DE3130041A1 - Dihydropyridines having a positive inotropic effect, novel compounds, their use in medicaments, and processes for their preparation - Google Patents

Abstract

The present invention relates to the use of novel and known dihydropyridines in medicaments having a positive inotropic effect, which dihydropyridines are of the general formula I <IMAGE> in which n, R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and R<7> have the meaning given in the description, to novel compounds of this class of substances, to medicaments containing them, and to their preparation.

Description

Dihydropyridines with positive inotropic effects, new

Compounds, their use in pharmaceuticals and processes for their Manufacture The present invention relates to the use of new and known Dihydropyridines in drugs with a positive inotropic effect, new compounds from this class of substances, medicinal products containing them and their manufacture.

It has already become known that 1,4-dihydropyridines are vasodilators Possess properties and are used as coronary drugs and antihypertensive drugs can (see British patent 1 173 062; British patent 1 358 951; DE-OS 2 629 892 and DE-OS 2 752 820).

It is also known that 1,4-dihydropyridines act as calcium antagonists cause an inhibition of the force of contraction of smooth and cardiac muscles and can be used to treat coronary and vascular diseases (cf. A. Fleckenstein, Ann. Rev. Pharmacol. Toxicol. 17: 149-166 (1977)).

When these properties of the dihydropyridines were recognized, it was not predictable that the compounds according to the invention from this class of substances are not contraction-inhibiting, but rather one that increases the force of contraction, on the heart muscle have a positive inotropic effect.

The invention relates to the use of 1,4-dihydropyridines of the general formula (I) in which n stands for 0, 1 or 2, R1 a) stands for hydrogen, a straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical which optionally contains 1 to 3 identical or different hetero-chain members from group 0, CO, SO (m = 0, 1 or 2), = N-, NRI or SiR11R111 and where this hydrocarbon radical is optionally substituted by halogen, NO2, CN, N3, hydroxy, aryl or heteroaryl or b) stands for an aryl or heteroaryl radical, these radicals optionally having 1 to 5 identical or different substituents from the group consisting of aryl, alkyl, alkenyl, alkynyl, alkenoxy, alkynoxy, aralkyl, acyl, alkylene, dioxyalkylene, halogen, CF3, OCF3, SCF3, NO2, NO, CN, N3, Carry CO3IV, COORV, ORVI, NR or NR R RVIII, where the alkyl, alkoxy and aryl radicals of the abovementioned substituents can in turn be substituted by halogen, V or NRVII RVIII, or c) represents the radical NRVII R1, and where the under a), b) u nd c) said radicals RI, RII, RIII, RIV, RV, RVI, RVII and RVIII have the meaning given below, R² a) stands for one of the substituents given under R¹ absr does not have to be identical with this or b) for the radicals NHRI or stands, where R1, RIX and RX have the meaning given below, or the substituents R1 and R2 together form a 5- to 8-membered, saturated or unsaturated ring which optionally contains 1, 2 or 3 identical or different ring members from group O. , S, NR or CO and optionally contains 1 to 3 identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy, aryl or aralkyl, R³ stands for one of the substituents given under R², and is identical to or different from this is different, with only one of the two substituents R2 or R3 each standing for alkoxy, alkylthio or NHR1, R4 a) for hydrogen, NO2, NO, CN, SOm-RX (m = 0, 1 or 2), halogen, stands, where RI, RVII, RVIII, RXI and RXIII have the meaning given below, or b) stands for a branched or unbranched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical which is optionally substituted by halogen, OH, CN, alkoxy, alkylthio , Aryloxy, COORV or where RV, RVII and RVIII have the meaning given below, or c) for an aromatic hydrocarbon radical or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 4 identical or different hetero members from the group 0, S, -N =, NR, where this hetero ring is linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom, and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 to 3 identical or different substituents from the group consisting of halogen, OH, CN, CF3, OCF3, SCF3 , NO2, alkyl, alkoxy, aryl and wear, or d) for the rest where X is oxygen, sulfur or NRI, and Y is a single bond, O, S or NRI, and R6 has the meaning given for R¹ and is the same as or different from the substituent R¹, or e) for the rest stands, i 1 1. , where n ', R1, R2, R3 1 R5, R6 and R7 have the meanings given for n, R¹, R², R³, R5, R6 and R7 and are identical to or different from these, and R4 @ and R4 @@ are identical or different and each represent a radical reduced by one hydrogen of the substituents given for R4 under a) to dr, or R² and R4 together form a branched, unbranched, saturated or unsaturated 5- to 8-membered ring, which optionally has 1 , 2 or 3 identical or different ring members from the group O, CO, CS, C = NRi, = N-, NRI, SO (m = 0, 1 or 2) or SiRII RIII, and which is optionally substituted by halogen , Hydroxy, alkoxy, aryl, aralkyl, or is disubstituted by a straight-chain or branched alkylene chain having 3 to 8 carbon atoms, this common ring of R2 and 4 also being fused directly to the common ring of R1 and R2, the radicals RI, RII, RIII, RVII, RVIII being those given below R5 has the meaning given for R4 and is identical to or different from R4, or R5 and R3 together form a ring which is identical to or different from the ring formed by R2 and R4, R6 for hydrogen, alkyl or haloalkyl, and R7 a) is a saturated, unsaturated, cyclic, straight-chain or branched aliphatic hydrocarbon radical which is optionally substituted by halogen, aryl or heteroaryl, or b) is an aryl or heteroaryl radical which is optionally 1 to 5 identical or different substituents from the group NO2, CN, N3, NO, CF3, halogen, CORIV, COORV, ORVI SOmRXI (m = 0, 1 or 2), Contains alkyl, aryl, alkenyl, alkynyl, alkenoxy, alkynoxy, aralkyl, acyl, alkylene, or dioxyalkylene, the aforementioned alkyl and aryl substituents in turn being replaced by halogen, COORV or may be substituted, and where in the aforementioned definitions of the substituents R1 to R8 R1 represents hydrogen, alkyl, aryl, aralkyl, heteroaryl or acyl, RII and R111 are identical or different and each represent alkyl, aryl, aralkyl or heteroaryl, RIV , RV and RVI are each identical or different and represent hydrogen, alkyl, aryl, aralkyl or heteroaryl, RVI1 and RVIII are each identical or different and represent hydrogen, aryl or aralkyl or represent alkyl, which is optionally replaced by 0, S or NRI is interrupted, stand or together with the nitrogen atom form a 5- to 7-membered ring which can contain 1 or 2 identical or different hetero-ring members from the group O, S or NRI or where one of the radicals RVII or RVIII represents an aliphatic acyl group up to 6 carbon atoms, RIX, RX ,, RXI 'RXII and RXIII are each identical or different and are alkyl, aryl or aralkyl, where those under R1 to R8 and Alkyl, aryl, aralkyl, heteroaryl and acyl radicals mentioned under RI to RXIII and the hetero ring formed with RVII and RVIII are in turn optionally substituted by OH, CF3, OCF3, CN, NO2, halogen, lower alkyl, lower alkoxy, aryl or aralkyl, and the following substituents may be mentioned as heteroaryl: thienyl, furyl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, pyridazinyl, quinazolyl, quinoxalyl, benzothienyl, pyrazolyl, imidazolyl, oxazoliazole, isoxazolyl, thiazyl, pyrazolyl, trrazolyl, thiazolyl, trrazolyl, Oxazinyl, thiazinyl, indolizinyl, indolyl, benzofuranyl, indazolyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benztriazolyl, benzoxadiazolyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pharmaceutically acceptable, racial isomers, and pharmaceutically, racial isomers, and also of their pharmaceutical, raciphenyl, and benzotriazolyl isomers, and their pharmaceutical, raciphenyl, isomers, and benzimidazolyl, benzothienyl, benzimidazolyl, isomers, and also of their pharmaceutical, racial, isomers, and of their pharmaceutical, racipic, isomers and mixtures of optical, racial, and antimicrobials , in drugs with a positive inotropic effect, which are particularly suitable as cardiotonics.

