DE2335466A1 - ALCOXY ALKYL-1,4-DIHYDROPYRIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents

Description

Alkoxyalkyl-1,4-dihydropyridines, process for their preparation as well as their use as pharmaceuticals

The present invention relates to new 1,4-dihydropyridines, several processes for their production and their use as medicaments, preferably as vascular-influencing agents, especially as a coronary agent.

It is already known that certain 1,4-dihydropyridines have interesting pharmacological properties (P. Bossert and W. Vater, Die Naturwissenschaften (1971), 58th year, issue 11, page 578).

It has been found that the new alkoxy alky Id ihydropyridine ester the formula

R ³ OOC

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(I)

409886/1452

in which

R stands for hydrogen or a saturated or unsaturated aliphatic radical,

R ^{1 represents} alkoxy alkyl,

"5
R and R are identical or different and represent a straight-chain or branched, saturated or unsaturated or cyclic hydrocarbon radical which is optionally substituted by 1 or 2 hydroxyl groups and / or optionally interrupted by 1 or oxygen atoms in the chain,

R ^ is hydrogen, alkyl, alkoxyalkyl or the - (CH ₂ ) _n -COOR ⁵ radical, where R ^{5 is} hydrogen or alkyl and η is a number from 0 to 3, and

X for an aryl radical, which can optionally be substituted one to three times by nitro, cyano, azido, alkyl, alkoxy, Hydroxy, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S (O) -alkyl, where m is a number from 0 to 2, phenyl, irifluoromethyl and / or halogen is substituted, the Substituents on the aryl radical can be identical or different, for benzyl, styryl, cycloalkyl, cycloalkenyl or for one optionally substituted by alkyl, alkoxy, dialkylamino, nitro or halogen Naphthyl, quinolyl, isoquinolyl, I ^ ridyl, pyrimidyl, diphenyl, furyl or lyrryl radical stands,

and their salts have potent vascular-influencing effects, in particular have a strong coronary effect.

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It has also been found that AUcoxyalkyl-1,4-dihydropyridines can be used of formula I obtained when one

a) ß-ketocarboxylic acid ester of the formula R ¹ -CO-CH ₂ -COOR ² (II)

in which

1 2
R and R have the meaning given above,

with amines of the formula

H ₂ NR (III)

in which

R has the meaning given above,

or their salts, if appropriate after isolation of the ß-ketocarboxylic acids and the amines or amine salts optionally resulting enamines of the formula

R ¹ -C = CH-COOR ² (IV)

in which

12th
R, R and R have the meaning given above,

with ylidene derivatives of the formula

X-CH-C-C-R * (V)

COOR ^

in which

3 4
X, R ^ and R ^ have the meaning given above,

implements;

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b) ß-ketocarboxylic acid ester of the formula

R ^4- CO-CH ₂ -COOR ⁵ (VI)

in which

R and R have the meaning given above,

with amines of the formula

H ₂ NR (III)

in which

R has the meaning given above,

or their salts, if appropriate after isolation from the β-ketocarboxylic acid esters and the amines or amine salts optionally resulting enamines of the formula

ΪΗ-R = CH-COOR ⁵ (VII)

in which

R, R ^ and R ^ "have the meaning given above,

with ylidene derivatives of the formula

X-CH = C-CO-R ¹ (VIII)

'COOR

in which

1 2
R, R and X have the meaning given above,

implements;
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c) ß-ketocarboxylic acid ester of the formula

(VI)

in which

R ⁵ and R ^ have the meaning given above,

with enamines of the formula

i-R

KH-

ν I / ■ * / ·

R'-C = CH-COOR ² (IV)

in which

1 2
R, R and R have the meaning given above,

and with aldehydes of the formula

X-CHO (IX)

in which

X has the meaning given above,

implements;

d) ß-ketocarboxylic acid ester of the formula

R ¹ -CO-CH ₂ -COOR ² (II)

in which

1 2
R and R have the meaning given above,

with enamines of the formula Le A 15 o52 - 5 -

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(YIi)

In we .ι rather

R, R ¹ and ^ι 'Λ .JIe have the meaning given above, and with aldehydes ί & γ formula

X-OHO (IX)

in which

X has the meaning given above,

implements;
or

e) if R ^{1 is} identical to R ⁴ and R is identical to R ⁵ , two parts of ß-ketocarboxylic acid ester of the formula

R ^4- CO-CH ₂ -COOR ⁵ (VI)

in which

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

with part amine of the formula

H ₂ NR (III)

in which

R has the meaning given above,

or its salt and with part of the aldehyde of the formula

X-CHO (IX)

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BATH ORIGINAL

in what ^T

X has the meaning given above,

reacts and if necessary from the compounds obtained according to process variants a) to e) with an acid that makes salt.

The alkoxyalkyl-1,4-dihydropyridines according to the invention surprisingly show a very strong vascular influencing, especially coronary effect. The substances according to the invention thus represent an enrichment for pharmacy.

A) If one uses 3,4,5-trimethoxybenzylidene-acetic acid methyl ester, / '- Isopropoxy-acetic acid methyl ester and methylamine (or ß-methylamino- ^ -isopropoxy-crotonic acid (IV) as starting materials, the course of the reaction for variant a) can be reproduced by the following diagram will:

^0H 3 ° -v

CH ₅ OOC

CH ₃ O

OCH

HN!

! CH ₅

COOCH ₅

OCH,

H COOCH ₅

CH ₂ O-CH ^

"CH,

B) If you use 3-chlorobenzylidene T ^ -methoxy-aceteeeigsäureäthylester, Acetondicarboxylic acid diethyl ester and ammonia (or ß-imino-glutaric acid ethyl ester (VII)) as starting components, bo the reaction sequence for variant b)

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can be represented by the following equation:

H ₅ C ₂ OOC

H ₅ C ₂ OOCCH ₂

COOC ₂ H ₅

H ₅ C ₂ OOCCH ₂ H ^CH 2 ^OCH 3

C) If 3-ethyl-sulfonylbenzaldehyde, ß-aminomethoxycrotonic acid propyl ester is used and ethyl propionylacetate as starting components, the course of the reaction for variant c) can be given by the following equation be reproduced:

H ₅ C ₂ OOC H ₅ C ₂

H ₅ C ₂ OOC

SO ₂ -C ₂ H ₅

CHO

H ₂ N

SO ₂ C ₂ H ₅

COOC ₃ H ₇

CH ₂ OCH ₃

(C)

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D) Using Iyridin-2-aldehyde, / "- Methoxyacetessigsäuremethylester and ß-amino- /""- ethoxy-crotonsäureäthylester be, so the reaction can for variant d) by the following Pormelschema reproduced as starting materials:

H ₅ C ₂ OOC HH ₅ C ₂ OCH ₂

H ₅ C ₂ OOC I «

COOCH,

H ₅ C ₂ OCH ₂ j ^ CH ₂ OCH ₅

, COOCH, CH ₂ OCH ₅

(D)

B) If 3-nitro-benzaldehyde, 2 parts / "- Methoxyacetoacetic acid diethyl ester is used and ammonia as starting materials, the reaction sequence for variant e) can go through the following formula scheme can be reproduced:

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Jfi

CHO

H ₅ C ₂ OOC H H k H COOC ₂ H ₅ CH ₅ OCH ₂ - ^ ^^^ CH ₂ OCH ₅

H ₅ C ₂ OOC

CH ₅ OCH ₂

/ COOC ₂ H ₅ JjT ^ CH ₂ OCH ₅

(E)

In the formulas I, III, IT and VII , the saturated or unsaturated aliphatic radical R preferably denotes straight-chain or branched alkyl having 1 to 4, in particular 1 to 3 carbon atoms, such as methyl, ethyl, n- and i-propyl, n- , i- and t-butyl, or straight-chain or branched alkenyl with 2 to 4, in particular 2 or 3 carbon atoms, such as ethenyl, propenyl (1), propenyl (2) and butenyl (3).

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1 4 In the formulas, the alkoxy alky Ir esters R and R preferably those of the formula -Y-O-Z, in which Y represents straight-chain or branched alkylene with 1 to 4 », preferably 1 or 2 carbon atoms, such as methylene, ethylene and n- and i-propylene, and Z is alkyl of 1 to 4, preferably 1 or 2 carbon atoms, such as methyl, ethyl, n- and i-propyl, n-, i-, see * - and t-butyl.

