DD274026A5 - PROCESS FOR THE PREPARATION OF DIHYDROPYRIDINAMIDES - Google Patents

Abstract

Dihydropyridine amides of the formula I <IMAGE> in which R<1> to R<8> have the meaning given in the description, are used in particular as circulation-influencing medicaments.

Description

-Λ-

Process for the preparation of Dihydropyridinamiden A field of application of the invention

The compounds produced by the process according to the invention are used ir. Of the pharmaceutical industry, in particular for the synthesis of drugs *

Characteristic of the known state of the art

It is known that ethyl diethyl pyridine-3,5-dicarboxylate is obtained by reacting ethyl benzylideneacetate with ethyl β-aminocrotonate or ethyl acetoacetate and ammonia / E.Knoevenagel, Ber, Dschem Chem, Ges. 31, 743

Furthermore, it is known that certain 1,4-dihydropyridines have interesting pharmacological properties / F, Bossert, VV, Vater, Naturwissenschaften 58, 578 (197I) _- /,

ZJeI ₁ the invention

The process according to the invention provides novel dlhydropyridineamides which have a valuable spectrum of pharmacological activity.

Explanation of the essence of the invention

The invention has for its object to provide new Dihydropyridinamide available.

The present invention relates to processes for the preparation of novel dihydropyridineamides of the general formula (I)

(I)

in which

R * and R are the same or different binders and

- for straight-chain, branched or cyclic B alkyl. with up to 6 carbon atoms "which is optionally substituted by hydroxy, cyano, phenyl or halogen, or

'· Represent cyano or phenyl, 20

R ² - eteht a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms which may be interrupted by an oxygen atom or a sulfur atom in the chain and / or which may be substituted by halogen, cyano, hydroxy, acetoxy , Pyridyl or by an optionally substituted by halogen, cyano, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl substituted

substituted phenyl, phenoxy or phenylsulfonyl group,

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g R ³ and R ^ are the same or different and

- represent hydrogen, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, cyano, 'nitro, dialkylamino each having up to 4 carbon atoms per alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy or trifluoromethylthio .

R ⁵ - for a group of the formula -O- (CH ₂ Jn-R ^1J ,

-S- (CH ₂ ) _n -R ⁿ , -O-SO ₂ -R ¹¹ , -CO- (CH ₂ J) _n -R ^{1 J} , -O-CO- (CH ₂ J _n -R ¹¹ , - C0 -NH- (CH ₂ ) _n -R ⁿ , -NH-C0- (CH ₂ ) _n -R ⁿ , -NH-SO ₂ - (CH ₂ J _n -R ¹¹ ,

wherein

η - 0 to 4 means, and

R ¹¹ - aryl having 6 to 12 carbon atoms, 2g equal to or different by up to 4 times

Halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, amino, alkylamino having

up to 6 carbon atoms, dialkylamino each having up to 6 carbon atoms per alkyl group or acetylamino may be substituted or - a 5- * bite 7-membered saturated or un-3g saturated heterocyclic ring means

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as heteroatoms an oxygen atom, a sw

may contain felatom or two nitrogen atoms,

and

R ⁶ and R are the same or different and each

- for hydrogen,

- For cycloalkyl having 3 to 8 carbon atoms or

- for straight-chain or branched alkyl, alkenyl

or alkynyl having in each case up to 1 carbon atoms which may be substituted by halogen, hydroxy, alkoxy having up to 8 carbon atoms, alkylthio having up to 8 carbon atoms, alkylcarbonyl having up to 8 carbon atoms in the alkyl radical, carboxy or alkoxycarbonyl having up to 8 carbon atoms , by phenyl, which is optionally substituted by nitro, cyano, trifuoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms, by cyano and / or by a group of the formula -NR ⁹ R *,

wherein

R ⁹ and R ^{1 are the} same or different and each is hydrogen, alkyl of up to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, aryl of 6 to 12 carbon atoms, acyl of up to 7 carbon atoms, alkylsulfonyl of up to 6 carbon atoms, or arylsulfonyl having 6 to 12 carbon atoms,

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or R ⁶ and R ⁷ respectively

- stands for aryl with 6 to 12 carbon atoms «

which may be identical or different through nitro, cyano, halogen, alkyl with up to 6 carbon atoms, alkoxy with up to 6 carbon atoms, alkylthio with up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl with up to 6 carbon atoms each Alkyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino having up to 8 carbon atoms, dialkylamino each having up to 8 carbon atoms per alkyl group, acetylamino or benzoylamino may be substituted, or

- represent a 5- to 7-membered saturated or non-2Q saturated heterocyclic ring which as heteroatom may contain an oxygen atom, a sulfur atom or two nitrogen atoms,

and their physiologically harmless salts «

The compounds according to the invention exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereozoans). The invention relates

₃ Q both the antipodes ale and the raceme forms as well as the diastereomer mixtures. The racemic forms and the diastereomers can be separated in a known manner into the stereoisomerically uniform constituents (compare EL, Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

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Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid "hydrobromic acid" phosphoric acid or sulfuric acid or salts jQ with organic carboxylic or sulfonic acids such as acetic acid "maleic acid" fumaric acid, xic acid "citric acid" tartaric acid, lactic acid "benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, Toluene sulfonic acid or naphthalenedisulfonic acid ·

Preference is given to compounds of the general formula (I)

in which

R and R ° are the same or different and each

- represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxy, phenyl, fluorine, chlorine or bromine, or

- stand for cyano or phenyl,

Vr - is a straight-chain or branched "saturated or unsaturated Kohlenwasserstoffreet having up to β carbon atoms" which may be interrupted by an oxygen atom in the chain and / or may be substituted by fluorine, chlorine, bromine, cyano, hydroxy or by an optionally phenyl, phenoxy, substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or by x-, ß- or V-pyridyl,

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g R ³ and R ^{4 are the} same or different and each

- are hydrogen, fluorine, chlorine, bromine, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, methylthio, cyano, nitro, trifluoromethyl or trifluoromethoxy,

R ⁵ - for a group of the formula -O- (CH ₂ ) J ₁ -R ¹¹ *

-S- (CH ₂ ) HR ¹¹ I -O-SO ₂ -R ¹¹ I -O-C0- (CH ₂ ) _n -R ^U , -NH-C0- (CH ₂ ) _n -R ⁿ , -NH- SO ₂ - (CH ₂ J _n -R ¹¹ is

wherein

η - 0 to 3 means

and

R ^{11 is} phenyl or naphthyl which is up to 3-fac

may be the same or different substituted by fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl with up to 4

Carbon atoms, alkoxy with up to 4 carbons

atoms, methylthio, amino, alkylamino having up to 4 carbon atoms, dialkylamino having in each case up to 4 carbon atoms per alkyl group, acetylamino, or

3Q - pyridyl, thienyl, furyl, pyrimidyl or pyrazine

nyl means

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^and

R ° and R 'are the same or different and each

- represent hydrogen, cycloalkyl having 3 to 7 carbon atoms or

jQ - represent g? Radkettiges or branched alkyl or alkenyl having up to 14 carbon atoms which may be substituted by fluorine, chlorine, bromine, hydroxy, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, alkylcarbony1 with up to

j5 6 carbon atoms in the alkyl radical, carboxy, alkoxycarbonyl having up to 6 carbon atoms, phenyl optionally substituted by nitro, trifluoromethyl, methyl or methoxy, by cyano and / or by a group of the formula -NR ⁹ R ¹⁰ ,

,

wherein

R ⁹ and R ^{10 are the} same or different and each

Hydrogen, alkyl of up to 6 carbon atoms, benzyl, phenethyl, phenyl, acetyl, benzoyl,

Alkylsulfonyl having up to 4 carbon atoms or phenylsulfonyl,

or

OQ - stand for phenyl or naphthyl, which can be substituted up to 3 times the same or different leg by nitro, fluorine, chlorine, bromine, alkyl with up to

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4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, alkylamino having up to 6 carbon atoms, dialkylamino each having up to 6 carbon atoms per alkyl ^ group, acetylamino or by benzoylamino, or are pyridyl, pyrimidyl, thienyl or furyl,

and their physiologically harmless salts «

Particularly preferred compounds of the general

Formula (I),

in which

R * and R ° are the same or different and each

- represent methyl, ethyl or benzyl,

R 1 - represents a straight or branched hydrocarbon radical of up to 6 carbon atoms which may be interrupted by an oxygen atom in the chain and / or which may be substituted by fluorine, chlorine, cyano, hydroxy, phenyl, oc-, B - or V-pyridyl,

p3 and R ^ are the same or different and each

- represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, nitro or trifluoromethyl,

