DD292451A5 - PROCESS FOR PREPARING BASIC NITRO-PHENYL-DIHYDROPYRIDINAMIDES - Google Patents

Abstract

The invention relates to a process for the preparation of basic nitro-phenyl-dihydropyridine amides on new intermediates. The compounds are used as circulatory drugs for the treatment of pathologically altered blood pressure and heart failure. According to the invention, compounds of the formula (Ia) are prepared in which R1, R2, R3, R4, X and Y have the meaning given in the description and in the claims. Formula (I a) {novel basic nitrophenyl dihydropyridine amides; Medicinal products, influencing the circulation; Hypertension; Herzrhythmusstoerungen; Electrolyte and fluid balance}

Description

Field of application of the invention

The present invention relates to a process for the preparation of partially known nitrophenyl-dihydropyridinamidon. The compounds according to the invention are used as circulation-influencing drugs, for example for the treatment of hypertension, cardiac arrhythmias, renal insufficiency, cirrhosis, ascites, edema, glaucoma and diabetes.

Characteristic of the known state of the art

It is already known that basic 4-aryl-dihydropyridineamines are used as intermediates for the preparation of 1,4-dihydropyridine hydroxyalkylamines (cf EP-A179386).

In this publication dihydropyridine derivatives are described which carry a hydroxyalkylamine ester group in the 3-position. The substituent X in the 5-position in its general meaning also includes amide radicals. The preparation of the active ingredients described there takes place, inter alia, via dihydropyridineamines of the general formula (II), which are used there as intermediates. The general definition of these intermediates of formula (II) includes, among others, dihydropyridinamides, but without naming a specific representative of this class. This publication also contains no indication of any pharmacological effect of these intermediates used there. In DE-OS 2228377 dihydropyridine carboxylic acid amides, several processes for their preparation and their use as circulation-influencing agents are described. The compounds mentioned therein differ from the active compounds according to the invention in that the 3- and 5-positions of the dihydropyridine ring either simultaneously carry an amide group or one of these positions carries an ester group which, however, in turn contains no basic groups. In contrast, the ester radical of the compounds to be used according to the invention always contains a basic radical (see definition X and Y).

Also in EP-A 0220653 dihydropyridine derivatives are described which contain an amide group in the 3-position and an ester group in the 5-position. Also in this case, the ester group no longer carries a basic radical. These known monoamides also have circulatory effects.

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties which are suitable, for example, for the treatment of hypertension and cardiac insufficiency.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

It has been found that the 4-nitrophenyl-dihydropyridineamides of the general formula (I)

in which

R ¹ and R ^{2 are the} same or different and are ¹ and

- mean hydrogen, or

- represent cycloalkyl having 3 to 8 carbon atoms, or

- represent straight-chain or branched alkyl or alkenyl, each having up to 12 carbon atoms, optionally

are 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, carboxy or alkoxycarbonyl having up to 8 carbon atoms or by Phenyl, which in turn is substituted by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl of up to 4 carbon atoms

or alkoxy having up to 4 carbon atoms or may be substituted by a group -NR ⁵ R ⁹ ,.

wherein'

R ⁵ and R ^{e are the} same or different and denote hydrogen, alkyl having up to 8 carbon atoms, aryl or aralkyl,

- are phenyl which is up to 3 times the same or different from nitro, cyano, halogen, alkyl having up to 6 carbon atoms,

Alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino having up to 8 carbon atoms per alkyl group, dialkylamino having up to 8 carbon atoms per alkyl group, acetylamino or benzoylamino may be substituted, or

R ¹ and R ² together form a 5- to 7-membered saturated or unsaturated, heterocyclic ring which may contain as additional heteroatom an oxygen atom, a sulfur atom, a nitrogen atom, or a radical NR ⁷ , wherein R ^{7 is} hydrogen, Ci-Ce- Alkyl, aryl or aralkyl

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

- represent straight-chain, branched or cyclic alkyl having up to 8 carbon atoms, optionally by

Substituted hydroxy, cyano, phenyl or halogen X - for a goradkettigen, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to

12 carbon atoms, optionally substituted by an oxygen, sulfur or nitrogen atom, or a

Group NR ^{8 is} interrupted,

wherein

R ^{8 is} hydrogen, or

- is alkyl having up to 6 carbon atoms, which may be optionally substituted by halogen, hydroxy, acetoxy, carboxy, Ci-C ₈ alkoxycarbonyl or phenyl, which in turn may be substituted by halogen, C, -C ₆ alkyl, C ) -C ₆ -alkoxy, halomethyl, halomethoxy or cyano,

Y - pyridyl means, or

- represents a group of formula NR ⁹ R ^t0 ,

wherein

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

- mean hydrogen, or

represent straight-chain or branched alkyl, alkenyl or alkynyl having in each case up to 12 carbon atoms which may be substituted by halogen, hydroxy, alkoxy having up to 8 carbon atoms, cyano, trifluoromethyl, alkylthio having up to 8 carbon atoms, alkylcarbonyl having up to 8 carbon atoms , Alkoxycarbonyl having up to 8 carbon atoms or by phenyl, which in turn may be substituted by nitro, phenyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms, halogen or alkoxy having up to 4 carbon atoms, or

- represent cycloalkyl having 3 to 8 carbon atoms, or

- are aryl having 6 to 10 carbon atoms, which are up to 3 times the same or different by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthk. with up to 6 carbon atoms, carbamoyl.Dialkylcarbamoyl each having up to 6 carbon atoms per alkyl group,

Trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino with up to

β carbon atoms, dialkylamino each having up to 8 carbon atoms per alkyl group may be substituted, or

R ⁹ and R ¹⁰ together form a 5- to 7-membered, saturated or unsaturated, heterocyclic ring containing a Oxygen atom, a sulfur atom or an additional nitrogen atom may be included, optionally

a radical R "is substituted,

wherein

R "- is hydrogen, or

for a straight-chain or branched, saturated or unsaturated alkylene group up to

10 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by halogen, C, -C ₄ alkyl, C ₁ -C ₄ -alkoxy, nitro or haloalkyl having up to 4 carbon atoms, or

- is phenyl, which is optionally substituted by halogen, cyano, nitro, alkyl of up to 4 carbon atoms, alkoxy of up to 4 carbon atoms or haloalkyl of up to 4 carbon atoms,

surprisingly, in addition to the expected calcium antagonist activity, also show a strong antiarrhythmic activity and influence the salt and fluid balance and are thus suitable for use in the control of hypertension and cardiac insufficiency.

