CS271486B2 - Method of new dihydropyridinamides production - Google Patents

Description

The present invention relates to a process for the production of novel dihydropyridinamides having valuable pharmacological properties, in particular the ability to affect blood circulation and can therefore be used as medicaments.

It is known that 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diethyl ester is obtained by reacting ethyl benzylideneacetic acid ethyl ester with β-aminocrotonic acid ethyl ester or ethyl acetate with acetic acid and ammonia / cf. E. Knoevenagel, Ber. Dtsch. Chem. Ges. 31, 743 (1898)].

It is further known that certain 1,4-dihydropyridines have interesting pharmacological properties (cf. F. Bossert, W. Vater, Naturwissenschaften 58 «578 (1971) / *

The present invention relates to a process for the preparation of the novel dihydropyridinamides of the formula I. ______________ ve

R ¹ which

H ⁸

R ²

R ³

R ⁴

R ⁵

(AND)

They are the same or different from each other and represent a straight or branched alkyl group having 1 to 6 carbon atoms;

is a straight or branched (C 1 -C 6) alkyl group which is optionally interrupted in the chain by an oxygen atom and is optionally substituted by a (C 2 -C 6) alkoxycarbonyl or phenyl group which are the same or different from each other and represent a hydrogen atom or an alkoxy group up to 4 carbon atoms.

—O— (CH8) _n -phenyl,

-O- (CH 8) _n -pyridyl,

-S-CCH 8) - phenyl or

-O-SOg-phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl or halogen;

7 '

R and R 'are the same or different from each other and are

- hydrogen atom,

- C 3 -C 8 -cycloalkyl,

- a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having up to 5 carbon atoms which may be optionally substituted by hydroxy, C1-C4alkoxy, C2-C5alkylalkyl, phenyl, dialkylamino having 1 to 4 carbon atoms in both alkyl moieties, * cycloalkyl having 3 to 6 carbon atoms or pyridyl, l-phenyl optionally substituted by carbamoyl, acetylamino or benzoylamino, or

a pyridyl group;

* as well as their physiologically acceptable salts ·

The compounds of formula (I) produced by the process of the invention exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates to both antipodes and racetic forms as well as mixtures of diastereomers. Rac ethnicities can also be resolved as diastereomers in a known manner into athereomeric unitary constituents (cf. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Physiologically acceptable salts can be salts of compounds of formula I with inorganic or organic acids. Preferred are salts with inorganic acids such as 8 hydrochloric acid, hydrobromic acid, phosphoric acid or 8 sulfuric acid, or salts with organic carboxylic acids or sulionic acids, such as 8 acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Preferred are compounds of formula (I) wherein

I Ω

R and R are the same or different from each other and signify

straight or branched (C 1 -C 4) alkyl, o

* R represents a straight or branched alkyl group having 1 to 6 carbon atoms, which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by a phenyl group, *

R ^ and R ^ are the same or different from each other and represent a hydrogen atom or an alkoxy group having from 1 to 4 carbon atoms,

-O- (CH 2) _n -phenyl, * -O- (CH ₂ ) _n -pyridyl,

-S-C (CH 3) 4 -phenyl or

-O-SOg-phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl or fluoro, chloro or bromo, _R 6 _{and R} 7 they are the same or different from each other and mean

- a hydrogen atom or a C 3 -C 7 cycloalkyl group,

- a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having 8 to 5 carbon atoms which may be optionally substituted by hydroxy, alkoxy having 1 to 4 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, phenyl, dialkylamino having 1 up to 4 carbon atoms in both alkyl moieties,

phenyl optionally substituted by acetylamino or benzoylamino, or

- the pyridyl group and their physiologically acceptable salts;

Particularly preferred are compounds of formula I wherein:

Η * ¹ μ H ⁶ are the same or different and are methyl or ethyl,

R ² represents a straight or branched alkyl group having 1 to 6 carbon atoms which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted phenyl, _and R4 are identical or different and represent hydrogen, methoxy or ethoxyekupinu,

R 1 represents -O-CH 2 -phenyl, -O-CH ₂ -pyridyl, -S-CH ₂ -phenyl or -O-SO ₂ -phenyl, the phenyl moiety optionally being substituted up to twice with the same or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluoro or chloro, r6 is hydrogen or alkyl of 8 to 4 carbon atoms, and

