conditions described above

Trans-2- (2-phenylcyclopropyl) -3,5-dicarbethoxy-4 (m-nitrophenyl) -e-methyl-1,4-dihydropyridine, tran8-2- (2-phenylcyclopropyl) -3-carbethoxy -5-carbmethoxy-4- (mchlorphenyl) -e-methyl-1,4-dihydropyridine, trans- (2-phenylcyclopropyl) -3 ·

carbothioxy-5-carbomethoxy-4-methyl-m-trifluoromethyl-phenyl) 6-methyl-1,4-dihydropyridyltran8 · 2 (2-phenyl-cyclopropyl) -3-carbethoxy-S-carb-isopropoxy-n-proprophenyl -e-methyl-dihydropyrimidate, the following mixtures are obtained

Olastereolsomeren of 2 · (3 · εηΙθΓ · 3 · ρηοηνΙ) · ρΓοργΙ · 6 · ηΐθ% Ι · 1.4 · ύΙηγαΓοργΓΐαΙη obtained:

3, S-Olcarbethoxy> 4 '(m> nltrophenyl)

a-carbethoxy-B-carbmethoxy ^ -lm-chlorophenyl),

a-carbethoxy-B-carbmethoxy ^ dn-trlfluornrethyl-phenyl),

3-carbethoxy-5-carb-isopropoxy-4- (nvnltrophenyl).

Using the reaction conditions described above, the following compounds were also named Mixtures of stereoisomers obtained:

2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5-nHro-4- (m-nitrophenyl) -e-methyl-1,4-di-hydropyridine; 2- | 3-chloro-3- ( pyrld-3-yl) propyl | -3, B-dlcarbethoxy-4- (m-methyl-thlophenyl) -e-methyl-1,4-dihvdropyrldln; 2-l3-chloro-3- (4 * methoxy ^ henyl) * 4-dihydropyridln (m methyMhiophenyl) ^ methyM - propyl) 4,6-dicarbethoxy ^; 2 * l3 · chlorine · 3 · (4 · · nltro phβnyl) propyl) · 3, B · dlcarbβthoxy × 4 × (m · methyl-thloph-phenyl) -β-methyl-ethyl-1,4-dibutylpyridine, 2- (3-chloro-3- (3-thlenyl) propyl] -3,5-dicarbethoxy-4- (m-nitro-phenyl) -e-methyl -1,4-dlhydropyridin.

Example 8

1.5 ml of a 4% (w / v) solution of hydrobromic acid in acetic acid was added at room temperature to a stirred suspension of the mixture of the stereoisomers of 200 mg of trans-2- (2-phenylcyclopropyl) -3-carbethoxy-5- cnrbmethoxy-4- (mnitrophenyl) -6-methyl, 4-dihydropyridine added dropwise in 2 ml of ethanol. After 5 minutes, the solution is poured into 20 ml of water / ice and extracted 3 times with 20 ml of ethyl ether. The organic phase is washed 3 times with 10 ml of a 5% solution of NaHCOy, dried and concentrated in vacuo. There were thus obtained 190 mg of 2- (3-bromo-3-phenyl-propyl) -3-cerbethoxy-5-carbmethoxy-4- (m-nitro-phenyl) -e-methyl-1,4-diphohydro-pyridine as an amorphous solid.

NMR (CDClI) δ (TMS): 1.00-1.20 (3H, t); 2.20 (3H, s); 2.20-3.10 (4H, m); 3.70 (3H, β); 3.80-4.10 (2H, q); 4.80-6.00 (3H, s + m); 6,10 (1H, s, wide); 7.00-8.10 (9H, m).

Example α

S ml of a solution of Bromwasseretoffsflure in 30% acetic acid at 25 ⁰ C under inert gas atmosphere to a solution

of 0.6 g of the less polar diastereoisomers of trane -U-phenyM-cyclopropyl-S-carbethoxy-S-cyano-e-methyl-tm-nitrophenyl) -1,4-dihydropyridine added in 6 ml of chloroform. After 1 hour, the mixture is poured into 60 ml of water and extracted with 26 ml of diethyl ether. The phases are separated and washed 3 times with 60 ml each of an aqueous 5% solution of NaHCO3 and twice with 60 ml of water each time, dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure. There are obtained 600 mg of the polar acid diastereoisomer of 2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-cyano-e-methyl-4- (m-nitro-phenyl) -1,4-dihydropyridine as an amorphous solid ,

NMR (OCDCI ₁ ): 7.9-7.2 (ιτ », 9Η); β, 5 (8 ^ 1Η); 5.2 (8,1Η); 5.1 (t, 1H); 4.1 (q, 2H); 3, e (s, 3H); 2, & - 1.9 (m, 4H), 2.3 (8,3H); 1.2 (t, 3H). Using the reaction conditions described in Examples 8 and 9, the following compounds were used as Mixtures of the diastereoisomers obtained:

2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-nit'o-e-methyl-4- (m-nitrophenyl) -1,4-dlhydropyridin2 · (3 · Phβnyl · 3 · bromopropyl) · 3 · carbethoxygamma-6-cyano · β · methyl · 4 · (m · chloro-phenyl) 1,4 · dihydropyridine; 2 · (3 · phenyl-3 · bromopropyl) -3 · carbethoxy-5-carbonylmethyl · β · methyl · 4 · (m · nitro · phenyl) · 1,4 dihydropyridine.