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R ⁵ - is a group of the formula -O-CH ₂ -F ¹¹ * -S-CH ₂ -R ¹¹ or -O-SO ₂ -R ¹¹ ,

wherein

jQ R ¹¹ - phenyl means "which may be substituted equally or differently up to twice by fluorine, chlorine, nitro, trifluoromethyl, methyl, methoxy, amino, methylamino, dimethylamines, ethylamino, diethylamino or acetylamino, or

jg - an oc-, β- or a V-pyridyl group means

R ⁶ - is hydrogen or alkyl having up to 2U 4 carbon atoms

^and

R ^ - for hydrogen, cyclopropyl, cyclopentyl,

Cyclohexyl, or - represents straight-chain or branched alkyl or alkenyl

2g having up to 10 carbon atoms, which may be substituted by fluorine, chlorine, hydroxy, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, alkylcarbonyl having up to 4 carbon atoms in the alkyl, carboxy, alkoxycarbonyl

₃ Q having up to 4 carbon atoms, phenyl and / or a group of the formula -NR ⁹ R ¹⁰ ,

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wherein

R ⁹ and R ^{10 are} identical or different and are hydrogen, alkyl having up to 4 carbon atoms, benzyl, phenyl or acetyl, or R ⁷

- represents phenyl, which may be substituted identically or differently up to 2 times by nitro, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino having up to 2 carbon atoms, dialkylamino having in each case up to 2 carbon atoms each Alkyl group, acetylamino or Benzoylatnino, or represents cc, ß- or v-pyridyl,

and their physiologically acceptable salts,

The compounds of the general formula (1) according to the invention,

in which

R * - R ° have the abovementioned meaning, 2Q is obtained by reacting

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[A] aldehydes of the general formula (II)

R ⁴

^CH0 in which

R ³ , R ⁴ and R ^{5 have} the meaning given above »

and ^ -ketocarboxylic acid esters of the general formula (III)

R ² OOC 20

a.

in which

R ¹ and R ^{2 have} the abovementioned meaning, 25 with β-ketocarboxamides of the general formula (IV)

/ R ⁶ (IV) ^ 8

in which

R * R and R are as defined above «

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and ammonia »optionally in the presence of inert solvents reacted.

or by

[B] aldehydes of the general formula (II) with β-ketocarboxylic esters of the general formula (III) and enaminocarboxamides of the general formula (V)

15 H ^ CON

1 _a \ R ⁷ (V) ⁸

in which

R, R 'and R have the meaning given above

20 a 7 R, R '

if appropriate in the presence of inert solvents t

²⁵ · a "

or by

CC] aldehydes of the general formula (II) with & - Ketocarbonsaureamiden of the general formula (IV) and

Enaminocarboxylic esters of general formula (VI) 30

R ² OOCVyXH

Jl (VI)

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in which

R * and R ^ have the meaning given above »

if appropriate in the presence of inert solvents,

or by

[D] ^ -Ketocarboxylic acid esters of the general formula (III) with ammonia and ylidene-.beta.-ketocarboxamides of the general formula (VII)

r3 / r6 (VII)

in which 25

- ro £ _e Q] _36n have the meaning given,

if appropriate in the presence of inert solvents, the reaction is carried out at t 30

or by

[E] -ketocarboxamides of the general formula (IV)

with ammonia and ylidene-.beta.-ketocarboxylic esters of

general formula (VIII)

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(VIII) 10

in which

R * - R * have the abovementioned meaning, if appropriate in the presence of inert solvents,

or by 20

[F] Yliden-β-ketocarboxamides of the general formula (VII) with enaminocarboxylic esters of the general formula (VI), if appropriate in the presence of inert solvents,

odor by

[G] yliden-.beta.-ketocarboxylic acid ester of the general formula CVIII) with enaminocarboxamides of the general formula (V), if appropriate in the presence of inert solvents,

or by 35

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[H] Dihydropyridine monocarboxylic acids of the general formula (IX)

Wο Www ^^ »» * ^^^^^ w wwfl

(IX)

RlX ^ sNX ^ R ⁰

in which R ¹ - R ⁵ and R ^{8 have} the abovementioned meaning,

optionally via a reactive acid derivative with amines of the general formula (X)

HN (X)

\ ⁷

in which

R ° and R are as defined above «

optionally reacted in the presence of an inert organic 3Q Losemittels.

Examples of reactive acid derivatives which may be mentioned are: activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides or the reaction in the presence of cyclohexylcarbodiimide.

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Depending on the nature of the starting materials used, the synthesis variants for the compounds according to the invention can be represented by the following equation schemes:

CA]

CHO

H ₃ COOOv

-CH ₂ -C ₆ H ₅

/ CO-N (CH ₂ )

H ₃ C

NH-

[B]

H ₃ C00Cv _{> T} / ^> v _r ^ c0N (CH ₃ )

H ₅ C ₂ OOC

CHO

OOCN ₁ HN / CO

H ₃ C ^ ND H ₂ N ^ NCH

-NH-CHO

CCO

S-CH ₂ -C ₆ H ₅

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[C]

[D]

-SO ₂ -C ₆ H ₅

CHO.

HoC '^ Nl ·

/ CO-NH-C ₆ H ₅

₃ C- ^ NH ₂

Η "

ZHC

H ₃ COOC ^ H ^^ Y ^ CO-NH-C ^ s

-CH ₂ -C ₆ H ₅

0-CH ₂ -C ₆ H ₅ CO-NH-C ₂ H ₅

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274 O 2

[E]

NH-

) -NH-C ₃ H ₇

[F]

H ₇ C ₃ OOC

-CH ₂ -C ₆ H ₅ CO-NH-C ₃ H ₇

0-CH ₂ -C ₆ H ₅

0-CH ₂ -C ₆ H ₅

HgCOOCVyX ^ s ^ CO-NH-C ^

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27 4 0

[G]

'0 -CH ₂ -C ₆ H ₅

10 15 [Η]

-CH ₂ -C ₆ H ₅

H ₃ COOC

-CH ₂ -C ₆ H ₅ CO-N ^ J H-,

HoCOOC

H, C

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Process variants A-G

Suitable solvents are water or all inert organic solvents which do not change under the reaction conditions. These include, preferably, alcohols

IQ, 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 hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine.

The reaction temperatures can be varied within a substantial range. In general, one works between + 10 ⁰ C and +150 ⁰ C, preferably between +20 ⁰ C and +100 ⁰ C. In particular at the boiling temperature of the respective solvent.

The reaction can be carried out at normal pressure, but also at elevated or reduced pressure. In general, one works at atmospheric pressure.

In carrying out process variants A-G according to the invention, the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants. The isolation and purification of the substances according to the invention is preferably carried out in such a way that the solvent is distilled off in vacuo and the optionally crystalline obtained after ice cooling residue from a suitable solvent

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recrystallised · In some cases it may be necessary to purify the compounds according to the invention by chromatography.

The aldehydes of general formula (II) used as starting materials are known or can be prepared by known methods [DOS 21 65 26Oj 24 01 665J TD Harris, 6, P. Roth, J. Org. Chem. Mi 2004 (1979); W.J, Dale, HE Henni, J. Am. Chem. Soc. 7JB, 2543 (1956); Chem, Abstr. 5_9, 13929 (1963)].

15

The ^ -Ketocarbonsäureester used as starting materials

of general formula (III) are known or can be prepared by known methods [D. Corrmann in Houben Weyl's "Methods of Organic Chemistry" Vol. VII / 4, 2Q 230 (1968); Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org <Chem. 43, 2087 (1978)].

The ^ -Ketocarbonsäureamide used as starting materials of the general formula (IV) are known or can be prepared by known methods [DOS 11 42 859].

The enaminocarboxylic acid amides of the general formula (V) used as starting materials are known or can be prepared by known methods [DOS 2 228

^377] «

The enaminocarboxylic acid esters of general formula (VI) used as outer ingredients are known or can be prepared by known methods [F, A. Clickman, g ₅ AC Cope, 3, Am «Chem. Soc. 6J7, 1017 (1945)].

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The yliden-.beta.-ketocarboxamides of the general formula (VII) used as starting materials and the ylidene-.beta.-ketocarboxylic acid esters of the general formula (VIII) used as starting materials are known or can be prepared by known methods [G. Jones "The Knoevenagel Condensation" in Organic Reactions Vol. XV, 204 (1967)],

The implementation of process variant H according to the invention is based on the literature-known methodology for the conversion of carboxylic acids into carboxylic acid amides. The carboxylic acid is first transformed into an activated form such as e.g. the acid chloride or imidazolide, which are either isolated as such and reacted in a second reaction step, or in situ directly to

2Q be amidated compounds erfindungegemäßen. As activating reagents in addition to the inorganic halides such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or the carbonyldiimidazole, carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexy1-3- [2- (N-methyl-morpho1ino) ethyl] carbodiimide p-toluenesulfonate or N-hydroxyphthalimide or N-hydroxy-benzotriazole in the presence of dicyclohexylcarbodiimide exemplified. Naturally, the dihydropyridine monocarboxylic acids can also be used in the form of their salts. [The method

3Q dik of amidation is exemplified by 'Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & 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); W.A, Bonner,

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PI McNamee, J. Org. Chem. 26, 254 (1961); HA Staab, Angew. Chemistry Int. Ed. 1, 351 (1962); Fieser & Fieser, Reagents for Organic Synthesis, John Wiley £ Sons Inc. 1967 , 116, 114; HC Beyerman, UO van der Brink, Re. Trav, 8_0, 1372 (1961); CA. Buehler, DE Pearson, John Wiley Sons, Volume I (1970), page 895 ff, Volume II, (1977)].