R ⁷ denotes

a hydrogen atom, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, or

- a straight or branched alkyl group of up to 10 carbon atoms or an alkenyl group of up to 5 carbon atoms optionally substituted by hydroxy, C1-C4 alkoxy, C1-C4 alkylcarbonyl, phenyl, or a (C 1 -C 4) dialkylamino group in the alkyl moieties; or

R ⁷ denotes

a phenyl group optionally substituted by an arylamino or benzoylamino group, or

- a dt -, β -, or -pyridyl group, and their physiologically acceptable salts;

According to the invention compounds of formula I wherein R ¹ R® have the abovementioned meanings, are prepared by reacting an ester ylidene- -ketokarboxylové β acids of the formula VIII X '. CS 271487 B2

(VIII) wherein ¹ ''

5

R @ 1 to R @ 2 are as defined above, in reaction with the enaminocarboxylic acid amides of formula (V)

in which ----------- -------- f. Π O

R, R 'and R are as defined above, optionally in the presence of inert solvents, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts.

The process according to the invention can be illustrated by the following reaction scheme in the specific case of the starting compounds:

Suitable solvents for the reaction according to the invention are water or all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol, isopropyl alcohol, ethers such as diethyl ether, dioxin, tetrahydrofuran, glycol monomethyl ether, or glycol dimethyl ether, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine.

The reaction temperatures may vary within a wide range. In general, the reaction is carried out at temperatures between 4-10 ° C and +150 ° C, preferably at temperatures between +20 ° C and +100 ° C.

The reaction can be carried out at atmospheric pressure but also at elevated or reduced pressure.

The ratio of the starting materials involved in the reaction according to the invention is arbitrary. In general, however, molar amounts of reactants are used.

The isolation and purification of the compounds obtained by the process according to the invention is preferably carried out by distilling off the solvent under reduced pressure and recrystallizing the residue, if any, only after ice-cooling in a crystalline state from a suitable solvent. In some cases, it may be necessary to purify the compounds obtained by the process of the invention by chromatography.

The enaminocarboxylic acid amides of the general formula V which are used as starting materials are known or can be prepared according to known methods (cf. D08 2,228,377 /.

The ylidene-β-ketocarboxylic acid esters of formula VIII which are used as starting materials in the process of the invention are known or can be prepared according to known methods (cf. G. Jones The Knoevenagel Condensation in Organic Reactions, Vol. XV, 204 (1967) /

The compounds of formula (I) produced by the process of the present invention exhibit an unpredictable spectrum of valuable pharmacological effects. These compounds affect heart contractility, smooth muscle tone, and electrolyte and fluid levels.

The compounds can be used in medicaments for the treatment of pathologically altered blood pressure and cardiac insufficiency, as well as as coronary therapeutics.

In addition, the compounds may be used to treat disorders of the heart rhythm, renal insufficiency, cirrhea of the liver, ascites, pulmonary edema, brain edema, pregnancy edema, glaucoma or diabetes (Diabetes mellitus).

The activity of the compounds produced by the process of the invention on the activity of the heart was determined on isolated, stimulated papillary muscle of the guinea pig heart. To this end, the test animals (guinea pigs of both sexes weighing 200 g) are sacrificed, their chest open and their heart removed. For the experiments, small papillary muscles are then removed from the right ventricle and fixed horizontally in the organ bath. One end of the muscle is trapped between two metal electrodes, which simultaneously irritate the specimen, while the other end of the muscle is connected by a fiber to the force transducer. An organ bath of about 2 ml is continuously washed with Krebs-Henseleite solution (concentration in mmol: NaCl 118; NaCO ₃ 25; KCl 10; KH ₂ PO ₄ 1.2; MgSO ₄ 1.2; CaCl ₂ 1.8; glucose 10, pH 7.4) at a rate of 4 ml / min at 32 ° C. Papillary muscle contraction is measured isometrically via a connected force transducer and recorded using a recorder.

