CS271496B2 - Method of new dihydropyridinamides production - Google Patents

Abstract

New compounds of the formula I, in which R<1> and R<8> means C1-6-alkyl, R<2> means C1-6-alkyl that can be in a strand interrupted by oxygen and can be substituted by C2-6-alkoxycarbonyl or phenyl, R<3> and R<4> means hydrogen or C1-4-alkoxy, R<5> means -O-(CH2)n-phenyl, -O-(CH2)n -pyridyl, -S-(CH2)n-phenyl or -O-SO2-phenyl, where n = 1 or 2 and phenyl can be substituted by the nitro group, CF3, C1-3-alky or halogen, R<6> and R<7> means hydrogen, C3-8-cykloalkyl, C1-12-alkyl or C2-5-alkenyl, which can be substituted by OH, C1-4-alkoxy, C2-5-alkylcarbonyl, phenyl, di-C1-4-alkylamino group, C3-6-cykloalkyl or pyridyl, they also mean phenyl, which can be substituted by the carbamoyl group, a acetyl amino group, or benzoylamino group or they mean the pyridyl group, as well as their physiologically utilizable salts are prepared via a reaction of aldehydes of the formula II and esters of β ketocarboxylic acid of the formula III with amides of β-ketocarboxylic acid of the formula IV with ammoniac, or in the presence of inert solvents and the acquired compounds are eventually converted to their physiologically utilizable salts. The produced compounds can be used in pharmaceuticals.<IMAGE>

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 ethyl O-aminocrotonic acid ester or ethyl acetate 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. Valter, Naturwissenschaften 58, 578 (1971)).

ce I

The present invention relates to a process for the preparation of novel dihydropyridinamides of the general formula:

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, a straight or branched (C 1 -C 6) alkyl group optionally interrupted by an oxygen atom in the chain and optionally substituted by an alkoxycarbonyl C 2 -C 6 or phenyl are the same or different from each other and are hydrogen or C 1 -C 4 alkoxy;

-O- (CH ₂ ) _n -phenyl,

-O- (CH ₂ ) _n -pyridyl,

-S- (CH ₂ ) _n -phenyl or

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

EN 271 4

they are the same or different from each other and mean

- a t c m hydrogen,

- C 3 -C 3 cycloalkyl,

- a straight-chained alkyl group of up to 12 carbon atoms or an alkenyl group of up to 5 carbon atoms which may be optionally substituted by a hydroxy group, a C1-C4 alkoxy group, a C2-C5 alkylcarbonyl group, a phenyl group, a C1-C4 dialkylamino group up to 4 carbon atoms in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl,

- a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or

a pyridyl group and their physiologically acceptable salts.

The compounds of formula (I) produced by the process of the invention exist in stereoisomeric forms which either behave as images and mirror images (enantiomers) or which do not behave as images and mirror images (diastereomers). The invention relates to both antipodes and racemic forms as well as mixtures of diastereomers. Racemic forms can also be resolved as diastereomers in a known manner into stereoisomeric unitary components (cf. E. L. Eliel, Stereochemistry of Carbon Comounds, Моггам 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 hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulfonic acids such as 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:

Ί Я

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

- straight or branched (C1-C4) alkyl,

represents a straight or branched (C1-C6) alkyl group optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group which are the same or different from one another and are hydrogen or (C1-C4) alkoxy;

-O- (CH ₂ ) _p -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or -O-SO ₂ -phenyl in which the number is 1 or 2 and the phenyl moiety is optionally substituted one to three times by nitro, trifluoromethyl, alkyl of 1 to 3 carbon atoms

CS 271 496 B2

or a fluorine, chlorine or bromine atom, are the same or different from each other and are

- 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 up to 5 carbon atoms, which may optionally be substituted by a hydroxy group, a C1-C4 alkoxy group, a C2-C5 alkylcarbonyl group, a phenyl group, a 1-dialkylamino group up to 4 carbon atoms in both alkyl moieties,

a phenyl group which is optionally substituted by an acetylamino or benzoylamino group or a pyridyl group, and their physiologically acceptable salts.

Particularly preferred are compounds of formula I wherein:

are the same or different and are methyl or ethyl, are straight or branched (C 1 -C 6) alkyl optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group are the same or different and are hydrogen , methoxy or ethoxy means -O-CH2-phenyl, -O-CH2-pyridyl, -S-CH2-phenyl or -O-Si-phenyl, the phenyl moiety being optionally substituted up to twice the same or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluorine or chlorine, represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and

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 dialkylamino C 1 -C 4 alkyl or

phenyl optionally substituted by acetylamino or benzoylamino, or

An O- or N-pyridyl group as well as a physiologically acceptable salt thereof.