This contraction force-increasing effect is also based on the fact that the compounds according to the invention increase the Ca influx into the cell and thus also for the treatment of hypotonic circulatory conditions, to lower blood sugar, for the decongestion of mucous membranes and for Influencing the salt and fluid balance are suitable.

Those compounds of the general formula (1) are emphasized, those from a concentration of 10 g / ml on the left atrium of the isolated guinea pig heart show a positive inotropic effect in the following test set-up: test set-up The left atria of guinea pig hearts are isolated and placed in a thermostated Organ bath hung, which is an isotonic mineral salt solution, which the ionic environment and is adapted to the pH of body fluids and contains suitable nutrients.

This organ bath is made with a gas mixture consisting of oxygen and carbon dioxide fumigated, the carbon dioxide content being such that the pH value of the organ bath remains constant. The left atria are clamped into the organ bath, the tension is registered by means of a force transducer, with a certain The basic tone is set. Subsequently, the left atria become continuous Electrically stimulated at certain intervals and the resulting contractions registered. After adding the active ingredient, the contractions are still registered. A contraction gain of at least 25% is considered to be a significant positive inotropic Effect.

The compounds of the general formula (I) according to the invention can can be prepared in various ways by conventional methods. Your synthesis he follows e.g.

A) by direct construction of the hydropyridine structure according to known Dihydropyridine syntheses or B) by converting functional groups on the dihydropyridine structure according to known reaction schemes.

A) Construction of the 1,4-dihydropyridine basic structure The construction of the 1,4-dihydropyridine basic structure can be carried out by adding 1. carbonyl compounds of the general formula (II) in which R6 and R7 have the meaning given above, with ketones of the formula (III) and (IV) in which R2, R3, R4 and R5 have the meaning given above, and primary amines of the formula (V) H2N- (COJn-R (V) in which n = 0 and R1 has the meaning given above, optionally in the presence of inert ones Converts solvents, or 2. carbonyl compounds of the formula (II) in which R6 and R7 have the meaning given above, with enamines of the formula (VI) in which R1, R2, R4 and n have the meaning given above and ketones of the formula (IV) R3 -CO-CH2-R5 (IV) in which R3 and R5 have the meaning given above, optionally reacts or in the presence of inert solvents 3. Enamines of the formula (VI) in which R11, R2, R4 and n have the meaning given above with ylidene compounds of the formula (VII) in which R3, R5, R6 and R7 have the meaning given above, optionally reacted in the presence of inert solvents.

B) Conversion of the functional groups by converting an or several functional groups of known dihydropyridines or new dihydropyridines which were obtained according to process A) 1. to 3. can also be used according to the invention Compounds of the general formula (I) can be prepared by customary methods (cf. Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart 1966; Organicum, VEB Deutscher Verlag der Wissenschaften, Berlin 1969; W. Foerst, Newer methods of preparative organic chemistry, Vol. 1-5, Verlag Chemie, Weinheim 1961; C. Ferri, reactions of organic chemistry, Georg Thieme Verlag, Stuttgart 1978; Fieser + Fieser, Reagents for Organic Synthesis, Vol. 1-8, J. Wiley & Sons, Inc., London 1967.

Preferred conversion reactions are: acidic or basic catalyzed hydrolysis, esterification or transesterification, lactamization, condensation, Acylation, reduction or cyclization with suitable reactants in each case or intramolecular. Lactonization may be mentioned as being particularly advantageous.