The compounds of the invention are dissolved in Krebs-Henseleit solution at a concentration of 10 µg / ml, optionally using a co-solvent (dimethylsulfoxide up to 0.5%). The dihydropyridine carboxylic acid amides according to the invention exhibit, by comparison with the values obtained in a control experiment, a reduction in the force of contraction of the palatial muscle by more than 10%.

The novel active compounds can be converted in a known manner into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The therapeutically active compound is to be present in each case in a concentration of from about 0.5 to 90% by weight, based on the total mixture, i.e. in amounts which are sufficient to achieve the said dosage range.

The formulations are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with emulsifiers and / or dispersants, where in case of use (water as diluent) optionally organic solvents can be used as co-solvents.

Excipients which may be mentioned are, for example: water, non-toxic organic solvents such as paraffinic hydrocarbons (e.g. petroleum fractions), vegetable oils (e.g. a mixture of peanut oil and sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers such as natural stone meal (e.g., kaolins, alumina, talc, chalk), synthetic stone meal (such as highly disperse silicic acid, silicates), sugars (e.g., cane sugar, milk sugar and grape sugar), emulsifiers (e.g., polyoxyethylene fatty acid esters, fatty alcohol polyoxyethylene ethers, alkylsulfonates , arylsulfonates), detergents (e.g., lignin, sulfite waste liquors, methylcellulose, starches and polyvinylpyrrolidone) and glidants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in a conventional manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, tablets may contain. Of course, in addition to the aforementioned carriers, additives such as sodium citric acid, calcium carbonate and dicalcium phosphate together with various additives such as starches, preferably potato starch, gelatin and the like may also contain lubricants such as magnesium stearate, sodium lauryl sulfate and talc. which are used as tableting aids. In the case of aqueous suspensions, in addition to the abovementioned excipients, various flavor enhancers or colorants may be added to the active ingredients.

For parenteral administration, solutions of the active compounds using suitable liquid carriers can be used.

In general, it has proven advantageous to use an amount of from about 0.001 to 1 mg / kg, preferably from about 0.01 to 0.5 mg / kg body weight, for intravenous administration in order to achieve effective results. For oral administration, the dose is from about 0.01 to 20 mg / kg, preferably from 0.1 to 10 mg / kg of body weight.

However, in some cases, it may be necessary to deviate from the indicated amounts, depending on body weight, the mode of administration, the individual behavior of the medicament, the manner in which it is administered, and the time or interval to which the administration occurs. done. Thus, in some cases it may be sufficient to use less than the minimum listed above, while in other cases the above upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide this into several individual doses administered during the day.

In the following examples, the R ^ values were determined on aluminum foil for thin layer chromatography (Merck), layer thickness 0.2 mm, silica gel 60 F 254; solvent system: a 1: 2 by volume mixture of toluene and ethyl acetate.

EXAMPLE 1 4- (2-Benayloxyphenyl) -1,4-dihydro-2,6-dinethylpyridine-3,5-dicarboxylic acid, 5-cyclopropyl-propyl ester

3.1 g (10 mmol) of 2-benzyloxybenzylideneacetacetic acid methyl ester is boiled in 30 ml of isopropyl alcohol 8 1.4 g (10 mmol) of β-aminocrotonic acid cyclopropylamide for 4 hours. Then the reaction mixture is cooled, concentrated to a concentrated residue. acetonitrile is added and the mixture is concentrated again, the residue is stirred with a small amount of acetonitrile and then the product is filtered off and washed with acetonitrile. 3.26 (74.1% of theory) of colorless crystals of melting point 194 DEG C. are obtained.

Example 2

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-phenylamide

3.1 g (10 mmol) of 2-benzyloxybenzylideneacetacetic acid methyl ester is boiled in 20 ml of ethanol 8 1.76 g (10 mmol) of benzamide / 3-aminocrotonic acid for 3 hours. Then the reaction mixture is cooled and concentrated. after evaporation, it is triturated with 8 ether, the mixture is filtered and the residue on the filter ee is recrystallized from acetonitrile. 2.4 g (51.3% of theory) of colorless crystals of melting point 194 DEG C. are obtained.