Suitable solvents for process variant H are, in addition to water, all inert organic solvents which do not change under the reaction conditions. These include preferably ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or halogenated hydrocarbons, such as dichloromethane, trichloromethane or tetrachloromethane, or amides, ie dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons, such as benzene, toluene or xylene, or acetonitrile, nitromethane, pyridine It is also possible to use mixtures of the solvents mentioned above If the activated intermediates of the dihydropyridine monocarboxylic acids are isolated, the amines of the formula (X) can also be used alone as diluent.

The reaction temperatures can be varied within a wide range. In general, one works in a range from -70 ⁰ C to + 140 ⁰ C, preferably from -20 ° C to + 100 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated or reduced pressure. In general, one works at atmospheric pressure.

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When carrying out process variant H according to the invention, the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants · However, it has proven to be beneficial to use the amine in a 5- to 10-fold molar excess. Particularly expedient, the amine is used in a large excess directly as a solvent.

The Dihydropyridinmonocarbonsäuren the general formula (IX) used as starting materials are known or can be prepared by known methods [DOS 2,847,236; 3,206,671; 2,962,241].

The amines of the general formula (X) used as starting materials are known or can be prepared by known methods [Houben Weyl'β "Methods of Organic Chemistry" Bd XI / 1; Pauleen, Angewandte Chemie 7JJ, 501-566 (1966)].

The compounds according to the invention show an unpredictable "valuable spectrum of pharmacological action. They influence the contraction force of the heart, smooth muscle tone and the electrolyte and fluid balance.

They can therefore be used in medicines for the treatment of

pathologically altered blood pressure and heart failure, as well as used as coronary therapeutics.

In addition, they can be used for the treatment of cardiac arrhythmias, renal insufficiency, cirrhosis of the liver, ascites, pulmonary edema, brain edema, pregnancy edema, gloukoma or diabetes mellitus.

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The cardiac activity of the compounds according to the invention was found on isolated, stimulated Papi1 iglmuskel dee the guinea pig heart · For this, the experimental animals (200 g guinea pigs of both sexes) were killed, opened the thorax and the heart removed. For the experiments, the smallest possible papillary arms were then removed from the right ventricle and fixed horizontally in an Orran bath. One end of the muscle was held by two metal electrodes, which simultaneously stimulated the preparation, while the other end of the muscle was connected to a force transducer via a thread. The papillary muscle was irritated at a frequency of 1 Hz. The organ bath, approximately 2 ml in volume, was continuously treated with Krebs-Henseleit solution (concentration in NaCl 118, NaCO ₃ , KCl 10, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 1.8, glucose 10) , pH 7.4) at a rate of 4 ml / min at a temperature of 32 ° C. The contractions of the papillary muscle were measured isometrically via the connected force transducer and recorded on a recorder.

The substances according to the invention were dissolved in the Krebs-Henseleit solution at a concentration of 10 μg / ml, optionally with a solubilizer (DMSO up to a concentration of 0.5%). The dihydropyridircarbonamides according to the invention showed an inhibition of the contraction force of the papillary muscle by more than 10% relative to the control values.

The new active substances can be converted in a conventional manner into the usual formulations, such as tablets,

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274024

g dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. In this case, the therapeutically active compound in each case in a concentration of about 0.5 to jQ 90 wt .-Ji of the total mixture, ie in amounts sufficient to achieve the stated dosage margin.

The formulas are prepared, for example, by suspending the active ingredients with solvents and / or

Excipients, optionally using emulsifiers and / or dispersants, e.g. in the case of using water as a diluent, organic solvents may optionally be used as the auxiliary solvent.

Examples of adjuvants include: water, non-toxic organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g.

Peanut / sosame oil), alcohols (eg ethyl alcohol, glycerol),

Carriers, such as e.g. natural rock powders (eg kaolins, clays, talc, chalk), ground synthetic minerals (eg highly siliceous silicic acid, silicates), sugars (eg pipe, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, Alkyl sulfonates, aryl sulfonates), detergents (eg lignin, liquors liquors, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate),

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The application is carried out in the usual way "preferably orally or parenterally" in particular perlingually or intravenously. In the case of oral administration, tablets may of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium, in addition to the said carriers.

IQ phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various Geschmacksaufbesserem or dyes.

In the case of parenteral administration, solutions of the active substances using appropriate liquid carrier materials may be used «

In general, it has proved to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results when administered intravenously, and for oral administration, the dosage is about 0 _f 01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or mode of administration, individual behavior towards the drug, the nature of its formulation and the time or interval at which it is administered he follows. So it can be in some

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274 02 $

In the event of a fall, it shall be sufficient to pay for it with less than the said minimum quantity, while in other cases the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute them in several single doses throughout the day.

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embodiments

Rr values: DC aluminum foil Merck, layer thickness 0.2 mm, silica gel 60 F 254? Flow agent toluene / ethyl acetate in the volume ratio 1: 2

example 1

4- (2 ~ benzyloxy-phenyl) -l, 4 ~ dihydro-2, G-dimethyl-pyridin-3-carbonsäuremethylester-5-carboxylic acid dimethylamide

H ₃ CCOC ^%

^H 3 ^C

Process variant A

2.12 g (10 mmol) of 2-benzyloxybenzaldehyde are boiled with 1.16 g (10 mmol) of methyl acetoacetate, 1.29 g of acetoacetic acid dimethylamide and 1 ml of ammonia for 18 hours, and the mixture is cooled and concentrated. The evaporation residue is taken up in ethyl acetate, washed twice with water, dried and concentrated. It is purified over a silica gel column with toluene / ethyl acetate mixtures. The pure fractions are collected and concentrated. The product crystallized on trituration with ether / ethyl acetate 10: 1 «0.8 g (19 % of theory) of colorless crystals of mp, 162 163 ⁰ C,

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27 ^ 02 *

5 Process variant E

2 g (6.45 mmol) of 2-benzyloxy-benzylidene-acetoacetic acid methyl ester are added to 0.83 g (6.45 mmol) of acetylacetic acid dimethylamide and 0.53 ml of ammonia for 18 hours to yield ^. heated up. It was cooled ¹ and concentrated. The evaporation residue is taken up in ethyl acetate, shaken twice with water, dried and concentrated. The product mixture is purified on a silica gel column with a toluene / Eesigester mixture. The clean fractions are pooled and concentrated. The product crystallizes on trituration with ether and little eeigeeter. It is sucked off. This gives 0.6 g (22.9% of theory) of a colorless substance of mp. 163-165 ⁰ C, Rf value = 0.118

Example 2

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethy1-pyridine-3-carboxylic acid ^ thy1ester-5-carboxylic acid phenylamide

H-jCOOC

H, C

Process variant G

3.1 g (10 mmol) of methyl 2-benzyloxybenzylideneacetate are boiled in 20 ml of ethanol with 1.76 g (10 mmol) of β-aminocrotonic acid benzamide for 3 hours. It is canceled

Le A 25 087

27402 *

- 32 -

Cooled and concentrated. "The solid evaporation residue is stirred with ether, filtered with suction and recrystallized from acetonitrile. 2.4 g is obtained (51,3V of theory.) Of colorless crystals of melting ": 194 ⁰ C.

Example 3

4- (2-Benzyloxyphenyl) -1,3-dihydro-1'-dimethylcarboxylic acid methyl ester 5-carboxylic acid cyclopropylamide

H ₃ COOC

Process variant H

20 g (45.14 mmol) of 4- (2-benzyloxy-phenyl) -1,4-dihydro-2,6-dimethy1-pyridine-3-carboxylic acid ^ thy1ester-5-carboxylic acid imidazolide be in 130 ml of abs. Dissolved dimethylformamide with 5.63 ml (80.1 mmol) of cyclopropylamine and stirred under argon at 90-100 ⁰ C for 20 hours. It is cooled and concentrated. The evaporation residue is taken up in Eseigester, washed with water, IN hydrochloric acid, water, sodium bicarbonate solution and again with water, dried and concentrated. The evaporation residue is stirred with toluene, filtered off with suction and washed with toluene. Recrystallization from about 60 ml of toluene gives 14.95 g (76.7 "of theory) of colorless crystals.

M .: 191 - 193 ⁰ C '.