Straight or branched chain, saturated or unsaturated

2 "5

or cyclic hydrocarbon radicals R and R, which optionally substituted by 1 or 2 hydroxyl groups and / or are optionally interrupted by 1 or 2 oxygen atoms in the chain, are preferably alkyl, alkenyl, Alkynyl and cycloalkyl.

2 3
The alkyl R and R are straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include methyl, n- and i-propyl, n-, i- and t-butyl.

2 "5
Alkenyl R and R are straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4, carbon atoms. Ethenyl, propynyl (1), propenyl (2) and butenyl (3) may be mentioned as examples.

2 "5
The alkynyl R and R ^ are straight-chain or branched alkynyl having preferably 2 to 6, in particular 2 to 4, carbon atoms. Ethynyl, priopynyl (1), propynyl (2) and butynyl (3) may be mentioned as examples.

2 "Ί
Cycloalkyl R and R ^ is mono-, bi- and tricyclic cycloalkyl with preferably 3 to 10, in particular 3, 5 or 6 carbon atoms. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo- / ~ 2,2,1-7-heptyl, bicyclo- / ~ 2,2,2-7-octyl and adamantyl may be mentioned as examples.

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2 ^

These alkyl, alkenyl, alkynyl and cycloalkyl radicals R and R ^ can be substituted by 1 or 2, preferably 1, hydroxyl group and / or be interrupted by 1 or 2, preferably 1, oxygen atom.

Alkyl R and R ^ means straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 carbon atoms. Examples are methyl], ethyl, n- and i-propyl, called n-, i- and t-butyl.

The optionally substituted aryl radical X means aryl with preferably 6 or 10, in particular 6 carbon atoms in the aryl part. Optionally substituted phenyl or naphthyl may be mentioned as examples.

The aryl radical X can have one or more, preferably 1 to 3, in particular 1 or 2 identical or different substituents wear. The following are listed as substituents: phenyl; Alkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl; Alkoxy with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methoxy, ethoxy, n- and i-propyl and n-, i- and t-butyloxy; Trifluoromethyl; Hydroxy; Halogen, preferably Fluorine, chlorine, bromine and iodine, especially chlorine and bromine; Cyano; Nitro; Azido; Amino; Monoalkyl and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, n- and i-propylamino and methy 1-n-butylaALno; Carbalkoxy having preferably 2 to 4, in particular 2 or 3 carbon atoms, such as carbomethoxy and carboethoxy; Acylamino with preferably 1 to 4, in particular 2 or 3 carbon atoms, such as acetylamino and propionylamino; Acyloxy with preferably 2 to 6, in particular 2 to 4 carbon atoms,

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such as acetyloxy and propionyloxy; S (O) _m -alkyl, in which m is a number from 0 to 2 "and alkyl preferably contains 1 to 4, in particular 1 or 2, carbon atoms, such as methylthio, ethylthio, methylsulfoxyl, ethylsulfoxy I, methylsulfonyl and ethylsulfonyl.

Cycloalkyl X is preferably mono-, bi- and tricyclic cycloalkyl with preferably 3 to 10, in particular 3, 5 or 6 carbon atoms. Examples include: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, bicyclo- / "2,2,1-7-heptyl, bicyclo- / 5,2,2-7-octyl and adamantyl.

Cycloalkenyl X is preferably mono-, bi- and tricyclic Cycloalkenyl with preferably 5 to 10, in particular 5, 6 or 7 carbon atoms. Examples are cyclopentenyl, Called cyclohexenyl and cycloheptenyl.

Alkyl and alkoxy as substituents in the naphthyl, quinolyl, Isoquinolyl, pyridyl, pyrimidyl, diphenyl, puryl or Pyrryl radical X denotes straight-chain or branched alkyl and alkoxy with preferably 1 to 6, in particular 1 to 4 Carbon atoms. Examples include methyl, ethyl, n- and i-propyl, n-, i- and t-butyl and methoxy, ethoxy, n- and called i-propoxy and n-, i- and t-butoxy.

Halogen as a substituent of the naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, puryl and pyrryl radical X means fluorine, chlorine, bromine and iodine, especially fluorine and Chlorine.

Dialkylamino as a substituent of the naphthyl, quinolyl, isoquinolyl, Pyridyl, pyrimidyl, diphenyl, furyl or

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Pyrryl radical X preferably contains 1 to 4, in particular 1 or 2 carbon atoms per alkyl group. Examples of alkyl groups are: methyl, ethyl, n- and i-propyl and n-, i- and t-butyl.

R is preferably hydrogen, R is alkoxyalkyl with 1 or 2 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part, R ² and R ^{5 are} alkyl with 1 to 4 carbon atoms, in particular methyl and ethyl, R ^{4- is} alkyl with 1 to 4 carbon atoms, in particular for methyl or ethyl, for alkoxyalkyl with 1 or 2 carbon atoms in the alkyl part and 1 to 3, in particular 1 or 2 carbon atoms in the alkoxy part, for carboxyl, -CH ₂ -COO-alkyl or -COO-alkyl, where alkyl denotes an alkyl radical having 1 to 4, in particular 1 or 2, carbon atoms and X denotes phenyl, or phenyl, which is replaced by alkoxy or alkylthio with

1 or 2, especially 1 carbon atom, cyano, nitro, Hydroxy, trifluoromethyl, fluorine, chlorine, iodine, carboalkoxy with

2 to 4, preferably 2 or 3 carbon atoms and / or alkylsulfony 1 with 1 to 4, preferably 1 or 2 carbon atoms is substituted once or twice, preferably once, as well as for pyridyl and 2-dimethylaminopyrlmidyl.

Salts of the compounds of the formula I are all non-toxic, physiologically acceptable acid addition salts. As inorganic and organic acids which form such salts with the compounds of the formula I are mentioned by way of example: Hydrohalic acids, e.g. B. hydrochloric and hydrobromic acid, especially hydrochloric acid, phosphoric acids, Sulfuric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. B. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, Sorbic acid, lactic acid and 1,5-naphthoic acid.

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The salts are by generally customary methods, for. B. by dissolving the base in ether and adding the solution relevant acid produced.

The β-ketocarboxylic acid esters which can be used according to the invention of the formula II are known or can be prepared by known processes (cf. B. Johnson and H. Chesnoff, J.A.C. p. 36, 1744- (1914)).

Examples are:

jT-Methoxyacetessigsäuremethylester / VMethoxyacetessigsäureäthylester, 7 ^ -Methoxyaeetessigsäurepropylester, / ^ - Methoxyacetessigsäureisopropylester, / ^ - Methoxyacetessigsäure-butyl-jp Athoxyaeetessigsauremethylester, ^ -Äthoxyacetessigsäureäthylester / VÄthoxyacetessigsäurepropylester, JT Propoxyacet essigsäur eäthy read it, / ^ - Propoxyacetessigsäureisopropylester, T ^ -I ^ opoxyaeetessigsäure-tert.-butylester, / "- IsopropoxyacetessigsäuremethyleBter, /" - Isopropoxyacetessigsäur ebuty lest he, / "- But oxy acet acetic acid ether, 7 ~ -Butoxyacetoacetic acid isobutiony, ^ - isethobutoxyacetoacetate, ^ - isethobutoxyacetypropylester, ^ - isethobutoxyacetoacetylester, ^ - emo-butoxyacetacetylester, He, 7 ~ -Methoxy propionylessigsäureäthyIe st he, / ~ -ΐτ opoxypropi ony1-acetic acid propyl ester, S -ithoxypropionyl acetic acid ethyl ester and S- methoxy- T ^ -äthylpropionylessigsäureäthylester.

The amines of the formula III which can be used according to the invention are already known.

Examples are:

Ammonia, methylamine, ethylamine, propylamine, butylamine, Isopropylamine, isobutylamine, allylamine.

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The enamine-β-keto-carbonyl compounds which can be used according to the invention of the formula IV can be prepared from the corresponding β-diketo compounds by generally known methods (A. C. Cope, J. A. C. S. 67., 1017 (1945)).