The following compounds were prepared in an analogous manner to those described in Examples 1 and 2:

Example 3

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3-methyl ester-5-dimethylamide

-3,5 dicarboxylic acids

m.p. Mp 162-165 ° C

_Rf = 0.118

Example 4

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

m.p. Mp 156-157 ° C.

Example 5

1,4-Dihydro-2,6-dimethyl-4- [2- (3-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

СЗ 271486 В2

m.p. 176 ° С.

Example 6

3-methyl-5-cyclopropylamide 4- / 2- (4-ohlorbenzyloxy) phenyl / _f 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

m.p. 17 ° C

Example 7

4- [2- (4-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-pyridyl) -amide

mp 201-204 ° C.

Example 8

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-pyridyl) amide

m.p. Mp 164-165 ° C.

Example 9

4- [2- (4-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-diethylamino-ethyl) -amide

m.p. from 80 ° C.

Example 10

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-diethylaminoethyl) amide

m.p. from 95 ° C.

Example 11

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyleater-5- (4-carbamoylphenyl) amide

m.p. over 3θθ 0 ·

Example 12

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-acetylaminophenyl) amide

m.p. 298 ° C (dec.).

Example 13.

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-benzoylaminophenyl) amide

m.p. 197 ° C. .

Example 14

(R, S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (mixture of R, S) h ₃ c

H-COCO

m.p. from 162 ° C.

Example 15 '

(R) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide (R-form)

m.p. 82 ° C.

Example 16

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-6- (3-dimethylaminopropyl) -amide

m.p. Mp 89-90 ° C.

Example 17

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-methyl-ethyl-5-cyclohexylamide

m.p. Mp 108-111 ° C.

Example 18

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-methyl-ethyl-5-tert-butylamide

m.p. 148 [deg.] C

Example 19

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-propylamide

Foam, Rp = 0.37

Example 20

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide

m.p. 134 ° C.

Example 21

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-N-benzyl-N-tert-butylamide

m.p. 128 [deg.] C

Example 22

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dithioethylpyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl-laraid

m.p. 105 ° C.

Example 23

3-methyleater-5-ethylamide, 4- (2-benzyloxyphenyl) -l, _{4-dihydro-6-f} 2 diinethylpyridin-3,5-dicarboxylic acid

tet. Mp 172 ° C.

Example 24

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide

Foam, R _f * 0.1.

Example 25

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-methylamide

Foam, R _f = 0.07 ·

Example 26

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-methylpropyl) amide

Foam, R _f = 0.25 ·

Example ⁴ 27

4- [2- (3,4-Dichlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Cl

HjCOOC

m.p. 195 ° C.

‘3

Example 28

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid methyl ester-5-cyclopropyl-amide

m.p. 178 ° C.

Example 29

4- [2- (2,6-Di-chlorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-methyl-propyl) -amide

Foam, R ^ = 0.36 *

Example 30

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

m.p. 133 ° c.

CS 271436 B2

Example 31

4- [2- (3,4- ^{Dichlorobenzyloxy} ) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

m.p. 120 [deg.] C.

Example 32

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

m.p. 202 DEG.

Example 33

4- [2- (2-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Cl

m.p. 185 ° C.

CS 27X486 B2

Example 34

4- / 2- (2-Chloro-benzyloxy) -phenyl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methyl-amide

m.p. 170 [deg.] C.

Example 35

4- [2- (3-Fluorobenzoyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide

t9δ 0 »

Example 36

3-methyl-5-cyclopropylamide l, _{4-dihydro-2H-l} 6-dimethyl-4- / 2- (3-trifluoromethyl-benzyloxy) phenyl / pyridine-3,5-dikarboxylovd acid

m.p. 148 [deg.] C.

CS 271486 B2

Example 37

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-methyl-petroleum) -amide

Foam, R _f = 0.44

Example 38

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-i8-propylamide

m.p. 106 ° c.

Example 39

1,4-Dihydro-2,3-a-diethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-cyclopropylamide

h ₃ ch ₂ ch ₃ c

Foam, R _f = 0.31.

Example 40

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-dicurboxylic acid 3-methyl ester-5-cyclopropylamide

m.p. 197 ° C.

Example 41

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5- (1-methylpropyl) amide

m.p. 126 [deg.] C.