The physiologically acceptable acid addition salts of the compounds of the general formula (I) as well as the racemic forms, the antipodes and the diastereomer mixtures are preferably suitable for this novel use.

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

R ¹ and R ^{2 are the} same or different and

- mean hydrogen, or

- represent cycloalkyl having 3 to 8 carbon atoms, or

- represent straight-chain or branched alkyl or alkenyl, each having up to 10 carbon atoms, which are optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonyl, C 1 -C 4 -alkyl, Alkoxycarbonyl, carboxy or by phenyl, which in turn may be substituted by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl, methoxy or by a group of the formula -NR ⁶ R ⁸ ,

R ⁶ and R ^{s are the} same or different and

are hydrogen, C 1 -C 6 -alkyl, benzyl, phenethyl or phenyl,

- represent phenyl which is optionally substituted up to 2 times identically or differently substituted by fluorine, chlorine, C, -C ₄ alkyl, Ci-C ₄ -alkoxy, Ci-C ^ AIkylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or

R 'and R ² together are pyridyl, pyrrolidyl, piperidyl, morpholinyl, or

- are optionally substituted by C, -C ₄ alkyl, benzyl or phenethyl substituted piperazinyl, R ³ and R ^{4 are the} same or different and \

- represent straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by fluorine, chlorine, phenyl or hydroxyl,

X - is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms, which is optionally interrupted by an oxygen, a sulfur or a nitrogen atom, or by a radical NR ⁸ , wherein

R * - hydrogen means, or

- is C ₁ -C ₄ -A ^ yI, which is optionally substituted by fluorine, chlorine, hydroxyl, carboxyl or by phenyl, which in turn by fluorine, chlorine, C, -C ₄ alkyl, Ci-C ₄ -AIkOXy , Trifluoromethyl or trifluoromethoxy may be substituted,

Y - pyridyl means, or

- represents a group of the formula NR ⁹ R ¹⁰ ,

wherein

R ⁹ and R '° are the same or different and

- mean hydrogen, or

- represent straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be substituted by fluorine, chlorine, hydroxyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -AlkVHhIO, CHVAIkylcarbonyl, carboxy or Ct-C _e -alkoxycarbony I, or by phenyl, which in turn may be substituted by trifluoromethyl, C ₁ -C ₂ -AIRyI, fluorine, chlorine or Ci-C ₂ alkoxy, or

are cycloalkyl having 3 to 8 carbon atoms, or

stand for phenyl which is up to 2 times by identical or different nitro, cyano, fluorine, chlorine, bromine, C _t -C ₄ alkyl,

C ₁ -C ₄ -alkoxy, Ci-C ₄ alkylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, Trif luormethylthio. amino, Alkylamino may be substituted with up to 4 carbon atoms, or

R ⁹ and R ¹⁰ together form a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain an oxygen or sulfur atom or an additional nitrogen atom optionally substituted by an R ¹ 'radical wherein R "- represents hydrogen, or

for a straight-chain or branched, saturated or unsaturated alkyl group with up to

4 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by fluorine, chlorine, C ₁ -C ₂ -AlkYl, C ₁ -C ₂ -alkoxy or C ₁ -C ₂ haloalkyl, or

- represents phenyl which is optionally substituted by fluorine, chlorine, cyano, C ₁ -C 2 alkyl, C ₁ -C ₂ -alkoxy or C, -C ₂ -haloalkyl substituted

and their physiologically acceptable salts for the control of hypertension and heart failure.

Particular preference is given to compounds of the general formula! (I) used

in which

R ¹ and R ^{2 are the} same or different and

- represent hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

- represent straight-chain or branched alkyl or alkenyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, hydroxyl, C ₁ -C ₄ -alkoxy, C) -C ₄ alkylthio, carboxy, CH ^ alkoxycarbonyl or by Phenyl, which in turn may be substituted by chlorine, fluorine, methyl or methoxy, or

- represent phenyl, which may be substituted by fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, R ³ and R ⁴

- stand for methyl and

X - is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, which is optionally interrupted by an oxygen, sulfur or nitrogen atom, or by a radical NR ⁸ , where R ^{8 is} - hydrogen, or

- is methyl, ethyl, benzyl, phenethyl or phenyl, which is optionally fluorine, chlorine, methyl, methoxy,

Trifluoromethyl or Trifluorniethoxy is substituted, Y - is pyridyl, or ^v

a group of formula NR ⁹ R ¹⁰ wherein R ⁹ and R ^{10 are the} same or different and

- mean hydrogen, or

represent straight-chain or branched alkyl or alkenyl having up to 4 carbon atoms, which may be substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxycarbonyl or by phenyl, which in turn may be substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy, or are cyclopropyl, cyclopentyl or cyclohexyl, or

- are phenyl which is up to twice the same or different by fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, amino, C, -C ₂ alkylamino or C, -C ₂ dialkylamino may be substituted or

R ⁹ and R '° together form a 5- to 7-membered saturated ring which is an oxygen, sulfur or a

may additionally contain nitrogen atom, which is optionally substituted by a radical R ¹¹ , wherein

R ^{11 is} hydrogen, C ₁ -C ₄ alkyl, benzyl or phenethyl, or

- is phenyl which may be substituted by fluorine, chlorine, methyl or methoxy and their physiologically acceptable salts in the control of hypertension and heart failure.