If, under the same reaction conditions, the pure diastereoisomers of trans-2- (2-phenylcyclo) are also used.

1-cyclopropyl) -3-carbethoxy-e-methyl-5-carbmethoxy-4- (m-chloro-phenyl) -1,4-dihydropyridinundtran8-2- (2-phenyl-1-cvclopropyO ^ arbethoxy-e ^ arbmethoxy- e-methylmethylmethylthiophenylMadihydropyridine gives the pure

Diastereoisomers of:

2 · (3 · · Phθnyl 3-bromopropyl) · 3-carbothoxy-5 carbmθthoxy · · β · methyl · 4 · (m · chloroethyl phenyl) · 1,4 · dihydropyridinund2 · (3 · Phβnyl · 3 · bromopropyl) · 3-carbethoxy x 5 x carbmβthoxy · β · mβthyl × 4 × (m · methyl · thiophθnyl) · 1,4 · dίhydropyrίdin.

Example 10

0.12 g of sodium azide, 6 mg of tetrabutylammonium bromide and 2 ml of water become a solution of 0.2 g of the less polar

Dia3tereolsomerenvon2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-carbmethoxy-6-me (hyl-4- (m-nitrophenyl) -1,4-

dihydropyridin in 2ml benzene added; then the biphasic mixture is 5 hours with vigorous stirring on

Reflux cooked. The mixture is then cooled to 25'C, poured into water, extracted m.i 20ml diethyl ether, over Dried sodium sulfate, filtered and the solvent distilled to dryness under reduced pressure. It will

180mg of the less polar diastereoisomer of 2- (3-phenyl-3-azidopropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-5- {m-nitro-phenoxy-1,4-dihydropyridine.

NMR (δ CDCl ₃ ): 7.9-7.2 (m, 9H); 6.5 (s, 1H); 5.2 (t + s, 2H); 2.8-1.9 (m, 4H); 2,3 (s, 3H); 1,2 (t, 3H). Under the conditions described above, but using the bromopropyl derivatives of Example 9, the

The following compounds are obtained both as pure D.astereoisomers and as mixtures thereof:

2- (3-phenyl-3-a2idopropyl) -3-carbethoxy-5-cyano-6-methyl-4- (m-nitrophenyl) -1,4-dihydropvridin; 2- (3-phenyl · 3 · azidopropyl ) -3-carbethoxy · 5 · nitro 6 · methyl-4- (m-nitrophenyl) -1,4 · dihydropyridine; 2- (3-Phonyl-3-azido-propyl) -3-carbethoxy-5-carbmethoxy -6-methyl-4- (m-chloro-phenyl) -1,4-dihydropyrldin;

2- (3-phenyl-3-azidopropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-methyl-thiophenyl) -1,4-dihydropyridine.

Under the conditions described above, in place of the sodium azide, sodium thiomethoxide, sodium thiophenoxide

and potassium thioacetate are used, the following compounds are obtained:

2- (3-phenyl-3-phenylthiopropyl) -3,5-diccrbethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-methylthiopropyl) - 3-carbmethoxy-5-carbethoxy-4- (m-chloro-phenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-acetylthiopropyl) -3,5-dicarbr "ethoxy- (m trifluoro-methyl-phenyl) -6-methyl-1,4-dihydropyridine.

Example 11

0.2 ml of triethyl phosphite are added to a solution of 0.5 g of the mixture of diastereoisomers of 2- (3-phenyl-3-azidopropyl) .S-carbethoxy-.beta.-carbmethoxy-e-methyl-1-methyl-nitrophenyl. I ^ -dlhydropyridine was added to the mixture in 6 ml of cold benzene and the mixture was stirred at 25.degree. C. for 24 hours under an inert gas atmosphere. Thereafter, 1 ml of ethanol saturated with HCl * is added and stirred at room temperature for a further 24 hours. The mixture is then poured into water-Ele-Mlschung, the aqueous phase is made alkaline with 5% aqueous NaHCOj solution and extracted with 3 times 60ml diethyl ether. The phases werdan separated, the organic phase is dried over sodium sulfate and filtered off. There are thus obtained 300 mg of 2- (3-phenyl-S-amylpropyD-S-carbmethoxy-e-methyl-fm-n-indiphenyl-1-dihydropyridine as diastereol isomers in the form of an amorphous solid.

NMR (OCDCI ₁ ): 7.9 »7.2 {m, 10H); e.4 (m, 2H); 5.1 (8.1H); 4.8 {m, 1H); 4.1 (q, 2H) ; 3, e (e, 3H); 2 ₍ 9-1.9 (m, 4H); 2,3 <e, 3H); 1,2 (t, 3H).

