CS271495B2 - 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-η 5 -dicarboxylic acid diethyl ester is obtained by reacting ethyl benzylideneacetic acid ethyl ester with β-aminocrotonic acid ethyl ester or β-ethyl acetic acid ethyl ester and ammonia fsrov. E. Knoevenagel, Ber. Dtsch. Chem. Ges. 31.743 (1898) J ·

Furthermore, certain 1,4-dihydropyridines are known to have interesting pharmacological properties (cf. Bossert, V. Vater, Naturwissenschaften 58, 578 (1971)).

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

in which

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 represents a straight or branched alkyl group having from 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 ³ and R ⁴ are identical or different and represent hydrogen or alkoxy having 1 to 4 carbon atoms,

R is

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

7

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

- hydrogen atom,

- a cycloalkyl group having from 3 to 8 carbon atoms,

CS 271 495 B2

- 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, dialkylamino β1 up to 4 carbon atoms in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl,

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

- the 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 act as images and mirror images (enantiomers) or do not behave as images and mirror images (diastereomers). The invention relates to both antipodes and racetic forms. as well as mixtures of diastereomers. The racemic forms of Bé can also be separated as diastereomers in a known manner into stereoisomeric unitary components (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, for example, 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:

R ¹ and R ^d are the same or different from each other and are

- a straight or branched alkyl group having 1 to 4 carbon atoms,

R? represents a straight or branched alkyl group having from 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,

Я ³ and R ⁴ are the same or different from each other and represent a hydrogen atom or an alkoxy group of 1 to 4 carbon atoms,

-O- _(CHG) -phenyl, -O- (CH) _n pyridyl, -S- (CH) _n -phenyl or -O-BOG-phenyl, wherein 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,

CS 271 495 B2

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;

Particularly preferred are compounds of formula I wherein:

R ¹ and R ⁸ are the same or different and are methyl or ethyl,

R ⁷ represents 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 ⁸ and R ⁴ are the same or different and are hydrogen, methoxy or ethoxy,

R 6 represents -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 by the same or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluorine or chlorine, are hydrogen or alkyl of up to 4 carbon atoms, and

R is

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 a hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, phenyl or dialkylamino group C 1 -C 4 -alkyl;

R 'is

phenyl optionally substituted by acetylamino or benzoylamino, or

Or a β-pyridyl group, and physiologically acceptable salts thereof.

According to the invention compounds of formula I wherein R ¹ to R ⁸ have the above meanings, and their physiologically acceptable salts are prepared by

CS 271 495 B2 ее aldehydes of formula II

R ⁴

(II)

CHO in which r 1, R ⁴ and R ⁴ have the meanings given above, in the reaction of β ethers-ketocarboxylic cyeelines of the general formula III r ² ooc

(III)

in which

R ¹ and R? are as defined above, and the enaminocarboxylic acid amides of formula V

(V) in which r \ R? and R ⁶ have ehora hereinbefore defined, optionally in the presence of inert solvents, then the ee obtained compound optionally converted into their physiologically acceptable salts ·

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

CS 271 495 B2

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, isopropanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether or amides such as dimethylformamide, dimethylacetamide or hexamethyltriamide phosphoric acid, or glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine.

The reaction temperatures can be varied within a wide range. In general, temperatures between + 10 ° C and +150 ° C are used, preferably at temperatures between + 20 ° C and +100 ° C. The boiling point of the solvent is particularly preferably carried out.

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.

СВ 271 495 В2

In general, however, the molar amount of the reactants works.

Even Leathers and purification of compounds lískaných inventive process is preferably carried out as a _T-solvent oddestlluje a reduced pressure and the residue nískaný form only after oohlasení ice in a crystalline state · ae překryataluje and a suitable solvent · In some případeoh wůle be employ purify compounds · which were obtained by the process of the invention by chromatography.

The aldehydes of general formula IX which are used as starting materials for the process according to the invention are known or can be prepared according to known methods DOB 21 65 260; 24 01 665; T D · · · GP Harris Roth J Org · · · ££ _T Chem 2004 (1979); W. J · Dale _t . E. Hennis, J. Am, Chem, Boc, 2, pp _. 2543 (1956); Chem. Abstr. ££ · 13929 (1963).