The compounds of the invention show an unpredictable, valuable, pharmacological spectrum of activity. you

affect the contraction force of the heart, the smooth muscle tone and the electrolyte and

Fluid balance. They may therefore be used for the manufacture of medicaments for the treatment of pathologically altered blood pressure and the Heart failure and coronary therapeutics. In addition, they may be used in the manufacture of medicaments for the treatment of cardiac arrhythmias, Renal insufficiency, liver cirrhosis, ascites, pulmonary edema, cerebral edema, pregnancy edema, glaucoma or diabetes mellitus

be used.

The invention further relates to novel 4-nitrophenyl-dihydropyridinamides of the general formula (Ia)

coo-xY ^(la)

in which

R * and R ^{2 are the} same or different and

- mean hydrogen, or

- represent cycloalkyl having 3 to 8 carbon atoms, or

- represent straight-chain or branched alkyl or alkenyl, each having up to 12 carbon atoms, which are optionally 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, carboxy or alkoxycarbonyl having up to 8 carbon atoms or by phenyl, which in turn may be substituted by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms or by a group --NR ⁶ R ⁶ ,

R ⁵ and R ^{e are the} same or different and

for hydrogen, alkyl having up to 8 carbon atoms,

- are phenyl which is up to 3 times the same or different by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoro. iiethylthio, amino, alkylamino mtt may be substituted up to 8 carbon atoms, dialkylamino having up to 8 carbon atoms per alkyl group, acetylamino or benzoylamino, or

R 'and R ² together form a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain, as an additional heteroatom, an oxygen atom, a sulfur atom, a nitrogen atom or an NR ⁷ radical, wherein R ^{7 is} hydrogen, C ₁ -C ₆ -AIkYl, aryl or aralkyl

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

- represent straight-chain, branched or cyclic alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy, cyano, phenyl or halogen.

X - for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to

12 carbon atoms which is optionally interrupted by an oxygen, a sulfur or a nitrogen atom, or a group NR ^{8 is} interrupted.

wherein

R ^{8 is} hydrogen, or

- represents alkyl having up to 6 carbon atoms, which may be optionally substituted by halogen, hydroxy, acetoxy, carboxy, Ci-Ce-alkoxycarbon / I or phenyl, which in turn may be substituted by halogen, C | -C _e alkyl, C C ₁ -C ₈ -alkoxy, halomethyl, halomethoxy or cyano,

Y - pyridyl means, or

- represents a group of the formula -NR ⁹ R ¹⁰ ,

wherein • R ⁹ and R '° are the same or different and

- is hydrogen or straight-chain or branched alkyl, alkenyl or alkynyl, each with up to

12 carbon atoms, which may be substituted by halogen, hydroxy, alkoxy having up to 8 carbon atoms, cyano, trifluoromethyl, alkylthio having up to 8 carbon atoms, alkylcarbonyl having up to 8 carbon atoms, alkoxycarbonyl having up to 8 carbon atoms or by phenyl, which in turn may be substituted by nitro, phenyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms, halogen or alkoxy having up to 4 carbon atoms, or

- represent cycloalkyl having 3 to 8 carbon atoms, qder

are aryl having 6 to 10 carbon atoms, which are up to 3 times the same or different from 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 I having in each case up to 6 carbon atoms per alkyl group,

Trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino with up to

8 carbon atoms, dialkylamino each having up to 8 carbon atoms per alkyl group may be substituted, or

R ⁹ and R ¹⁰ together form a 5- to 7-membered, saturated or unsaturated, heterocyclic ring containing a Oxygen atom, a sulfur atom or an additional nitrogen atom may be included, optionally

a radical R "is substituted,

wherein

R ¹¹ - is hydrogen, or

for a straight-chain or branched, saturated or unsaturated alkylene group up to

10 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by halogen, C, -C ₄ alkyl, C ₁ -C ₄ -alkoxy, nitro or haloalkyl I having up to 4 carbon atoms, or

- is phenyl, which is optionally substituted by halogen, cyano, nitro, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or haloalkyl having up to 4 carbon atoms,

and their physiologically acceptable salts.

The compounds of the invention exist in stereoisomeric forms, which are either like image and mirror image

(Enantiomers) or which do not behave like image and mirror image (diastereomers). The invention relates to both the

Antipodes as well as the racemic forms and the diastereomer mixtures. The Racemformen can be just like the Separate diastereomers in a known manner into the stereoisomerically uniform components (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962). Physiologically acceptable salts may be salts of the compounds of the invention with inorganic or organic Be acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid. Phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, Maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, Ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Preference is given to compounds of the general formula (Ia)

in which

R ¹ and R ^{2 are the} same or different and

- mean hydrogen, or

- represent cycloalkyl having 3 to 8 carbon atoms, or

represent straight-chain or branched alkyl or alkenyl, each having up to 10 carbon atoms, which are optionally substituted by fluorine, chlorine, hydroxyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₄ -alkylcarbonyl, Ce-alkoxycarbonyl, carboxy or by phenyl, which in turn may be substituted by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl, methoxy or by a group of the formula -NR ⁶ R ⁶ ,

R ⁶ and R ^{s are the} same or different and

are hydrogen, C ₁ -C ₆ -alkyl, benzyl, phenethyl or phenyl,

- are phenyl, which is unfolded up to twice the same or different substituents by fluorine, chlorine, C, -C ₄ alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy , or

R ¹ and R ² together represent pyridyl, pyrrolidyl, piperidyl, morpholinyl, or

- are optionally substituted by C ₁ -C ₄ alkyl, benzyl or phenethyl substituted piperazinyl, R ³ and R ^{4 are the} same or different and

- represent straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by fluorine, chlorine, phenyl or hydroxyl,

X - represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 10 carbon atoms, which is optionally interrupted by an oxygen, a sulfur or a nitrogen atom, or by a radical NR ⁸ .