Le A 25 087

\) V. J

27402a

Example 4

l, 4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl-3-pyridylcarboxylate-methylene-5-carboxylic acid amide

10 15

H ₃ COOC

3.5 g (6.8 mmol) of 1,4-dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl-pyridine-S-carboxylic acid methyl ester-5-carboxylic acid imidazolide (obtained from Dihydro-?, 6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) -phenyl-pyridine-s-dicarboxylic acid monomethyl ester by reaction with carbonylbisimidazole in tetrahydrofuran). Were stirred without further purification with 40 ml of methylamine solution (40%) overnight. The precipitated product is filtered off and washed well with water. Ee is dried and recrystallized from a little toluene. This gives 1.3 g (40.3X of theory) of a colorless product. Mp .: 156 - 157 ° C

Analogously to Examples 1 to 4 were prepared: Example 5

Ethyl l, 4-dihydro-2,6-dimethyl-4- [2- (3-methylbenzyloxy) phenyl] pyridine-S-carboxylate-S-carboxylic acid cyclopropylamide

Le A 25 087

- 34 -

10

Schmp.S 176 ⁰ C

H ₃ COOC

Example 6

Methyl 4- [2- (4-chloro-benzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-S-carboxylate-S-carboxylic acid cyclopropylamide

20 25

H ₃ COOC

Schmp.i 178 ⁰ C

Example 7

4-C2- (4-chloro-benzyloxy) -phenyl] -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester 5-carboxylic acid (2-pyridyl) -amide 35

Le A 2S 087

  j. '

- 35 -

H ₃ COOC

-CH

CO-NH - <_)>

Schmp.i 201-204 ⁰ C

Example 8

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridin-3-carbonsauremethylester-S-carboxylic acid (2-pyridyl) amide

HoCOOC

M.p. 5 164 - 165 ⁰ C

Example 9

4- [2- (4-chloro-ben2yloxy) phenyl3-1,4-dihydro-2, 6-dimethylpyridine-3-carbonsäuremethylester-5-carboxylic acid (2-diethyl · amino-ethyl) amide

Le A 25

- 36 -

27402s

HoCOOC

Schmp.: From BO ⁰ C example

4- (2-Benzyl-oxy-phenyl) -l, 4-dihydro-2 _# 6-dimethyl-pyridine-3 · carboxylic acid methyl ester-5-carboxylic acid (2-diethyl-aminoethyl) -amide

CH.

/ C ₂ H ₅ - (CH ₂ J ₂ -N

\ C ₂ H ₅

Mp. S from 95 ° C

example

4- (2-Benzyloxy-phenyl) -l _f 4-dihydro-2,6-dimethyl-pyridin-3-carbonsaurernethylester-5-carboxylic acid (4-carbamoyl-phenyl) amide ·

Le A 25

, 7 ..! '-. :. (. ''

- 37 -

27,402.5

H ₃ COOC HoC

M.p .:> 300 ° C

example

4- (2-Benzyloxyphenyl) -1-methylcarboxylate-S-carboxylic acid (4-acetylamino-phenyl) -amide

NH-CO-CH ₃

M.p .: 29B ⁰ C decomposition

30 example

4- (2-Benzyloxy-phenyl) -l _# 4-dihydΓo-2 # 6-dimethyl-3-pyΓidin carbonsäuromethy1euter-5-carboxylic acid (4-benzoylaminophenyl) amide 35

Le A 25

20

2740 * 6

- 38 -

H ₃ COOC

NH-C

M.p .: 197 ⁰ C

Example 14

(R, S) -4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2, 6-dimethy1-pyridin-3-carbonsauremethylester-5-carboxylic acid (1-phenyl · ethyl) amide (RS mixture )

M. Ί from 162 ⁰ C onwards

0-CH ₂

(R ₁ S) / = \ CO-NH-CH- ( ^ ρ

H ₃ COOC

Example 15

(R) -4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethy1-pyri din-S-· carbonsauremethylester-S-cerboneäure- (1-phenylethyDamid (R-form) 35

Le A 25 087

- 39 -

M .: 82 ⁰ C

example

HoCOO

CH.

(R) CO-NH-CH-

4- (2-Benzyloxy-phenyl) -1-dicarboxylic acid ^ -theterylene-5-carboxylic acid- (3-dimethylamino-propyl) -amide

H ₃ COOC

-CH-

/ CH ₃ CO-NH- (CHo) ₃ -N

M.p. 89-90 ° C

example

4- (2-Benzyloxy-phenyl) -l, A carboxylic acid methyl ester-5-carboxylic acid cyclohexylamide

Le A 25

27402 *

- 40 -

CH.

HnCOOC

CO-NR

App. J 108 - Ul ⁰ C

example

4 - (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethy1-pyridine-3 · carboxylic acid ethylter-5-carboxylic acid tert -butyl amide

M.p .: 148 ⁰ C

-CH-

CH ₃

I ³

) -NH-C-CH ₃ I ₃ CH ₃

example

4- (2-benzyl oxy-phenyl) -l _# 4-dihydro-2,6-dimethyl-pyridin-3-carbonsauremethylester-5-carbonsaurepropylamid

Le A 25

- 41 -

Foam R _f = 0.37

example

~ CH ·

H ₃ COOCV _T ^ ^V NX'CO-NH-CH ₂ -CH ₂ -CH 3

4- (2-Benzyloxyphenyl) -l ^

carbonsäuremethylester-5-carboxylic acid (2-methyl-propyl)

amide

-CH-

HoCOOC

HoC

C0-NH-CH ₂ -CH (CH ₃₎ 2 H ₃

Schmp.i 134 ⁰ C

example

4- (2-Benzyloxy-phenyl) -l, 4-dihydΓo-2 _# 6-dimethyl-3-pyΓidin · caΓbonBäuΓemet.hyleεter-5-carbonBβuΓe-N · benzyl-N-teΓt, bu-35 tylamid

Le A 25

- 42 -

HoCOOC

Mp 128 ⁰ C

-CH

CO N-CH ₂

H ₃ C (CHg) ₃

example

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

-CH

! 105 ° H ₃ C00C C [fil / CO-NH-CH el 23 H ₃ C> H ¹ VCH ₃ mp, BeisDi

4- (2-Benzyloxyphenyl) -1-carboxylic acid ethyl ester 5-carboxylic acid ethylamide

Le A 25

¹ J w> .. ',

- 43 -

274

-CH-

H ₃ ^COOC> N _r X ^'v N _r ^ CO-NH-CH ₂ -CH ₃

Mp.! 172 ⁰ C example

1,4-Dihydro-2 _# 6-dimethyl-4-t2- (2-pyridyl) meihoxy-phenyl] pyridine-3-carboxylic acid butyryl-S-carboxylic acid cyclopropylamide

-CH-

Η ₉ σ ₄ ΟΟϋΝγ ^ \ ^ 00-ΝΗ N '^ CHr

<3

Foam R _f = 0.1

example

1 _# 4-Dihydro-2: 6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-S-carboxylic acid butyl ester S-carbonic acid methylamide

Le A 25

- 44 -

27402s

Foam R _f = 0.07

example

1,4-Dihydro-2,6-dimethy1-4 - [2- (2-pyridyl) methoxyphenyl] pyridine-3-carboxylic acid butyl ester 5-carboxylic acid (i-methylpropyl) -amide

CO-NH-CH-CHo-CH

Foam R _f = 0.25

3Q example

4- [2- (3,4-Dichloro-benzyloxy) -phenyl 3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid] thy1-ester-5-carboxylic acid anepropylamide

Le A 25

- 45 -

27402 *

10

Schinp ,! 195 ⁰ C

Cl

20 25

28

4- [2- (2,6-dichloro-benzyloxy) -phenyl] -l, 4-dihydro-2,6-dimethy1-pyridine-3-carboxylic acid ^ thyese-5-carboxylic acid cyclopropylamide

Cl

H ₃ COOC

M.p .: 178 ⁰ C

Example 29

4- [2- (2,6-dichloro-benzyloxy) -phenyl] j-1 _# 4 = dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ^ thy 1-ester-5-carboxylic acid · (1-methyl-propyl-vanadium 35

Le A 25 087

- 46 -

$ 27,402

Foam R _f = 0.36

Cl

-CH-

H ₃ COOCV / \ / CO-NH-CH-CH, -CH '

Cl C]

CH ₃

example

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ^ thylester-5-carbon-acid-methyl-amide

-CH

Cl CO-NH-CH ₃

H ₃ COOC

M.p .: 133 ° C

at

31

4- [2- (3,4-Dichloro-benzyloxy) phenyl] -l, 4-dihydro-2,6-dimethyl-pyridin-S-S-carboxylic acid carbonBäuremethylester

Le A 25

7 /,

- 47 -

Cl

H ₃ COOC

Mp 120 ⁰ C

Example 32

4- [2- (3-Fluoro-benzyl-oxy) -3-methoxy-phenyl-1,3,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ethyl 5-carbon-βauraeye-1-propyl-amide

H ₃ COOC

Mp. '. 202 ° C

Example 33

4- [2- (2-Chloro-benzyloxy) -phenyl] -l, 4-dihydro-2,6-dimethylpyridine-3-carboxylic acid methyl ester-5-carboxylic acid cyclopropyl amide

Le A 25 087

- 48 -

2740 * $

Cl

185 ° C H ₃ COOC 34 H ₃ C mp .: BeisDiel

4- [2- (2-chloro-benzyloxy) phenyl? -L _# 4-dihydro-2, FC-di-pyridin-S-S-carboxylic acid carbonBäuremethylester

Cl

H ₃ COOC

Mp.! 170 ⁰ C

example

4-t 2 - (3-Fluoro-benzyloxy) -3-methoxy-phenyl-3-l # 4-dihydro-2,6-dimethyl-pyridine-S-carboxylic acid methyl ester-D-carboxylic acid (2-methyl-propyl) -amide