For this purpose, compounds of the general formula (I) in which the Substituents R2 and R4 or / and R3 and R5 are free and / or blocked by protective groups Contain hydroxyl and carboxylic acid functions, under suitable basic or acidic catalyzed reaction conditions, if appropriate with preceding whole or partial splitting off of the protective groups, to lactones according to the invention of the general Formula (I) cyclized.

In the German Offenlegungsschrift No. 26 29 892 some of the possible manufacturing methods described in more detail.

Preferred compounds of the general formula (I) are those in which n is 0, 1 or 2, R1 a) is hydrogen, a straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally 1 or 2 identical or different hetero chain members from the group O, CO, 5, SO2, = N- or NRI and this hydrocarbon radical being optionally substituted by halogen, NO2, CN, N3, hydroxy, with 1 to 4 carbon atoms, phenyl , Naphthyl or heteroaryl or b) represents a phenyl, naphthyl or heteroaryl radical, these radicals optionally having 1 to 3 identical or different substituents from the group consisting of phenyl, alkyl, alkenyl, alkynyl, alkenoxy, alkynoxy each having up to 4 C- Atoms, aralkyl with 7 to 14 carbon atoms, acyl with up to 6 carbon atoms, alkylene, dioxyalkylene with up to 4 carbon atoms in the alkylene chain, halogen, CF, OCF3, SCF3, NO2, CN, N3, CORIV, ORVI, NRI or NRVIIRVIII carry, where the alkyl, alkoxy and aryl radicals of the abovementioned substituents can in turn be substituted by halogen, COORV or NRVII RVIII or c) represents Res NRVIIRI, and the radicals mentioned under a), b) and c) R1, RII, RIII, RIV RV, RVI, RVII and RVIII have the meaning given below, R2 is a) for one of the substituents indicated under R1 but does not have to be identical to them or b) for the radicals NHRI or stands, where R1, RIX and RX have the meaning given below, or the substituents R1 and R2 together form a 5- to 7-membered saturated or unsaturated ring which optionally contains one or two identical or different ring members from the group O, S , NRI or CO and which optionally contains one to three identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy with 1 to 4 carbon atoms, phenyl, naphthyl or aralkyl with 7 to 14 carbon atoms, R3 for stands for one of the substituents indicated under R2 and is identical to or different from this, with only one of the two substituents R² or R³ each being alkoxy, alkylthio, or NHR1, R a) being hydrogen, NO2, NO, CN, SOm- RIX (m = 0 or 2), halogen, stands, where R1, RVII, RVIII, RXI and RXIII have the meaning given below, or b) represents a branched or unbranched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally substituted by halogen, OH , CN, alkoxy 'alkylthio each having 1 to 4 carbon atoms, phenyloxy, naphthoxy, COORV or where RV, RVII and RVIII have the meaning given below, or c) for an aromatic hydrocarbon radical with 6 to 10 carbon atoms or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 3 identical or different hetero members from the group O, S, -N =, NR, this hetero ring being linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom, and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 to 3 identical or different substituents from the group consisting of halogen, OH, CN , CF3, OCF3, SCF3, NO2, alkyl, alkoxy each with 1 to 4 carbon atoms, phenyl, naphthyl and wear, or c) for the rest where X is oxygen, sulfur or NRI and Y is a single bond, O, S or NRI, and R8 has the meaning given for R¹ and is the same as or different from the substituent R1, or e) is the radical where n ', R1', R2 ', R3', R5 ', R6' and R7 'have the meanings given for n, R¹, R², R³, R5, R6 and R7 and are identical to or different from these , and 4 * R and R are identical or different and each represent a radical of the substituents specified for R4 under a) to d) less one hydrogen, or R² and R4 R2 and R4 together represent a branched, unbranched, saturated or unsaturated 5 - Form up to 7-membered ring which optionally contains 1, 2 or 3 identical or different ring members from group 0, CO, CS, C = NR11 = N-, NRI or SOm (m = 0 or 2) and which is optionally substituted is by halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 14 carbon atoms, or is disubstituted by a straight-chain or branched alkylene chain having 3 to 8 carbon atoms, it being possible for this common ring of R2 and R4 also to be gelled directly to the common ring of R1 and R2, the radicals RI RII RIII RVII RVIII having the meaning given below , R5 has the meaning given for R4 and is identical to or different from R4, R6 is hydrogen, alkyl or haloalkyl each having 1 to 4 carbon atoms and R7 a) is a saturated, unsaturated cyclic, straight-chain or branched aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally substituted by halogen, phenyl, naphthyl or heteroaryl or b) a phenyl, naphthyl or heteroaryl radical, which optionally has 1 to 3 identical or different substituents from the group NO2, halogen, CN, N3, NO, CF3, CORIV, COORV, OR SOmRXI (m = 0, 1 or 2), Alkyl with 1 to 4 carbon atoms, phenyl, naphthyl, alkenyl, alkynyl, alkenoxy, alkynoxy with up to 4 carbon atoms each, aralkyl with 7 to 14 atoms, acyl with 1 to 4 carbon atoms, alkylene or dioxyalkylene each with Contains up to 4 carbon atoms, the aforementioned alkyl and aryl substituents in turn by halogen, COOR or can be substituted, and where in the aforementioned definitions of the substituents R1 to R7 RI stands for hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms, heteroalkyl or acyl with up to 7 carbon atoms Atoms, RII and RIII are identical or different and each represent alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms or heteroaryl, RVII RV and RVI R, R and R are each identical or are different and represent hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms or heteroaryl, RVII and RVIII are each identical or different and represent hydrogen, phenyl, -naphthyl or aralkyl with 7 to 12 carbon atoms or alkyl with 1 to 6 carbon atoms, which is optionally interrupted by 0, S or NRI, or together with the nitrogen atom form a 5- to 7-membered ring which is 1 or 2 identical or different hetero ring members from group 0, S or NRI contain k ann or where one of the radicals RVII and RVIII is an aliphatic acyl group with up to 6 carbon atoms, RIX, RX, RXII and RXIII are each identical or different and for alkyl with 1 to 6 carbon atoms, phenyl, naphthyl or aralkyl with 7 to 12 C atoms, where the alkyl, aryl, aralkyl, heteroaryl and acyl radicals mentioned under R1 to R8 and under RI to RVIII and the hetero ring formed with R6 and R7 are in turn optionally substituted by OH, CF3, OCF3, CN , NO2, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, phenyl or benzyl and the following substituents being mentioned as heteroaryl: thienyl, furyl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, pyridazinyl , Quinazolyl, quinoxalyl, benzothienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxydiazolyl, pyrazinyl, oxazinyl, thiazinyl, indolizinyl, indolyl, benzofuranyl, indazolyl, benzothienyl, benzimoxazolyl, benzimidazolyl, benzimidazolyl. Benztriazolyl, benzoxadiazolyl, cinnolinyl, phthalazinyl, naphthyridinyl or benzotriazinyl, in the form of isomers, isomer mixtures, racemates and optical antipodes and their pharmaceutically acceptable salts.