Examples are:

/ ^ - Methoxy-ß-aminocrotonic acid methyl ester, / ~ -Methoxy-ß-aminocrotonic acid ethyl ester, / V Ethoxy-ß-aminocrotonic acid propyl ester, / "- Isopropoxy-ß-methylaminocrotonic acid ethyl ester and y ^ -Butoxy - /" - methy It reads 1-ß-aminocrotonic acid.

The ylidene-β-ketocarboxylic acid esters which can be used according to the invention of the formula V are partly known or can be prepared by generally known methods (Org. Reactions XI, 2o4 ff, (1967)).

Examples are:
Ylid en-ß-ketocarboxylic acid ester:

Benzylidene-Z ^ -methoxyacetessigsaureathylester, 2'-nitrobenzylidene - / "- methoxyacetessigsäureäthylester, 3 'methoxybenzylidene - /" - äthoxyacetessigsäuremethylester, 3 ^I -4 ^I -Dimethoxybenziyliden - / ^ - propoxyacetessigsäurepropylester, 2' -Trifluormethylbenzyliden-7 ~ "" ^m ethoxyacetessigsäur eäthy he read, 2-chlorobenzylidene ^ -äthoxyacetessigsäurepropylester, 3-Mercaptobenzyliden - / ^ - butoxyacetessigsäureäthylester, Benzylidenacetessigsäuremethylester, 2'-nitrobenzylidene acetoacetate, J'-Nitrobenzylidenacetessigsäurepropargylester, 3'-Nitrobenzylidenacetessigsäureallylester, 3'-Nitrobenzylidenacetessigsäure-ß-äthoxyäthylester, 4'-Nitrobenzylideneacetoacetate, 3'-nitro-6'-chlorobenzylideneacetoacetate, 2'-cyanobenzylidene propionylacetate, 3'-cyanobenzylideneacetacetate, 3'-liitro-4- ^f- chlorobenzylidene,

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Λ-

· 2-nitro-4 '-methoxy benzy lester lidenacetessigsäuremethy, 2'-cyano-4 -methylbenzylidenacetessigsäureäthylester ^1, 2'-Azidobenzylidenacetessigsäureäthylester, 2'-Methylmercaptobenzylidenacetessigsäureisopropylester, 2'-SuIfinylmethy1-benzylidenacetessigsäureäthylester, 2-Sulfonylmethylaeetessigsäureäthylester, 2'-Nitrobenzylidenoxalessigsäurediäthylester, 2 «-4'-Dioxymethylenbenzylidenoxalessigsäuredimethy lester, 3'-Ätlioxy-benzy liden-ß-ketoglutarsäurediäthy lest he, (2'-Ethoxy-1'-naphthylidene) -acetoacetic acid methyl ester, (1 '-Emethyetolyl ^ A. Methylidenacetolyl ^ A. methyl lyridylmethylideneacetoacetate, et - ^ yridylmethylidenacetoacetic acid allyl ester, öt -I ^ ridylmethylidenacetoacetic acid cycloliexyl ester, BI ^ ridylmethylidenacetoacetic acid-ß-methoxy, hy lester, 6-methyl- oC-methylidyl acetate, 6-methyl-oC-methylidyl-acetate, 6-methyl-o-ethyl-pyridyl-4'-pyridyl-pyridyl-6'-pyridyl acetate methylidene acetoacetic acid ethyl ester, (2'-thenyl) -methylidene acetoacetic acid ethyl ester, (2'-I'uryl) -methylideneacetoacetic acid Saur eally lester, (2'-Iyrryl) -methylidenacetessigsäuremethylester, oO-.i> yridy lmethy lid enpropionylessigsäuremethy read it, 2 * -, 3 'or 4'-Methoxybenzylidenacetessigsäureäthylester, 2 ^I -Methoxybenzylidenacetessigsäurepropargylester, 2'-Isopropoxybenzylidenacetessigsäureäthylester, 3' -Butoxybenzylidenacetessigsäuremethylester, 3 ^1, 4 ', 5'-Trimethoxybenzylidenacetessigsäureallylester, 2'-methy1-benzylidenpropionylessigsäuremethy read it, 2'-Methylbenzylidenacetessigsäure-ß-propoxyäthylester, 3 ¹ ^' - dimethoxy-S'-brombenzylidenacetessigsäureäthylester, 2 ', 3' - Or 4'-chloro / bromine / fluorine / iodobenzylideneacetoacetate, 3'-chlorobenzylidenepionylacetate, 2'-, 3'- or 4'-trifluoromethylbenzylideneacetacetate, 2'-garbethoxybenzylideacetyl acetate, cyclohexyl isopropyl isopropyl acetate, cyclohexyl isopropyl isopropyl acetate, cyclohexyl isopropyl acetate, 4-hexyopropyl isopropyl acetate, cyclohexyl isopropyl acetate, cyclohexyl isopropyl acetate, 4-hexyl isopropyl acetate, 4-hexyopropyl acetate, cyclohexyl isopropyl acetate, 4'-chlorobenzylidene propionyl acetate.

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The β-ketocarboxylic acid esters of the formula VI which can be used according to the invention and the enamino-β-ketocarboxylic acid esters of the formula VII are known or can be produced by generally known processes (B. Johnson and H. Chesnoff , J. A. as. 36., 1744 (1914); Pohl, Schmidt, U.S. Patent 2,351,366; AG Cope, JACS, 67, 1017 (1945)).

Examples are:

ß-Dicarbony! compounds:

/ Mlethoxyacet acetic acid emethy! Ester, / ^ - Methoxyacet acetic acid ethyl ester, / ^ - Methoxyacetoacetic acid propyl ester, T ^ -Methoxyacetoacetic acid isopropyl ester, / "" - Methoxyacetoacetic acid butyl ester, / "- Ethoxyacetoacetate, /" - Ethoxyacetoacetate, ethyl acetate, / "- Ethoxyacetacetic acid ethyl ester, /" / ^ - Propoxyacetoacetic acid ethyl ester, T ^ propoxyacetoacetic acid isopropyl ester, P ^ -propoxyacetoacetic acid tert-butyl ester, T ^ -Isopropoxyacetoacetic acid methyl ester, 7 ^ -isopropoxyacetoacetate, / ^ - isopropoxyacetoacetate, / ^ - butoxyacetoacetate, / ^ - butoxyacetoacetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetic acid butoxyacetoxyacetoxyacetoxyacetoxyacetoxyacetoxyacetoxyacetoxyacetoxy-butoxyacetyl acetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetate, ^^ - butoxyacetoacetic acid isopropoxyacetoxyacetoxyacetoxy acetate, ^^ T ^ -Methoxypropionyl acetic acid ethyl ester, T'-I'-propoxypropionyl acetic acid propy! Ester, E-Ethoxypropionyl acetic acid ethyl ester, ο -Methoxypropionyl acetic acid ethyl ester, ο -Met η oxy- / ^ "- aO ^ lpropionyies Ethyl acetate, 3,5-formyl acetate, methyl acetate, methyl acetate, pormyl acetic acid , Acetoacetic acid emethy lese er, Ac; etessig3äureisoprop yl ester, butyl acetoacetate, tert-butyl acetoacetate, acetoacetic acid ( ^Cl - or ß -) - hydroxyethyl ester, acetoacetic acid (oc- or ß-j-methoxyäthyleßfcer, acetoacetic acid (ÖC- or ß-) - ethoxyethyleBter - or ß -) - n-propoxyethyl ester, allyl acetoacetate, propargylic acetoacetate, ethyl propionyl acetate, ethyl butyrylacetate, ethyl isobutyrylacetate, dimethyl oxaloacetate, oxaloacetic acid isopropyl isopropyl acetate,

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BATH ORIGINAL

ester, dimethyl acetone dicarboxylate, diethyl acetone dicarboxylate, Acetondicarboxylic acid dibutyl ester, ß-ketoadipic acid diethyl ester.

Enamine carboxylic acid ester:

/ ^ - methyl methoxy-ß-aminocrotonate, / ^ - ethyl methoxy-ß-aminocrotonate, / ^ - ithoxy-ß-aminocrotonic acid propy 1-ester, / ^ - Isopropoxy-ß-methylaminocrotonic acid eäthy lest he, / VButoxy- / "- me thy 1-ß-aminocrotonic acid ethyl ester.