Esters / 3-keto kyeeliny XXI _t which are likewise used as starting materials> are known or can be prepared by known methods D. Borrmann · Houben-Weyl, Methoden der organischen Chemie Vol · · VH / 4 _t 230 (1968); Y. Oikawa, K. Sugano _t 0 «Yonemitsu · J. Org · Chem · 43 · 2087 (1978) ·

Amides enamino ester of general formula V _t which are used as starting substances · are known or can be prepared by known methods DOS 2,228,377 ·

The compounds of formula (X) 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 may be used in medicaments for the treatment of pathologically altered blood pressure and cardiac insufficiency as well as as coronary therapeutics.

In addition, these substances can be used to treat heart rhythm disorders · renal insufficiency · liver cirrhosis · aecites · pulmonary edema · brain edema · pregnancy edema · glaucoma or diabetes mellitus ·

The activity of the compounds according to the invention on the activity of the heart was determined on an isolated stimulated papillary muscle of the guinea pig heart. To this end, the test animals (guinea pigs of both sexes of 200 g) were sacrificed. For the experiments, small papillary muscles are always prepared from the right ventricle and fixed horizontally in the organ bath. One end of the muscle is trapped between two metal electrodes · simultaneously irritating the specimen · while the other end of the muscle is connected by a fiber to the force sensor papillary muscle was stimulated at 1 Hz over the threshold · Organ lČ2eň a volume of about 2 ml by continuously promívá Krebs-Henseleit solution (concentration in mmol: NaCl 118; Na ₂ CO-25; KC1 10; KH ₂ PO ₄ l _t 2; MgSO ₄ 1 _t 2; CaCl ₂ 1 _t 8; glucose 10 _t pH 7> 4) at 4 ml / min at 32 ° C. Papillary muscle contraction is measured by isometry through a connected force transducer and recorded using a recorder.

The compounds according to the invention are dissolved in Krebs-Henseleit solution at a concentration of 10 .mu.g / ml, optionally using a co-solvent (dimethylsulfoxide up to 0.5%). The dihydropyridine carboxylic acid amides of the present invention contraction of the papillary muscle by more than 10

The new active substances can be converted in a known manner into the usual preparations · such as tablets · dragees · pills · granules · aerosols · syrups · emulsions · suspensions and solutions ·

CS 271 495 B2 uses 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 (for example petroleum fractions), vegetable oils (for example a mixture of peanut oil and sesame oil), alcohols (for example ethyl alcohol, glycerol); (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 (eg, lignin, sulfite waste liquors, methyl cellulose, starches and polyvinylpyrrolidone) and glidants (eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate) ·

In the case of oral administration, tablets may, of course, contain, in addition to the excipients mentioned, 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. Furthermore, they 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, various substances may be added to the active ingredients flavor enhancers or colorants ·

In the case of 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. up to 20 mg / kg, preferably from 0.1 to 10 mg / kg 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 amount mentioned above, while in other cases the above upper limit must be exceeded. during the day ·

CS 271 495 B2

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

Example 1

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 1.15 g (10 mmol) of methyl acetic acid ester and 1.4 g (10 mmol) of cyclopropylamide (β-aminocrotonic acid) for 4 hours. The reaction mixture was cooled and concentrated and the evaporation residue was purified over a silica gel column to give 1.4 g of colorless crystals, m.p. 193 ° C.

The compounds of the following examples were also prepared in an analogous manner to that described in Example 1.

Example 2

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

H

СВ 271 495 В2

Melting point 162-165 ° C.

Example 3

3-methyl-5-fenylainid 4- (2-ben »yloxyfanyl) _-l> 4-dihydro-2,6-diBethylpyridin-3,5-dicarboxylic acid

Mp 194 ° C.

Example 4

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

Melting point 156-157 ° C.

Example 5

1,4-Dihydro-2,6-dinethyl-4- [2- (3-methylbenzyloxy) phenyl] -3-methyl ester-5-cyclopropylamide

CS 271 495 (nyl) pyridine-3,5-dicarboxylic acid

Melting point 176 ° C.

Example 6

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

Mp 17 ° C.

Example 7

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

H 2 COOC

/ * 1

CS 271 495 B2

Mp 201-204 ° C.

Example 8

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

H-COCO

H ₃ C

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

H 2 COOC

H ^ C

Melting point: from 80 ° C.