Example 42

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl ester-5-methylamide)

Foam, Rp = 0.48

Example 43

1,4-Dihydro-2,6-dimethyl-4- [2- (3-nitrobenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide

Foam, R _f = 0.24

Example 44

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-propylamide

m.p. 210 ° C.

Example 45

(R) -4- [2- (4-Fluoro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- (1-phenylethyl) -amide form)? Currency, R _f = 0.56

H

Example 46

3-methyl-5- (2-methylpropyl) 4- (4-benzyloxyphenyl) -l _available 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

mp 202 ° C.

Example 47

4- / 2- (4-Fluorobenzyloxy) phenyl-1,4-dihydro-2,6-diinethylpyridine-3 * 5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide

m.p. 159 ° C

Example 48

4- [2- (4-Fluorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dioiethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

m.p. 154 [deg.] C

Example 49

(S) -4- (4-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenylethyl) -amide (S-form)

m.p. 141 ° C.

Example 50

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-isopropylamide

m.p. Mp 162 ° C.

Example 51

(R) -4- (4-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-ether-5- (1-phenylethyl) -amide (R-form, diastereomer A)

m.p. 196 ° C.

Example 52

4- [2- (3-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3- (methyl-5-cyclopropylaniide)

m.p. 174 ° C.

Example 53

3-methyl-5-cyklopropylaaiid 4- / 2- (4-fluorobenzylthio) phenyl / -l, _{4-dihydro-2'6dimethylpyridin-3,5-dicarboxylic} acid

Example 54

(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dioiethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (diastereomer B) (R-form) )

'N' H

t./t. 202 DEG.

Example 55

(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form, diastereomeric mixture)

m.p. 110-166 ° C.

Example 56

(S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (S-form, diastereomer A)

m.p. Mp 172 ° C.

Example 57

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3- (methyl-5- (1-phenylethyl) -amide) (S-form, diastereomer B) )

Foam, R _f = 0.53

''

H

Example 58

(H) -4- [2- (4-Fluoro-benzyloxy) -phenyl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide

Foam, R _f = 0.52

Example 59

1,4-Dihydro-2,6-dimethyl-4- [2- (3-methylbonzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-butyl-tert-5-cyclopropylamine

Foam ³ _of R _f 0.31

Example 60

(R) -1,4-Dihydro-2,6-dimethyl-4- [2- (3-methyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-phenyl-ethyl) -amide

oil R _f = 0.88.

CS 271486 31

Example 61 '

(R) -4- [2- (3-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenyl-ethyl) -amide (R-form)

Foam R _f = 0.73.

Example 62

(R) -4- (3-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenyl-ethyl) -amide (R-form)

m.p. from 143 ° EXAMPLE 63

4- (3-Benzylox7-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-methyl ester-5-cyclopropylamide-

3,5-dicarboxylic acids

m.p. 144 ° C

Example 64

(R) -4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5 '(1-phenylethyl) amide form)

Foam

R _f = 0.47

Example 65

(S) -4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide form)

Foam, Rf = 0.48

Example 66

3-methyl-5-allyl amide 4- / 2- (4-fluorobenzylthio) phenyl / _{-l) 4-dihydro-2>} 6-dimethyl-pyridine-3,5-dicarboxylic acid

tft. 177 ° C «

Example 67 ‘

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

m.p. 148 ° C ·

Example 68

(R) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5 - (- 1-phenylethyl) -amide (R-form)

m.p. 175 ° C.

Example 69

(R) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form, diastereomer B)

m.p. Mp 169 ° C.

CS 271466 B2

Example 70

3-methyl-5- (2-phenylethyl) amide

4- (Sbenzyloxyphenyl) -1,4-dihydro-2,3-dimethylpyridine-3,5-dicarboxylic acid

oil

Example 71

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-benzylamide

m.p. Mp 148-149 ° C.

Example 72

4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. 202-204 ° C

Example 73

4- (3-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. Mp 152-154 ° C.

Example 74

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. 183-185 ° C-

Example 75

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-amide

m.p. 188 [deg.] C.

Example 76

4- (2-Benayloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-diethylamide

m.p. 135 ° C.