CS 271 496 B2

R

According to the invention, the compounds of the formula I in which R to R have the meanings given above, and their physiologically acceptable salts, are prepared by preparing aldehydes of the formula P

(II) in which

R ³

R ⁵ have the abovementioned meaning, are reacted with amides of o-ketocarboxylic acid of formula IV

(IV) wherein

7 β

R, R and R are as defined above, and the enaminocarboxylic acid esters of formula VI

in which

R ¹ and R ² have the above meanings,

CS 271 496 B2 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 on a specific example of starting materials:

Suitable solvents for the reaction according to the invention are water or any 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, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amines such as dimethylformamide, dimethylacetamide or hexamethyltriamide of the acid.

Or glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine.

The reaction temperatures can be varied within a wide range. Generally working at temperature between 10 * C and> 150 ³ C, preferably at temperatures between +20 ° C and +100 ° C. The boiling point of the solvent is particularly preferably used.

The reaction can be carried out at atmospheric pressure, but also at elevated or reduced pressure. Generally, the process is carried out at atmospheric pressure.

The ratio of the starting materials involved in the reaction according to the invention is arbitrary. In general, however, the reaction is carried out using mole amounts of reactants.

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 necessary only after cooling in the 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 aldehydes of the formula II which are used as starting materials for the process according to the invention are known or can be prepared according to known methods CDOS 21 65 160;

01 665; Harris, T. D., Roth, G. P., 3. Org. Chem. 44, 2004 (1979); W. 3. Furthermore, Η. E. Hennis, 3rd Am. Chem. Soc. 78, 2543 (1956); Chem. Abstr. 59, 13929 (1963)].

The .alpha.-ketacarboxylic acid amides of the general formula (IV), which are further used as starting materials, are known or can be prepared according to known methods of C-DOS 11 42 859J.

The enaminocarboxylic acid esters of formula VI which are used as starting materials are known or can be prepared according to known methods. A. Glickman, A. C. Cope, 3. Am. Chem. Soc. 67, 1017 (1945)].

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, as well as 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, liver cirrhosis, 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 heart activity was determined on isolated, stimulated papillary muscle of guinea pig heart. To this end, the test animals (guinea pigs of both sexes weighing 200 g) are sacrificed, their chest is opened and the heart is removed. For the experiments, the small papillary muscles are then removed from the right ventricle and fixed horizontally in the organ bath. In this case, 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 a force sensor. The papillary muscle is irritated at a frequency of 1 Hz above the threshold. An organ bath of about 2 ml is continuously washed with Krebs-Henseleit solution (concentration in mmol: NaCl 118;

1,2; MgSO 4 1.2; NaClg 1.8; glucose 10, pH 7.4) at a rate

C. Contraction of the papillary muscle is measured by an isometrically 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 a concentration of 0.5%). The dihydropyridine carboxylic acid amides according to the invention exhibit a reduction in the papillary muscle contraction force by more than 10% relative to the values obtained in a control experiment.

CS 271 496 B2

The novel active compounds can be converted in a known manner into conventional preparations such as tablets, dragees, pills, granules, ssrosols, 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 preparations are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with the aid of emulsifiers and / or dispersants, whereby, if water is used as the diluent, optionally organic solvents can be used as auxiliary solvents.

As excipients, for example: water, nontoxic 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, the tablets may, of course, contain, in addition to the abovementioned 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. stearic acid, 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 compounds. '

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 at which the administration is performed. . 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, 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.

CS 271 496 B2

Example 1 θ

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

2.12 g (10 mmol) of 2-benzyloxybenzaldehyde is boiled in 20 ml of isopropyl alcohol with 1.4 g (10 mmol) of β-aminocrotonic acid methyl ester and 1.4 g of acetopropyl acetic acid cyclopropylamide for 6 hours. The reaction mixture was then cooled and evaporated. The evaporation residue is purified over a silica gel column. 0.8 g of colorless crystals of melting point 190 DEG-192 DEG C. is obtained.

In a manner analogous to that described above, the following Examples are also prepared:

Example 2

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

Melting point 162-165 ° C.

CS 271 496 B2

Example 3

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

Mp 194 ° C.

Example 4

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

Melting point 156-157 ° C.

CS 271 946 B2

Example 5

3-methylestег-5-cyclopropylamide 1,4-dihydro-2,6-dimethyl-4- [2-C3-methylbenzyloxy) phenyl

3-pyridine-3,5-dicarboxylic acid

Melting point 176 ° C.