Example 10

3-methyleeter-5- (2-diethylamino-ethyl) amide 4- (2-bensyloxyfenyl) _-l> 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

CS 271 495 B2

Melting point: 95 ° C.

Example 11

3-methyl-5- (4-carbamoyl-phenyl) amide 4- (2-ben «yloxyphenyl) _t -L 4-dihydro-2,6-diinethylpyridin-315-dicarboxylic acid

Melting point above 300 ° C.

Example 12

3-no thylester-5- (4-acetylaeinofenyl) 4- (2-benmyloxyfenyl) _{-1-1 4-dihydro-2H-f} 6-dimethyl pyridine-3, 5-dicarboxylic acid

CS 271 495 B2

Mp 298 ° C (dec.).

Example 13

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-di- (3-methyl-5- (4-benzoylaminophenyl) amide)

Melting point 197 ° C.

Example 14

3-methyle8ter-5- (1-phenylethyl) amide (R _t S) -4- (2-benzyloxyphenyl) -1,4-dihydro-2 _F 6-dimethylpyridine-3> 5-dicarboxylic acid (a mixture of R _f S)

Melting point: from 162 ° C.

CS 271 494 B2

Example 15

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

Melting point 82 ° 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-ether-5-cyclohexylamide

CS 271 495 B2

Melting point 108-111 ° C.

Example 18

3-methyl-5-tert-butyl 4- (2-benzyloxyphenyl) _-l-t 4-dihydro-2,6-dicarboxylic acid dimethylpyridin5

Mp 148 ° C _t

Example 19

3-methyl-5-propyl 4- (2-benzyloxyphenyl) _{-1-t4-dihydro-2H-1} 6-dimethylpyridine-3> 5-

'' H

CS 271 495-2

Example 20

4- (2-benoxyloxyphenyl) -1,4-dihydro-2,3-diethylpyridine-3,5-dicarboxylic acid 3-ethyl-ether-5- (2-ethylpropyl) anide

EjCCOC

Melting point 134 ° C.

Example 21

5-H-benxyl-K-tert-butyl-4- (2-benxyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester

Melting point 128 ° C.

Example 22

4- (2-benxyloxyphenyl) -1,4-dihydro-2,6-dinethylpyridine-3,53-ethyl ester-5-methyl amide

CS 271 494 B2

Melting point 105 ° C.

Example 23

3-methyl-5-ethylamide, 4- (2-benzyloxyphenyl) -l ₁ 4-dihydro-2 _{t 6-dimethylpyridine-3>} 5-di-carboxylic acid

Melting point 172 ° C.

Example 24

_3-butyl-5-t cykIopropylaaid l 4-dihydro-2 _t 6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] -pyrldin _3-t 5-dicarboxylic acid

Foam _t »0 _t l ·

Example 25

ButyleBter-3-methylamide 5-L, 4-dihydro-2,6-di®ethyl-4- 2- (2-pyridyl) methoxyfenylJpyridin _3-f 5-dicarboxylic acid

CS 271 494 B2

Foam _t R _f = O _t O7.

Example 26

3-butyl-5- (1-methyl-prop-1) amide 4-1 _t 2 _t dihydro-6-Dimethyl-4- 2- (2-pyridyl) _{3-methoxyfenylJpyridin>} 5-dicarboxylic kyeeliny

Foam, Rf = 0 _t 25.

Example 27

3-methyleeter cyklopropylaeid-5-4-2- (3 ₊ 4-dichlorobenzyl «yloxy) -phenyl -l _J> 4-dihydro-2,6-dimeihylpyridin _3-t 5-dicarboxylic kyeeliny

N · 'H

CS 271 494 B2

Mp 195 ° C.

Example 28

5-Cyclopropyl-5- (2,6-dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dia-ethyl-pyridine-3,5-dicarboxylic acid 3-ethyl-5-cyclopropyl ester

H ^ C

H ₃ COOC

Melting point 178 ° C.

Example 29

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

Example 30

3-Bethylester methylaBid-5-4- (2- (2,6-dichlorbensyloxy) phenyl-l, 4-dihydro-2,6-diBethylpyridin _3-t 5-dicarboxylic acid

CS 271 494 B2

133 ° C ·

Example 31

3-methyl-5-amide 4- [2- (4-3 _t dichlorbensyloxy) phenyl] _-1H-1 4-dihydro-2,6-dimethyl-1-pyridin-3,5-dicarboxylic acid

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-cyclopropylaeid

CH, J

CS 281 495 B2

Melting point 202 ° C.