Example 77

5-Cyclopropyl-1,1,4-dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester

m.p. Mp 238-242 ° C.

Example 76

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide

m.p. 225 [deg.] C.

Example 79

4- (2- (2,6-Dichloro-benzyloxy) -phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Example 80

Pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

4- [2- (3,4-dichlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethyl acid

m.p. 178-180 ° C.

Example 81

Pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

1,4-dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) phenyl] acid

.t. Mp 159-161 ° C.

Example 82

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

m.p. Mp 168-170 ° C.

Example 83

1,4-Dihydro-2,6-dimethyl-4- (2-phenylnulfonyloxyphenyl) pyridine-N-dicarboxylic acid 3-methyl-ether-5-mothylamide

m.p. Mp 171-173 ° C.

Example 84

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

• N H

m.p. Mp 188-190 ° C.

Example 85

1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-diethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide

m.p. 147-149 ° C ·

Example 86

1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

H

m.p. Mp 111-113 ° C.

Example 87

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-allylamide

m.p. Mp 154-156 ° C.

Example 88

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-pyridyl) amide

m.p. from 240 ° C (decomposition)

Example 89

4- [2- (4-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

m.p. 145 ° C.

Example 90

4- (3-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

m.p. Mp 99-98 ° C.

Example 91

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

m.p. Mp 168-170 ° C.

Example 92

3-Methyl ester-5-allylamide

4- [2- (2,6-dichlorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

m.p. 132-134 ° C. ”----- -

Example 93

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- (2-hydroxyethyl) amide

m.p. 148-150 ° C.

Example 94

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyleater-5-ethylaidide

m.p. Mp 171-173 ° C.

Example 95

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-2- (4-pyridyl) ethylamide

Example 96

3- <nethyleeter-5 -methyl-l, 4-dihydro-2,6-sditnethyl-4- / 2- (3-pyridyl) tnethoxyf phenyl / _pyridine-3-R 5 dikarboxylov4 kyeeliny

m.p. from 210 ° C.

Example 97

1,4-Dihydro-2,6-dimethyl-4- [2- (3-pyridyl) coethoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. Mp 122-125 ° C.

Example 98

1,4-Dihydro-2,6-dimethyl-4- [2- (4-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. Mp 95-100 ° C.

Example 99

5-Methyl-1,4-dihydro-2,6-dimethyl-4- [2- (4-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester

m.p. from 203 ° C (decomposition)

Example 100

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5- (cyclopropylmethyl) amide

m.p. 186 [deg.] C.

Example 101

(+) - 4- (2-Benzylxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. 147 ° C / + 4 ° = + 29.68 c = 0.91 (DO?)

Example 102

(-) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylainide

m.p. 148 / <% · 4 ° = ° C -29.92

c = 0.805 (IMP)

Example 103

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methylamide

m.p. 179 ° C.

Example 104

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide

m.p. Mp 161-164 ° C.

Example 105

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-ethoxycarbonylethyl) amide

R _f = 0.35

CS 271 486 B2

Example 106

4- (2-benzyloxyphanyl) -1,4-dlhydro-2,6-denoxypyridine-3,5-dicarboxylic acid S-methyl-ether-S-tethoxycarbonylmethyl-aaid

R _f = 0.408.

Example 107

3-methyl-5-octylamide 4- (2-benzyloxyfeayl) -l, _4-dihydro-2> 6-dimethyl-pyridine-3,5-dicarboxylic acid

R _f = 0.53

Example 108

4- (2-Beazyloxy-phenyl) -1,4-dihydro-2,6-diethyl-pyridine-3 ₍ 5-dicarboxylic acid 3-methyl-ester) -5-nonylamide

R _f = 0.55

CS 2714-6 B2

Example 109

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 2-methyl ester-5-decylamide

m.p. 111 ° C. ~

Example 110

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methoxyethyl) amide

CH ₂ -CH ₂ -OCH ₃

H-COCO

H ₃ G

H

m.p. 145 ° C.

Example 111

4- (2-Benzyloxyphenyl) -1,4'-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-methoxypropyl) amide

_{R f} = 0.19

Example 112

(R, R) -4- (2-Bonzyloxy-phenyl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5---hydroxy-1-methyl-2-phenyl) -ethylamide h ₃ c

HjCOOC

_Rf »0.35 / Z25 / p °« -47.93 (chloroform).

