CS271500B2 - 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

(57) The new compounds of formula I in which A Κθ represent C ^ alkyl, R ² is C ^ _ ^ - alkyl, which is optionally in the chain interrupted by oxygen and optionally substituted C 2 _ ^ - alkoxycarbonyl ° ^N yl, or phenyl, and R * are hydrogen or Ci-C4-alkoxy, R is -0- (CH2) _n-phenyl, -O-CCHoln-yl, -S- (CH2) _n - ^phenyl, or -0-S02-phenyl, where p = 1 or 2 and phenyl is optionally substituted with nitro. CF 3, C 1-4 alkyl or halogen, R ⁶ and R 7 represent hydrogen, C 1-8 -cycloalkyl, C 1-4 -alkyl or C 2-5 -alkenyl which may be substituted by OH, C 1-4 -alkoxy, C 2-5 -alkylcarbonyl, phenyl, di-C 1-4 -alkylamino, C 1-4 -cycloalkyl or C-pyridyl, further denote phenyl, which is C 1 -C 4 -alkylamino; optionally substituted carbamoyl group; and their physiologically acceptable salts are prepared by reacting the pyridine monocarboxylic acid dihydrate of the formula IX, optionally in the form of a reactive acid derivative, with the amines of the formula X, optionally in the presence of an inert organic solvents, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts. The compounds produced can be used as medicaments.

The present invention relates to a process for the production of novel dihydropyridinides 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 [3-aminocrotonic acid ethyl ester or ethyl acetate and ammonia] cf. E. Konoevenagel, Ber. Dtsch. Chem. Ges. 21 (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 dihydropyridineimides of the formula I

(I) in which

Ί Q

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,

4

R and R are the same or different from each other and are hydrogen or (C 1 -C 4) alkoxy,

R ⁵ represents

-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 by nitro, trifluoromethyl, alkyl of 1 to 3 atoms carbon or halogen,

R ⁶ and R ⁷ 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 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, 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 from Carbon Compounds, McGraw Hill, 1962).

Physiologically acceptable salts may be salts of the 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:

8

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

- straight or branched (C1-C4) alkyl,

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,

4

R and R are the same or different from each other and are hydrogen or (C 1 -C 4) alkoxy,

R 6 represents

-O- (CH 2) _n -phenyl,

-O-CCl 4 -pyridyl, -S-CCl 4 -phenyl or -O-SO 4 -phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl , (C1-C3) -alkyl or fluorine, chlorine or bromine;

R ^ and R? they 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 be optionally substituted by hydroxy, C1-C4alkoxy, C2-C5alkylcarbonyl, phenyl, C 1 -C 4 dialkylamino 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:

8

R 2 and R 2 are the same or different and are methyl or ethyl, R 2 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 are identical or different and represent hydrogen, methoxy or ethoxy,

R ⁵ represents

-O-C 1-6 -phenyl,

-O-CH 2 -pyridyl,

-S-CH ₂ -phenyl or

-O-SO ₂ -phenyl, wherein the phenyl moiety is optionally substituted up to twice with the same or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluoro or chloro,

R @ 1 represents a hydrogen atom or an alkyl group of up to 4 carbon atoms;

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-C4alkoxy, C1-C4alkylcarbonyl, phenyl or dialkylamino group C 1 -C 4 -alkyl;

phenyl optionally substituted by acetylamino or benzoylamino, or

A ¢ 6-, β-5 or β-pyridyl group, and physiologically acceptable salts thereof.

8

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 the preparation of dihydropyridine monocarboxylic acids of the formula IX in which:

R ¹ to R ⁵ and R ⁸

are as defined above, optionally in the form of a reactive v of the X____ acid derivative in reaction with amines

(X) wherein and R ⁷ are as defined above, optionally in the presence of an inert organic solvent, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts.

Oako reactive acid derivatives include, for example: activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides or reaction products in the presence of cyclohexylcarbodiimide.

The process according to the invention can be illustrated by the following reaction scheme on a specific example of starting materials:

The process according to the invention can be carried out according to the methodology known for converting carboxylic acids to carboxylic acid amides, which is described in the literature. The carboxylic acid is first converted to an activated form, such as an acid chloride or an imidazolide, and is isolated either as such and reacted in a second reaction step or reacted directly in situ to give the compounds of formula I. activating agents may be mentioned in addition to inorganic halides such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole, carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexyl-3- [2- (N-methylmorpholino) ethyl] carbodiimide p-toluenesulfonate or N-hydroxyphthalimide; N-hydroxybenztriazole in the presence of dicyclohexylcarbodiimide. Naturally, dihydroxypyridine monocarboxylic acids can also be used in the form of their salts. The amidation methodology is described, for example, in the following literature: Fieser & Fieser, Reagents for Organic Synthesis, John Wiley &amp; Sons Inc. (1967), pages 231-236; J. C. Shihan and G.P. Hess, J. Am. Chem. Soc. 77, 1067 (1955); U. Goodman, G.W. Kenner, Adv. in Protein Chem. 12, 488 (1957); Bonner, W.A., McNamee, P.I., J. Org. Chem. 26, 254 (1961); H.A. Staab, Angev. Chemie Int., 1st edition, 351 (1962); Fieser Fieser, Organic Synthesis Reagents, John Wiley & Sons Inc. 1967, 116, 114; H. C. Beyerman,

U. 0. Van der Brink, Re. Trav. 80, 1372 (1961); Buehler C.A. Pearson, E. Wiley & Sons, Vol. I (1970), p. 895 et al., Vol. II, (1977) ./

Suitable solvents for the process according to the invention are, in addition to water, any inert organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or halogenated hydrocarbons, such as dichloromethane, trichloromethane or carbon tetrachloride, or amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons, or acetonitrile, nitromethane, pyridine, dimethylsulfoxide or ethyl acetate. Mixtures of the solvents mentioned may also be used. If activated intermediate dihydropyridine monocarboxylic acids are isolated, the amines of formula X may also be used as diluents.

б

The reaction temperatures can be varied within a wide range. Generally, temperatures of from -70 ° C to +140 ° C, preferably from -20 ° C to +100 ° C, are employed.

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

In the process according to the invention, the ratio of the components involved in the reaction is arbitrary. In general, however, molar amounts of reactants are used. However, it has been found to be advantageous to use the amine in 5- to 10-fold molar amounts. It is particularly advantageous to use the amine in large excess simultaneously as a solvent.

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 dihydropyridine monocarboxylic acids of the general formula (IX) which are used as starting materials are known or can be prepared according to known methods (DOS 2 847 236; 3 206 671; 2 962 241).

The amines of the formula (X) which are used as starting materials are known or can be prepared according to known methods (Houben-Weyl Methoden der organischen Chemie, Vol. XI / 1; Paulsen, Angewandte Chemie 78, 501-556 (1966)].

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.

Said 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 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 is opened and the heart is removed. For the experiments, small papillary muscles are then removed from the right ventricle and fixed horizontally in the organ bath. Here, 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. The organ bath of about 2 ml is continuously washed with Krebs-Henseleite solution (concentration in mmol: NaCl 118; Na ₂ CO-25; KCl 10; КН ₂ Р0д 1,2; MgSO 4 1,2; CaCl ₂ 1,8) glucose 10, pH 7.4) at 4 ml / min at 32 ° C. Papillary muscle contraction is measured isometrically via a connected force transducer and recorded with a recorder.

The substances according to 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.

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 preparations are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with emulsifiers and / or dispersants, whereby organic solvents can be used as auxiliary solvents if water is used as the diluent.

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, silicate), 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 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. magnesium stearate, sodium lauryl sulfate and talc, which are used as tableting aids. In the case of aqueous suspensions, in addition to the abovementioned substances, 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 it is administered. . 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, _Rf value determined on an aluminum sheet 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.

'' К

CS 271500 В2

Example 1

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

g (45.14 mmol) of 4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-imidazolide was dissolved in 130 ml of absolute dimethylformamide and the obtained 5.63 ml (80.1 mmol) of cyclopropylamine was added to the obtained solution, and the reaction mixture was stirred at 90-100 [deg.] C. for 20 hours under argon. The reaction mixture was then cooled and concentrated. The residue is taken up in ethyl acetate, washed with water, 1N hydrochloric acid solution, again with water, sodium bicarbonate solution and again with water, then dried and concentrated. The evaporation residue is triturated with toluene, the mixture is filtered and the residue on the filter is washed with toluene. Recrystallization from about 60 ml of toluene gave 14.95 g (76.7% of theory) of colorless crystals. Mp 191-193 ° C.

Example 2

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

3,5-g (6,8 mmol) of 1,4-dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-methyl ester-5-imidazolide ( which was obtained from 1,4-dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid monomethyl ester by reaction with carbonylbisimidazole in tetrahydrofuran) was stirred with 40 ml without further purification solution of methylamide (40%) overnight. The precipitated product is filtered off and washed well with water. The product is then dried and recrystallized from a small amount of toluene. 1.3 g (40.3% of theory) of a colorless product are obtained. Melting point 156-157 ° C.

In an analogous manner to that described in Examples 1 and 2, the compounds shown in the following Examples are also prepared.