Of particular interest are compounds of the general formula (I) in which n is 0 or 1, R1 a) is hydrogen, a straight-chain, branched cyclic saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally represented by a or contains two identical or different hetero chain members from the group O, CO, S, = N- or NRI and this hydrocarbon radical is optionally substituted by F, Cl, Br, NO2, CN, OH, phenyl or pyridyl or b) for one Phenyl, naphthyl or pyridyl radical, these radicals optionally having 1 or 2 identical or different substituents from the group consisting of phenyl, alkyl, alkenyl, alkoxy, alkenoxy each with up to 4 carbon atoms, benzyl, acetyl, alkylene, dioxyalkylene with 2 Carry up to 4 carbon atoms, fluorine, chlorine, bromine, CF3, OCF SCF3, NO2, CN, COORV, ORVI, NRI or NRVIIRVIII, the alkyl, alkoxy and aryl radicals of the above-mentioned substituents in turn being halogen-substituted or c) stands for the radical NRVIIRVIII, and where the radicals RI to RVIII mentioned under a), b) and c) have the meaning given below, R2 a) stands for one of the substituents given under R1, but are not identical to them must or b) for the residues NHRI or stands, where RI, RIX and RX have the meaning given below or the substituents R1 and R2 together form a 5- to 7-membered saturated or unsaturated ring which optionally contains 1 or 2 identical or different ring members from the group O, S, NRI or CO and which optionally contains 1 or 2 identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy, each with 1 to 4 carbon atoms, phenyl or benzyl, R3 stands for one of the substituents specified under R2 and is the same as this or is different from this, where only one of the two substituents R² or R³ each represents alkoxy, alkylthio or NHRI, R4 a) represents hydrogen, NO2, CN, XI SO2RXI, or stands, where RI, RVI, RVII, RVIII and RIX have the meaning given below, b) stands for a branched or unbranched alkyl or cycloalkyl radical with up to 8 carbon atoms, which is optionally substituted by halogen, hydroxy, cyano, alkoxy with 1 to 4 carbon atoms, phenyloxy, COORV or where RV, RVII and RVIII have the meaning given below or c) for an aromatic hydrocarbon radical with 6 to 10 carbon atoms or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 3 identical or different hetero members from group O , S, = N-, NRI, where this hetero ring is linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 or 2 identical or different substituents from the group consisting of halogen, hydroxy, cyano, CF3 , NO2, phenyl, alkyl and alkoxy with 1 to 4 carbon atoms each, or d) for the remainder where X is oxygen or NRI and Y is a single bond, oxygen or NRI and R8 has the meaning given for R1 and is identical to or different from the substituent, or e) is the radical where n, R11, R21, R ', R5', R6t and R7 'have the meanings given for n, R1, R2, R3, R51, R6 and R7 and are identical to or different from these, and R4 * and R4 ** are identical or different and each stand for a radical of the substituents specified for R4 under a) to d) less one hydrogen, or R² and R4 together form a branched, unbranched, saturated or unsaturated 5- to 7-membered ring, which optionally contains 1 or 2 identical or different ring members from the group O, CO, CS, C = NR1, = N- or NRI and which is optionally substituted by halogen or hydroxy, where R1 has the meaning given below, R5 that for R4 has given meaning and.mit R4 is the same or different from these or R5 and R3 together form a ring as defined for R2 and R4 and identical to or different from this, R6 for hydrogen or alkyl with 1 to 4 C -Atomen stands which, if necessary, dur ch fluorine, chlorine or bromine is substituted and R7 a) stands for a saturated, unsaturated cyclic, straight-chain or branched aliphatic hydrocarbon radical with up to 8 carbon atoms, which is optionally substituted by halogen, or b) stands for a phenyl or heteroaryl radical , which optionally contains 1 to 3 identical or different substituents from the group NO2, CN, N3, CF3, halogen, CORIV, CORV, ORVI SRXI, Contains phenyl, alkyl with 1 to 4 carbon atoms, benzyl or acyl with 1 to 4 carbon atoms, where in the aforementioned definitions of the substituents R1 to R8 RI stands for hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, Benzyl, phenethyl, heteroaryl or acyl with up to 4 carbon atoms, RII and RIII are identical or different and each represent alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, benzyl or heteroaryl, RIV, RV and RVI, respectively are identical or different and represent hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, benzyl or heteroaryl, RVII and RVXII, which are each identical or different and represent hydrogen, phenyl or benzyl or represent alkyl with 1 to 6 Stand carbon atoms, which is optionally interrupted by 0 or NRI, or together with the nitrogen atom form a 5- to 7-membered ring which can contain 1 or 2 identical different hetero ring members from the group O, S or NRI, or where one of the radicals RVII or RVII I stands for an aliphatic acyl group with up to 6 carbon atoms and RIX, RX, RXI, RXII and RXIII are each identical or different and stand for alkyl with 1 to 6 carbon atoms, phenyl or benzyl, the following substituents being mentioned as heteroaryl: Thienyl, furyl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, pyridazinyl, quinazolyl, quinoxalyl, benzothienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxydiazolyl, benzothazinyl, oxydiazolyl, benzothazinyl, indiazolyl, indiazolyl, benzothurole Benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benztriazolyl or benzoxadiazolyl.