Example 33

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

Mp 185 ° C.

Example 34

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

Cl

Melting point 170 ° C.

CS 271 494 B2

Example 35

3-methyl-5- (2-methylpropyl) AAID 4- [2- (3-fluorobenzyloxy) -3-®ethoxyfenyí] -L _{t 4-dihydro-2H-6-t-dimethylpyridine} 3i 5-dicarboxylic acid

Melting point 98 ° C.

Example 36

3-methyl-5-cyclopropylamide 4 l _{t-dihydro-2 t} 6-dimethyl-4-2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridin-3 ₁ 5-dicarboxylic acid

Mp 148 ° C.

Example 37

3-methyl-5- (l- «propyl) -amide _l> 4-dihydro-2 _t 6-dimethyl-4- £ 2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridin-3> 5-dicarboxylic acid

CS 271 494 B2

Foam, R ^ ^and 0.44,

Example 38

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

Melting point 106 ° C.

Example 39

3- (l-Bethylpropyl) eeter cyklopropylaBÍd 5-L, _{4-dihydro-2,6-dimethyl-t-4-yl} 2- (4-nethylbanzyloxy) phenyl pyridine-3 »5-dicarboxylic acid

CS 271 494 B2

Foam, R _f = 0.31.

. Example 40

3-methyleeter cyklopropylaeid-5-4- (4-benayloxyfenyl) _t -L _{4-dihydro-2H-6-t} diaethylpyridin-

Example 41

1,4-Dihydro-2,6-diaethyl-4- [2- (4-acetylbenzyloxy) phenyl] pyridine-3,5- (1-methylpropyl) ester-5- (1-methylpropyl) amide -di carboxylic acids

Melting point 126 ° C.

CS 271 494 B2

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 = 0.24.

Example 44

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

CS 271 494 B2

Melting point 210 ° C.

Example 45

5- (1-phenylethyl) aaid (R) -4-C2- (4-fluorobenzyloxy) phenyl] -1,4-dihydro-2,6- 3-ethyl ester. dimethylpyridine-3 _t 5 dikarboxyloré acid (R-form)

Foam, «0.56 ·

Example 46

3-Methyl-ether-5- (2-methyl-propyl) -amide 4- (4-benxyloxy-phenyl) -1,4-dihydro-6,6-dimethyl-pyridine-3,5-di-carboxylic acid

CS 271 494 B2

Melting point 202 ° C ·

Example 47

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

Mp 159 ° C.

Example 48

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

N · 'H

СБ 271 495 В2

Melting point 154 ° С «

Example 49

3-methyl-5- (LF enyletbyl paraben pyridin-3 _t 5-dicarboxylic acid (S) -4- (4-bensyloxyf phenyl) -1,4-dihydro-2, 6-dimethyl

Melting point 141 ° C.

Example 50

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

Mp 162 ^C C

CS 271 494 B2

Example 51

(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethyl-1- (3-methyleater-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-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-ether-5-cyclopropylamide

С6 271,495 В?

Melting point 202 ° С «

Example 54

3-methyl-5- (l-phenylethyl) amide (K) -4- (4-beniyloxyrenyl) _-L-t dihydxv 4> -2,6-dimethylpyridine-3,5-dicarboxylic acid (Diastereomer B) (B- fcrma)

Melting point 202 ° C.

Example 55

3-methyl-5- (l-phenylethyl) amide (B) -4- (4-beMyloxyfe ^ R *) - l, _{4-dihydro-2H-f} 6-dimethylpyridine-3,5-dicarboxylic acid (B-form, diastereotaer mixture)

31EN 271 495 B2

Melting point 110-166 ° C.