Example 6

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

H

Melting point 178

CS 271 496-2

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

Melting point 164-165 ° C.

CS 271 496 B2

Example 9

4- 2- (4-Chlorobenzyloxy) phenyl-1,4-dihydro- 3- (2-diethylaminoethyl) amide 3-methyl ester

2,6-dimethylpyridine-3,5-dicarboxylic acid

Melting point: 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

Melting point: 95 ° C.

CS 271 496 B2

Example 11

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

Melting point above 300 ° C.

Example 12

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

Mp 298 ° C (dec.).

CS 271 496 B2

Example 13

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

Melting point 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)

Melting point: from 162 ° C.

EN 271 496 02

Example 15

3-methyle5ter-5- (l-íeriylethyl) and a halide (R) -4- (2-benzyloxyphenyl) _-l> 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid (R-form)

Melting point 82 ° C.

Example 16

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

Mp 89-90 ° C.

CS 271 496 B2

Example 17

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

Melting point 108-111 ° C.

Example 18

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

Temperature

148

CS 271 496 B2

Example 19

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

Foam, R _f = 0.37.

Example 20

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

Melting point 134 ° C.

CS 271 496 B2

Example 21

4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5-N-benzyl-N-tert-butylamide

Melting point 128 ° C.

Example 22

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

Melting point 105 ° C.

CS 271 496 B2

Example 23

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-methyl-5-ethyl-ylamide

-dicarboxylic acids

Melting point 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

0,1 *

CS 271 496 B2

Example 25

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

Example 26

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

Foam = 0.25.

CS 271 496 B2

Example 27

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

Melting point 195 ° C,

Example 28

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

Cl

Melting point 178 ° C.

CS 271 496 82

Example 29

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

Foam = 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

H-COCO

Temperature 133 ° C.

EN 271 496 02

Example 31

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

Melting point 120 ° C.

Example 32

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

Mp 202 ° C.

CS 271 496 B2

Example 33

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

H ₃ CH CH ₃

Mp 185 ° C.

Example 34

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

N H

Melting point 170 ° C.

CS 271 496 B2

Example 35

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

Melting point 98 ° C.

• Example 36

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

Mp 148 ° C.

CS 271 496 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-propyl) -amide

Foam, Rf = 0.44.

Example 38

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

Melting point 106 ° C.

CS 271 496 B2

Example 39

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

Foam, Rf = 0.31.

Example 40

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

Melting point 197 ° C.

CS 271 496 В2

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

Melting point 126 ° C.

Example 42

1,4-Dihydro-2,6-dimethyl-4- 12- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-methylamide

Foam, Rf = 0.48.

CS 271 496 82

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

Melting point 210 ° C.

CS 271 496 B2

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 (R-form)

Foam, Rf = 0.56.

Example 46

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

Melting point 202

• X H

CS 271 496 B2

Example 47

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

Mp 159 ° C.

Example 48

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

Melting point 154 ° C.

CS 271 496 B2

Example 49

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

Melting point 141 ° C.

Example 50

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

Melting point 162 ° C.

CS 271 496 82

Example 51

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

Melting point 196 ° C.

Example 52

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

Melting point 174 ° C.

CS 271 496 B2

Example 53

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

Melting point 202 ° C.

Example 54

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

Melting point 202 ° C.

CS 271 496 B2

Example 55

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

Melting point 110-166 ° C.

Example 56

(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 A)

Melting point 172 ° C.

CS 271 496 B2

Example 57

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

Foam, Rf = 0.53.

Example 58

(R) -4- C2- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form)

Foam, R _f = 0.52.

CS 271 496 B2

Example 59

1,4-Dihydro-2,6-dimethyl-4- C2- (3-methylbenzyloxy) phenyl pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide

Foam, Rf = 0.31.

Example 60

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

Oil, _Rf = 0.88.

EN 271 496 02

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-phenylethyl) -amide (R) -form)

Foam, Rf = 0.73.

Example 62

3-methyl-5- (l-phenylethyl) amide (R) -4- (3-benzyloxyphenyl) -l, _{4-dihydro-2H-1} 6-dimethylpyridine-3,5-dicarboxylic acid (R-form)

Mp 143 ° C.

CS 271 496 B2

Example 63

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

-dicarboxylic acids

Mp 144 ° C.

Example 64

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

Foam, _Rf = 0.47.

CS 271 496 B2

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 (S-form) )

S-CH ₂

F (S)

Foam, R _f = O, 48th

Example 66

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

Melting point 177 ° C.