In particular, compounds of the general formula (I) may be mentioned in which n is 0, R1 a) is hydrogen, an aliphatic hydrocarbon radical with up to 6 carbon atoms, which may optionally be a hetero chain member from group 0, CO, = N- or Contains NRI and which is optionally substituted by halogen, nitro, hydroxy or phenyl or b) represents a phenyl or pyridyl radical, which is optionally substituted by halogen, NO2, CF3, OCF3, CN, COORV or NRVIIRVIII R2 for one of the under R1 specified substituents, but need not be identical to them or represents one of the radicals NHRI or N = CRXRXI, R³ represents one of the substituents specified under R² and is identical to or different from this, R4 a) represents hydrogen, NO2, NR R or halogen, or b) stands for an alkyl radical with 1 to 4 carbon atoms which is optionally substituted by halogen, OH, CN, alkoxy with 1 to 4 carbon atoms, COORV or NRVII RVIII or c) for phenyl , Pyr idyl or thienyl, which are optionally substituted by halogen, OH, CN, alkyl or alkoxy each having 1 to 4 carbon atoms or by NRVII RVIII or d) for the remainder where X is oxygen and Y is a single bond, oxygen or NRI and R8 has the meaning given for R1 and with the substituent R1 is the same or different, or e) is the radical where n ', R1', R2 ', R3', R5 ', R6' and R7 'have the meanings given for n, R11, R², R³, R5, R6 and R7 and are identical to or different from these, and R4 * and R4 are identical or different and each represent a radical, reduced by one hydrogen, of the substituents specified for R4 under a) to d), or R² and R4 together form a 5- to 7-membered ring which optionally has 1 or Contains 2 different ring members from the group O, CO, CS or C =NRI and which is optionally substituted by halogen, R5 has the meaning given for R4 and with 4 R is the same or different, R6 is hydrogen or alkyl with 1 to 4 carbon atoms and R7 has the meaning given above, the substituents R1 to RVIII in the above definitions having the meaning given above.

Particular emphasis should be given to connections in which at least one the substituents R4 and R5 stand for NO2 and / or in which R2 and R4 together or R3 and R5 together form a lactone ring.

The preparation of the 1,4-dihydropyridine derivatives according to the invention with positive inotropic effect takes place according to the usual methods for the production of 1,4-dihydropyridines are known (see e.g. British Patent 1 305 793; British U.S. Patent 1,358,951; DE-OS 2 752 820; DE-OS 2,847,237; DE-OS 2 629 892; DE-OS 2 658 804).

Some of the compounds that can be used in the present invention are already known from the prior art. The compounds of preparation examples 1 to 10, 19 to 23, 26, 28, 29, 30, 31, 32, 35 to 38, 41, 42, 43 and 45 are new. These new connections are partly

through general definitions of substituents in the standard of the technology includes without, however, being named so far.

The present invention also relates to the new compounds under of the general formula (I), their preparation and their use in medicaments with positive inotropic effect.

Compounds of the general formula (I) in which R² is selected from R³ or R4 is different from R5 may be due to the presence of an asymmetric carbon atom in the 4-position of the dihydropyridine ring as racemic mixtures or in the form of optical isomers can be obtained. Some of the compounds of the invention die contain at least 2 asymmetric carbon atoms, can be in the form of individual Diastereomers or in the form of mixtures thereof are obtained. The diastereomer Mixture can be separated using conventional methods. For example by fractional recrystallization or by chromatographic methods. Racemic Mixtures can be prepared by customary methods, for example by splitting, by fractional recrystallization of a salt with optically active acids in separate the respective optical isomers.

By defining the substituents of the general formula (I) also includes some compounds that do not have a positive inotropic effect.

By the test method given above on the isolated Guinea pig forecourt however, it is unproblematic for the person skilled in the art to use the compounds according to the invention to recognize with positive inotropic effect and of the possibly included compounds with a negative inotropic effect. The present application is on such compounds are directed from a concentration of 10 5 g / ml in the above indicated test on the left isolated atrium of the guinea pig heart showed an amplification of contraction effect by at least 25%.

The following table shows an example of the positive inotropic resp. Contraction force-enhancing effect by at least 25% of some of the invention Links.

Table example active ingredient example active ingredient no. concentration no. concentration in g / ml in g / ml 1 10-7 26 10-7 2 10-5 27 10-7 3 10-6 28 4 3x10-7 29 10-7 5 10-5 30 6 10-7 31 10-6 7 10-7 32 10-7 8 10-6 33 10-7 9 10-7 34 10 10-7 35 10-6 11 10-5 36 10-6 12 10-6 37 10-6 13 10-6 38 10-6 14 10-6 39 15 10-5 40 10-6 16 10-6 41 10-6 17 10-7 42 10-5 18 3x10-6 43 10-6 19 10-5 44 10-6 20 3x10-7 45 10-6 21 1017 22 10-6 23 3x10 24 10 5 25 10-6 The compounds according to the invention show an unforeseeable and valuable spectrum of pharmacological effects. They can serve as cardiotonics to improve heart contractility. About that In addition, by increasing the influx of Ca into the cell, they can act as antihypotonic agents, to lower blood sugar, to decongest mucous membranes and to influence the salt and fluid balance can be used.