ß-aminocrotonic acid methyl ester, ß-aminocrotonic acid ethyl ester, ß-aminocrotonic acid isopropyl ester, ß-aminocrotonic acid butyl ester, ß-aminocrotonic acid ^{C 0 ^ - or ß -) - methoxyethyl ester, ß-aminocrotonic acid-ß-aminocrotonic acid-ß-aminocrotonic acid-aminocrotoxy ester,} butyl ester, .beta.-Aminocrotonsäurecyclohexylester, .beta.-amino-.beta.-ethyl-ethyl acrylate, Iminobernsteinsäuredimethylester, Iminobernsteinsäurediäthylester, Iminobernsteinsäuredipropylester, Iminobernsteinsäuredibutylester, ß-Iminoglutarsäuredimethylester, ß-Iminoglutarsäurediäthylester, ß-Iminoadipinsäuredimethy1 ester, .beta.-Iminoadipinsäurediisopropylester, ß-Methylaminocrotonsäuremethylester, ß -Ethylaminocrotonic acid ethyl ester, ß-methylinoglutaric acid diethy1 ester.

The ylidene-β-ketocarboxylic acid esters which can be used according to the invention of formula VIII are not yet known. As already mentioned for connections to the iOrmel V. well-known methods are produced.

Examples are:

Yliden-ß-ket © carboxylic acid ester:

Benzylidene- / "- ethoxy-acetic acid methyl ester, 2'-nitrobenzy lid en- / ^ - propoxy-acetacetic acid methyl ester, 3'-nitro-

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to

methyl benzylidene / methoxyacetacetate, propyl 3'-nitrobenzylidene acetoacetate, methyl 4'-nitrobenzylidene-7-methoxy-acetoacetate, 3'-nitro-6-chlorobenzylidene- 7- ispropoxy-acetic acid methyl ester, 2 ' - / Vrx-butoxy-acetic acid methyl ester, 2'-cyanobenzylidene-4-ethoxy-propionyl acetic acid ethyl ester,

2 · -Nitro-4'-methoxybenzy liden- / ~ -propoxy-acetic acid methyl ester, 2'-azidobenzylidene-Z ^ -methoxy-acetic acid ethyl ester, 2 '-Methylmercaptobenzy lidene- / ^ - ethoxy-acetacetic acid methyl ester, 3'-methylmercaptobenzylidene- / " -methoxyacetessigsäureisopropylester, 2 ^f -Sulfinylmethylbenzylidenacetessigsäureäthylester, 2 ^l -Sulfonylmethyl- / ^v -methoxyacetessigsäureätbylester, (2'-ethoxy-1 ^l -naphthyliden) - / ^v -meth.oxyacetessigsäuremethylester, (1 ^l -Isochinolyl) -methyliden- JT ethoxy acetic acid methyl ester, ot-pyridylmethylidene - / ^ · propoxy-acetic acid ethyl ester, 4 ^!, 6 '-Dimethoxy- (5' -pyrimidyl) -methy lid en- / "- methoxy-acetic acid-ethyl ester, (2'-thenyl) - '/ ^ -metb.oxy-inethylidenacetessigsäureäthylester, (2 '-Fury I) - 7 ^ -ethoxy -methy lidenacet acetic acid ebuty lest er, 2'-, 3 ¹ - or 4'-Meth.oxybeiizy liden- / ^ - methoxy- ac et acetic acid ethyl ester, 2 '-isopropoxy benzy lidene - / "- isopropoxyacetoacetic acid ethyl ester, 3' -butoxybenzylidene-Z ^ -methoxyacetoacetic acid methyl ester, 3 ^1, 4 ', 5' -Trimethoxy benzy lid 7 ~ ene-propoxy-acetesBigsäurepropylester, 2 '-Me thy Ib en zy lid ene b methoxy-propionylessigsäuremethylester, 2'-, 3'- or 4'-Trifluormethylbenzyliden- 7 ~ -methoxy-acetic acid propyl ester, 2'-trifluoromethylbenzylidene- ^ -methoxy-acetic acid isopropyl ester,

3 ^l -! Erifluorπlet ■ nyl-benzylidene - / ^ - ethoxyacetoacetic acid methyl ester, 2 '-carbathoxybenzylidene-Z ^ -methoxy-acetoacetic acid ethyl ester, 3' -carboxymethylbenzylidene - ^ - ethoxy-acetic acid methyl ester, 4-carboxy isopropyl isopropylbenzyl-acetate, 4-carboxy isopropylbenzylbenzylester, 4-carboxy isopropylbenzylbenzylidester.

Le A 15 o52 - 2o -

409886 / UE2

The aldehydes of the formula IX which can be used according to the invention are already known or can be prepared by known methods (E. Mosettig, Org, Reactions, VIII, 218 ff, (1954)).

Examples are:
Aldehydes:

Benzaldehyde, 2-, 3- or 4-methoxybenzaldehyde, 2-isopropoxybenzaldehyde, 3-butoxybenzaldehyde, 3,4-dioxymethylenebenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2-, 3- or 4-chlorine / bromine / iodine / Fluorobenzaldehyde, 2,4- or 2,6-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-diisopropyl-4-methoxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, 2,4- or 2,6- Dinitrobenzaldehyde, 2-nitro-6-bromobenzaldehyde, 2-nitro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-4-chlorobenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde 2-, 3- or 4-dimethylaminobenzaldehyde, 4-dibutylamia.obenzaldehyde, 4-acetaminobenzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2-nitro-4-cyanbenzaldehyde, 3-chloro-4-cyanobenzaldehyde, 2-, 3- or 4-MethyImeroaptobenzaldehfd, 2-Methylmercapto-5-nitrobenzaldehyde, 2 "= ButyXiaercaptobenzaldehyd, 2-, 3- or 4-Methylsulfinylb @ iiaaIdehyd, 2-, 3- or 4-Methylsulfonylbenzaldehyd, Benzaldehyde-2-Carbonsäureäthylester, Benzaldehyde-2-carboxylic acid ethyl ester -isopropyl carboxylate, benzaldehyde-4-carboxylic acid ebatyl ester, 3-nitrobenzaldehyde-4-carboxylic acid ethyl ester, cinnamaldehyde, hydrocinnamaldehyde, formylcyclohexa, i-formylcyclohexene-3, 1-fonayl-cyclohexin-1, 3, 1-formylcyclopenten-3, <! -, β- or / ^ - iyridaldehyde , 6-methylpyridine-2-aldehyde, furan-2-aldehyde, thiophene-2-aldehyde and iyrrole-2-aldehyde, N-methylpyrrole-2-aldehyde _s 2-, 3- or 4-azidobenzaldehyde, iyrimidine-4-aldehyde , 5-nitro-6-methylpyridine-2-aldehyde, 1- or 2-naphthaldehyde, 5-bromo-i-naphthaldehyde, ghinolin-2-aldehyde, 7-methoxy-quinoline-4-aldehyde, isoquinoline-1-aldehyde.

Le A 15 o52 - 21 -

40I88S / U52

Suitable diluents in process variants a) to e) are water and all inert organic solvents. These preferably include alcohols, e.g. B. lower alkyl alcohols with preferably 1 to 4 carbon atoms, such as ethanol, methanol, isopropanol, ether, e.g. B. lower dialkyl ethers _:. (preferably 3 to 5 carbon atoms), such as diethyl ether or ring ethers such as tetrahydrofuran, dioxane, lower aliphatic carboxylic acids (preferably 2 to 5 carbon atoms) such as acetic acid, propionic acid, lower dialkylformamides (preferably 1 or 2 carbon atoms per alkyl group), such as dimethylformamide, lower ones Alkyl nitriles (preferably 2 to 4 carbon atoms), such as acetonitrile, dimethyl sulfoxide, liquid heteroaromatic bases such as lyridine, and mixtures of these solvents including water with one another.

The reaction temperatures can be varied over a wide range in process variants a) to 4). In general one works between about 20 and about 150 ° C., preferably between 50 and 100 ° C., in particular at the boiling point the solvent used.