CS 271 496 B2

Example 67

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

Mp 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)

Melting point 175 ° C.

CS 271 496 B2

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) )

Melting point 160 ° C.

Example 70

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

Oil.

CS 271 496 82

Example 71

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

M.p. 148-149 ° C.

Example 72

3- (4- [2- (4-Fluorobenzylthiophenyl) -1,4-dihydro-2, a-dimethylpyridine-3,5-dicarboxylic acid, n-ethyl ester)

Mp 202-204 ° C.

CS 271 496 B2

Example 73

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

Example 74

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

Mp 183-185 ° C.

CS 271 496 862

Example 75

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

Mp 188 ° C.

Example 76

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

Melting point 135 ° C.

CS 271 496 B2

Example 77

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

Mp 238-242 ° C.

Example 78

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

M.p. 228 ° C.

CS 271 496 B2

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

Melting point 174-176 ° C.

Example 80

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

Cl

Cl

Melting point: 178-180 ° C.

CS 271 496 B2

Example 81

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

M.p. 159-161 ° C.

Example 82

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

Melting point 168-170 ° C.

CS 271 496 82

Example 83

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

CO-NH-CH ₃ CH ₃

Melting point 171-173 ° C.

Example 1 a d 84

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

Mp 188-190 ° C.

CS 271 496 B2

Example 85

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

Mp 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

N H

CS 271 496 B2

Example 87

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

Mp 154-15 ° C.

Example 88

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

H-COCO

H ^ C

Melting point: 240 DEG C. (decomposition).

CS 271 496 B2

Example 89

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

145 ° C.

Example 90

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

N H

Melting point 95-98 ° C.

CS 271 496 B2

Example 1 a d 91

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

Melting point 168-170 ° C. Example 92

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

M.p. 132-134 ° C.

CS 271 496 B2

Example 93

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

Melting point 14B to 150 ° C.

Example 94

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

Melting point 171-173 ° C.

CS 271 496 B2

Example 1 a d 95

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

Example 96

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

Melting point: 210 ° C.

CS 271 496 B2

Example 97

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

Melting point 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

Melting point 95-100 ° ^C.

CS 271 496 B2

Example 99

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

Melting point: 203 DEG C. (decomposition).

Example 100

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

Melting point 166 ° C.

CS 271 496 B2

Example 101

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

Melting point 147 ° C

CoU = + 29.68, c = 0.91 (DMF).

D

Example 102

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

Mp 148 ° C ²⁰ = -29.92 °,

D = 0.805 (OMF).

CS 271 496 B2

Example 103

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

Mp 179 ° C.

Example 104

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

Mp 161-164 ° C.

CS 271 496 82

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.

Example 106

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

R _f = 0.408.

CS 271 496 B2

Example 107

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

R _f = 0.53.

Example 108

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

0.55.

CS 271 496 B2

Example 109

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

Melting point 111 ° C.

Example 110

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

145 ° C.

CS 271 496 B2

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-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5- (3-methyl-5- (2-hydroxy-1-methyl-2-phenyl) ethylamide) dicarboxylic acids

R _f = 0.35

-47.93 ⁰ Cv chloroform).

CS 271 496 B2

Example 113

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

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

И - ⁰ 9.37 (CHCl,).

O

CS 271 496 В2

Example 115

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

R _f = 0.19 r ^ CU ²⁰ - 10.8 ⁰ (CHCl,).

>

Example 116

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

R _f = 0.21 й = - 17.37 ⁰ (CHCl,).

^and

CS 271 496 02 β6

Example 117

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

Mp 205 ° C.

Example 118

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

Melting point: 178-181 ° C

[Α] D = 38.20 ° (c = 0.569, chloroform).

589

CS 271 496 B2

Example 119

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

Temperature mp 178-181 ° C ад ²⁰ = + 36.56 ⁰ (c = 0.52, chloroform). • 589 Example 120

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

Melting point 133 ° C.

CS 271 496 B2

6Θ

Example 121

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

Mp 205 ° C.

Example 122

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

Melting point 135 ° C.

CS 271 496 82

Example 123

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

Example 124

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl ester) -5-amide h ₃ coh ₂ ch ₂ c-ooc h ₃ c

Melting point 165 ° C.

CS 271 496 B2

Example 125

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

Melting point 144-14 ° C.

Example 126

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

CS 271 496 B2

Example 127

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

Melting point 115 ° C.

Example 128

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

Melting point 178 ° C.

CS 271 496 B2

Example 129

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

M.p. 133-135 ° C.

Example 130

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

Melting point 111 ° C.