The compounds according to the invention can in a known manner in the customary formulations are transferred.

The new active ingredients can be converted into the customary formulations in a known manner be transferred, such as tablets, capsules, coated tablets, pills, granules, aerosols, Syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. Here the therapeutic active compound each at a concentration of about 0.5 to 90% by weight of the Total mixture, i.e. in amounts sufficient to achieve the specified To achieve dosage latitude.

The formulations are produced, for example, by stretching of the active ingredients with solvents and / or carriers, if appropriate with use of emulsifiers and / or dispersants, e.g. in the case of use of water as the diluent, optionally organic solvents as auxiliary solvents can be used.

Examples of auxiliaries are: water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerine), glycols (e.g. propylene glycol, Polyethylene glycol), solid carriers such as natural rock flour (e.g. Kaolins, clays, talc, chalk), synthetic rock flour (e.g. highly dispersed Silicic acid, silicates), sugar (e.g. cane, milk and grape sugar), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g.

Lignin, sulphite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenterally, especially perlingually or intravenously. In the case of oral use Tablets can of course also contain additives in addition to the carrier substances mentioned, such as sodium citrate, calcium carbonate and dicalcium phosphate along with various Additives such as starch, preferably potato starch, gelatin and the like contain.

Lubricants such as magnesium stearate and sodium lauryl sulfate can also be used and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs intended for oral use are, can the active ingredients, in addition to the above-mentioned auxiliaries, with various flavor enhancers or dyes are added.

In the case of parenteral use, solutions of the active ingredients can be used be used using suitable liquid carrier materials.

In general, it has been found to be beneficial when administered intravenously Application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg Body weight to be administered for effective results, and when administered orally Administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

Even so, it may be necessary to use the above Quantities vary, depending on the body weight of the test animal or the type of application route, but also due to the species and their individual Behavior towards the drug or its type of its formulation and the Time or interval at which the administration takes place. So it may in some In some cases it is sufficient to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. in the If larger amounts are applied, it may be advisable to split them up in several To distribute individual items over the day. For application in human medicine the same dosage range is provided. The above also apply accordingly Executions.

Preparation Examples Example 1 2-Methyl-4- (2-trifluoromethylphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuroL5,4-bvpyridine-3-carboxylic acid ethyl ester 50 mmol each of 4-acetoxy-3-oxo-butyric acid ethyl ester, 3-aminocrotonic acid ethyl ester and 2-trifluoromethylbenzaldehyde were refluxed in 100 ml ethanol for 24 hours, then 2 g potassium hydroxide were added and the mixture was boiled for a further hour. After cooling, it was precipitated with a water / sodium chloride mixture and recrystallized from methanol.

Yield: 45% of theory; M.p .: 195 ° C.

Example 2 2-Methyl-4-t3-methoxyphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuroL7,4-k7-pyridine-3-carboxylic acid ethyl ester Representation analogous to Example 1 with 3-methoxybenzaldehyde instead of 2-trifluoromethylbenzaldehyde.

Yield: 30% of theory; M.p .: 1800C.

Example 3 2-Methyl-4- (3-chlorophenyl) -5-oxo-1,4-dihydro-5,7-dihydrofluoro [3,4-b] pyridine-3-carboxylic acid ethyl ester Representation analogous to Example 1 with 3-chlorobenzaldehyde instead of 2-trifluoromethylbenzaldehyde.

Yield: 50% of theory; Fp .: 1960C.

Example 4 2-Methyl-4- (3-chlorophenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuro [3,4-b] pyridine-3-carboxylic acid propyl ester Representation analogous to Example 1 with 3-chlorobenzaldehyde instead of 2-trifluoromethylbenzaldehyde and propyl 3-aminocrotonate instead of ethyl 3-aminocrotonate.

Yield: 42% of theory; M.p .: 1660C.

Example 5 2-Methyl-4- (3-nitrophenyl) -5-oxo-1,4-dihydropyridine-5,7-dihydrofurog3,4-bgpyridine-3-carboxylic acid propyl ester Representation analogous to Example 1 with 3-nitrobenzaldehyde instead of 2-trifluoromethylbenzaldehyde and propyl 3-aminocrotonate instead of ethyl ester.

Yield: 50% of theory; Fp .: 1960C.

Example 6 2-Methyl-4- (2-trifluoromethylphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuroL), 4-b-pyridine-3-carboxylic acid isopropyl ester Representation analogous to Example 1 with isopropyl 3-aminocrotonate instead of ethyl ester.

Yield 18% of theory; M.p .: 219-2230C.

Example 7 2-Methyl-4- (2-trifluoromethylphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuro β, 4-b-pyridine-3-carboxylic acid butyl ester Representation analogous to Example 1 with butyl 3-aminocrotonate instead of ethyl ester.

Yield: 10% of theory; M.p .: 194-1950C.

Example 8 2-Methyl-4- (2-triEluoromethylphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuroL7,4-b-pyridine-3-carboxylic acid (2-methoxy) -ethyl ester Representation analogous to Example 1 with 3-aminocrotonic acid (2-methoxy) ethyl ester instead of 3-aminocrotonic acid ethyl ester. Yield: 16% of theory; M.p .: 196-1970C.