Example 56

3-oethylester-5- (l-phenylethyl) amide (S) -4- (2-benzyloxyphenyl) -l, 4-dihydro-2 _t 6-dimethylpyridine - ^^ - dicarboxylic acid (S-form, diastereomer A)

Melting point 172

Example 57

3-methyleeter-5- (l-phenylethyl) amide (B) -4- (2-benzyloxyphenyl) -l, 4-dihydro-2,6-dimethyl-3 _t 5-dicarboxylic acid (S-form, diastereomer B)

СЕ 271 495 В2

Foam, R _f = 0.53 *

Ρ ž Í к 1 and d 5β

3-Methylether-5- (1-phenylethyl) amino-4- [2- (4-fluorobutyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid ( K-forea)

Foam, Rf @ 0.5 0.52.

Example 59

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

Foam, R ^ = 0 _t 31.

Example 60

3-butyle8ter-5- (l-FE5?! Ethyl; mid-CB3 L _f 4-dihydro-2,6-Dimethyl-4- £ 2- (3-eethylbenzyloxy) phenyl] pyridine-3,5 ~ <± Lkarb 7-Acid acids

CS 271 494 B2

01ej _t R _f = 0 _t 88 ·

Example 61

3-methyleeter-5- (1-phenylethyl) amide (R) -4- [2- (3-chlorbensyloxy) phenyl] -1 ₁ 4-dihydro-2,6-dimethylpyridine-3 »5-dicarboxylic acid (R- form)

H 2 COOC

H ₃ C

Foam, R _f «O | 73 ·

Example 62

3-methyl-5- (1-phenylethyl) amide (R) -4- (3-bensyloxyfenyl) _t -L 4-dihydro-2 _t 6-dimethylpyridine-3 _t 5-dicarboxylic acid (R-form)

B2 271

Melting point: from 1 * 3 ° C.

Example 63

4- (3-Benyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3-methyl-ether-5-cyclopropylanide

Mp 144 ° C.

Example 64

(R) -4-? - (4-Isopropylthio) thenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) anide (R-form)

H 2 COOC

H ₃ c

Foam _t R _f ^s 0.47.

Example 65

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

CS 271 494 B2

Foam, _Bf = 0.48.

Example 66

3-aethylester allyIamid-5-4 - [, 2- (4-Fluorobenzylthio) _{phenyl-l> 4-dihydro-2H-l} 6-dimethylpyridine-З »5-dicarboxylic acid

Melting point 177 ° C.

Example 67

3-methyl-5-allyl amide 4- (2-ben »yloxyphenyl) -l, 4-dihydro-2,6-dimethylpyridine-3 ₁ 5-dicarboxylic acid

CS 271 495 в?

148 ° C ·

Example 68

5- (1-Phenylethyl) id (H) -4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester (R-form) _β с

H 2 COGC

Melting point 175 ° C.

Example 69

(R) -4- (2-Benayloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenyl-ethyl) -amide (R-foraa, diastereoner B) )

Melting point 169 ° C.

Example 70

3-methyl-5- (2-phenylethyl) AAID 4- (2-benzyloxyphenyl) -l, 4-dihydro-2 _t 6-dimethylpyridine-3,5-dicarboxylic acid

CS 271 494 B2

Oil.

Example 71

3-methyleBter-5-benzylamide 4- (2-benzyloxyphenyl) _{-l> 4-dihydro-2> 6-dimethyl-3>} 5-

M.p. 148-149 ° C.

Example 72

3-methyle8ter-5-ethylamide 4-2- (4-Fluorobenzylthio) _phenyl-l> 4-dihydro-2,6-dimethylpyridine-3j5-dicarboxylic acid

CS 271 494 B2

Mp 202-204 ° C

Example 73

3-methyl-tert-5-ethyl-dicarboxylic acid amide

- (3-benayloxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-

Mp 152-154 ° C.

Example 74

3-Methyl ester-5-ethylamide

-dicarboxylic acids

- (4-benxyloxyphenyl) -1,4-dlhydro-2,6-diethylpyridine-3,5HgCOOC

H ^ C '

Mp 183-185 ° C.

Example 75

3-Methyl-ether-5-aad.d 4- (2-bentyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid

CS 271 494 B2

3S

188 ° C,

Example 76

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-oethyleater-5-diethylamide

Melting point 135 ° C.

Example 77

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

CS 271 494 B2

Mp 238-242 ° C.

Example 78

3-methyl-5-athylamid l, 4-dihydro-2,6-dimethyl-4- [2- (4-aethylfenyl8ulfonyloxy) - phenyl] pyridine-3-dicarboxylic acid ₁ 5 kyeeliny

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-ether-5-ethylamide

HjCOOC

Melting point 174-176 ° C.