Example 12

120 ml of water are added to a suspension of 30 g of sodium borohydride in 120 ml of toluene, 2.27 g of hexadecyltributylphosphonium bromide and 15 g of the less polar diastereoisomer of 2- (2-phenyl-3-azldopropyl) -3-carbethoxy-5-carbmethoxy-e-methyl-4-. (m-nitro-phenyl) -1,4-dihydropyridine. The mixture is stirred at 70 ° C. for 24 hours, then cooled to room temperature, poured into 200 ml of water, extracted with 200 ml of ethyl acetate, with water

washed until a pH of 7 is reached, dried and evaporated under reduced pressure. The crude oil (15 g) is purified by chromatography (460 g silica gel, eluent, ethyl acetate-ethyl ester) to give 7.69 g of the less polar

Diastereoisomers of 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (m -nitrophenyl) -1.4 ·

dihydropyridine be obtained as a glassy foam. This is dissolved in 35 ml of ethyl acetate, and to this are added 1.87 g

Maleic acid is added to give 8.2 g of the maleate: C _n H _n O (N ₃ .C ₄ H ₄ O ₄ (bright yellow crystals),

F - 149-152 ^e C.

Using the same conditions as in Examples 11 and 12, the following compounds are described as Mixtures of the diastereoisomers obtained:

2 · (3 · phenyl · 3 aminopropyl) · 3-carbethoxy-5 carbmθthoxy · · 6-mθthyl × 4 × (m · methyl · thiophenyl) · 1,4-dihydropyr> din; 2- (3-phenyl-3 aminopropyl) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (m-chlorophenyl) -1,4-dihydropyridln; 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy- 6-methyl-4- (m-trifluormethy -phenyl) -1,4-dihydropyridine; 2- (3-pyrid-3-yl) -3-aminopropyl] -3,5-dicarbethoxy-6-methyl-4- (m-methvl'thiophenyl) -1,4-dihydropyridine; 2- [3- (4-methoxyphenyl) -3-aminopropyl) -3,5-dicarbethoxy-6-methyl-4- (m-methyl: thiophenyl) -1,4-dlhydropyridin; 2- | 3- (4-nitrophenyl) -3-aminopropyl) -3,5-dicarbethoxy-6-methyl-4- (m-methyl-thiophenyl) -1,4-dihydropyridine, 2 - [3- (3-thienyl) -3-aminopropyl) -3,5-dicarbethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine.

Example 13

0.48 ml of triethyl phosphite under inert gas atmosphere to 14 ml of a benzene solution of 1.4 g of the less polar

Diastereoisomers of S-carbethoxy-S-carbmethoxy-e-methyl-tm-nitropheny-D-O-azldopropyl-i-di-nydropyridine

added and then boiled for 3 hours at reflux. Thereafter, the mixture is cooled to room temperature and in

Vacuum evaporated. The crude oil crystallizes from 15 ml of diisopropyl ether and gives 0.95 g of the less polar DiastereoleomerenvonS-carbethoxy-B-carbmethoxy-e-methyM-tm-nitrophenyD ^ -O-phenyl-S-

diethoxyphosphorylamidopropyl-M-dihydropyridine, F = 136-139 ⁰ C as a white powder. Used under the same

conditions

2- (3-phenyl-3-azidopropyl) -3 ^ arbethoxy-5 <arbmethoxy4- (m <hlorphenyl) - & methyM, 4-dihydropyridine, 2- (3-phenyl-3-a2idopropyl) -3-carbethoxy-5- carbmethoxy-4- (m-methylthiophenyl) -e-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-a2idopropyl) -3 - <: arbethoxy-5-carbmethoxy-e-methyl-4- (o -tri-methyl-phenyl) -1,4-dihydropyridine, the following compounds are obtained in the form of the mixtures of their diastereoisomers:

2- (3-phenyl-3-phosphorylamidopropyl) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (m-chlorophenyl) -1,4-dihydropyridine; aO-phenyl-S-S-carbethoxy-phosphorylamidopropyH S-carbmethoxy-e-methyl ^ -lm-methylthiophenyD-i ^ -dihydropyridin; 2- (3-phenyl-3-phosphorylamidopropyl) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (o-trifluoromethyl-phenyl ) -1,4-dihydropyridine.

Example 14

0.65 ml of chloroformate are added to a solution of 200 mg of the polar diastereoisomer of 2- (3

Phenyl-S-aminopropyD-S-carbethoxy-S-carbmethoxy-e-methyl-im-nitrophenyD-I-dihydropyridine in 2 ml of anhydrous Toiuen given. After two hours at room temperature, the mixture is poured into water / ice and washed with 5% aqueous NaHCO solution made alkaline. This mixture is extracted with SOmI diethyl ether; the organic phase is washed twice

washed 20 ml of water, dried over sodium sulfate, filtered and the solvent was distilled off under reduced pressure.

There are 200 mg of the less polar diastereoisomer of 2- (3-phenyl-3- (N -ethoxycarbonylamino) propyl] -3-carbethoxy-5-

carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine as a transparent oil.