Le λ 25

/ '·

- 49 -

OCH ₃ F

-CH _:

H ₃ s C00C ^N _r / \ _T ^ 'C0-NH-CH ₂ -CH (CHg) ₂ H ₃ C ^ "rc" ^ n ₃

Mp 98 ⁰ C

15 Example 36

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3-carboxylic acid ethyl ester-5-carboxylic acid eye lopropyl amide

M.p .: 148 ⁰ C

30 Example 37

1 _t 4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-1-benzyl-oxy) -phenyl] -pyridine-3-carboxylate-5-carboxylic acid - (1-methyl-propyl) -amide 35

Le A 25 087

- 50 -

20 25 30

HoCOOC

H, C

10

Foam R _f = 0.44

Example 38

4- [2- (3-Fluoro-benzyloxy) -3-methoxyphenyl 3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ethyl 5-carboxylic acid isopropylamide

H ₃ COOC H ₃ C

OCH,

-CH-

CO-NH-CH (CH ₃ ) ₂

 CH,

35

Mp 106 ⁰ C

At game 39

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methyl-benzyloxy) -phenyl-3-pyridine-S-carboxylic acid-d-methyl-propyl) -ester-5-carboxylic acid cyclopropylamide

Le A 25 087

- 51 -

274024

HNC HC-OOC

³ I

Foam R _f 8 0.31

example

4- (4-benzyloxyphenyl) -l ^

carbonsauremethyl it ter-5-carboxylic acid cyclopropylamide

H ₃ C

H ₃ COOC V _r ^ v ^ CO - NH <] ^ N ^ _CH3

Mp.! 197 ⁰ C.

example

1,4-Dihydro-2,6-dimethyl-4-t 2 - (4-methyl-benzyloxy) -phenyl] -pyridine-3-carboxylic acid (1-methyl-propyl) -ester-5-carboxylic acid- (1-methyl- propyl) amide

Le A 25

- 52 -

274025

H ₁ C-CH-OOC

C-How "3" '

»H ₃ CHo ^- CH ₃

Mp 126 ⁰ C

example

1,4-Dihydro-2,6-dimethyl-4-C2- (4-methyl-benzyloxy) -phenyl] -pyridine-3-carboxylic acid (1-methyl-propyl) ether-5-carboxylic acid methylamide

H ₃ C-CH-OOC

H ₃ C

Foam R _f = 0.48

example

1,4-dihydro-2,6-dimethyl-4- [2- (3-nitro-benzyloxy) phenyl] -pyridine-d-carboneäureethyleeter-S-carbonsäurecycloprcipylamid

Le A 25

- 53 -

27 ^ 0 26

H ₅ C ₂ OOC

Foam R _f * 0.24

Bei 15 p iel 44

4 "* (4-benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester S-carboxylic acid propylamide

0-CH ₂

# H ₃ COOC 210 ⁰ C el H ₃ C 45 Mp. Ββίερϊ

CO-NH-CH ₂ -CH ₂ -CH ₃ 3

(F) -4- [2- (4-Fluoro-benzyloxy) phenyl-1,3-l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ethyl ester-5-carboxylic acid (1-phenyl-ethyl) -amide (R. '-Shape)

Le A 25 087

- 54 -

Foam Rf = 0.56

Example 46

H ₅ C ₂ OOC HoC

CH-

4- (4-Benzyloxy-phenyl) -l, 4-dihydro-2 | 6-dimethyl-pyridin-3-carbons3uremethyl8ster-5-carboxylic acid (2-methyl-propyl) -amide

HoCOOC

CO-NH-CH ₂ -CH (CH ₃ ) ₂ 3

Schmp.S 202 ⁰ C

Example 47

4- [2- (4-fluoro-benzyloxy) -phenyl] -l _# 4-dihydro-2,6-dimethyl p} rridin-3-carbonEaureethyleBter-5-carbon6aurecyclopropyl · amide

Le A g * 087

- / k H ' r ' ¹ Uo

- 55 -

274 02 $

Schmp.S! 59 ⁰ C

Example 48

4- [2- (4-Fluoro-benzyloxy) phenyl] -l, 4-dihydro-2,6-dimethylpyridine-S-S-carbonsauremethylester-carbonsaurecyclopropyl ·

amide

154 ° C H ₃ COOC 49 H ₃ C Mp.! example

(S) -4- (4-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethylpyridine-3-carboxylic acid methyl ester 5-carboxylic acid (1-phenylethyl) amide (S-form)

Le A 25 087

27402s

- 56 -

O-CH.

HoCOOC

(S) / Cu-NH-CH-CH ₃

Schmp.S 141 ⁰ C

Example 50

4- (4-Benzyloxy-phenyl) -l _# 4-dihydro-2,6-dimethyl ^< 'pyridin-3-carbonsäuremethylester-5-carboxylic acid isopropylamide

O-CH

M ₃ COOC

CO-NH-CH (CH ₃ ) _?

Schmp.S 162 ⁰ C

Example 51

(R) -4- (4-benzyl oxy-phenyl) -l, 4-dihydro- 2, 6-dimethy1-pyridin-S-S-carboxylic acid-carbonsäurerr.ethylester-d ·-phenyl ethyl) -amide (R form , Diastereomeros A)

Le A 25 087

- 57 -

$ 27,402

-CH-

H ₃ COOC

(R) CO-NH-CH

H »> C

Mp 196 ⁰ C

Example 5 2

1-C2- (3-Chloro-benzyloxy) -phenyl3-l, 4-dihydro-2,6-dimethylpyridine-3-carboxylic acid ^ thy1ester-5-carboxylic acid cyclopropyl amide

H ₃ COOC

M.p .: 174 ⁰ C

Example 53

4-C2- (4-fluoro-benzylthio) -phenyl] -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester-5-carboxylic acid cyclopropylamide

Le A 25 087

- 58 -

H ₃ COOC

Mp. S 202 ° C

example

(R) -4- (4-Benzyloxy-phenyl) -1-pyridine-S-carboxylic acid, methyl ester-S-carboxylic acid (1-phenyl-ethyl) -amide (R-Forro) (Diastereomer B)

0-CH ₂

H ₃ COOC

(R) CO-NH-CH

H ₃ CH ₃

M.p .: 202 ⁰ C

Le A 25

- 59 -

Example 55

(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethy1-pyridine-S-carboxylic acid methyl ester S-carboxylic acid (1-phenylethyl) amide (R-form, mixture of diastereomers )

0-CH ₂

H ₃ COOC

Schmp.: IJO - 166 ⁰ C

Example 56

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

M.p .: 172 ⁰ C

H-jCOOC

Le A 25 087

- 60 -

Unit,

Example 57

(S) -4- (2-Benzyloxy-phenyl) -?, 4-dihydro-2,6-dimethy1-pyridine-3-carboxylic acid ethyl 5-carboxylic acid (1-phenyl-ethyl) -amide (S-). Form, diastereomer B)

-CH

N H

-CH-CH

Foam R _f = 0.53

Example 58

(R) -4- [2- (4-Fluoro-benzyloxy) -phenyl3-1,4-dihydro-2,6-dimethyl-1-pyridine-3-methyl-5-carboxylic acid (1-phenylethyl) amide ( R-form)

HoCOOC

Foam = 0.52

Le A 25 087

- 61 -

27402ο

Example 59

1,4-Dihydro "2,6-dimethyl-4- [2- (3-methyl-benzyloxy) phenyl] -pyridin-S-S-carbonsaurebutylester-carbonsaurecyclopropyl-

amide

H ₉ C ₄ OOC

Foam R _f = 0.31

Example 60

(R) -I, 4-Dihydro-2,6-dimethyl-4- [2- (3-methyl-benzyloxy) -phenyl-pyridine-S-carboxylic acid butyl ester-S-carboxylic acid (1-phenyl-ethyl) -amide ( R-form)

CH,

H ₉ C ₄ OOC

oil

= 0.88

Le A 25 087

- 62 -

27402 *

Example fcl

(R) -4- [2- (3-Chloro-benzyloxy) phenyl] -l, 4-dihydro-2 _# 6-dimethyl-pyridine-3-carboxylic acid, methyl ester-5-carboxylic acid · {1-phenyl-ethyl) -amide (R -Shape)

Cl

H ₃ COOC

CHr

Foam R _f = 0.73

Example 62

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

H ₃ COOC

CH-

M.p. 5 from 143 ⁰ C

Le A 25 087

j -

- 63 -

Example 63

Methyl 4- (3-benzyloxyphenyl) -1-> 4-dihydro-2,6-dimethylpyridine-3 · carboxylic acid isopropyl acetate

H ₃ COOC

Mp.5 144 ⁰ C

Example 64

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

Foam R _f = 0.47

Le A 25 0B7

- 64 -

₅ Example 65

dimethylpyridine-S-carbonyl-methylester-S-carboxylic acid · (1-phenyl-ethyl) -amide (S-form)

S-CH ₂ '

(S) CO-NH-CH-CH ₃

Foam R _f = 0.48

Example 6ft

4-L2- (4-fluoro-benzylthio) phenyl] -l, 4-dihydro-2,6-dimethyl-. pyridine -carboxylic acid methyl ester-S-carbonsaurealiyl amide

M.p .: 177 ⁰ C

Le A 25 087

- 65 -

274 O

example

4- (2-Benzyl oxy · phenyl) -1, 4-dihydro-2,6-dimethyl-pyridin-3-carbonsäuremethylester-5-amide carboneäurealIyI

CH.