CS 271 .496 B2

Example 131 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-methylamide

Melting point 140-143 ° C.

Example 132

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

M.p. 132-135 ° C.

CS 271 496 B2

Example 133

4- (2-Benzyloxyphenyl) 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-isopropylamide h ₃ ch ₃ c

Melting point: from 110 ° C.

Example 134

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

Melting point 184 ° C.

CS 271 496 B2

Example 135

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

Melting point 1-6 ° C.

Example 136

4- (2-Benzyloxyphenyl) -1,4-dihydric-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (S) - (1-isopropoxycarbonylethyl) ester-5-cyclopropylamide

CS 271 496 B2

Example 137

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

Example 138

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

m.p. Mp 119 ° C.

»1

CS 271 496 B2

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-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-octylamide

= 0.44 in toluene / ethyl acetate 1: 1

CS 271 496 B2

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of the novel dihydropyridinamides of the general formula I R ⁴ in which 1 R R and R are the same or different from each other and represent a straight or branched alkyl group having 1 to 6 carbon atoms; R is a straight or branched (C 1 -C 6) alkyl group optionally interrupted in the chain by an oxygen atom and optionally substituted by a (C 2 -C 6) alkoxycarbonyl or phenyl group, R ³ a are the same or different from each other and are hydrogen or C 1 -C 4 alkoxy, R 6 represents -O-CCHPr 4 -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or -O-SO ₂ - phenyl in which the number is 1 or 2 a R ⁶ The R ⁷ phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl or halogen, being the same or different from each other and - hydrogen atom, - C 3 -C 8 -cycloalkyl, - a straight or branched alkyl group having up to 12 carbon atoms or an alkene CS 271 496 B2 C 1 -C 5 alkyl which may optionally be substituted by hydroxy, C 1 -C 4 alkoxy, C 2 -C 5 alkylcarbonyl, phenyl, C 1 -C 4 dialkylamino in both alkyl portions , (C 3 -C 6) cycloalkyl or pyridyl, - a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or - a pyridyl group and their physiologically acceptable salts, characterized in that the aldehydes of the general formula II (II) in which: 3 4 5 R, R and R are as defined above, react with 6-ketocarboxylic acid amides of formula IV (IV), CR iii _R 8 in which 6 7 8 R, R and R are as defined above, and the enaminocarboxylic acid esters of formula VI (VI), CS 271 496 B2 Kterém in which R @ 2 and R @ 2 are as defined above, optionally in the presence of inert solvents, and the compounds obtained are optionally converted into 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 starting materials used are corresponding compounds of formula II, IV а VI to give compounds of formula I in which _f 1 6 R 2 and R 2 are the same or different from each other and represent a straight or branched (C 1 -C 4) alkyl group, R is a straight or branched (C 1 -C 6) alkyl group optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group, R ³ and R ⁴ they are the same group with 1 or different from each other and are hydrogen or alkoxy to 4 carbon atoms, R ⁵ means - (CH ₂ ) _{n -} - a phenyl group, - (CH ₂ ) _{n -} - a pyridyl group, -s- (CH ₂ ) _n a phenyl group, or -0-SO ₂ a phenyl group in which: n means the number 1 or 2 and the phenyl moiety is optionally substituted one to three times by fluorine, chlorine, bromine, nitro, trifluoromethyl or C 1 -C 3 alkyl, R ^e 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 up to 5 carbon atoms, which may optionally be substituted by a hydroxy group, a C1-C4 alkoxy group, a C2-C5 alkylcarbonyl group, a phenyl group, a 1-dialkylamino group 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. CS 271 496 B2 4. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas II, IV and VI are used as starting materials to give compounds of the formula I in which: 1a R and R are the same or different and are methyl or ethyl, R is a straight or branched (C 1 -C 6) alkyl group which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by a phenyl group, and R 6 is the same or different and represents a hydrogen atom, a methoxy group or an alkyl group; ethoxy group, 5 · R is -O-CH ₂ -phenyl, -O-CH ₂ -pyridyl, -S-CH ₂ -phenyl or -O-SO 2 -phenyl, the phenyl moiety optionally being up to twice substituted with the same or different substituents selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl or methyl, R @ 1 represents a hydrogen atom or a C1 -C4 alkyl group; R? means a hydrogen atom, a cyclopropyl group, a cyclopentyl group or 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 in the alkyl moiety, phenyl or dialkylamino having 1 to 4 carbon atoms in the alkyl moieties, or phenyl optionally substituted by acetylamino or benzoylamino, or A N, O or N-pyridyl group, as well as physiologically acceptable salts thereof.