The reaction can be carried out under normal pressure, but also under increased pressure. Generally one works at Normal pressure.

When the process according to the invention is carried out variants a) to e), the starting materials involved in the reaction are used preferably each used in approximately molar amounts. The amine used or its salt is expediently in An excess of 1 to 2 moles was added. The molar ratio can be varied over a wide range without adversely affecting the result.

Le A 15 o52 - 22 -

409885/1462

As new active ingredients, in addition to those in the examples compounds described in detail:

1 -Methy 1-2,6-d imethoxy meihy 1-4- (3 ', 5' -dioxy-4 '- 3 odpheny 1) -1 ^ -dihydropyrid.in ^ jij-dicarboxylic acid dipropy lester,

2-Eropyl-6-propoxymethy1-4- (2'-methylsulfenylphenyl) -1,4-dihydropyridine - ^ - carboxylic acid propyl ester-S-carboxylic acid isopropyl ester,

1-Isopropy1-2,6-dimethoxymethy1-4- (3-aziä opheny1) -1,4-dihydropyridine-3, 5-hy dicarbonsäurediät lester,

2,6-dimethoxymethyl 1-4- (3-carboxyphenyl) -1,4-dihydropyridine-3,5-d dibutyl icarboxylate,

1-Benzy1-2,6-dipropoxymethy1-4- (3'-quinoly1) -1,4-dihydro ~ pyridine ^ -carboxylic acid methyl ester-S-carboxylic acid propyl ester,

1,2-dibutyl-6-butoxyethyl-4- (oL-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester,

2,6-diethoxyethyl-4- (isoquinolyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid isobutyl ester,

2,6-Dimethoxymethyl-4- (5 '- / ~ 4,6-dimethoxy-7-pyrimidyl) -1,4-dihydropyridine-3 »5-dicarboxylic acid diet lester,

1 -ethyl-2-methoxyäthy l-6-propyl-4- (2 ^f - / ~ 5 '-nitrofuryl ^ -) - 1,4-dihydropyridine-3-carboxylic acid ß- (ethoxyethyl ester),

2,6-dibutoxymethyl-4- (2'-H-propylpyrryl) -1,4-dihydropyridine-3 * 5-dicarboxylic acid dimethyl ester,

Le A 15 o52 - 23 -

4Ö988S / HE2

2,6-dimethoxy methy1-4- (3'-nitro-4'-oxy-pheny1) -1,4-dihydropy ridine-S-carboxylic acid methyl-S-carboxylic acid isopropyl ester,

2-methoxymethyl-6-isopropoxyethyl-4- (2 ^l - / "* 4 ^l -t) romthienyl7) -1,4-dihyropyridine-3-carboxylic acid methyleter-5-carboxylic acid propyl ester.

Le A 15 o52 - 24 -

409886/1462

The new compounds can be used as medicaments, in particular as active ingredients that influence blood vessels and circulation.

The inventive compounds have a wide range of options versatile pharmacological spectrum of activity.

In detail, the compounds according to the invention have the following main effects on:

1) The new compounds cause parenteral, oral and perlingual gift a clear and long-lasting Expansion of the coronary vessels.

This effect on the goronary vessels is caused by a simultaneous nitrite-like relieving effect on the heart reinforced. They influence or change the metabolism in terms of energy savings.

2) The new compounds lower the blood pressure of normotensive and hypertonic animals and can thus be used as ant! Hypertensive Funds are used.

3) The excitability of the stimulation and conduction system inside the heart is reduced so that an anti-fibrillation effect can be demonstrated in therapeutic doses results.

4) The tone of the smooth muscles of the vessels is under the effect of the compounds is greatly reduced. This vascular spasmolytic effect can affect the entire vascular system take place or are more or less isolated in circumscribed vascular areas (such as the central nervous system) manifest.

Le A 15 o52 - 25 -

409886/1462

5) The compounds have strong muscular-spasmolytic effects, those on the smooth muscles of the stomach, intestinal tract, the genital tract and the respiratory system become clear

6) The compounds influence the cholesterol or lipid level in the blood.

The new connections are therefore for prevention, improvement or healing of diseases in which in particular the above-mentioned effects are desired.

The present invention includes pharmaceutical preparations, the one or more compounds in addition to non-toxic, inert pharmaceutically suitable carriers of the formula I and / or their salts or those of one or more compounds of the formula I and / or their Salts exist as well as processes for the production of these preparations.

The present invention also includes pharmaceuticals Preparations in dosage units. This means that the preparations in the form of individual parts z. B. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. B. T, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. Contains a single dose preferably the amount of active ingredient that is administered in one application and which is usually a whole, corresponds to half a day or a third or a quarter of a daily dose.

Le A 15 o52 - 26 -

40988S / U62

23354S6

Among non-toxic, inert pharmaceutically acceptable Carriers are solid, semi-solid or liquid diluents, To understand fillers and formulation auxiliaries of all kinds.

Preferred pharmaceutical preparations are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, Called suspensions and emulsions.

Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B "Starches, milk sugar, Cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrants, e.g. B. agar agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. B. paraffin, and (f) absorption accelerators, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. B. kaolin and bentonite, and (i) Lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) - (i).

The tablets, coated tablets, capsules, pills and granules can optionally contain opacifying agents with the usual Coatings and sheaths can be provided and also be composed in such a way that they only or prefer the active ingredient (s) in a specific part of the intestinal tract, if appropriate release delayed, with such. B. polymer substances and waxes can be used.

The active ingredient (s) can optionally also be used in microencapsulated form with one or more of the abovementioned carriers Form.

Le A 15 o52 - 27 -

409886/1462

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble carriers, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat, and higher esters (z. B. C ₁₄ -AIkOhOl with CL ^ -fatty acid) or mixtures of these ötoffe.

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, ζ. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycolic acid, glycolic acid, polyhydric alcohol and fatty alcohol of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers, such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agent, ζ. Β. ethoxylated isosteary! alcohols, poly oxyäthylensorbit- and -sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, Contain bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving agents Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. contain saccharin.

Le A 15 o52 - 28 -

40988B / UB2

The therapeutically active compounds should be present in the abovementioned pharmaceutical formulations in a concentration of about o, 1 to 99.5, preferably from about O ₅ H birch 95 percent by weight of the total mixture.

In addition to compounds of the formula I and / or their salts, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.

The manufacture of the pharmaceutical listed above Preparations are carried out in the usual way by known methods, for. B. by mixing the active ingredient (s) with the carrier or substances.

The present invention also includes the use of the compounds of the formula I and / or their salts and of pharmaceutical preparations containing one or more compounds of the formula I and / or their salts contain, in human and veterinary medicine for prevention, improvement and / or cure the diseases listed above.

The active ingredients or the pharmaceutical preparations can preferably orally, parenterally and / or rectally, preferably orally and parenterally, in particular perlingually and intravenously be applied.

In general, it has proven to be advantageous to use the active ingredient or ingredients in the case of parenteral (intravenous) administration in amounts of about 0.05 to about 10, preferably from 0.02 to 5 mg / kg of body weight per 24 hours and in the case of oral Application in amounts of about 0.1 to about 50, preferably 1 to 30 mg / kg of body weight per 24 hours, if necessary

Le A 15 o52 - 29 -

409885/1462

to be administered in the form of several single doses to achieve the desired results. A single gift contains the or the active ingredients, preferably in amounts of from about to about, in particular up to mg / kg of body weight. It. however, it may be necessary to deviate from the dosages mentioned, depending on the type and the Body weight of the object to be treated, the type and severity of the disease, the type of preparation and the Application of the drug and the period or interval within which the administration takes place. So can in some cases it may be sufficient to manage with less than the above-mentioned amount of active ingredient, while in in other cases the amount of active ingredient listed above must be exceeded. The determination of the required optimal dosage and type of application of the active ingredients easily done by any skilled person on the basis of his or her specialist knowledge.

Ie A 15 o52 - 3o -

409885/1452

The coronary effect of some characteristic inventive Compounds can be demonstrated by the experimental results contained in Table I.

Table I.