wherein

R ^{8 is} hydrogen, or

is C 1 -C ₄ -alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, carboxyl or by phenyl, which in turn is substituted by fluorine, chlorine, C ₁ -C ₄ -AIM / C ₁ -CrAlkoxy, trifluoromethyl or

Trifluoromethoxy may be substituted, Y - pyridyl means, or

- is a group of formula NR ⁹ R ' ⁰ , wherein

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

- is hydrogen or straight-chain or branched alkyl or alkenyl, each having up to 8 carbon atoms

stand, which can be substituted by fluorine, chlorine, hydroxyl, C ₁ -C ₄ -alkoxy, C, -C ₄ alkylthio, Ci-CrAlkylcarbonyl, carboxy or Ci-Ce-alkoxycarbonyl, or by phenyl, which in turn, by trifluoromethyl C ₁ -C ₂ -alkyl, fluorine, chlorine or C ₁ -C ₂ -alkoxy may be substituted, or represent cycloalkyl having 3 to 8 carbon atoms, or

- stand for phenyl which is up to 2 times by identical or different nitro, cyano, fluorine, chlorine, bromine, C, -C ₄ alkyl, C) -C ₄ -alkoxy, C | -C 4 alkylthio, trifluoromethyl, trifluoromethoxy, Difluoromethoxy, trifluoromethylthio, amino,

Alkylamino may be substituted with up to 4 carbon atoms, or

R ⁹ and R ¹⁰ together form a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain an oxygen or sulfur atom or an additional nitrogen atom which is optionally substituted by a radical R ¹ 'wherein R "- represents hydrogen , or

for a straight-chain or branched, saturated or unsaturated alkyl group with up to

4 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by fluorine, chlorine, Ci-C ₂ -alkyl, C ₁ -C ₂ -alkoxy or C ₁ -C ₂ -haloalkyl, or

- is phenyl, which is optionally substituted by fluorine, chlorine, cyano, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy or C 1 -C ₂ -haloalkyl

and their physiologically acceptable salts.

Particular preference is given to compounds of the general formula (Ia)

in which

R * and R ^{2 are the} same or different and

- represent hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

- represent skeletal or branched alkyl or alkenyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, hydroxyl, C ₁ -C ₄ -alkoxy, C) -C ₄ alkylthio, carboxy, Cr-Q-alkoxycarbonyl or by phenyl, which in turn may be substituted by chlorine, fluorine, methyl or methoxy, or

- represent phenyl, which may be substituted by fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, R ³ and R ⁴

- stand for methyl and

X - represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms, which is optionally interrupted by an oxygen, sulfur or nitrogen atom, or by a radical NR ⁸ , wherein R ^{8 is} hydrogen, or

- is methyl, ethyl, benzyl, phenethyl or phenyl which is optionally substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy,

Y - stands for pyridyl, or

- represents a group of the formula -NR ⁸ R ¹⁰ , in which

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

are hydrogen or straight-chain or branched alkyl or alkenyl having up to 4 carbon atoms, which may be substituted by fluorine, chlorine, hydroxyl, Ct-C ^ alkoxycarbonyl or by phenyl, which in turn may be substituted by fluorine, chlorine, trifluoromethyl, methyl or methoxy , or

- represent cyclopropyl, cyclopentyl or cyclohexyl, or

- are phenyl which is up to twice the same or different by fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, amino, C, -C ₂ alkylamino or C, -C ₂ dialkylamino may be substituted or

R ⁹ and R ¹⁰ together form a 5- to 7-membered saturated ring containing an oxygen, sulfur, odor

may contain additional nitrogen atom which is optionally substituted by a radical R ¹ ', wherein

R "- is hydrogen, Ci-C ₄ alkyl, benzyl or phenethyl, or

- is phenyl which may be substituted by fluorine, chlorine, methyl or methoxy and their physiologically acceptable salts.

Very particularly preferred compounds of general formula (I a) and (I) in which R ¹ and R ² are the same or different for each elndojnd

- hydrogen, alkyl with 1-4 C atoms, or

- represent cyclopropyl or cyclopentyl,

R ³ and R ^{4 are} methyl, X is a straight-chain or branched alkyl chain having up to 4 carbon atoms, and Y is pyridyl or morpholino or is a group of the formula -NR ⁹ R ¹⁰ , wherein R ⁹ and R ^{10 are the} same or different

and each represents hydrogen, methyl, ethyl or benzyl, and their physiologically acceptable salts

 The new compounds of the formula (Ia) according to the invention also show an unpredictable, valuable spectrum of pharmacological activity. They influence the contraction force of the heart, the tone of the smooth muscle as well as 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 Coronary therapeutics are used. In addition, they may be used to treat cardiac arrhythmias, renal insufficiency, cirrhosis, ascites, Pulmonary edema, cerebral edema, pregnancy edema, glaucoma or diabetes. The compounds of the general formula (I) or (Ia) according to the invention

COO-XY ^(l)

in which

R ', R ² , R ³ , R ⁴ , X and Y have the abovementioned meaning, is obtained by reacting

[A] aldehydes of the general formula (II)

(H)

CHO

and β-ketocarboxylic acid esters of general formula (III) Y-X-OOC ^

F ³ ^

in which

R ³ , X and Y have the meaning given above, optionally after isolation of the Yiidenverbindung resulting therefrom

of general formula (IV)

(IV)

in which

R ³ , X and Y have the abovementioned meaning, with β-ketocarboxamides of the general formula (V)

rS-CO-C-COO-X-Y

CO-N

\ _R 2 (V)

in which

R ¹ , R ² and R ^{4 have} the abovementioned meaning and ammonia bzv /. directly with the produced from it

ß-Aminocrotonsäureamiden the general formula (Vl)

in which

R ', R ² and R ^{4 have} the o' .. given meaning, implements, or By

[B] aldehydes of the general formula (II) and β-ketocarboxamides of the general formula (V) or their ylidene compounds of the general formula (VII)