NMR (δ CDCl ₃ ): 8.0-7.2 (m, 11H); 5.1 (s, 1H); 4.9 (m, 1H); 4.2 (q, 2H), 4.0 (q, 2HI, 3.6 (s, 3H), 2.9-1.0 (m, 4H), 2.3 (s, 3H), 1, 2 (t,

3H); 1,1 (t, 3H).

Using the conditions described above, the following mixtures of diastereoisomers or pure diastereoisomers were prepared:

2- (3-Phenyt-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m -chlorophenyl) -1,4-dihydropyridine and 2 (3-phenyl-3-aminoprop) - 3-Carbethoxy-5-carbmethoxy-6-methyl-4- (o-trifluoromethylphenyl) -1,4-dihydropyridine the following compounds are obtained: 2- [3-phenyl-3- (N -ethoxycarbonylam; iio) propyl] 3-carbethoxy-5-carbmethoxy-6-methyl-4- (m -chlorophenyl) -1,4-dihydropyridine and 2- (3-phenyl-3- (N -ethoxycarbonylamino) -propyl-3-carbethoxy-5-carbomethoxy 6-methyl-4- (o-trifluoromethylphenyl) -1,4-dihydropyridine

both as pure diastereoisomers and as mixtures of diastereoisomers.

Example"

2.4 ml of a 35% solution of NaOH and 10 mg of tetrabutylammonium bromide are added to a solution of a mixture of

Diastereoisomers of 2 · (3 · ηβηνΙ · ΙιναΓϋχγρΓθρνΙ) · 3 · οβΓΟθίΙιοχγ · 5 · οβΓΟηηθΙΙιοχν · 6 ^ θίΙιγΙ · 4 · (Γη · η! Ϊ́ΓορΗθηνΙ) · 1,4 ·

dihydropyridine (200mg) added in 2ml ethyl alcohol. The mixture is stirred at 40 ° C for 3 hours, then poured into 20 ml of water and 20 ml of ethyl ether and the phases are separated. The organic phase is washed twice with 60 ml of water each time, over

Dried sodium sulfate, filtered and concentrated under reduced Drur ¹ :. There will be 220mg of the mixture of Diastereoisomers of 2- (3-phenyl-3-ethoxypropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4 ·

obtained dihydropyridine as a transparent oil.

NMR (OCDCI,): 8.0-7.0 (m, 10H); 5.1 (sb, 1H), 4.3 (t, 1H), 4.1 (q, 2H), 3.6 (β, 3Hi 3.3 (q, 2H), 2.9-1 , 9 (ηι, 4Η), 2,3 (8,3Η), 1,2 (1.

3H); 1.1 (t, 3H).

Under the same conditions, but using the mixture of diastereoisomers of 2- (3-phenyl-3-hydroxypropyl) -3-carbethoxy-5-carboethoxy-e-methyl-4- (m-methylthiophenyl) -1 ₍ 4- dihydropyridine and 2- (3-phenyl-3-hydroxypropyl) -3-carbethoxy-5-carbmethoxy- & methyl- (m-trifluoromethylbenzene, 4-dihydropyridine, the following mixtures of diastereoisomers are obtained:

2- (3-phenyl-3-ethoxypropyl) -3-carbethoxy-6-carbomethoxy-6-methyl-4- (m-methylthiophenyl) -1,4-dihydropyridine and 2- (3-phenyl-3-ethoxy) propyl ) -3-carbethoxy-5-carbmethoxy-e-methyl-4- (m-trifluoromethylphenyl) -1,4-dihydropyridine.

Example 16

1 ml of acetic anhydride becomes a solution of the polar Ciastereoisomeren of 2- (3-phenyl-3-hydroxypropyl) -3-carbethox / · 5 ^ arbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyrk! in (1 g) in 2 ml of anhydrous pyridine. The mixture is stirred for 1 hour at room temperature, then poured into 20 ml of water / ice and extracted with 50 ml of diethyl ether.

The organic phase is washed with a 5% aqueous Schwerfeisäure and 5 times with 40 ml of water, over Dried sodium sulfate and the solvent was evaporated, whereby 1 g of the polarest Distereoioo neren of 2- (3-phenyl-3

acetoxypropyD-S-carbethoxy-S-carbmethoxy-e-methyl-dn-nitrophenyD-M-dihydropyridine is obtained as a yellow glassy foam.

NMR (δCDCIj): 8.0-7.2 (m, 9H); 6.5 (sb, 1H); 5.5 (t, 1H); 5.2 (sb, 1H); 4.2 (q, 2H); 3.5 (s, 3H); 1.9-2.7 (m, 4H); 2.2 (s, 3H); 2.0 (s,

3H); 1,2 (t, 3H).