Connection Clearly recognizable increase in oxygen saturation in the coronary sinus from the example No dose duration of action

(mg / kg - IV) (minutes)

1 1, o 2o

2 1, o 12o

3 o, 1 45

4 o, 1> 18o

7 o, o3 45

8 o, 3> 6o 1o 1o, o> 15o

12 1o, o> 3o

13 - 5, o 45

14 2, o 45

15 3, o 2o 17 3, o 2o

i.v. = intravenous

The coronary effect was generally known from the literature Methods on anesthetized cardiac catheterized Hybrid dogs by measuring the increase in oxygen saturation detected in the coronary sinus.

The preparation of the new compounds is illustrated by the following examples.

Le A 15 o52 - 31 -

409885/1452

example 1

H ₅ C ₂ OOC

CH ₂ -OC ₂ H ₅

After several hours of heating a solution of 10.6 g of benzylaldehyde, 17.4 g / VÄthoxyacetessigsäureäthylester and 13g ß-aminocrotonic acid ethyl ester in 80 ml of ethanol, the 2-ethoxymethyl-6-methyl-4-phenyl-1 ^ -dihydropyridine, 5-dicarboxylic acid diethyl ester in a yield of 65 fi of theory in the form of yellow crystals with a melting point of 112 ^° C.

Example 2

COOC ₂ H ₅

A solution of 5 »8 g of 3-iodine benzaldehyde, 4> 4 g / ^ - Ethoxyacetoacetic acid ethyl ester and 3.3 g of ß-aminocrotonic acid ethyl ester in 3o ml of ethanol is heated to boiling overnight and then chilled. After cooling, the 2-ethoxymethyl-6-methy1-4- (3'-ό od pheny1) -1,4-dihydropyride in-3,5-dicarboxylic acid diethyl ester obtained in a yield of 60% of theory in the form of light yellow crystals which melt at 124.degree.

Le A 15 o52 - 32 -

409886 / U62

Example 3

H ₅ C ₂ OOC

CO OC

15 g of 3-nitrobenzaldehyde, 18 g of 7 ^ -Äthoxyacetessigsäureäthylester and 13 g ß-Aminocrotonsäureätiiylester about 5 hours in 60 ml of ethanol, cooled, sucked at and washed with cold ethanol. There is obtained 2-ethoxymethyl-6-methyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarbonsäurediäthylester in the form of pale yellow crystals of Pp. 12o 122 ⁰ C in a yield of 7o $ of theory .

Example 4

H ₅ C ₂ OOC

COOC ₂ H ₅

CH ₂ -OC ₂ H ₅

After several hours of refluxing a solution of 14 g of 2-chlorobenzaldehyde, 17.4 g / '- ethoxyacetoacetate and 13 g of ß-aminocrotonic acid ethyl ester in 80 ml of ethanol, 2-ethoxymethyl-6-methyl-4- (2'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was obtained after cooling in the form of pale yellow crystals with a melting point of 115 ^° C. in a theoretical yield of 55%.

Le A 15 o52

- 33 -

409886 / U52

Example 5

OCH,

H
C ₂ H ₅ -OOC ^^^ W COOC ₂ H ₅

CH ₂ OC ₂ H ₅

The mixture was heated, 15.4 g of 3-i ^I luor-4-methoxybenzaldehyde, 17.4 g of 7 "-Äthoxyacetessigsäureäth.ylester and 13 g of .beta.-Aminocrotonsäureäthylester in 80 ml ethanol overnight to boiling, cooled and, after filtration with suction and washing with cold ethanol the 2-ethoxymethyl-6-methyl-4- (3'-fluoro-4'-methoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester in 35 fi yield (theory) in the form of white crystals from Pp. 12o ° C.

Example 6

CH ₅ OOC

COOC ₂ H ₅ CH ₂ OCH ₅

After 6 to 8 hours of refluxing a solution of 6.2 g of 2-nitrobenzaldehyde, 6.6 g / ^ - methoxyacetoacetate and 4.8 g of ß-aminocrotonic acid methyl ester in ethanol, the mixture is cooled, filtered off with suction and washed with a little cold ethanol. The 2-methoxymethyl-6-methyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-carboxylic acid ethyl ester is obtained

Ie A 15 o52

- 34 -

409885 / H52

5-carbonsäuremethylester in the form of pale yellow crystals of Pp 143 -. 145 ⁰ O.

Yield: $ 45 of theory.

Example 7

H ₅ G ₂ OOG

0OC ₂ H ₅

CH ₃ H ^LH 2 ^L.

7.4 g of 2-trifluoromethybenzaldehyde, 17.4 g of ethyl acetate and 13 g of ß-aminocrotonate are refluxed in 80 ml of ethanol overnight, and the 2-ethoxymethyl-6-methyl-4- is obtained. (2'-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarbonsäurediäthylester vreißgelber in the form of crystals of Pp. 112 ⁰ C in a yield of 55 $ of theory.

Example 8

H ₅ C ₂ OOC

COOC ₂ H ₅

CH ₅ CH ₂ -OCH

CH ₅

The solution is kept from 10.4 ml of yridine-2-aldehyde, 19 g ^ -Isopropoxyacetoacetic acid ethyl ester (bp. 1o6-1o8 ° C / 12mm) and 13 g of ß-aminocrotonic acid ethyl ester in 60 ml of ethanol 6-8 hours at the boil, then cools and maintains the

Le A 15 o52

- 35 -

409885/1462

2-Isopropoxymethyl-6-methyl-4-o (.- pyridyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester in the form of pale yellow crystals of pp. 184 ⁰ G in a yield of 35 $ of theory.

Example 9

H ₅ C ₂ OOC

0OC ₂ H ₅

CH ₂ -OC ₂ H ₅

6.5 g of 3-cyanobenzaldehyde, 8.7 g / ^ - ethyl ethoxyacetoacetate and 7.2 g of ß-amino-ß-ethyl acrylate in 80 ml of ethanol are heated under reflux overnight, cooled and obtained after suction and washing with cold ethanol the 2-ethoxymethyl-6-ethyl-4- (3 ^l -cyanphenyl) -1,4-dihydiopyridine-3,5-dicarboxylic acid diethyl ester in the form of light yellow crystals with a melting point of 125 ° C. in a yield of 42,76 of theory.

Example 1o

H ₅ C ₂ OOC

CH ₃

H COOC ₂ H ₅

7.5 g of 2-dimethylaminopyrimidine-5-aldehyde, 8.7 g, are heated / V Ethoxyacetoacetic acid ethyl ester and 6.5 g ß-aminocroton

Le A 15 052

- 36 -

409886 / UB2

ethyl acid ester in 40 ml of ethanol to boil overnight and after cooling and suction the 2-ethoxymethyl-6-methyl-4- (2 ^f -dimethylaminopyrimidyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester in the form of light beige crystals from Pp. 124 ⁰ C in a yield of 40 $ of theory.

Example 11

H ₁ -G ₀ OOC

COOC ₂ H ₅

GHn OCqH ₁ -

7.5 g of 2-Iyridine aldehyde and 15 g of ethyl ethoxyacetoacetate are heated and 9.1 g of ß-aminocrotonic acid ethyl ester 5-6 hours in 60 ml of ethanol to boiling and obtained after Cooling and suction of the 2-ethoxymethyl-6-methyl-4- <x - pyridyl-1 ^ -dihydropyridine, 5-dicarboxylic acid diethyl ester in the form light yellow crystals with a bp. 135 ° C in a yield of 35 $ of theory.

Example 12

H ₅ C ₂ OOC

CH ₅ O-CH ₂

COOC ₂ H ₅

CH ₂ -OCH ₃

The solution of 14 g of 2-chlorobenzaldehyde, 32 g, is heated / ^ ■ Methoxyacetoacetic acid ethyl ester and 1o ml of concentrated aqueous Boil ammonia in 60 ml of ethanol overnight

Le A 15 052

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409885 / US2

and receives after suction the 2,6-dimethoxymethyl-4- (2'-chloropheny I) -I, ^ - dihydropyridine, 5-dicarboxylic acid e-ethyl ester in the form of light yellow crystals of pp. 133-134 ⁰ C in

a yield vcu 55 $ of the theory.