Example 3

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

Melting point 162-165 ° C.

Rf = 0.118.

Example 4

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

Mp 194 ° C.

Example 5

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

Melting point 176 ° C.

CS 271500 02

1G

Example 6

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

Melting point 170 ° C.

Example 7

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

Mp 201-204 ° C.

Example 0

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.

Example 9

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

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.

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.

1 ?.

Example 12

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

Mp 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

Melting point 197 ° C.

Example 14

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

Melting point: from 162 ° C.

CS 271500 82

Example 15

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

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

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

Mp 148 ° C.

Example 19

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

Foam, R _f = 0.37.

Example 20

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

Melting point 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

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.

Example 23

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

Melting point 172 ° C.

'' IW

Example 24

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

Foam, Rf - 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, Rf = 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 27

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

Mp 195 ° C.

Example 2B

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

Melting point 17B ° C.

Example 29

3-methyl-5- (l-methylpropyl) 4- [2- (2,6-dichloro-benzyloxy) -phenyl] _{-l) 4-dihydro-2>} 6-dimethyl-pyridine-3,5-dicarboxylic acid

Foam, R _f = 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

Melting point 133 ° C.

Example 31

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

Melting point 120 ° C.

Example 32

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

Melting point 202 ° C.

19 Dec

CS 271500 · B2

Example 33

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

Mp 185 ° C.

Example 34

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

Melting point 170 ° C.

Example 35

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-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-cyclopropyl-amide

Mp 148 ° C.

Example 37

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

Example 39

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

Foam = 0.31.

Example 40

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

Melting point 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

Melting point 126 ° 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, R _f = 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 _________ ________

H

Melting point 210 ° C,

Example 45

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

H-COCO

--- CO-NH-CH ₂ -CH (CH _{3) 2}

Melting point 202 ° C.

Example 47

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

Mp 159 ° C.

Example 48

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

Melting point 154 ° C.

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 (S-form).

Melting point 141 ° C.

Example 50

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

Melting point 162 ° C.

Example 51

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

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.

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.

CS 271500 02

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 0) (R-form) )

Melting point 202 ° C.

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)

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-phenyl-ethyl) -amide (S-form, diastereomer A) _____

Melting point 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, Rf = 0.53.

Example 58

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

Foam, R _f = 0.52.

Example 59

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

CH

Foam, R _f = 0.31.

CS 271500 02

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-phenylethyl) -amide acid

Oil, Rf = 0.88.

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 form) h ₃ c

H? COCC

Foam, R _f = 0.73.

Example 62

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

Mp 143 ° C.

Example 63

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

Melting point 144 ^D 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 (R) -form)

Foam, _Rf = 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, R _f = 0.48.

'' H

CS 271500 В2

Example 66

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

3,5-dicarboxylic acids

Melting point 177 ° C.

Example 67

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

Melting point 14 ° C.

Example 68

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

Melting point 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) )

Melting point 169 ° C.

Example 70

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

Oil.

Example 71

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

Example 72

4-Q2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Mp 202-204 ° C.

Example 73

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

Mp 152-154 ° C.

Example 74

3-methyl-5-ethylamide 4- (4-benzyloxyphenyl) -l, _{4-dihydro-2,6-dimethylpyridine-3)} 5-dicarboxylic acid _______ ___ ____

Mp 183-185 ° C.

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.

Example 77

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

Melting point: 23Θ to 242 ° C.

Example 78

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

M.p. 228 ° 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

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

Melting point: 178-180 ° C.

Example 81

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

Melting point: 16Θ to 170 ° C.

Example 83

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

Example Θ4

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

Mp 188-190 ° C.

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

Melting point 111-113 ° C.

Example 87

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

M.p. 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 h ₃ c

H 2 COOC

Melting point: 240 DEG C. (decomposition).

Example 89

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

145 ° C.

Example 90

3-methyl-5-allyl amide 4- (3-benzyloxyphenyl) -l, _4-dihydro-2> 6-dimethyl-pyridine-3,5-dicarboxylic acid

Melting point 95-98 ° C.

Example 91

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

M.p. 132-134 ° C.

Example 93

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

h ₃ cooc

M.p. 148-150 ° C.

Example 94

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

Melting point 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) 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.

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.

Example 99

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

Melting point: 203 DEG C. (decomposition).

Example 100.

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

Melting point 1B6 ° C.

Example 101

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

Melting point 147 ° C.

[.Alpha.] D @ 20 = + 29.68; c = 0.91 (DMF).

Example 102

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

Mp 148 ° C.

[.Alpha.] D @ 20 = -29.92 DEG, C = 0.805 (DMF).