(VII)

in which

R ¹ , R ² and R ^{4 have} the abovementioned meaning, with β-ketocarboxylic acid esters of the general formula (III) and ammonia

or directly with the aminocrotonic acid esters of the general formula (VIII) prepared therefrom

Y-X-

in which

R ³ , X and Y have the abovementioned meaning, or to give compounds of the general formula (I),

in which

R ¹ , R ² , R ³ , R ⁴ and X have the abovementioned meaning, Y is a group of the formula NR ⁹ R ¹⁰ and R ⁹ and / or R ^{10 are} reactive hydrogen, suitably

by

(C) benzylidene compounds of the general formula (VII) first with compounds of the general formula (VIII a)

(Villa)

in which R ³ and X have the meaning given,

Z is an acylated amino protecting group, preferably tert-butoxycarbonylamino or phthalimide, to compounds of the

general formula (IX)

coo-xz ^(IX >

in which R ¹ , R ² , R ³ , R ⁴ and X have the abovementioned meaning, and Z - for the group

-N-COO-C-CH ₃

or

stands,

deblocked in a further step by known methods and the resulting intermediate compounds of the formula (IXa),

R ² /

N-OC

(IXa)

in which R ¹ , R ¹ , R ³ , R ⁴ , X and R ^{9 have} the abovementioned meaning, to compounds of general formula (I), in which

Y is the group NR ⁹ R ' ⁰ , wherein R ⁹ and R ^{10 have} the abovementioned meaning, with the proviso that R ⁹ and / or R ¹⁰

are different from hydrogen, further reacted, or by

[D] Dihydropyridine monocarboxylic acids of the general formula (Xa) or (Xb)

HOO

COO-X-Y

COOH

(Xa)

(Xb)

in which

R ¹ , R ² , R ³ , R ⁴ , X and Y have the abovementioned meaning, optionally via reactive acid derivatives with amines of

general formula (XIa)

(XIa)

in which

R ¹ and R ^{2 have} the abovementioned meaning, or with compounds of the formula (XIb)

HO-X-Y

(XIb)

in which

X and Y have the meaning given above, wherein in each case only (Xa) is reacted with (XI a) and (Xb) with (XIb). Examples of reactive acid derivatives which may be mentioned are:

activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides or the reaction in

Presence of cyclohexylcarbodiimide. Depending on the nature of the starting materials used, the synthesis variants for the compounds of the invention by

the following formula schemes are displayed:

option A

HoC ³

, "3 ^l

NH ₂ CH ₂ C-OOCX ^ TXH

H ₃ C

H ₃ C

NH ₂ CH ₂ C-

Variant B

HoC ³

^H 5 ^C 2

NH ₂ CH ₂ C-OOCs ^ H

CO-NH-CH-

H ₃ C

H ₅ C ₂ H ₃ C- - v - n ₃

Variant D

-00C

N-C-N

N =

/ -H ₂ CN- (H ₂ C) ₂ -OOC

CH

H ₃ C

/ -H ₂ CN- (H ₂ C) ₂ -OOC CH ₃ H ₃ C

HOOC

'CO-NH-C ₄ H ₉

HCC,

DCC / N-CHO-CH ₉ -OH ^H 5 ^C 2

N- (H ₂ C) ₂ -OOC

^H 5 ^C 2

CO-NH-C ₄ H ₉

Process variants A-D

Suitable solvents are water or all inert organic solvents which do not change under the reaction conditions. These include, preferably, alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides such as dimethylformamide, dimethylacetamide or 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 + 1O ⁰ C and + 15O ⁰ C, preferably between + 2O ⁰ C and + 10O ⁰ C _1, in particular at the boiling point 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-D 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 takes place vorzugswe ises such that the solvent is distilled off in vacuo and recrystallized, if appropriate, the crystalline obtained after cooling with ice from a suitable solvent. In some cases, it may be necessary to purify the compounds of the invention by chromatography.

The aldehydes of the general formula (II) used as starting materials are known or can be prepared by known methods (DOS 2165260, 240166E, TD Harris, GP Roth, J. Org.Chem 44, 004 (1979), WJ Dale, HEHennis J. Am. Chem. Soc. 78, 2543 (1956); Chem. Abs. 59, 3929 [1963]).

The β-ketocarboxylic acid esters of general formula (III) used as starting materials are known or can after

Bomas, in Houben Weyl's "Methods of Organic Chemistry" Vol. VII / 4,230 [1968]; Y. Oikawa, K. Suugano, O. Yonemitsu, J. Org. Chem. 43,2087 [1978]. ).

The enamines of the general formulas (VI) and (VIII) used as starting materials are known or can be prepared by known processes Methods (DOS 2228377; F. A. Gickman, A. C. Cope, J. Am. Chem. Soc., 7, 1017 [1945j]. The implementation of the process variant D according to the invention is based on the literature-known methodology for the transfer

of carboxylic acids in carboxylic acid amides. The carboxylic acid is first in an activated form such. For example, the acid chloride or imidazolide, which are either isolated as such and reacted in a second reaction step, or which are amidated in situ directly to the compounds of the invention. 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-cyclohexyl-3- [2- (N-methylmorpholino) ethyl | carbodiimide p-toluenesulfonate or N-hydroxyphthalimide or N Hydroxy benzotriazole in the presence of

Dicyclohexylcarbodiimide exemplified. Naturally, the Dihydropyridinmonocarbonsäuren also in the form

their salts. (The method of amidation is described, for example, Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc. [1967], pages 231-236, JC Shihan and GP Hess, J. Am. Chem. Soc., 77, 1067 [1955]; U.Goodman, GWKenner.Adv. In Protein Chem., 12, 488 [1957]; WABonner, PIMcNamee, J. Org. Chem. 26, 254 [1961]; HAStaab, Angew. Chemie 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. Tr at v. 80, 1372 (19Θ-1); CABuehler, DE Pearson, John Wiley & Sons, Volume I11970], page 895 et seq., Volume II, [1977]).