Example 13

H ₅ C ₂ OOC

OH,-

₅ -OCH ₂

COOC ₂ H ₅

CH ₂ -OCH ₃

8.7 g of 2-trifluoromethybenzaldehyde, 16 g of ethyl methoxyacetoacetate and 5 ml of concentrated aqueous ammonia in 3ο ml of ethanol are heated to boiling overnight, the mixture is cooled and the 2,6-dimethoxymethyl-4- (2 ^l - trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarbonsäurediäthylester light brown crystals in Porm Pp. 133 - 134 ⁰ C in a yield of 60 56 of theory.

Example 14

H ₅ C ₂ OOC C ₂ H ₅ OCH ₂

/ COOC ₂ H ₅

CH ₂ OC ₂ H ₅

The solution of 15 g of 2-nitrobenzaldehyde, 35 g of ethyl ethoxyacetoacetate and 11 ml of aqueous concentrated ammonia in 80 ml of ethanol is heated to boiling overnight

Le A 15 o52 - 38 -

40988S / U62

and then cooled after the suction gives the 2,6- (diethoxymethyl) -4- ^(t 2 -nitrophenyl) -1,4-dihydropyridine-3,5-dicarbonsäurediäthyIester in the form of yellow crystals having a melting point of 138 -. 14o C in a yield of 50 # of theory.

Example 15

H ₅ C ₂ OOC

H ₅ C ₂ OCH ₂

0OC ₂ H ₅

H CH ₂ OC ₂ H ₅

5.2 ml of pyridine-2-aldehyde, 17.4 g of ethyl ^ -ethoxyacetoacetate and 5 ml of concentrated aqueous ammonia in 40 ml of ethanol are heated to boiling overnight, the mixture is cooled, filtered off with suction and the crystals obtained (mp. Ho ⁰ C ) in ether and the HCl salt is precipitated with ethereal hydrochloric acid. The hydrochloride of the 2,6- (diethoxymethyl) -4 - <** - pyridyl-1,4-dihydropyridine-Jji-dicarboxylic acid diethyl ester with a melting point of 168-170 ° C. is obtained.
Yield: 45 # of theory.

Example 16

H ₅ C ₂ OOC

SO ₂ -CH ₃

Le A 15 052

CH, H

COOC ₂ H ₅

CH ₂ OCH ₃

- 39 -

40988B / UB2

233546G

The solution of 9.2 g of 4-methylsulfonylbenzaldehyde, 8 g of methoxyacetoacetic acid and 6.5 g of ß-aminocrotonic acid ethyl ester in 40 ml of ethanol is heated to the boil and, after cooling, the 2-methoxymethyl-6- methyl-4- (4'-methylsulfonylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic bonsäur ed iäthylester yellow in the form of crystals of mp. yield: 65 i <> of theory.

156 - 158 ^U C.

Example 17

COOC ₂ H ₅

/ GH ₅ OOC

CH

After several hours of heating a solution of 8.9 g of 3-carbethoxybenzaldehyde, 8 g / -Methoxyacet acetic acid ethyl ester and 6 g of ß-aminocrotonic acid methyl ester in 3o ml of ethanol, the 2-methoxymethyl-6-methyl-4- (3'-carbäthoxyphenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethyl ester was obtained in the form of light yellow crystals with a melting point of 108 ° -11o ° C.
Yield: 60 # of theory.

Example 18

-CH,

H ₅ C ₂ OOC

CH, OCH.

COOC ₂ H ₅

CH ₂ -OCH ₃

Le A 15 052

- 4o -

409885 / H52

7.6 g of 4-methylmercaptobenzaldehyde, 16 g of methoxyacetoacetate and 6 ml of concentrated aqueous ammonia in 30 ml of ethanol are heated to boiling for 6-8 hours and the 2,6-dimethoxymethyl 4- (4 1 -methylmercaptophenyl ^{) is obtained} ) -1,4-dihydropyriäin ~ 3,5-dicarbonsäurediäthylester in the form of beige crystals, mp 136-138 ⁰ C. yield:. 5o $ of theory.

a) The same compound of melting point 137-138 C is obtained if 7.6 g of 4-methylmercaptobenzaldehyde and 16 g of ß-amino

7 ~ -methoxycrotonic acid ethyl ester and g / ^ - methoxyacetoacetic acid ethyl ester Heated to boiling overnight in 40 ml of ethanol.

Example 19

H ₅ C ₂ OOG CH ₅ OCH ₂

OCH

COOC ₂ H ₅ CH ₂ OCE

7.6 g of 3-methoxy-4-hydroxybenzaldehyde, 16 g / "- Methoxymethylacetessigsäureäthylester and 12 ml of aqueous concentrated ammonia in 3o ml of ethanol are heated to boiling overnight and after cooling, the 2,6-dimethoxymethyl-4- (3'-methoxy-4'-hydroxyphenyl) -1 ^ -dihydropyridin ^^ - dicarbonsäurediäthylester in the form of light yellow crystals, mp 14o -. 142 ⁰ C in a yield of 4o% of theory.

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Example 2o

H ₅ C ₂ OOc

NO,

_/ COOC ₂ H ₅

CH ₂ OCH ₃

After heating a solution of 15.1 g of 3-nitrobenzaldehyde, 16 g of ß-amino / "" - methoxycrotonic acid ethyl ester and 19 g of oxaloacetic acid diethyl ester under reflux in 60 ml of ethanol for 12 hours, the solution is evaporated in vacuo and the 2-methoxymethyl is in a fixed quantitative yield -4- (3'-nitrophenyl) -1 ^ -dihydropyridine, 5 »6-tricarboxylic acid triethyl ester in the form of a yellow oil (n ^ ° = 1.5353).

Example 21

H ₅ C ₂ OOC

HOOC

COOC ₂ H ₅ CH ₂ OCH ₃

23 g of the Trieste obtained according to Example 2o are heated to boiling overnight after the addition of a solution of 1.15 g of sodium in 25 ml of ethanol in a total of 2oo ml of ethanol, then concentrated in vacuo, taken up in water and precipitated after suction dilute sulfuric acid. The 2-methoxymethyl-4 - (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarbonsäurediäthylester-6-carboxylic acid is obtained in the form of yellow crystals, melting at 146 ⁰ C in a yield of 96 5o of theory. .

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Example 22

"fa

H ₅ C ₂ OOC-OH ₂

The solution of 10.2 ml of pyridine-3-aldehyde, 16 g of methyl methoxyacetoacetate and 20 g of ß-iminoglutaric acid ethyl ester in 40 ml of ethanol is heated to boiling overnight and then cooled. After cooling, the 2-methoxymethyl-4- (β-pyridyl) -1, ^ - dihydropyridine-J ^ - dicarboxylic acid diethyl ester-6-acetic acid ethyl ester is obtained in the form of pale yellow crystals of pp. 104-1o6 ° C. in a yield of 65 $> the theory.

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Example 23

H ₅ C ₈ 0OC ^, M. ^ COOC ₂ H ₅ CH ₂ OCH ₃

The solution of 5.2 ml of pyridine-2-aldehyde is heated, 8 g of ethyl isobutyroyl acetate and 8 g of ß-amino-γ-methoxycrotonic acid ethyl ester (Kp.ll2-ll6 ° / 10 mm) in 40 ecm of ethanol to boil overnight, concentrates, takes up in ether and precipitates the 2-methoxymethyl-6-isopropyl-A- (a-pyridyl) -l, 4-dihydropyridine ~ 3,5-dicarboxylic acid diethyl ester as hydrochloric acid salt with ethereal hydrochloric acid.

Light yellow crystals with a melting point of 198-200 °, yield

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Example 24

H ₅ C ₂ OOC ^ As. COOC ₂ H ₅ CH, OCH ₉ xSff A CH ₂ OCH ₃

7.5 g of 3-nitrobenzaldehyde and 16 g of γ-methoxyacetoacetate are heated and 5 g methylamine chlorohydrate in 40 ecm pyridine 5-6 hours at 90-100 °, concentrated i.V., takes up in ether, washes with dilute hydrochloric acid and water and evaporates the ethereal solution after drying a. The 1-methyl-2,6-dimethoxymethyl-4- (3'-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained as a brown oil in 90 # yield.