CO-NH-CH ₂ -CH = CH ₂

HoCOOC

Schmp.i 148 ⁰ C

example

(R) -4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2, 6-dimethy1-pyridin-3-carboxylic acids-5-^ thy1ester carbonsaure- (1-phenyl ·

ethyl) amide (R-form)

-CH

HoCOOC

HoC

(R) C

CO-NH-CH-> j > H

Mp 175 ⁰ C

Le A 25

CV, XY 'J

- 66 -

Example 69

(R) -4- (2-benzyl oxy-phenyl) -l, 4-dihydro- 2, 6-dimethy1-pyrid in -? - carbonsäuremethylester-5-carboxylic acid (1-phenyl · ethyl) amide (R-form ₄ diesteromer B)

H ₃ COOC

Schmp.S 169 ⁰ C

CH-

Example 70

4- (2-Benzyloxy-phenyl) -l, 4-dihydro- _2f- 6-dimethyl-pyridine-3-carboxylic acid methylbter-S-carbonic acid (2-phenyl-ethyl) -amide

oil

H ₃ COOC

Le A 25 087

CO-NH-CH ₅ -CH-

$ 27,402

example 71

4- (2-benzyloxy-phenyl) -1 _# 4-dihydro-2 _# 6-dimethyl-pyridin-3 x ^ carboxylic acids methyl ester-5-carbonsäurebenzy! Amide

CH.

HoCOOC

CO-NH-CH ₂

App. Ί 148 - 149 ⁰ C

Example 72

4- [2- (4-fluoro-benzylthi o) phenyl 3-1, 4-dihydro -.?, 6-dimethyl · pyridin-S-S-carboxylic acid ethylamide carbonßäuremethylester-

H ₃ COOC

CO-NH-CH ₂ -CH ₃

Schmp, ί 202 - 204 ° C

Le A 25 0B7

' 4 li.v ::'.) · -) ···

- 68 -

example

4- (3-Benzyloxy-phenyl) -l, 4-dihydro-2 _# 6-dimethyl »pyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethylamide

0-CH

H ₃ COOCN _T / \ ^ CO-NH-CH ₂ -CH ₃

M.p .: 152 - 154 ⁰ C

example

4- (4-Benzyl-oxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester-5-carbonoic acid ethylamide

O-CH '

H ₃ COOC H ₃ C

CO-NH-CH ₂ -CH ₃ H ₃

Mp S 183 - 185 ⁰ C

Le A 25

J v.- ¹

- 69 -

$ 27,402

Example 75

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,0-dimethyl-pyrcarboxylic acid methyl & ter-S-CBronsäure

-CH-

CO-NH-

M.p .: 188 ⁰ C

Example 76

Ar- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester 5-carboxylic acid diethylamide

CH.

H ₃ COOC

CO-N (C ₂ H ₅ J ₂

M.p .: 135 ⁰ C

Le A 25 087

- 70 -

274025

example 77

1,4-Dihydro-2,6-d> -methyl-4- [2- (4-methyl-phenyl-onefyloxy) -phenyl D-pyridine-S-carboxylic acid-methylester-S-carboxylic acid recyclopropylamide

H ₃ COOC

Schmp! 238-242 ° C

Example 78

1,4-Dihydro-2,6-dimethy1-4-C2- (4-methyl-phenylsulfonyloxy) -phenyl-pyridine-S-carbonic acid methyl ester-S-carboxylic acid ethylamide

HoCOOC

H .C

M .: 228 ⁰ C

Le A 25 087

- 71 -

$ 27,402

5 example

4- [2- (2,6-dichloro-benzyloxy) -phenyl] -l, 4-dihydro-2- »6-dimethyl-pyridine-3-carboxylic acid ^ thy-ester-5-carboxylic acid

ethylamide

H ₃ COOC

Schmp. S 174 - 176 ⁰ C

Cl

CH.

Cl is CO-NH-CH ₂ -CH ₃

H,

example

4- [2- (3,4-Dichloro-benzyloxy) phenyl] -l, 4-dihydro-2,6-ciimethy1-pyridin-3-carbonsäuremethy1ester-5-carboxylic acid ethylamide

H ₃ COOC

M.p .: 178 - 180 ⁰ C

CO-NH-CH ₂ -CH ₃ H,

Le A 25

- 72 -

274

example

1 ₍ 4-Dihydro-2,6-dimethy1-4-t2- (2-pyridylmethoxy) phenyl) -pyridine-S-carboxylic acid methyl ester S-carboxylic acid ethylamide

HoCOOC

M.p .: 159 - 161 ⁰ C

O-CH

CO-NH-C ₂ H ₅

example

1, 4-Dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyl) oxy) phenyl] pyridine-S-carboxylic acid ethyl ester-S-carboxylic acid cyclopropyl

diisopropylamide

H ₃ COOC

Mp ί 168 · - 170 ⁰ C

Le A 25

- 73 -

Beipsiel

1,4-dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxy-phenyl) -pyridine-S-carboxylic & Duremethylester-S-cerbonsäuremethylamid

HoCOOC

M.p .: 171 - 173 ⁰ C

example

1-.4-dihydro-2,6-dimethyl-4- (2-phenylbonyloxy-phenyl) pyridine-3-carboxylic acid ethyl ester 5-carboxylic acid ethylamide

H ₃ COOC

CO-NH-C ₂ H ₅

Schmp. S 188 - 190 ⁰ C

Le A 25

- 74 -

27

Example 85

1,4-dihydro-4- [2- (4-fluoro-benzyloxy) -phenyl] -2, 6-dimethyl · pyridine-3-carboxylate-5-carbonsaureethylamid

M.p .: 147 - 149 ⁰ C

Example B6

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

H ₃ COOC

Mp.! Ill - 113 ⁰ C

Le A 25 087

- 75 -

5 example

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3-carboxylic acid ethyl 5-carboxylic acid amide

0-SO ₂ -CO-NH-CH ₂ -CH = CH ₂

M.p .: 154 - 156 ⁰ C

example

114-Dihydro-2,6-dimethy1-4- (2-phenyl-sulfonyl-oxy-phenyl) -pyridine-3-carboxylic acid etheryl-5-carboxylic acid- (4-pyridyl) -amide

₂ - ^ ^ N

H ^ C ^^ N - ^^ CH-, ³ H

Mp .: from 240 ° C (decomposition)

Le A 25

- 76 -

274025

example

4- [2- (4-Chloro-benzyloxy) -phenyl3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid-n-ethyl-5-carboxylic acid amide

-CH-

CO-NH-CH ₂ -CH = CH ₂

0 / ι

Mp.! 145 ⁰ C example

4- (3-Benzyloxyphenyl) -l, 4-dihydro-2 _# 6-dimethyl-pyridine-3-carboxylic acid lithium amide-5-carboxylic acid allylamide

M.p .: 95 - 98 ° C

Le A 25

- 77 -

$ 27,402

example

1,4-Dihydro-2,6-dimethy1-4- [2- (4-methylphenyl) sulfonyloxy-biphenyllpyridine-S-carboxylic acid methyl ester-S -carbonsau reallylamid

H ₃ COOC

CO-NH-CHd-CH = CH

Mp i 168 - 170 ⁰ C

example

4- [2- (2,6-dichloro-benzyloxy) phenyl] -l, 4-dihydro-2,6-dimethyl-pyridin-3-carbonsauremethylester-5-carbonsäureallylamid

HoC = HC-H ₂ C-HN-OC

Cl

H ₃ C

Schmp! 132 - 134 ⁰ C

Le A 25

274 O U

- 78 -

example

4- (2-Benzyl-oxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester-5-carboxylic acid (2-hydroxyethyl) -amide

H ₃ COOC

-CH;

CO-NH-CH ₂ -CH ₂ -OH 3

Schmp! 148 -150 ⁰ C

example

4- [2- (3-fluoro-benzyl oxy) -3-methoxy-phenyl] -l14-dihydro 2, 6-dimethyl-pyridine-3-carboxylic acids it thy1 ^ ter-5-carboxylic · säurernethy! Amide

H ^ COOC

Schmp! 171 - 173 ⁰ C

Le A 25

J · / '

27Ί026

Example 95

4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acids; 1-tert-5-carboxylic acid 4- (4-pyridyl) -ethyl-amide

H ₃ COOC

CO-NH-CH ₂ -CH ₂ - ^ ^

mp .:

Example 96

1,4-dihydro-2,6-dimethy1-4-C2- (3-pyridyl) methoxy-phenyl] -pyridin-S-S-carboxylic acid carbonsäuremethylester