Under the conditions described above, but using 2- (3-hydroxypropyl) and 2- (3-aminopropyl) -1,4-dihydropyridines, the following -6-methyl-1-dihydropyridines are prepared: 2 - (3-acetoxy-3-phenylpropyl) -3,5-dicarbethoxy-4- (m-methylthiophenyl); 2- (2-acetoxy-3-phenylpropyl) -3,5-dlcarbethoxy-4- (2-fluoro-5-methylthiophenyl); 2- (3-acetoxy-3-phenylpropyl) -3-caroethoxy-5-carb-isopropoxy-4- (p-fluorophenyl); 2- (3-acetoxy-3-phenylpropyl) -3-carbethoxy-5-cyano-4- (m-nitrophenyl); 2- (3-acetoxy-3-phenylpropyl) -3,5-dicarbethoxy-4- (m-methylsulphinylphenyl); 2- (3-acetoxy-3-phenylpropyl) -3,5-dicarbethoxy-4- (2-nitro-5-methylthiophenyl); 2- | 3-acetoxy-3- (pyrid-3-yl) propyl] -3,5-dicarboethoxy-4- (m-methylthiophenyl); 2- (3-Acetoxy-3- (4-nitropheryl) propyl] -3,5-dicarbethoxy-4- (m-methylthiophenyl); 2- (3-Acetoxy-3- (2-thienyl) propyl) -3- carbethoxy-5-ca-methoxy-4- (m-nitrophenyl); 2- [3-acetoxy-3- (4-bromophenyl) propyl) -3-carbethoxy-4- (m-nitrophenyl); 2- [3-acetamido 3-phenylpropyl-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl); 2- (3-acetamido-3-phenylpropyl) -3-carbethoxy-5-corbmethoxy-4- (o-methylthiophenyl); 2 - (3-acetamido-3-phenylpropyl) -3,5-dicarbethoxy-4- (m-methylthiophenyl); 2- [3-Acetamido-3- (2-thienyl) -propyl-3-carbethoxy-5-carbmethoxy-4 - (m-nitrophenyl); 2- [3-Acetamido-3- (4-methoxyphenyl) propyl) -3,5-dicarbethoxy-4- (m-methylthiophenyl).

Example 17 A solution of 2.0 g of 2- (3-hydroxy-3-phenyl) propyl-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-

dihydropyridine, 0.85 g of p-nitrobenzoyl chloride and 0.64 g of triethylamine in 20 ml of methylene chloride is hot for 24 hours

Room temperature stirred. Thereafter, 0.3 g of p-nitrobenzoyl chloride and 0.20 ml of triethylamine are added and more

Stirred for 72 hours. Finally, the mixture is concentrated in vacuo and diluted with 50 ml of ethyl ether. The organic

Mixture is washed 3 times with 10 ml of water, twice with 5 ml of 1N NaOH 5 times 10 ml of water, dried over Na ₂ SO ₄ and

concentrated in vacuo to give 2.15 g of 2-3 - [(p-nitrobenzoyloxy) -3-phenyl] -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine glassy solid, F = 75-9O ⁰ C, are obtained.

In the same way but using benzoyl chloride and pivaloyl chloride in place of

p-Nitrobenzoyl chloride, the following derivatives were prepared:

2- (3-t-butylcarbonyloxy-3-phenyl) propyl-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridinund2- (3-benzoyloxy-3-phenylpropyl) -3-carbethoxy-5-cdrbmethoxy-A- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine.

Example 18

A solution of 100 mg of the diastereoisomers of 2- (3-hydroxyphenyl) propyl-3-carbethoxy-5-carbmethoxy-4- (mnitrophenyl) -6-methyl-1,4-dihydropyridine in 2 ml of formic acid is stirred at room temperature for 24 hours, then diluted with 10 ml of water and extracted with 15 ml of ethyl ether. The organic phase is washed ₃ times with 5 ml of 5% aqueous NaHCO ₃ solution and ₃ times with 5 ml of water each time, dried over Na ₂ SO ₄ and concentrated in vacuo to give the mixture of diastereoisomers of 2- (3 Formyloxy-3-phenylpropyl) -3-carbethoxy-5-carbethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydric; -pyridine which is identical to the compound prepared in Example 1 has been.

Example 19 A solution of 1 g of the mixture of diastereoisomers of 2- (3-phenyl-3-bromopropyl) -3-carbethoxy-5-carbmethoxy-6-

methyl-4- (m-nitrophenyl) -1,4-dihydropyridine in 10 ml of water. THF is added at room temperature under nitrogen to a

Suspension of 120 mg LIAIH ₄ -PuIvCr in 2 ml of anhydrous THF. The mixture is refluxed for 6 hours, then cooled to 0 * C and poured with vigorous stirring in 100 ml of water / ice, acidified with 1N HCl to a pH of 3-4 and extracted twice with 50 ml of diethyl ether. The combined organic extracts are washed to neutrality with aqueous, 5% more NaHCOj solution and 3 times with 60 ml of water, dried over sodium sulfate, filtered off and the solvent was evaporated under reduced pressure. There are obtained 0.85 g of a yellow oil which is purified by column chromatography on 50 g of silica gel with isopropyl ether: hexane 3: 7 as eluent to give 0.22 g of 2- (3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-6- (m-nltrophenyl) -1,4-dihydropyridine as a yellow oil methyM- which spontaneously crystallized from isopropyl ether is recrystallised from ethanol and F of 125-127 ⁴ C. Untor the same conditions, but using the bromine derivatives such. B. 2- (3-phenyl-3-bromopropyl) -3-carbethoxy - / - 5-carbi-thio)> 7 e-methyl-4- (m-chlorophenyl) -1,4-dihydropyridine, 2- (3 -Phenyl-3-bromopropyl) -3-carbethoxy-5-carbirethoxy-6-methyl-4- (o-trifluoromethylphenyl) -1,4-diphohydryl, 2- (3-phenyl-3-bromopropyl) -3- carbethoxy-5-carb-isopropoxy-6-methyl-4- (m-methylthiophenyl) -1,4-dihydropyridine, the following compounds are obtained:

2- (3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m -chlorophenyl) -1,4-dihydropyridine, 2- (3-phenylpropyl) -3-carbelhoxy-5-carbomethoxy 6-methyl-4- (ctrifluoromethylphenyl) -1,4-dihydropyridine, 2- (3-phenylpropyl) -3-carbethoxy-5-carb-isopropoxy-6-methyl-4- (m-methylthiophenyl) -1, 4-dihydropyridine.

Example 20 A solution of 15 ml of formylacetic anhydride, which by heating a mixture of 5 ml of formic acid and

10 ml of acetic anhydride was prepared at 60 ° C., is added to a solution of 3.5 g of 2- (3-amino-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1 , 4-dlhydropyrldin in 35 ml of anhydrous 1,2-dimethoxyethane under nitrogen at ⁰ ° C. The mixture is stirred at room temperature for 4 hours, then poured into 250 ml of water / ice and extracted 3 times with 50 ml of ethyl acetate each time Wash 30 ml of a saturated, aqueous NaHCO ₃ solution and wash ₃ times with 30 ml of water each time, dry over Na ₂ SO ₄ and evaporate The residue is purified by chromatography on 90 g of silica gel with hexane: ethyl acetate 50:50 as eluent to give 2.8 g 2- (3-phenyl-3-formylamino-propyl-O-S-carbethoxy-B-carbmethoxy) -1-nitrophene, 1) -6-methyl-1,4-dihydropyridine in the form of the mixture of

Diastereoisomers as yellow foam. NMR (S CDCl ₃ ): 8.20-6.70 1.T) ₁ 12H); 5.10 (m, 2H); 4.1 (q, 2H); 3.6 (s, 3H); 2.8 to 1.9 (m, 4H); 2.3 (s, 3H); 1,2 (t, 3H). In the same manner, the following compounds were prepared.

2- (3-phenyl-3-formylaminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -e-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-formylamlnopropyl) - 3-carbethoxy'5-carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine.

Example 21

In a polyethylene flask, a mixture of 1 g of trans-2 (2-phenylcyclopropyl) -3-carbethoxy-5-carbmethoxy-4- (mnitrophenyl) -6-methyl-1,4-dihydropyridine and 0.4 g of KF dissolved in 10 ml of the HF / pyridine complex are stirred for 2 hours under nitrogen at 0 ⁹ C and then stirred for 24 hours at room temperature. Finally, this mixture is poured into 80 ml of a saturated aqueous KF solution and extracted with ethyl ether. The organic phase is washed 3 times with a saturated NaHCOa solution (50 ml each), then 3 times with 30 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by chromatography on 70 g of silica gel, eluting with isopropyl ether: hexane 90:10. In this way, 0.2 g of 2- (3-fluoro-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine as a mixture of diastereoisomers as amorphous Obtained solid. NMR (δ CDCl ₃ ): 8.10-7.00 (m, 9H); 6.10 (sb, 1H); 5.00 (s, 1H); 4.90 (m, 1H); 4.10-3.80 (q, 2H); 3.70 (s, 3H); 3.0-2.2 (m, 4H); 2,?, O (S, 3H); 1.2-1.10 (t, 3H).

Under the same conditions as described in Example 21, but using the more polar diastereoisomer of trans -IPhenylcyclopropyl-S-carbethoxy-S-carbmethoxy-Fm-nitropheny-E-methyl-i-dihydropyridine, this became less polar Diastereoisomers of 2- (3-fluoro-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (mnitrophenyl) -6-ethyl-1,4-dihydropyridine; and when the less polar diastereoisomers of trans-2- (2-phenylcyclopropyl-SH-carbamoyl-S-carbmethoxy) -im-nitrophenyl O-e-methyl, 4-dihydropyridine are used, the more polar diastereoisome € revon2- (3-fluoro-3 -phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine.

Under the same conditions as in Example 21, the following compounds were prepared: 2- (3-fluoro-3-phonylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4- dihydropyridine, 2- (3-fluoro-3-phiinylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-fluoro-3-phonylpropyl ) -3,5-dicarbethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine.

Example 22

A solution of 1 g of the mixture of diastereoisomers of 2- (3-bromo-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine in 10 ml of anhydrous THF is added to 0.5 g of anhydrous tetrabutylammonium fluoride in anhydrous THF and stirred for 5 hours. Thereafter, the mixture is poured into 50 ml of water and extracted twice with 20 ml of ethyl acetate. The organic phase is then washed with water, dried over NaI SO ₄ and evaporated to dryness to give 0.9 g of a crude product as a yellow oil which is purified by chromatography on 30 g of silica gel with diisopropyl etherhexane 90:10 as eluent to give 0 , 08g of the mixture of diastereoisomers of 2- (3-phenyl) -3-fluoropropyl) -3-carbethoxy-5-carbmethoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine as a yellow foam , This compound is identical to the sample obtained in Example 21.