Suitable solvents for process variant D, in addition to water, all inert organic solvents in question, which are among the Do not change reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, Glycol monomethyl ether or glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane

or tetrachloromethane, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or

Hydrocarbons such as benzene, toluene or xylene, or acetonitrile, nitromethane, Py ridin, dimethyl sulfoxide or ethyl acetate. Likewise, mixtures of the solvents mentioned can be used. Isolating the activated intermediate stages of the Dihydropyridine monocarboxylic acids, so the amines of formula (XIa) can be used alone as a diluent

become.

The reaction temperatures can be varied in a wide range. In general, one works in a range of

-7O ⁰ C to + 14O ⁰ C, preferably from -20 ⁰ C to + 100 ⁰ C.

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

you work at normal pressure.

When carrying out process variant D according to the invention, the ratio of the substances involved in the reaction is

any. In general, however, one works with molar amounts of the reactants. However, it has proved to be beneficial, the

Use amine in a 5- to 10-fold molar excess. Particularly useful is the amine in a large excess

used directly as a solvent.

The cleavage of the amino protecting group is carried out in a conventional manner, for example under acidic conditions, or

when Z is the phthalimide, the deprotection is usually carried out with hydrazine hydrate in organic

Solvents such as ethers, z. As tetrahydrofuran or dioxane, or alcohols ι. As methanol, ethanol or isopropanol. ' The Ai nine used as starting materials of the general formulas (Xl a) and (Xl b) are known or can be prepared by known Methods (Houben Weyl's. Methods of Organic Chemistry * Bd XI / 1; Paulsen, Angewandte Chemie 78,

501-566 (1966]).

The invention also relates to the novel intermediates of the general formulas (IX) and (IXa) N-O-C-O-C-N-O-C-C-O-N-OCV ^^^ COO-X-NH-R ⁹

(IX) (IXa)

in which

R ¹ , R ² , R ³ , R ⁴ , X, Z and R ^{9 have} the abovementioned meaning. The preparation of these new intermediates of general formulas (IX) and (IXa) is carried out by Benzylidenverbindungrn of the general formula (VII) with compounds of the general formula (Villa) optionally in Presence of inert organic solvents cyclized and the resulting compound of formula (IX) optionally

by deprotection of Z by known methods deblocked to compounds (IXa).

The new and known compounds of formula (I) and (Ia) show an unpredictable, valuable

pharmacological spectrum of action.They influence the contraction force of the heart, the smooth muscle tone as well as the electrolyte and fluid wedge.

You can therefore use in medicines for the treatment of pathologically altered blood pressure and heart failure, as well

used as coronary therapeutics.

In addition, they can be used to treat arrhythmias, renal insufficiency, cirrhosis of the liver, ascites, pulmonary soils, cerebral edema, pregnancy edema, glaucoma or diabetes mellitus. The cardiac activity of the compounds of the invention was found on the isolated, stimulated papillary muscle of the guinea pig heart. For this purpose, the experimental animals (200 g guinea pigs of both sexes) were killed, the thorax was opened and the heart removed. For the experiments, the smallest possible capillary muscles were then removed from the right ventricle and fixed horizontally in an organ 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 stimulated suprathreshold at a frequency of ¹ Hz. The organ bath, approximately 2 ml in volume, was continuously incubated with a Krebs-Henselelt solution (concentration in mM: NaC1118, NaHCO ₃ , KC110, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 1, Glucose 10, pH 7.4) at a rate of 4 ml / min at a temperature of 32 ⁰ C. The contractions of the papillary muscle were measured isometrically over the connected force transducer and registered on a recorder.

The substances according to the invention were optionally present in the Krebs-Henseleit solution at a concentration of 10 μg / ml

a solubilizer (DMSO to a concentration of 0.5%). The invention

Dihydropyridinecarbonamides showed an inhibition of the contraction force of the Papillary muscle by more than 10%. To test the renal effect, the substances were administered orally to awake male Wistar rats. After load

with saline, sodium excretion was measured in metabolic cages.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragees, Pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic,

pharmaceutically suitable carriers or solvents. Here, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90 wt .-% of the total mixture, d. H. in amounts sufficient to achieve the stated dosage margin.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or

Carriers, optionally using emulsifiers and / or dispersants, wherein z. B. in the case of Use of water as a diluent, where appropriate organic auxiliary solvents can be used. Examples of adjuvants are: Water, non-toxic organic solvents such as paraffins (eg petroleum fractions), vegetable oils (eg peanut / sesame oil), Alcohols (e.g., F'-ethyl alcohol, glycerin), carriers such as e.g. ground natural minerals (for example kaolins, clays, talc, chalk),

ground synthetic minerals (eg highly disperse silicic acid, silicates), sugars (eg cane, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates, arylsulfonates), detergents ( eg lignin-sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The application is carried out in the usual manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, tablets may of course be in addition to the mentioned excipients also additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients can be added to the abovementioned excipients with various flavor enhancers or dyes. In the case of parenteral administration, solutions of the active ingredients may be employed using suitable liquid carrier materials.

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 0.01 to 20mg / kg, preferably 0.1 to 10mg / kg of body weight. Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of administration route, the individual behavior towards the drug, the nature of its formulation and the time or interval at which it is administered , Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, 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 these in several single doses throughout the day.

embodiment

The invention is explained in more detail below with reference to some examples.

Herstellungsbefsplele Process variant D example 1

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid (2N-benzyl-N-methyl-ethyl) -ester-5-carboxylic acid ethylamide hydrochloride

H ₃ CNH ₂ CH ₂ C-OOC

H ₃ C

CO-NH-C ₂ H ₅

χ HCI

4g (7.5 mmol) of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-carboxylic acid (2-N-benzyl-N-methyl-ethyl-ester) -5-carboxylic acid imidazolide stirred with 40 ml of 50% ethylamine solution overnight. It is concentrated, taken up in ethyl acetate and washed twice with water, dried and concentrated. The resulting evaporation residue is purified over a silica gel. The clean fractions are concentrated and transferred to the hydrochloride. This gives 1.1 g of colorless crystals of melting point 150 ° C with decomposition.