Example 80

3-methyleeter-5-ethylamide, 4- [2- (3 »4 dichlorbensyloxy) phenyl-l, _{4-dihydro-2-f} 6-dimethylpyridine З» 5-dicarboxylic acid

СБ 271 495 В2

Melting point: 178-180 ° C.

Example 81

_{3-methyleeter-5-t} ethylenld L 4-dihydro-2,6-Dimethyl-4-2- (2-pyridylmethyloxy) phenyl] pyridine-3,5-dicarboxylic acid I -carboxylic acid

M.p. 159-161 ° C.

Example 82

3-Methyl-ether-5-cyclopropylaid-1,4-dihydro-2,6-diaethyl-4-N- (2-pyridyl-ethyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid

N H

CS 271 494 B2

Melting point 168-170 ° C.

Example 83

3-methyl-5-methylamide 1 _t 4-dihydro-2 _t 6-dimethyl-4- (2-fenylsulfonyloxyfenyl) pyridine-3, 5-dicarboxylic acid

Melting point 171-173 ° C.

Example 84

3-methyl-5-ethylamide, l-dihydro-s-Z-O-dimethyl-S-CS-fenylsulfonyloxyfenyDpyridin _3-t 5-dicarboxylic acid

Mp 188-190 ° C.

Example 85

3-ethyl-5-ethylaniid 1 ₁ 4-dihydro-4- ^ 2- (4-fluorobenzyloxy) phenyl 1J-2,6-dimethylpyridine-3> 5-dicarboxylic acid

CS 271 494 B2

Mp 147-149 ° C.

Example 86

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

Melting point 111-113 ° C.

Example 87

1,4-Dihydro-2,6-diaethyl-4- (2-phenyl-sulfonyloxy-phenyl) -pyridine-3,5-dicarboxylic acid 3-ethyl-5-allyl-amide

M.p. 154-156 ° C

CS 271 494 B2

Example 88

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

Melting point: 240 DEG C. (decomposition).

Example 89

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

145 ° C.

Example 90

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

CS 271 494 B2

“3 ^WJ

Melting point 95-98 ° C.

Example 91

1,4-Dihydro-2,6-dibethyl-4- [2- (4-Bethylphenylleulfonylox, v) -Xenyl] pyridine-2 '- 5-dicarboxylic acid 3-methyl ester-5-allyl amide

Melting point 168-170 ° C.

Example $ 2

3-Methyl-ether-5-allylaid 4- (2- (2,6-dichloro-benzayloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-

M.p. 132-134 ° C.

CS 271 494 B2

Example 93

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

Melting point 171-173 ° C.

Example 95

4- (2-Benayloxyphenyl) -1,4-dihydro-2,6-dimethyl-5- (2- (4-pyridyl) ethyl) amide 3-methyl ester

N H

CS 271 494 B2

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-ether-5-ethylamide

Melting point 122-125 ° C.

Example 98

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

CS 271 494 B2

Melting point 95-100 ° C.

Example 99

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

Melting point: 203 DEG C. (decomposition).

Example 100

5- (Cyclopropylmethyl) -4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-ethyl ester

Melting point 1-6 ° C.

Example 101

(+) - 4- (2-Benzyloxyphenyl-1,4-dihydro-2,6-dinethylpyridine-3,5-dicarboxylic acid 3-aethyleeter-5-ethylamide

CS 271 494 B2

Melting point 147 ° C

° α ° = + 29.6a, c = 0.91 (DMP).

Example 102

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

H ₃ COOC

H ₃ C

Melting point 148 DEG C. ^{[@ 20} = - 29.92 ° C "0.805 (DMP).

Example 103

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

CS 271 494 B2

Mp 179 ° C.

Example 104

4- (2-Benyloxy-phenyl) -1,4-dihydro-2,6-dinethyl-pyridine-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-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

CS 271 494 B2

R _f = 0) 408th

Example 107

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

in.

R _f = 0.53.

Example 108

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

CS 271 495 в?

R _f = 0.55.

Example 109

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

Melting point 111 ° C.

Example 110

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diaethyl pyridine-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 ester-5- (3-methoxypropyl) amide

CS 271 494 B2

R _f = 0.19.