Claims (7)

wherein X represents a -CO ₂ Rr, cyano, nitro or -COCHa group, wherein R and Ri, which may be the same or different, are a primary, secondary or tertiary, saturated or unsaturated, linear or branched C 1 - Ce alkyl group which may be unsubstituted or substituted by one or more hydroxyl, monoalkyla-, amino-, dialkylamino, Ci-C ₆ -Akoxy-, phenoxy or optionally substituted aryl groups; wherein R _{2 is} hydrogen, R _{3 is} hydrogen or a hydroxyl, -OCORs .OSORE, azide, amino-NHPO (OR ₇ ) ₂ , -NHCORe group, a Ci-C ^ alkoxy group, a fluoro, Chlorine, bromine or iodine atom, an SH group, a SCOR ₈ - or a Ci-Ce-alkylthio, phenylthio or benzylthio group, wherein R _{4 is} an optionally substituted aromatic or an optionally substituted, 5- or 6-membered heteroaromatic group in which Y represents one or more substituents which may be identical or different from one another, namely C 1 -C ₄ -alkoxy groups, halogens, nitro, cyano, C 1 -C 6 -alko-carbonyl, C 1 -C 6 -alkylthio, halogeno-C ^ Ce-alkyl, halo-Ci-Ce-alkoxy groups, wherein R ₅ represents hydrogen or a Ci-C ₄ -Aikyl-, trihalomethyl, C ₁ -C ₄ alkoxy, or an unsubstituted or substituted Phenyigruppe wherein R ₆ is hydrogen or a C ₁ -C ₄ -AIkYl-, trihalomethyl, phenyl or p-methylphenyl group, wherein R ₇ is a Cr-C ₄ alkyl or a phenyro group, their enantiomers and / or diastereoisomers, which may be isolated or in mixtures, and their salts with pharmaceutically acceptable acids or bases, characterized in that the cyclopropane ring of a compound of general formula II (II) wherein R, R ₄ , X and Y are as defined above, are cleaved by a molar excess of monobasic mineral acid or organic acid in an inert solvent, whereby a compound of formula I a COOR H ₃ C 1 ^ CH ₂ -OH ₂ -Lr ₄ R ¹ , in which X, Y, R and R4 are as defined above, while R'3 is an azide group, a fluorine, chlorine, bromine or iodine atom, an -OCOR ₆ group or a -OSO ₂ Re group. Group, and that the thus prepared compound of formula I a is subjected to one or more of the following reactions: Selective hydrolysis of ester groups represented by R'3 to give compounds of formula I in which Η _Λ = OH, which group may in turn optionally be etherified or esterified; Substitution of a halogen or a -OSO ₂ R _e group by an azide group; Reduction of an azide group to a primary and optionally acylated or alkylatable amino group; - Reductive substitution of a halogen or a -OSO ₂ R ₆ group by hydrogen; - optical resolution - Resolution of diastereoisomers; - salt formation. 2. The method according to claim 1, characterized in that compounds of formula I are prepared in which X is a carbmethoxy, carbethoxy, Carbisopropoxy-, cyano or nitro group, R is an ethyl group, R _{3 is} hydrogen, OH, -OCOR ₆ , OSO ₂ R ₈ , an azido, amino, -NHCOR ₅ , ethoxy group, fluorine, bromine or chlorine, an SH group, a SCOR ₆ - or a Cr-Ce-alkylthio, phenylthio or Benzylthio group, R _{4 is} a phenyl group, Y is chlorine, a nitro, trifluoromethyl or methylthio group, R _{5 is} hydrogen, a trifluoromethyl or ethoxy group, Re means a methyl group. 3. The method according to claim 1, characterized in that one of the following compounds is prepared: 2- (3-Formyloxy-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m -nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- {3-formyloxy-3-phenylpropyl] S-carbethoxy-B-carbmethoxy-im-chlorophenyl-e-methyl-IA dihydropyridine, 2- (3-Formyloxy-3-phenylpropyl) -3-carbethoxy-5-carbomethoxy-4- (m-trifluoromethyl-phenyl ) -6-methyl-1,4-dihydropyridine, 2- (3-trifluoroacetoxy-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-azido-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-hydroxypropyl ) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-hydroxypropyl) -3,5-dicarbethoxy-4- (m -methylthio-phenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-hydroxypropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluoromethyl-phenyl) -6-methyl- 1,4-dihydropropyridin, 2- (3-phenyl-3-hydroxypropyl) -3,5-dicarbethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-bromopropyl) -3- carbethoxy-5-cyano-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-Fluoro-3-phenylpropyl) -3-carbethoxy-5-cyano-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine _f 2- (3-alido-phenylpropyl) -3- Carbethoxy-5-nitro-4- (m -nitrophenyl) -6-methyl, 4-dihydro-pyridine, 2- (3-azido-3-phenylpropyl) -3-carbethoxy-5-carboisopropoxy-4- (m-nitrophenyl) - 6-Methyl-1,4-dihydropyridine 2- (3-Aido-3-phenylpropyl) -3-carbethoxy-5-carbethoxy-4- (m -chlorophenyl) -6-methyl-1,4-dihydroxy-pyridine, 2- 