Example 2

Process Variant A 1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3-carboxylic acid (p-N-morpholinoethyl) -ester-5-carboxylic acid cyclopentylamide

NH ₂ CH ₂ C-OOC

3.5 g MOmmol) 2-nitrobenzylidene-acetoacetic acid (β-N-morpholinoethyl) ester are boiled in 25 ml of isopropanol with 1.68 g (10 mmol) of β-aminocrotonic acid cyclopentylamide for 4 hours under argon. It is cooled, the precipitated crystals are filtered off with suction and washed with isopropanol. This gives 3.25 g of orange crystals of melting point 193 ° C. Analogously to the procedure for process variants A and D, the examples listed in the following table were prepared:

CM CC

α ·

(η ι_

a χι

CO

in

α χι

CO

in

in in

in ι

CM

in

R) Xl

in α in to

65 ° C

ID Xl VO CO

M CM CM CM O O O O O Z 2 2 2 2

CM X CJ? - O -CJ CM X U f- CD - CJ CM CJ as- η X - C J CM X U Γ ro 31 - <_> CM X O f- C7 - CJ CM CM CM CM CM CM SC O CM CM SC CJ CM. ac CJ CM CJ

η χ ο

α yes

Π «Η

ι /) α

α λ

(M CC (M «^

Λ JQ

»Η ι- <CD CD

β JQ

IT) «Ο

CD CD

CM ΙΛ ο ο

W

LO

OO

CM

»Η« Τ «Η I

(O

V)

CM CO CM (M CM O O O O O Z Z Z

<Μ

ο η

i-S

(M CJ

(M (M CJ

CM CJ

CM

CM

(M

ar.

JD Λ H

CJ

CJ

CJ

CJ

to

(Nl DS ι αι O. · in U (O Z Tabel "Dunz" <υ π Kort

α>

(D Xl

CJ

Ο *

(NJ

(Nl

SC X -CJ Y (Nl X O 1 Z -

(M (NI CJ

(M

(Nl

ac

CJ

y ν

α χι

η χι

Rome (M in ο in in h (M in

CJ

σ "

(NI (JN

(NJ (Nl (NJ (NJ (Nl O O O ο O Z Z ζ

(N] (Nl

(M

(NJ (NI CJ

(M (NI CJ (M

(NI CJ

ΙΛ ac χ ns (Nl (Nl O ο

in O

υ w

CJ

CJ

ω ο

CJ

CsI

CJ

"cm

(M

• -ι ι

O CM

CM O

I CM

CM O

I CO

CM O

CM

CM O

CJ

X CJ

CM CM CJ

CM CJ

η ι (M X CM CJ ac CM X ι O X -CJ I

(Z

ac

(M CJ

ιο

CM CJ

approx

O (M

CM CJ

(M

CM O

CM CM

p.

to to

Ot IO

σ) jj u O U.

Q. · CQ Z

"Ο

I CM

CM O

O ι

cn

CO co X X CJ U I cn ι ac ac ac CJ ο-γ

ro co

ΙΛ

CM CJ

• «3 · CM

Example 25

1,4-dihydro "2,6-dimethyl-4- (3-nitrophänyl) pyridine-3-carboxylic acid (2-aminometbvii-ester-5-carboxylic acid cyclopropylamir;

H ₂ N- (H ₂ C) 2-

A solution of 9.7 g (18.7 mmol) of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3-carboxylic acid (2-phthalimidoethyl) ester-6-carboxylic acid cyclopropylamide (Example 20) and 93.5 mmol of hydrazine hydrate in 200 ml of ethanol was boiled under reflux for 1 h. The mixture was cooled and the precipitate filtered off. Then the residue was with

Washed methylene chloride and the organic phase concentrated in vacuo. After adding methylene chloride, it was washed once with a 2N solution of potassium hydroxide and 3 times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. The product crystallizes on trituration with ether.

Yield: 5.95 g (82% of theory)

Melting point: 55-57 ⁰ C

Analogously to the procedure of Example 25, the compounds listed in Table 2 were prepared:

Table 2

γ-χ-ΟΟι

0-N

Example no.

Salt Schmp.

C ₂ H ₅ H - (CH ₂ ) ₂

3-NO

144-146 ⁰ C 0.18 ^d)

C ₂ H ₅ H -CH-CH ₂ --NH ₂

3-NO ₂ - 169-173 ⁰ C 0.52 ^d)

Both diastereomeric forms

CH,

H-CH-CH ₂ -

The following solvents are listed under a) - d):

a) Toluene / acetone (1: 1)

b) toluene / ethanol (3: 1)

c) methylene chloride / methanol (10: 1)

d) methylene chloride / methanol (5: 1)

3-NO ₂ - 185-188 ⁰ C

Both diastereomeric forms

Claims (1)