Example 9 2-Methyl-4- (2-benzylthiophenyl) -5-oxo-1,4-dthydro-5,7-dihydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester Representation analogous to Example 1 with 2-benzylthiobenzaldehyde instead of 2-trifluoromethylbenzaldehyde.

Yield 31% of theory; M.p. 189-1900C (from EtOH).

Example 10 2-Methyl-4- (2-methylphenyl) -5-oxo-1,4-dihydro-5,7-dihydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester- Representation analogous to Example 1 with 2-methylbenzaldehyde instead of 2-trifluoromethylbenzaldehyde.

Yield 45%, m.p. 196-1980C.

Example 11 33.8 g (90 mmol) of 2-amino-1,4-dihydro-2,6-dimethyl-4- {2-nitrophenyl) pyridine-3,5-dicarboxylic acid diethyl ester were together with 14.6 g (90 mmol) Dichloromethylenedimethylammonium chloride in 200 ml of chlorobenzene was stirred at 80 ° C. for 2 hours. It was then cooled with ice, and the precipitated product was filtered off with suction and taken up in a cold 10 own sodium bicarbonate solution.

The aqueous phase was extracted several times with methylene chloride. To Drying of the extracts over Na2SO4 and distilling off the solvent resulted 16.6 g (46% of theory) of the reaction product with a melting point of melting point: 216-2180C.

Example 12 1,4-Dihydro-2-methyl-5-oxo-7,7-pentamethylene-4- (2'-nitrophenyl) -7H-pyrano [4,3-b] pyridine-3-carboxylic acid methyl ester 4.6 g of 6,6-pentamethylenetetrahydropyrandione-2,4, 3.8 g of 2-nitrobenzaldehyde and 2.9 g of methyl 3-aminocrotonate are refluxed in 100 ml of ethanol / glacial acetic acid (5: 1) for 10 hours. It is cooled to room temperature and the precipitate is filtered off with suction. Recrystallized from ethanol, 6 g (58% of theory) with a melting point of 2280 ° C. are obtained.

Example 13 1,4-Dihydro-2,7-dimethyl-4- (2'-methylphenyl) -5-oxo-7H-pyrano [4,3-b] pyridine-3-carboxylic acid ethyl ester A solution of 4.3 g of 6-methyltetrahydropyrandione-2,4, 4.0 g of 2-methylbenzaldehyde and 4.3 g of ethyl 3-aminocrotonate in 80 ml of ethanol / glacial acetic acid (5.:1) is refluxed for 10 hours. It is concentrated in vacuo and the residue is recrystallized from ethanol: 5.3 g (50% of theory), melting point: 2130C.

The following were obtained analogously: Example 14 ethyl 1,4-dihydro-2,7-dimethyl-4- (3'-trifluoromethylphenyl) -5-oxo-7H-pyrano [4,3-b] pyridine-3-carboxylate, melting point: 2100C Example 15 Methyl 1,4-dihydro-2,7-dimethyl-4- (2'-chlorophenyl) -5-oxo-7H-pyrano [4,3-b] pyridine-3-carboxylate, m.p .: 252-254 ° C Example 16 1,4-Dihydro-2,6-dimethyl-3-nitro-4- (3-nitrophenyl) -pyridine-5-carboxylic acid cyclopentyl ester 15.1 g (0.1 mol) of 3-nitrobenzaldehyde are refluxed for 6 hours together with 16.9 g (0.1 mol) of B-aminocrotonic acid cyclopentyl ester and 10.3 g (0.1 mol) of nitroacetone in 150 ml of ethanol . After the reaction mixture has cooled, the solvent is distilled off in vacuo, the oily residue is taken up in a little chloroform and chromatographed on a silica gel column with chloroform with the addition of methanol.

The fractions containing the reaction product are concentrated, the residue in a little isopropanol, the nitrodihydropyridine crystallized in yellow Crystals of m.p. 1740C.

Yield: 37% of theory.

Example 17 1,4-Dihydro-2,6-dimethyl-3-nitro-4- (3-nitrophenyl) pyridine-5-carboxylic acid (β-n-propoxyethyl) ester 15; 1 g (0.1 mol) 3-nitrobenzaldehyde together with 18.8 g (0.1 mol) acetoacetic acid (Bn-propoxyethyl) ester and 10.2 g (0.1 mol) 2-amino 1-nitro-1-propene in 150 ml of ethanol heated to reflux for 6 hours. After cooling, the solvent is distilled off in vacuo, the oily residue is taken up in a little chloroform and chromatographed on a silica gel column with chloroform with the addition of methanol. The fractions containing the product are concentrated, the residue taken up in a little isopropanol, the nitrodihydropyridine crystallized in yellow crystals with a melting point of 1610C.

Yield: 41% of theory.

Example 18 1,4-Dihydro-2,6-dimethyl-3,5-dinitro-4- (3-nitrophenyl) pyridine 23.6 g (0.1 mol) of 2-nitro-1- (3-nitrophenyl) -buten-1-one-3 and 10.2 g (0.1 mol) of 2-amino-1-nitro-1- propene are refluxed in 150 ml of ethanol for 12 hours. After cooling, the solvent is distilled off in vacuo, the oily residue is taken up in chloroform and chromatographed on a silica gel column with chloroform with the addition of methanol. In isopropanol, the product forms yellow crystals of m.p.

237-2400C (dec.).

Yield: 38% of theory.

Example 19 Analogously to Example 16, 1,4-dihydro-2,6-dimethyl-4- (4 -pyridyl) -3-nitro-pyridine-5-carboxylic acid methyl ester of melting point 210 ° C. (decomposition) (isopropanol) obtained yield: 19% of theory.

Example 20 Analogously to Example 16, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (3-trifluoromethylphenyl) -pyridine-5 was obtained by reacting 50 mmol of 3-trifluoromethylbenzaldehyde with 50 mmol of nitroacetone and 50 mmol of methyl B-aminocrotonate -carboxylic acid methyl ester with a melting point of 1750C (isopropanol).