Example 112

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

R _f = 0.35 ~ .η and ^ o [XJ D '' ⁴⁷ · ⁹³ (chloroform).

Example 113

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

Rf ₌ 0.13

WJ D = ^{+ 7} ° ^'34 ° (CHCl.,).

CS 271 494 B2

Example 114

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

R _f = 0.15

J d ° ^: - ⁹ * ³⁷ ° ^(CHC1 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

CH ₃ CH ₃

R _f = 0.19 _W 2 °: -10.8 ° (CHCl 3).

Example 116

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

CS 271 494 B2

R _f = 0.21

LC d 0 = - ^{17 '37} ° (I want ₃ ).

Example 117

3-Methyl-5- (3-hydroxy-propyl) -a-4- (2-benzyloxy-phenyl) -1,4-dihydro-2,6-diaethyl-pyridine-3,5-dicarboxylic acid

Mp 205 ° C.

Example 118

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

CS 271 494 B2

Melting point: 178-181 ° C

589 ⁼ 38.28 (C = 0.569, chloroform).

Example 119

5-Cyclopropylaid (+) - 4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-diaethylpyridine-3,5-dicarboxylic acid 3-methyl ester

H 2 COOC

H ₃ C

Melting point: 178-181 DEG C. [.alpha.] D @ ₂₀ = + 36.56 DEG (c = 0.52;

CH.J chloroform).

CO-NH

Example 120

3-methyl-5-hexylamide 4- (2-benzyloxyřenyl) -l _l 4-dihydro-6-2 _{t-3 diniethylpyridin>} 5-dicarboxylic acid

Melting point 133 ° C.

Example 121

3-Aethyleeter-5-aid 4-N- (4-ethylbenzenesulfonyloxy) -phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acids

CS 271 494 B2

Mp 205 ° C.

Example 122

3-methyle8ter eek.butylaoid-5-4- (2-ben2yloxyřenyl) -1 _t 4-dihydro-2,6-dimethylpyridine-3 »5-dicarboxylic acid _

135 ° C ·

Example 123

3-iřOpropyleeter-5-4- (2-benzyloxyphenyl) -l, 4-dihydro-2 _t 6-dimethylpyridine-3 ₁ 5-di-

Mp 190 ° C

CS 271 494 B2

Example 124

3- (2-Aethoxyethyl ester) -5-aid 4- (-3,5-dicarboxylic acid)

2-benzyloxyphenyl) -1,4-dihydro-2,6-diaethylpyridineH ₃ COH ₂ CH ₂ C-OOC

Melting point 165 ° C.

H ₃ C

Example 125

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diaethylpyridine-3,5-dicarboxylic acid 3-methyleether-5-butylaid

Mp 144-148 ° C.

Example 126

3-Ifopropyl ester-5-ethylaid 4- (2-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-

Melting point 135 ° C

CS 271 494 B2

Example 127

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

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

CO-NH- _{(CH2) 5} OH

Melting point 176 ° C.

Example 1 a d 129.

3- (2-methoxyethyl) ester-5-methyl amide 4- (2-benzyloxyfenyD-l, 4-dihydro-2,6-dimeth.vlpy-. Naphthyridine-3 _{t-dicarboxylic} acid 5 "'

M.p. 133-135 ° C

CS 271 494 B2

Example 130

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

Melting point 111

Example 131

3-Isopropyl-5-methyl-4- (2-beneyloxy-phenyl) -1,4-dihydro-2,6-diethyl-pyridine-

Melting point 140-143 ° C.

Example 132

3-ieopropyleeter-5-cyclopropylamide 4 - (? - benzyloxyphenyl) _-l> 4-dihydro-2 »6-dinethylpyridin-3,5-dicarboxylic kyeeliny

M.p. 132-135 ° C.

CS 271 494 B2

Example 133

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-8-propylamide

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.

Example 135

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

CO-NH-CH3

Melting point 186 ° C.

CS 271 494 B2

Example 136

3- (S) - (l-ifiopropoxykarbonylethyl) ester-5-cyklopropylaiiiid 4- (2-ben2yloxyfenyl) -L _$ 4-dihydro-2,6-dimethylpyridine-3 ♦ 5-dicarboxylic acid

Example 137

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

Example 138

3- (2-phenylethyl) ester 5-propyl-4- (2-ben2yloxyfenyl) -l _l 4-dihydro-2 _t 6-dimethylpyridine-3,5-dicarboxylic acid

m.p. Mp 119 ° C.