Process for the preparation of compounds of general formula (I a) GOO-XY ^(la) in which R ¹ and R ^{2 are the} same or different and _N - mean hydrogen, or - represent cycloalkyl having 3 to 8 carbon atoms, or - represent straight-chain or branched alkyl or alkenyl, each having up to 12 carbon atoms, which are optionally 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, carboxy or alkoxycarbonyl having up to 8 carbon atoms or by phenyl, which in turn may be substituted by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkyl of up to 4 carbon atoms or alkoxy: ni up to 4 carbon atoms or by a group NR ⁵ R ⁶ , R ⁵ and R ^{6 are} identical or different and denote hydrogen, alkyl having up to 8 carbon atoms, - are phenyl which is up to 3 times the same or different from nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, Alkylamino may be substituted with up to 8 carbon atoms, dialkylamino having up to 8 carbon atoms per alkyl group, acetylamino or benzoylamino, or R ¹ and R ² together form a 5- to 7-membered saturated or unsaturated heterocyclic ring which may contain as an additional heteroatom an oxygen atom, a sulfur atom, a nitrogen atom, or a radical NR ⁷ , R ^{7 can be} hydrogen, C ₁ -C ₆ -alkyl, aryl or aralkyl and
R ³ and R ^{4 are the} same or different and - represent straight-chain, branched or cyclic alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy, cyano, phenyl or halogen X - is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 12 carbon atoms, which is optionally interrupted by an oxygen, sulfur or nitrogen atom, or a group NR ⁸ , wherein R ^{8 is} hydrogen, or - represents alkyl having up to 6 carbon atoms, which may be optionally substituted by halogen, hydroxy, acetoxy, carboxy, Cv-Ce-alkoxycarbonyl or phenyl, which in turn may be substituted by halogen, C ₁ -C ₆ -AlkYl, C ₁ -C ₆ -alkoxy, halomethyl, halomethoxy or cyano,
and
Y - pyridyl means, or - represents a group of the formula NR ⁹ R ¹⁰ ,
wherein R ⁹ and R ^{10 are the} same or different and - straight-chain or branched alkyl, alkenyl or alkynyl, each with up to 12 carbon atoms, which may be substituted by halogen, hydroxy, alkoxy having up to 8 carbon atoms, cyano, trifluoromethyl, alkylthio having up to 8 carbon atoms, alkylcarbonyl having up to 8 carbon atoms, alkoxycarbonyl having up to 8 carbon atoms or by plienyl which in turn may be substituted by nitro, phenyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms, halogen or alkoxy having up to 4 carbon atoms, or - represent cycloalkyl having 3 to 8 carbon atoms, or - stand for aryl having 6 to 10 carbon atoms, which are up to 3 times the same or different by nitro, cyano, halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 6 carbon atoms, carbamoyl, dialkylcarbamoyl having in each case up to 6 carbon atoms per 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, or R ⁹ and R ¹⁰ together form a 5- to 7-membered, saturated or unsaturated, hetero-cyclic ring which may contain an oxygen atom, a sulfur atom or an additional nitrogen atom optionally substituted by a radical R ¹¹ , wherein
R ¹¹ - is hydrogen, or - Is a straight-chain or branched, saturated or unsaturated alkylene group having up to 10 carbon atoms, which is optionally substituted by phenyl, which in turn by halogen, C ₁ -C ₄ -AlkYl, C ₁ -C ₄ -alkoxy, nitro or haloalkyl with can be substituted up to 4 carbon atoms, or - is phenyl, optionally substituted by halogen, cyano, nitro, alkyl with up to 4 carbon atoms, alkoxy having up to 4 carbon atoms or haloalkyl having up to 4 carbon atoms is substituted, and their physiologically acceptable salts and optionally their pharmaceutical administration forms, characterized in that [Aj aldehydes of the general formula (II) (II) GHO
and β-ketocarboxylic acid esters of the general formula (III) Y.-X-OOC (III) in which R ³ , X and Y have the abovementioned meaning, if appropriate after isolation of the resulting ylidene compound of the general formula (IV) (IV) CH F ^ -CO-C-COO-X-Y in which _v R ³ , X and Y have the abovementioned meaning, with β-ketocarboxamides of the general formula (V) / CO-N «« I Vr, 2 (V) in which R ¹ , R ² and R ^{4 have} the abovementioned meaning and ammonia or directly with the β-aminocrotonic acid amides of the general formula (V 1) prepared therefrom in which R ¹ , R ² and R ^{4 have} the abovementioned meaning, or by reacting [B] aldehydes of the general formula (II) and β-ketocarboxamides of the general formula (V) or their ylidene compounds of the general formula (VII) (VII) in which R ¹ , R ² and R ^{4 have} the abovementioned meaning, with β-ketocarboxylic esters of the general formula (III) and ammonia or directly with the aminocrotonic esters of the general formula (VIII) prepared therefrom (VIII) RJx → NH ₂ in which R ³ , X and Y have the abovementioned meaning, or to give compounds of the general formula (I) in which R ¹ , R ² , R ³ , R ⁴ and X have the abovementioned meaning, Y is a group of the formula NR ⁹ R ¹⁰ and R ⁹ and / or R ^{10 are} reactive hydrogen, suitably by [C] Benzylidene compounds of the general formula (VII) first with compounds of the general formula (Villa) Z-X-OO (Tv ^ H (Villa) in which R ³ and X have the meaning given, Z represents an acylated amino-protecting group, preferably tert-butoxycarbonylamino or phthalimide, to give compounds of the general formula (IX) (IX) COO-X-Z in which R ¹ , R ² , R ³ , R ⁴ and X are as defined above Kraben, and Z - for the group CH- -N-COO-C-CH ₃ or stands , deblocked in a further step by known methods and the resulting intermediate compounds of the formula (IXa), N-OC COO-X-NH- (IXa) in which R ¹ , R ² , R ³ , R ⁴ , X and R ^{9 have} the abovementioned meaning, to compounds of general formula (I) in which Y is the group NR ⁹ R ¹⁰ , wherein R ⁹ and R ^{10 have} the abovementioned meaning, with the proviso that R ⁹ and / or R ^{10 are} different from hydrogen, further reacted, or by [D] Dihydropyridine monocarboxylic acids of the general formula (Xa) or (Xb) HOOC OO-X-Y 0OH (Xa) (Xb) in which R ¹ , R ² , R ³ , R ⁴ , X and Y have the abovementioned meaning, if appropriate via reactive acid derivatives with amines of the general formula (XIa) (XIa) in which _K R ¹ and R ^{2 have} the abovementioned meaning, or with compounds of the formula (XI b) HO-X-Y '(XIb) in which X and Y have the abovementioned meaning, wherein in each case only (Xa) with (Xl a) and (Xb) with (Xtb) is reacted and optionally the compounds prepared by this process, using conventional excipients and carriers in a transferred suitable application form.