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Claims (17)

ClaimsHv 1.' Alkoxy alky ld ihydropyridine ester of the lormel ^H COOR ² in which R stands for hydrogen or a saturated or unsaturated aliphatic radical, R stands for alkoxy alkyl, 3
R and R are the same or different and for a straight-chain or branched, saturated or unsaturated or cyclic hydrocarbon radical, which is optionally substituted by 1 or 2 hydroxyl groups and / or optionally by 1 or 2 oxygen atoms in the Chain is broken, stand, B7 is hydrogen, alkyl, alkoxyalkyl or the '- (CH ₂ ) _n -COOR ⁵ radical, where R ^{5 is} hydrogen or alkyl and η is a number from 0 to 3, X is an aryl radical, which can optionally be substituted one to three times by nitro, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S (O) _m -alkyl, where m is a number from 0 to 2 be means phenyl, trifluoromethyl and / or halogen is substituted, where the substituents on the aryl radical can be the same or different, for benzyl, styryl, cycloalkyl, cycloalkenyl or Le A 15 o52 - 46 - 409885 / U52 represents a naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, puryl or pyrryl radical which is optionally substituted by alkyl, alkoxy, dialkylamino, nitro or halogen,
and their salts. 2. Compounds according to claim 1, wherein R is hydrogen, R for alkoxyalkyl with 1 or 2 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part stands, ^ i R and R ^ stand for alkyl with 1 to 4 carbon atoms, R for alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 or 2 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part, carboxyl, -CH ₂ -C00-alkyl or -COO -Alkyl, where alkyl is an alkyl radical having 1 to 4 carbon atoms, and X for phenyl, phenyl which by alkoxy or methylthio with 1 or 2 carbon atoms, cyano, nitro, hydroxy, trifluoromethyl, fluorine, chlorine, iodine, carboalkoxy with 1 to 4 carbon atoms and / or alkylsulfonyl with 1 to 4 carbon atoms is substituted one or two times, as well as for pyridyl and 2-dimethylaminopyrridyl stands. 3. 2-Ethoxymethyl-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and its salts. 4. 2-Ethoxymethyl-6-methyl-4- (3 ^f -iodophenyl) -1 ^ -dihydropyridines, 5-eicarboxylic acid diethyl ester and its salts. 5. Diethyl 2-ethoxymethyl-6-methyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-1-S-dicarboxylate and its salts; le A 15 o52 - 47 - 409886 / US2 «Ftf 6. 2-ethoxymethyl-6-methyl-4- (2'-chlorophenyl) - ^ ^ -dihydropyridines, 5-dicarboxylic acid diethyl ester and its salts. 7. 2-Ethoxymethyl-6-metb ^ l-4- (2 ^l -trifluoromethylpnenyl) -1,4-dihydropyridine-JjS-dicarboxylic acid diethyl ester in the form and its salts. 8. 2-Isopropoxymethyl-6-methyl-4-iX'-pyridyl-1,4-pyridine-3, ί5-eicarboxylic acid ethy lester and its salts. 9. 2-Ethoxymethyl-6-methyl-4- (2 -dimethylaminopyrimidyl) -1,4-dihydropyridine-3 »5 -dicarboxylic acid diethyl ester and its salts. 10. Ethyl 2,6-dimethoxymethyl-4- (2 ^f -chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and its salts. 11. 2,6-Dimethoxymethyl-4- (2 ^l -trifluoromethylphenyl) -1,4-dihydropyridine- ^ jS-dicarboxylic acid diethyl ester and its salts. 12. 2,6- (Diethoxymethyl) -4- (2'-nitrophenyl) -1,4-dihydropy Ridin-3,5-dicarboxylic acid diethyl ester and its salts. 13. Ethyl 2,6- (diethoxymethyl) -4-oC-pyridyl-1,4-dihydropyridine-3,5-dicarboxylate and its salts. 14. 2-Methoxymethyl-6-methyl-4- (3'-carbethoxyph. Enyl) -1,4-dibydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethyl ester and its salts. Le A 15 o52 - 48 - 409885 / U52 15. Process for the preparation of alkoxy alky ld ihydropyridine esters of the! formula R ³ OOC _ X '/ COOK' in which R stands for hydrogen or a saturated or unsaturated aliphatic radical, R ^{1 represents} alkoxyalkyl, "5 R and R are the same or different and for a straight-chain or branched, saturated one or unsaturated or cyclic hydrocarbon radical, which is optionally replaced by 1 or 2 hydroxyl groups substituted and / or optionally is interrupted by 1 or 2 oxygen atoms in the chain, stand, R ⁴ ″ represents hydrogen, alkyl, alkoxyalkyl, or represents the - (CH ₂ ) _n —COOR radical, where R represents hydrogen or alkyl and η represents a number from 0 to 3, and represents X is an aryl radical which can optionally be substituted one to three times by methyl, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbalkoxy, amino, acylamino, monoalkylamino, dialkylamino, S (O) _m -alkyl, where m is a number of 0 to 2 denotes, phenyl, trifluoromethyl and / or halogen is substituted, it being possible for the substituents on the aryl radical to be identical or different, for benzyl, styryl, cycloalkyl, cycloalkenyl or for an optionally substituted by alkyl, Le A 15 052 - 49 - A09885 / U52 Alkoxy, dialkylamino, nitro or halogen substituted naphthol, quinolyl, isoquinolyl, Pyridyl, iyrimidyl, diphenyl, furyl or Pyrryl radical, and their salts, characterized in that a) Q-Ke tocarboxylic acid esters of the formula R ¹ -CO-CH ₂ -COOR ² in which 1 2
R and R have the meaning given above, with amines of the formula H ₂ NO in which R has the meaning given above, or their salts, if appropriate after isolation the enamines optionally formed from the β-ketocarboxylic acid esters and the amines or amine salts. the formula i-R NH- R'-C = CH-COOR ² in which 1 2 R, R and R have the meaning given above,
with ylidene derivatives of the formula COOR ³ in which
X, R and R ^{4 have} the meaning given above, implements;
Ie A 15o52 - 50 - 409885/1452 or b) ß-Keto carboxylic acid ester of the formula R ^ -CO-CH ₂ -COOR ⁵ in which 'S? and R ^ have the meaning given above, with amines of the formula H ₂ NO in which R has the meaning given above, or their salts, if appropriate after isolation of the from the ß-ketocarboxylic acid esters and the amines or amine salts optionally resulting enamines of formula JH-R R ⁴ -C = CH-COOR ⁵ in which R, R and R have the meaning given above possess, with ylidene derivatives of the formula X-CH = C-CO-R ¹ 'COOR ^ in which 1 2
R, R and X have the meaning given above own, implement;
or
c) ß-ketocarboxylic acid ester of the formula in which 3 4 R and R have the meaning given above, Le A 15 o52 - 51 - 409885 / U52 with enamines of the formula I-R NH- R'-G = CH-COOR ² in which 1 R., R and R have the meaning given above own, and with aldehydes of the formula X-CHO in which X has the meaning given above, converts;
or
d) ß-ketocarboxylic acid ester of the formula R ¹ -CO-CH ₂ -COOR ² in which R and R have the meaning given above, with enamines of the formula NH-R R ^ -C = CH-COOR ⁵ in which 3 R, R ^ and R ^ have the meaning given above, and with aldehydes of the formula X-CHO in which X has the meaning given above, converts;
or Le A 15 o52 - 52 - 409885/1452 J ₃ ] e) if R ^{1 is} identical to R ^4- and R is identical to R *, two parts of ß-ketocarboxylic acid ester of the formula R ^ -CO-OH ₂ -COOR ⁵ in which B / and R ⁴ ″ have the meaning given above, with part of the amine of the formula H ₂ NO in which R has the meaning given above, or its salt and with part of the aldehyde formula X-CHO
in which X has the meaning given above, converts, and if necessary from the compounds obtained according to process variants a) to e) with a Acid makes the salt. 16. Medicines characterized by a content of at least one alkoxyalky! dihydropyridine ester according to Claim 1. 17. A process for the preparation of vascular influencing agents, characterized in that one AlkoxyalkyIdihydropyridinester according to claim 1 mixed with inert, non-toxic, pharmaceutically suitable carriers. Le A 15 o52 - 53- 409885/1452