CS 271 494 B2

Example 139

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

m.p. 152 [deg.] C.

Example 140

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

6-Dimethylpyridine-3,5-

³ 0.44 in toluene: ethyl acetate = 1: 1

Claims (3)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of the novel dihydropyridinamides of the formula I in which: R ¹ which R ⁸ R ² R ³ R ⁴ R 5 are the same or different C 1 -C 6 alkyl and are straight or branched 9 means C 1 -C 6 straight or branched alkyl optionally interrupted in the chain by an oxygen atom and optionally substituted by C 2 -C 6 alkoxycarbonyl C uhlíku-C nebo or phenyl, being the same or different from each other and representing a hydrogen atom, a (C až-C x) x-group, or -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl , -S- (CH2 _{) n} -phenyl or -O-SO4 -phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, alkyl in 1 to 3 the carbon atoms or the halogen atom, and R 7 are the same or different from each other and represent - hydrogen atom, - C 3 -C 8 -cycloalkyl, - straight or branched (C až-C alky) alkyl or (C nebo-C alk) alkenyl, which may be C 1-C alko alkoxy, (C až-C alkyl) alkylcarbonyl, phenyl, (C až-C dial) dialkylamino; in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl, - a phenyl group which is optionally substituted by carbamoyl, acetylamino or ben2oylamino, or - a pyridyl group, CS 271 495 B2 as well as their physiologically acceptable salts, characterized in that the aldehydes of the general formula II CHO in which R \ R ⁴ and _m Aji abovementioned meaning, are reacted в esters of β-ketocarboxylic acid of formula III R @ ² OOC wherein R ¹ and R ^? are as defined above, and the enaminocarboxylic acid amides of formula V R ⁶ / (V) in which R ⁶ , R ⁷ and R ⁸ 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. The process according to claims 1 and 2, characterized in that the corresponding compounds of the formulas II, III and V are used as starting materials to give compounds of the formula I in which: Ί 8 R and R are the same or different from each other and represent a straight or branched alkyl group 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, CS 271 495 B2 _and R ⁴ are identical or different and represent hydrogen or C 1 -C 4 » R is -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or -O-SO4 -phenyl in which n is 1 or 2 and the phenyl moiety is optionally eubetitected one to three times by fluorine, chlorine, bromine, nitro, trifluoromethyl or C1-C3 alkyl, 6 7 R and R 'are the same or different from each other and are - a hydrogen atom or a cycloalkyl group having from 3 to 7 carbon atoms, - a straight or branched alkyl group having from 1 to 12 carbon atoms or an alkenyl group having from 5 to 5 carbon atoms, which may optionally be substituted by hydroxy, alkoxy having from 1 to 4 carbon atoms, alkylcarbonyl having from 2 to 5 carbon atoms, phenyl, dialkylamino up to 4 carbon atoms in both alkyl moieties, - a phenyl group optionally substituted by an acetylamino or benzoylamino group, or - the pyridyl group, as well as their physiologically tolerable oils. 4. A process according to claim 1 or 2, characterized in that ee use the corresponding compounds of the formulas II, III and V as the starting materials to form compounds of the formula I in which: Ί Я R and R are the same or different and are methyl or ethyl, R ² represents a straight or branched alkyl group is 1 to 6 carbon atoms which is optionally přeruěena in the chain an oxygen atom and / or is optionally substituted phenyl, and iP jeou same or different and represent hydrogen, methoxy or ethoxyekupinu means -0 -CH ₂ -phenyl, -O-CH 2 -pyridyl, -S-CH 2 -phenyl or -O-SO ₂ -phenyl, the phenyl group optionally being up to twice eubetitized with 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 means a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, and CS 271 495 B2 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 a hydroxy, C1-C4alkoxy, C1-C4alkylcarbonyl, phenyl or dialkylamino group C 1 -C 4 -alkyl; a phenyl group which is optionally substituted with acetylamino or benzoylamino, or - / 3 * or pyr-pyridyl, as well as their physiologically acceptable salts.