H ₃ COOC

M.p .: from 210 ⁰ C

Le A 25 087

- 80 -

271026

Example 97

1,4-Dihydro-2,6-dimethyl-1-4- [2- (3-pyridyl) me, thoxy-phenyl] -pyridine-3-carboxylic acid ^ thylester-5-carboxylic acid ethylamide

10

H ₃ COOC

Size S 122 - 125 ⁰ C

O-CH ₂ -CO-NH-C ₂ H ₅

20 25 30

Example 98

1,4-Dihydro-2 _# 6-dimethyl-4- [2- (4-pyridyl) -methoxy-phenyl] -pyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethylamide

H ₃ COOC

Schmp, 5 95 - 100 ⁰ C

35

Le λ 25 087

- 81 -

27

Example 99

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

H ₃ COOC

Schmp: from 203 ° c (decomposition) Example 100

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2- _t- 6-dimethyl-pyridine-3-carbon s aure thyl-1-tert-carboxylic acid (cyclopropylmethyl) amide

-CH;

H ₃ C

Schmp.5 186 ⁰ C

H ₃ COOC Y ~ YCO-NH-CH ₂ - <3

Le A 25 087

- 82 -

27402 *

example

(+) - 4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethylpyridine-S-S-carbonsäuremethylester-carbonsiureethylamid

CO-NH-CH ₂ -CH ₃

Schmp #

147 ⁰ C '+ 29.68

c = 0.91 (DMF)

example

(-) - 4- (2-Benovinyl-phenyl) -1,4-dihydro-2,6-dimethy1-pyridine-3-carboxylic acid methyl ester 5-carboxylic acid ethylamide

Mp.! 14B ⁰ CC «] 20 = - 29.92

c = 0.805 (DMF)

Le A 2 5

- 83 -

274 0 2 (5

Example 103

4- (2-benzyloxy-phenyl) -1 ^

carboxylic sauree "hylester-5-carbonsauremethylamid

M.p. 179 ⁰ C

²⁰ Example 104

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridin-3-carbonsaureethy1ester-5-carbonsaureethylamid

H ₅ C ₂ OOC

M.p .: 161 - 164 ⁰ C

Le A 25 087

- 84 -

Example 105

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl gives 5-carboxylic acid (.--ethoxycarbonylethyl) amide

R _f = 0.35

HoCOOC

-CH ₂ -CO-NH- (CH ₂ ) ₂ -CO ₂ H ₅

Example 106

4- (2-Benzyloxyphenyl) 1 _# 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester 5-carboxylic acid (ethoxycarbonylmethyl) amide

R _f = 0.408

Le A 25 087

-CH _: CO-NH-CH ₂ -COOC ₂ H ₅

- 85 -

27402s

example

4- (2-Benzyloxyphenyl) -1-

carboxylic acid ethyl 5-carboxylic acid octyl amide

CO-NH- (CH ₂ ) ₇ -CH ₃

0.53

example

4- (2-Benzyl-oxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ethyl 5-carboxylic acid amylamide

R _f = 0.55

-CH

CO-NH- (CH ₂ J ₈ -CH ₃ 3

Le A 25

- 86 -

Beisjpel

4- (2-Benzyloxy-phenyl) -l | 4-dihydro-2,6-dimethyl-pyridin-3-carbonsauremethylester-5-carbonsauredecylamid

-CH ₂ "CO-NH- (CH ₂ ) ₉ -CH ₃

Schmp.S Hl ⁰ C

Example HO

4- (2-benzyloxyphenyl) -l ^ -

carbonsauremethylester-5-carbonsaure- (2-methoxy-ethyl)

amide

HoCOOC

H-aC

0-CH ₂ -

CO-NH-CH ₂ -CH ₂ -OCH ₃ H,

Schmp.i 145 ⁰ C

Le A 25

- 87 -

Example 111

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2 _# f> dimethyl-pyridin-3 · 1 carbonsäureinethy ester-5-carbonsaure- * (3-methoxy-propyl) -amide

R _f = 0.19

H-jCOOC

-CH ₂ "

CO-NH- (CH ₂ ) 3 -OCH ₃ H,

Example 112

(R, R) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2 _# 6-dimethylpyridine-3-carboxylic acid methyl ester-5-carboxylic acid (2-hydroxyl-methyl-2-phenyl) -ethylamide

Le A 25 087

$ 27,402

- 88 -

Process variant H (direct coupling with dicyclohexylcarbodiimide)

1 g (2.54 mmol) of 4- (2-benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid monomethyl ester are dissolved in 5 ml of dimethylformamide and 0.477 g (2 , 54 mmol) of L-norpseudoephedrine hydrochloride, 0.35 ml (2.54 mmol) of triethylamine and 0.629 g (3.05 mmol) of dicyclohexylcarbodiimide (solid). The mixture is stirred for 4 hours at room temperature, the urea is filtered off with suction and the filtrate is concentrated.

Column chromatography: Kieselgel 60, particle size 0.040 -

0.063 mm with CHCl ₁ / CH ₁ OH / NHY 20: 1: 0.05

Since the urea is sparingly soluble in ether and methylene chloride, the product is taken up several times in ether or methylene chloride, filtered off and concentrated. Yield: 0.9 g (67.3% of theory) R _f = 0.35

^ ⁰ : -47.93 (in CHCl ₃ ). '

Le A 25 087

- 89 -

Example 113

10

(S) -4- (2-Benzyloxy-phen; 1) -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid ethyl ester-5-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide

20

-CH-

(5)

H ₃ C00CV _T j ^ ^> s _{; r} xC0-NH-CH-CH ₂ 0H

HoC ^ MK ^ CHo CH-, 3 3

R _f = 0.13

: +7.34 _(CHCl3)

Example 114

(S) -4- (2-Ben-yl-2-yl-phenyl) -l _# 4-dihydro-2 _# 6-dimethyl-pyridine-S-carboxylic acid methyl ester S -carboxylic acid (1-hydroxy-methyl-propyl) -amide

30 35

R _f = 0.15

20

(XJj ": -9.37 (CHCl ₃ )

Le A 25 087

- 90 -

1U026

example

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

HoCOOC

H ₃ C

-CH-

(S) CO-NH-CH-CH ₇ -OH

CH-, CH

R _f =

0.19

-10.8 (CHCl ₃₎

example

(S) -4- (2-Benzyl-oxy-phenyl) -1 , A -dihydro-2 _# 6-dimethyl-pyridine-3-carboxylic acid-1-yl-1-ylcarboxylic acid (1-hydroxy-25-methyl-2-methyl-butyl) -amide

H ₃ COOC

-CH-

(S)

CO-NH-CH-CHO-OH

I

CH

35 R _f = 0.21 / u

: -17.37 (CHCl ₃₎

Le A 25

- 91 -

27402, $

Example 117

4- (2-Benzyloxyphenyl) -1- _t- 4-dihydro-2,6-dimethy1-pyridine-carboxylic acid methyl gives 5-carboxylic acid (3-hydroxypropyl) amide

H ₃ COOC

-CH - <\ 2V '

CO-NH- (CH ₂ J ₃ -OH 3

M .: 205 ⁰ C

Example 118

(-) 4- (2-Benzyloxy-phenyl) -1,4-dihydo-O-2,6-dimethyl-py-3-dinidine-3-cabonone-methyl-esth-5-carbonyl-3-cyclop0-o-pylamide

-CH

H ₃ COOC

O-NH- <]

M.p .: 178 - 181 ° c

[oc] ²⁰ β -38,28 (C = O, 569, chloroform) 589

Le A 25 087

274024

- 92 -

Example 119

(+) 4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-S-carboxylic acid methyl ester-S-carboxylic acid S-cyclopropylamide

H ₃ COOC

M.p .: 178 - 181 ⁰ C

[c.] ²⁰ = + 36.56 (c = 0.52, chloroform) 58V

Example 120

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid residue he-5-carboxylic acid hexyl amide

HgCOOCVj ^ V ^ CO-NH- (CH ₂ ) ₅ -CH ₃ H

HgC * n * ~ 'ling

M.p. 133 ⁰ C

Le A 25 087

- 93 -

Example 12 1

4-C2- (4-Methyl-1-yl-sulfonyloxy) -phenyl 3-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid methyl ester-5-carboxylic acid amide

H ₃ COOC

Schmp.J 205 ⁰ C

Example 122

4- (2-benzyloxy-phenyl) -1> 4-dihydro-2,6-dimethyl-pyridin-Z-carboneäuremethylester-ö-carboxylic acid sec "butylamide

H ₃ COOC

^CH 2 ^CH 3

Schmp: 135 ⁰ C

Le A 25 087

- 94 -

27102 ^

Example 123

4- (2-benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid isopropyl-5-carbonaaureamid

H ₃ C

CHOOC H ₃ C /

H ₃ C

Schmp.J 190 ⁰ C

Example 124

4- (2-benzyloxy-phenyl) -1 _t 4-dihydro- 2, 6-dimethyl-pyridine-5-carboxylic acid (2-methoxy-ethyl) -S-carboxamide

H ₃ COH ₂ CH ₂ C-

Schmp ,: 165 ⁰ C

Le A 25 087

- 95 -

27 * 0

Example 125

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2 "6-dimethyl-pyridin-S-carbonsäuremethylester-S-carboxylic acid bui.ylamid

-CH _; CO-NH- (CHg) ₃ -CH ₃

H ₃ COOC

Schmp,: 144 - 148 ⁰ C

Example 126

4- (2-benzyloxy-phenyl) -1,4-dihydro-2 "6-dimethyl-pyridine-3-carboxylic acid isopropy1ester-5-carboxylic acid ethylamide

H ₃ C

CH-OOC H ₃ C- /

H ₃ C

Mp S 135 ⁰ C

Le A 25 087

- 96 -

Example 127

4- (2-Benzyloxy-phenyl) -l, 4-dihydro-2,6-dimethyl-3-pyΓidin caΓbonsäuΓemethylestθΓ-5-caΓbon8äure- (3-ethoxypropyl} -amide

Schmp.J 115 ⁰ C

Example 128

4- (2-benzyloxy-phenyl) -1 ^ -dihydro-Zio-dimethyl-pyridin-3-carbonsäuremethylester-5-carboxylic acid- (5-hydroxypentyl) -amide

H ₃ C00C ^s s _r; ^ \ _t ^ C0-NH- (CH ₂ ) _& OH

• Ν 'K

M. Ί 178 ⁰ C

Le A 25 OS?