Example 113

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-ether-5- (2-hydroxy-1-methylethyl) -amide

_Bf = 0.13

Λθ °: +7,34 (CHC1 ₃₎

Example 114

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-propyl) -amide

R _f = 0.15 ° ^ ¢: -9.37 (CHC1 ₃₎

Example 115

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-2-methyl-propyl) -amide

R _f = 0.19

0-2 °: -10.8 (CHC1-j)

Example 116

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-2-methyl-butyl) -amide

_Rf = 0.21 & p = -17.37 ° (CHC1 ₃₎

CS 271466 B2

Example 117

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (methyl-5- (3-hydroxypropyl) amide)

m.p. 205 ° C.

Example 118

(-) 4- (2-Henzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methylterter-5-cyclopropylamide

m.p. 178-181 ° C / "38.28 (c, 0.59, chloroform)

Example 119

3-methyl-5-cyclopropylamide (♦) 4- (2-benzyloxyphenyl) _-l> 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

mp 178-181 ° C / ЯУ589 ^s * 36.56 (c = 0.52, chloroform)

Example 120

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-hexylamide

m.p. 133 ° c.

Example 121

4- / 2- (4-Methylbenzenesulfonyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-amide

m.p. 205 ° C.

Example 122

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-sec-butylamide

135

Example 123

3-oopropyliitor i - ^ - atiild 4- (2-bonzyloxyfenyl) -l, 4 * _dihydro-2-t 6 · 315 diinethylpyrldln-dicarboxylic acid

m.p. 190 ° C.

Example 124

3- (2-nethoxyethylester) -5-anid 4- (2-benzyloxyphenyl) -l, _4-dihydro-2> 6-dimethylpyridin _# -3,5-dicarboxylic acid

Example 125

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-butylamide

m.p. Mp 144-148 ° C.

Example 126

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-ethylamide

m.p. 135 ° C.

Example 127

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-ethoxypropyl) amide

m.p. 115 ° C.

Example 128

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (5-hydroxypentyl) amide

m.p. 178 ° C.

Example 129

4- (2-Benzylphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-ethoxyethyl) ester-S-oethylamide

Example 130

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5-ethylamide

m.p. 111 ° C.

Example 131

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl-ether-5-methyl-ethylate

m.p. Mp 140-143 ° C

AĎ

CS 271486 31

Example 132

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-cyclopropylaniide

Example 133

3 «-isopropylester-5-isopropylamide 4- (2-benzyloxyphenyl) ~ l, _4-dihydro-2> 6-dimethyl-pyridine-3,5-dicarboxylic acid

m.p. oa no ° c.

Example 134

1 ₎ 4-Dihydro-2,6-diethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

m.p. 184 ° C.

m.p. 184 ° C.

CS 271486 B2

Example 135

Oethylestex-3-methylamide 5-l _r 4-dihydro-2,6-dimett71-4- / 2- (4-a: ethylben2yloxy) phenyl / pyridine-3,5-dicarboxylic kyeeliny

m.p. 186 [deg.] C.

Example 136

3- (S) - (l-isopropoxykarbonylethyl) ester-5-cykloprapylaniid 4- (2-benzyloxyphenyl) -1,4-dihydro-2 _f б-dimethylpyridine-3,5-dicarboxylic acid

Example 137

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dioethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) trans-5-oethylamide

Cl

H

CS 271466 B2

Example 138

4- (2-Benzyloxyfexyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-propylamide

m.p. Mp 119 ° C.

Example 139

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-cyclopropylamide

m.p. 152 [deg.] C.