3-azido-3-phenylpropyl) -3-carbethoxy-5-carbethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-aminopropyl) -3-carbethoxy -5-carbm '', hoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-4- m-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4 dihydropyridine, 2- (3-phenyl-3-aminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluoromethyl-phenyl) -6-methyl-1,4; dihydropyridine, 2- [3-phenyl 3- (N-ethoxycarbonyl) aminopropyll-3-carbethoxy-5-carbmethoxy-4- (m-nitroph enyl) -6 · methyl-1,4-dihydropyridine, 2- (3-phenyl-3-formylaminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine , 2- (3-Phenyl-3-formylaminopropyl) -3-carbethoxy-5-carbmethoxy-4- (m-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-formylaminopiopropyl) 3-Carbethoxy-5-carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-ethoxy-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- {3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- {m-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenylpropyl) -3-carbethoxy-5-carbomethoxy 4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- {3-methylsulonyloxy-3-phenyl) -propyl-1-carbethoxy-B-carbmethoxy-1,1-nitrophenyl-B-methyl-1,4 -dihydropyridine, 2- (3-azido-3-phenylpropyl) -3-carbethoxy-5-cyano (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-chloro-3-phenylpropyl) -3,5-dicarbet: hoxy-4 (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m -chlorophenyl) -6-methyl-1, 4-dihydropyridine, 2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-trifluoroethylphenyl) -6-methyl-1,4-dihydropyridine, 2- (3-Chloro 3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-chloro-3-phenylpropyl) -3-carbethoxy-5- Carboisopropoxy-6-methyl-4- (m-nitrophenyl) -1,4-dihydropyridine, 2- (3-bromo-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6- Methyl 1,4-dihydropyridine, 2- (3-bromo-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4-im-chlorophenyl) -6-methyl-1,4-dihydropyridine, 2- (3 Fluoro-3-phenylpropyl) -3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-fluoro-3-phenylpropyl; -3-carbethoxy-5 -carbmethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- [3-formyloxy-3- (pyrid-3-yl) propyl] -3,5-dicarbethoxy-4- (m -methyltl.iphenyl) -6-methyl-1,4-dihydropyridine, 2- [3-formyloxy-3- (4-metho xyphenyl) propyl] -3 _/ 5-dicarbethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- [3-hydroxy-3- (4-nitrophenyl) propyl) -3,5-dicarbethoxy-4-m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-hydroxy-3- (3-thienyl) propyll * 3-carbethoxy-5-carbrnethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-Chloro-3- (3-thienyl) propyl) -3,5-dicarbethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2-l3-chloro-3- ( 4-methoxy ^ henyl) propyll-3,6-dicarbethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- [3- (4-methoxyphenyl) -3-aminopropyl (-3,5-dicarbethoxy-6-methyl-4- (m-methylthiophenyl) -1,4-dihydropyridine, 2- [3- (pyrid-3-yl) -3-aminopropyl) -3,5-dicarboxy-6-methyl-4- (m-methylthiophenyl), 4-dihydropyridine, 2- (3-acetamido-3- (2-thienyl) propyll-3-carbethoxy-5-carbmethoxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- [3-acetamido-3- (4-methoxyphenyl) propyll-3,5-dicarbethoxy-4- (m-methylthiophenyl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-phenylthiopropyl) -3,5-dicarboxy-4- (m-nitrophenyl) -6-methyl-1,4-dihydropyridine, 2- {3-phenyl-3-methylthiopropyl) -3- c8rbmethoxy-5-carbethoxy-4- (m-chlorphGi> yl) -6-methyl-1,4-dihydropyridine, 2- (3-phenyl-3-acetyl-thiopropyl) -3,5-dicarbmethoxy-im-trifluoromethyl-phenyl) -6-methyl-1,4-dihydropyridine as well as their enantiomers and / or diastereoisomers, isolated on their own and / or in mixtures and their salts in pharmaceutically suitable acids and bases. 4. The method according to claim 1, characterized in that the cleavage of the cyclopropane ring by hydrazoic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, Trifluoressjjsäure, methanesulfonic acid or trifluoromethanesulfonic acid is carried out. 5. The method according to claim 1 or 4, characterized in that the optionally taking place hydrolysis of ester groups represented by R'3 in the presence of alkali metal hydroxides ^ carbonates or bicubes is carried out at room temperature. 6. The method according to claim 1 or 4, characterized in that the optionally carried out reduction of the azide group is carried out to an amino group with sodium or lithium borohydride. 7. The method according to claim 1 or 4, characterized in that the optionally carried out reductive substitution of the halogens or the-OSC ^ Re group with tributyltin hydride or with LiAIH _{4 is} listed.