- 97 -

Example 129

4- (2-Benzyloxy-phenyl) -l ^ -dihydro ^ fb-dimethyl-pyridine-3-carboxylic acid (2-methoxy-ethyl) ester-5-carboxylic acid

H ₃ COH ₂ CH ₂ C-OOC

Schmp, ί 133 - 135 ⁰ C

Example 130

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethyl-1-pyridyl-3-carboxylic acid (2-methoxy-ethyl) -J-5-carboxylic acid ethylamide

H ₃ COH ₂ CH ₂ C-OOC

H ₃ C

M .: Hl ⁰ C

Le A 25 087

- 98 -

27402 ^

Example 131

4- (2-Benzyloxy-phenyl) -l, A-dihydro-zje-dimethyl-pyridin-3-carbonsäureisopropy1ester-5-carbonaäuremethylamid

) -CH '

CH-OOCN H ₃ C / I H ₃ C ^ ί year nn / / CO-NH-CH Γ ^ CH ₃

M.p. 5 140 - 143 ⁰ C

Example 132

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethy1-pyridine '1-carboxylic acid isopropyl ester 5-carboxylic acid eye 1-propyl amide

Schmp »: 132 - 135 ⁰ C Le A 25 087

- 99 -

Example 13 3

4- (2-benzyloxy-phenyl) -1> 4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid-.delta.-carboxylic acid isopropylamide

H ₃ C

CH-OOC H ₃ C /

H ₃ C

M.p .: from HO ⁰ C

Le A 25 087

Claims (1)

1. Process for the preparation of dihydropyridine amides of the general formula (I) , 4 R ^ OOC in which R ¹ and R ^{8 are the} same or different and are straight-chain, branched or cyclic alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, cyano, phenyl or halogen, or - are cyano or phenyl, R ^{2 represents} a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms which may be interrupted by an oxygen atom or a sulfur atom in the chain and / or which may be substituted by halogen, cyano, hydroxy, Acetoxy, pyridyl or by an optionally substituted by halogen, cyano, alkyl I ₁ lit up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or trifluoromethyl substituted phenyl, phenoxy or phenylsulfonyl group,. R ³ and R ^{4 are the} same or different and for hydrogen, halogen, Alkyi having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, cyano, nitro, dialkylamino each having up to 4 carbon atoms per alkyl group, trifluoromethyl, Trif luormethoxi, difluoromethoxy or trifluoromethylthio, R ^{5 represents} a group of the formula -O- (CH ₂ ) _n R ¹¹ , -S- (CH ₂ ) _n -R ¹¹ _/ -O-SO ₂ -R ¹¹ , -CO- (CH ₂ ) _n -R ¹¹ , -O-CO- (CH ₂ ) _n R ¹¹ , -CO-NH- (CH ₂ / _n -R ¹¹ , -NH-CO- (CH ₂ ) _n -R ¹¹ , -NH-SO ₂ - (CH ₂ ) nR ¹¹ stands in which n-0 to 4 means
and
R ¹¹ aryl having 6 to 12 carbon atoms, which is up to 4 times the same or different by halogen, cyano, nitro, trifluoromethyl, Trifluumethoxy, difluoromethoxy, trifluoromethylthio, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio with bis to 4 carbon atoms, amino, alkylamino of up to 6 carbon atoms, dialkylamino of up to 6 carbon atoms per alkyl group or acetylamino, or a 5- to 7-membered saturated or unsaturated heterocyclic ring containing as hetero atoms an oxygen atom, a sulfur atom or two nitrogen atoms can contain R ⁶ and R ^{7 are the} same or different and each
for hydrogen, for cycloalkyl of 3 to 8 carbon atoms or are straight-chain or branched alkyl, alkenyl or alkynyl having in each case up to 18 carbon atoms which may be substituted by halogen, hydroxy, alkoxy having up to 8 carbon atoms, alkylthio having up to 8 carbon atoms, alkylcarbonyl having up to 8 carbon atoms in the alkyl radical, Carboxy or alkoxycarbonyl having up to 8 carbon atoms, by phenyl optionally substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms, by cyano and / or by a group the formula NR ⁹ R ¹⁰ , wherein / Οή 274 02 « R ⁹ and R ^{10 are the} same or different and each is hydrogen, alkyl of up to 8 carbon atoms, aralkyl of 7 to 14 carbon atoms, aryl of 6 to 12 carbon atoms, acyl of up to 7 carbon atoms, alkylsulfonyl of up to 6 carbon atoms, or arylsulfonyl having 6 to 12 carbon atoms, or R ⁸ and R ⁷ respectively is aryl of 6 to 12 carbon atoms which are up to 3 times the same or different by nitro, cyano, halogen, alkyl of up to 6 carbon atoms, alkoxy of up to 6 carbon atoms, alkylthio of up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl each up to 6 carbon atoms per alkyl group, trifluoromethyl, Trif luormethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino having up to 8 carbon atoms, dialkylamino each having up to 8 carbon atoms per alkyl group, acetylamino or Be .zoylamino may be substituted, or are a 5- to 7-membered saturated or unsaturated heterocyclic ring containing as hetero atoms an oxygen atom, a sulfur atom or two nitrogen atoms can characterized in that [A] aldehydes of the general formula (II) (II) CHO in which R ³ , R ⁴ and R ^{5 have} the abovementioned meaning, and β-ketocarboxylic acid esters of the general formula (III) R ² 00C R ¹ A ₀ in which R ¹ and R ^{2 have} the abovementioned meaning, with β-ketocarboxamides of the general formula (IV) (IV) in which R ⁶ , R ⁷ and R ^{8 have} the abovementioned meaning, and ammonia, if appropriate in the presence of inert Lösemitten, or that [B] aldehydes of the general formula (II) with β-ketocarboxylic esters of the general formula (III) and enaminocarboxamides of the general formula (V) in which R ⁶ , R ⁷ and R ^{8 have} the abovementioned meaning, if appropriate in the presence of inert solvents, or that [C] aldehydes of the general formula (II) with β-ketocarboxamides of the general formula (IV) and enaminocarboxylic esters of the general formula (VI) (Vl) in which R ¹ and R ^{2 have} the abovementioned meaning, if appropriate in the presence of inert solvents, or that [D] β-ketocarboxylic acid esters of the general formula (III) with ammonia and ylidene-β-ketocarboxamides of the general formula (VII) »4 (VII) in which R ³ -R ^{8 have} the abovementioned meaning, if appropriate in the presence of inert solvents, or that [E] β-ketocarboxamides of the general formula (IV) with ammonia and ylidene-β-ketocarboxylic acid esters of the general formula (VIII) (VIII) in which R ^ R ^{5 have} the abovementioned meaning, if appropriate in the presence of inert solvents, or that [F] ylidene-.beta.-ketocarboxamides of the general formula (VII) with enaminocarboxylic esters of the general formula (VI), if appropriate in the presence of inert solvents, or in that [G] yliden-ß-ketocarboxylic acid ester of the general formula (VIII) with Enaminocarbonsäureamiden the general formula (V), if appropriate, in the presence of inert solvents, or in that [H] Dihydropyridine monocarboxylic acids of the general formula (IX) (IX) in which R ¹ -R ⁵ and R ^{8 have} the abovementioned meaning, optionally via a reactive acid derivative with amines of the general formula (X) // 03 ²⁷⁴ ° ²⁶ HN (X) in which R ⁶ and R ^{7 have} the abovementioned meaning, optionally in the presence of an inert organic solvent. 2. A process for the preparation of compounds of general formula (I) according to claim 1 by the process variants [A] - [G], characterized in that as the solvent water and inert solvents such as alcohols, ethers, amides, glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine and the Roaction carried out at temperatures between 10 and 15O ⁰ C.