Example 140

4- (2-Benzyloxyphenyl) -1,4-dihydro-2H-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-octylamide

_Rf = 0.44 in toluene / ethyl acetate 1: 1 ·

Claims (4)

A process for the preparation of novel dihydropyridinaids of the general formula I 4r (I) in which R ¹ and R ⁸ are the same or different from each other and represent a straight or branched (C 1 -C 6) alkyl group; R ² represents a straight or branched alkyl group having 1 to 6 carbon atoms! which is optionally interrupted in the chain by an oxygen atom and is optionally substituted by a (2-6C) alkoxycarbonyl or phenyl group, R 6 and R 6 are the same or different from each other and are hydrogen or C 1 -C 4 alkoxy; R ^ means * -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl CCl ^ -S ^ J Xenylovou group or -0-S0 ₂ -phenyl, wherein n is 1 or 2 and the phenyl portion is optionally mono- to trisubstituted by nitro, trifluoromethyl, alkyl having 1-3 carbon atoms or a halogen atom; 6 7 R and R are the same or different from each other and are - hydrogen atom, - C 3 -C 8 -cycloalkyl, - a straight or branched alkyl group having from 1 to 12 carbon atoms or an alkenyl group having from 1 to 5 carbon atoms, which may optionally be substituted by hydroxy, C1-C4alkoxy, alkylcarbonyl of 2 to 5 carbon atoms, phenyl, di (C 1 -C 4) alkylamino group in both alkyl moieties, (C 3 -C 6) cycloalkyl group or pyridyl group; - a phenyl group which is optionally substituted by a carbamoyl group, an arylamino group or a benzoylamino group, or a pyridyl group; as well as their physiologically acceptable salts, characterized in that the yliene-β-ketocarboxylic acid esters of the general formula (VIII): R ¹ to R ⁵ are as defined above, reacting the β-amides of the enaminocarboxylic acid of formula V (V) in which they are as defined above, optionally in the presence of inert solvents, and optionally converting the obtained compounds to their physiologically acceptable salts. . 2. Process according to claim 1, characterized in that water and inert organic solvents such as alcohols, ethers, amides, glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine are used as solvents and the reaction is carried out at temperatures between 10 and 150 ° C. . 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the general formulas (VIII) and (V) are used as starting materials to give compounds of the general formula (I) in which: Ί fí R and R are the same or different from each other and represent a straight or branched alkyl group having from 1 to 4 carbon atoms, R represents a straight or branched alkyl group having 1 to 6 carbon atoms, which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by a phenyl group, R 4 and R 4 are the same or different from each other and are hydrogen or (C 1 -C 4) alkoxy, -0- (CH _O) -phenyl, n * -O- (CHg) _and -pyridyl, -S- (CH ₂ ) _n -phenyl or 1 -O-SOg -phenyl in which n is 1 or 2a the phenyl moiety is optionally substituted one to three times by fluorine, chlorine, bromine, nitro, trifluoromethyl or C1-C3 alkyl , H ⁶ and R ⁷ are the same or different from each other and represent a hydrogen atom or a cycloalkyl group having from 1 to 7 carbon atoms, straight or branched (C 8 -C 12) alkyl or (C 5 -C 5) alkenyl which may optionally be substituted by hydroxy, C 1 -C 4 alkoxy, C 2 -C 5 alkylcarbonyl, phenyl, dialky a (C 1 -C 4) lamino group in both alkyl portions, a phenyl group optionally substituted by an acetylamino group or a benzoylamino group, or - the pyridyl group and their physiologically acceptable salts; 4 · Method according to items 1 and 2 ,. characterized in that the corresponding compounds of the general formulas (VIII) and (V) are used as starting materials to give compounds of the general formula (I) in which: R ¹ and R ⁸ are the same or different and have a methyl or ethyl group, π H represents a straight or branched alkyl group having 1 to 6 carbon atoms which is optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group, R ³ and R ⁴ are identical or different and represent hydrogen, methoxy, ethoxy not bo *, R 6 represents -O-CH 8 -phenyl, -O-CH 8 -pyridyl, -S-CH ₂ phenyl or -O-SO 8 -phenyl, the phenyl moiety optionally being up to twice substituted by the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a nitro group, a trifluoromethyl group or a methyl group, H ⁶ represents a hydrogen atom or an alkyl group of 8 to 4 carbon atoms and * 7 R is a hydrogen atom, a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, or - a straight or branched alkyl group having up to 10 carbon atoms or an alkenyl group having up to 5 carbon atoms, which are optionally substituted by hydroxy, alkoxy having 1 to 4 carbon atoms,