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.

Example 105

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

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

R _f = 0.55.

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.

Example 111

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

g (2.54 mmol) of 4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid monomethyl ester is dissolved in 5 ml of dimethylformamide and 0.477 g ( L-norpseudoephedrine hydrochloride, 0.35 mL (2.54 mmol) triethylamine and 0.629 g (3.05 mmol) dicyclohexylcarbodiimide (solid). The reaction mixture was stirred at room temperature for 4 hours, the urea was filtered off and the filtrate was concentrated.

Column chromatography: silica gel 60, particle size 0.040-0.063 mm using a 20: 1: 0.05 mixture of chloroform, methanol and ammonia as eluent

Since urea is poorly soluble in ether and methylene chloride, the product is taken up several times with ether or methylene chloride, then the urea is filtered off and the extract is concentrated.

Yield: 0.9 g (67.3% of theory).

R _f = 0.35.

~ ~ 47.93 (in chloroform).

CS 271500 02

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

R _f = 0.13.

| oO | 20_ ⁰ + 7.34 (CHCl₃).

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.

δ ° = - 9.37 ⁰ (CHCl 3).

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.

Iq R ° = - 10.8 ⁰ (CHCl₃).

Example 116

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

R _f = 0.21.

[Α] 16 D = -17.37 ⁰ (CHCl 3).

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.

I 12 ° = - 38 28 ⁰ (c = 0.569, chloroform).

Example 119

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

Melting point: 178-181 ° C. | [.Alpha.] ^D @ 20 = + 36.56 ^D (c = 0.52, chloroform).

Example 120

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

Melting point 133 ° C.

Example 121

4- N - (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.

Example 123

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

Mp 190 ° C.

Example 124

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

Melting point 165 ° C.

Example 125

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

Mp 144-148 ° C.

Example 126

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

Melting point 135 ° C.

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.

62

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.

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

Melting point 111 ° C.

Example 131

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

CH-OOC

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.

Example 133

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

CS 271500 82

Example 134

3-methyl-5-ethylamide, l, _4-dihydro-2> 6-dimethyl-4- [2- (4-methyl-benzyloxy) -phenyl] pyridine-3,5-dicarboxylic acid

Melting point 184 ° C.

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 186 ° C.

Example 136

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

COO-CH

CS 271500 82

Example 137

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

Example 138

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

Mp 119 ° C.

Example 139

3- (2-Phenethyl) ester-5-cyclopropylamide

-3,5-dicarboxylic acids

4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-

H

Melting point 152 ° C.

Example 140

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

^Rf = 0.44 in toluene / ethyl acetate = 1

SUBJECT OF THE INVENTION

Claims (4)

A process for the preparation of the novel dihydropyridinamides of the general formula I (I) in which 1 8 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, 3 4 R and R are the same or different from each other and are hydrogen or (C 1 -C 4) alkoxy, R 6 represents -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or O-SO 2 phenyl, wherein n is 1 or 2 a R ⁶ and R ⁷ phenyl optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl or halogen, 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 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, C 3 -C 6 cycloalkyl or pyridyl, - a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or - a pyridyl group as well as a physiologically acceptable salt thereof, characterized in that the dihydropyridine monocarboxylic acid of the general formula (IX): R ¹ to R ⁵ and R ⁸ (IX) are as hereinbefore defined, optionally in the form of a reactive acid derivative in reaction with amines of formula X (X) in which R ⁶ and R ⁷ are as defined above 2. Process according to claim 1, characterized in that water and inert organic solvents such as alcohols, ethers, amides, glacial acetic acid / optionally in the presence of an inert organic solvent are used as solvents, whereupon the obtained compounds are optionally converted into their physiologically usable solvents. salts. The reaction is carried out at temperatures between 10 ° C and 150 ° C. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas IX and X are used as starting materials to give compounds of the formula I in which a R ⁸ R ² R> R ⁴ R ⁵ are the same or different from each other and are straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 6) alkyl optionally interrupted in the chain by an oxygen atom and / or optionally substituted by phenyl are the same or different from each other and represent a hydrogen atom or a (C1-C4) alkoxy group, -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or -O-SOg -phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with fluorine, chlorine, bromine, nitro, trifluoromethyl or C 1 -C 3 alkyl, R ⁶ and R ⁷ 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, phenyl optionally substituted by acetylamino or benzoylamino, or - the pyridyl group and their physiologically acceptable salts. 4. Process according to claim 1 or 2, characterized in that the corresponding compounds of the general formulas (IX) and (X) are used as starting materials to give compounds of the general formula (I) in which: 1 8 R and R are the same or different and are methyl or ethyl;