Yield: 42% of theory.

Example 21 Analogously to Example 16, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-nitrophenyl) -pyridine-5- was obtained by reacting 50 mmol of 2-nitrobenzaldehyde with 50 mmol of nitroacetone and 50 mmol of methyl B-aminocrotonate. carboxylic acid methyl ester of melting point 1900C (isopropanol) obtained as a very light-sensitive compound.

Yield: 12% of theory.

Example 22 1,4-Dihydro-2,6-dimethyl-3-nitro-4- (4-nitrophenyl) pyridine-5-carboxylic acid (B-cyanoethyl) ester Analogously to Example 18, by reacting 50 mmol of 2-nitro-1 - (3-nitrophenyl) -buten-1-one-3 with 50 mmol of β-aminocrotonic acid β-cyanoethyl ester in 100 ml of ethanol, 1,4-dihydro-2 , 6-dimethyl-3-nitro-4- (3-nitrophenyl) pyridine-5-carboxylic acid (β-cyanoethyl) ester of m.p.

2100C (isopropanol) obtained.

Yield: 33% of theory.

Example 23 Analogously to Example 18, 1,4-dihydre-2,6-dimethyl-4- (2-methoxyphenyl) -3-nitro- pyridine-5-carboxylic acid methyl ester of melting point 2060C (ethanol).

Yield: 44% of theory.

Example 24 Analogously to Example 18, 1,4-dihydro-2t6-dimethyl-3-nitro-4- (3-nitro-4- (3 -nitrophenyl) pyridine-5-carboxylic acid (ß-trifluoroethyl) ester of melting point 1960C (ethanol).

Yield: 28% of theory.

Example 25 Analogously to Example 16, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (pyridyl-3) -pyridine-5- was obtained by reacting pyridine-3-aldehyde with ß-aminocrotonic acid ethyl ester and nitroacetone in ethanol. ethyl carboxylate of m.p.

2640C (isopropanol). Received.

Yield: 34% of theory.

Example 26 Analogously to Example 17, 4- (2-benzylthiophenyl) -1,4-dihydro-2,6-dimethyl-3-nitropyridine was obtained by reacting 2-benzylthiobenzaldehyde with 2-amino-1-nitro-1-propene and methyl acetoacetate in ethanol. 5-carboxylic acid methyl ester with a melting point of 1730C (isopropanol).

Yield: 21% of theory.

Example 27 Analogously to Example 16, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-trifluoromethylphenyl) -pyridine-5-carboxylic acid methyl ester from M.p. 1760C (ethanol).

Yield: 36% of theory.

Example 28 Analogously to Example 16, by reacting 2-chlorobenzaldehyde with ß-aminocrotonic acid methyl ester and nitroacetone in ethanol, 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-3-nitro-pyridine-5-carboxylic acid methyl ester of mp. 1670C (isopropanol) obtained.

Yield: 42% of theory.

Example 29 Analogously to Example 18, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (2 -trifluoromethoxyphenyl) pyridine-5-carboxylic acid methyl ester of melting point 1750C (isopropanol).

Yield: 39% of theory.

Example 30 The treatment of 1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-trifluoromethylphenyl) pyridine-5-carboxylic acid (β-cyanoethyl) ester in 1.2 equivalents of potassium hydroxide in aqueous ethylene glycol dimethyl ether After acidification with dilute HCl, room temperature gives 1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-trifluoromethylphenyl) pyridine-5-carboxylic acid with a melting point of 1830C (decomposition) (methanol).

Yield 89% of theory.

Example 31 When heated in ethanol with the addition of a trace of sulfuric acid, 1,4-dihydro-2,6-dimethyl-3-nitro-4- (trifluoromethylphenyl) -pyridine-5-carboxylic acid (Example 30) decarboxylates to 1,4-dihydro-2, 6-dimethyl-3-nitro-4- (trifluoromethylphenyl) pyridine with quantitative yield.

M.p. 201 ° C.

Example 32 Analogously to Example 18, by reacting ethyl 2-methylbenzylidene-acetic acid ester with 2-amino-1-nitro-1-propene in ethanol, 1,4-dihydro-2,6-dimethyl-4- (2-tolyl) -3-nitro -pyridine-5-carboxylic acid ethyl ester with a melting point of 1550C (isopropanol).

Yield 42% of theory.

Example 33 Diethyl 2-acetylamino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 8 g (0.03 mol) of 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are refluxed for 4 hours in 100 ml of acetic anhydride. It is concentrated to dryness in vacuo and the residue is recrystallized from ethanol. Yield: 5.4 g (58% of theory) of melting point: 1050C.

Example 34 2-Amino-6-methyl-1,4-dihydro-4- (2'-chlorophenyl) -pyridine-3-carboxylic acid ethyl ester After a solution of 18.1 g of 2'-chlorobenzylidene acetone and 13.0 g of ethyl amidinoacetate in 150 ml of ethanol has been boiled for 2 hours, the solvent is stripped off in vacuo. The residue is recrystallized from ethanol, yield 62% of theory, melting point 171.degree.

Example 35 1,4-Dihydro-4-phenyl-2,3,6-trimethylpyridine-5-carboxylic acid methyl ester 24.1 g (80 mmol) of 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylic acid methyl ester are poured into a solution of 12.2 g (320 mmol) of LiAlH4 in portions at 60 ° C. while stirring in 400 ml abs. Tetrahydrofuran entered (N2 atm) and stirred for 6 to 7 hours at 60.degree. After cooling, 19.7 ml of ethyl acetate, 15.9 ml of water, 19.6 ml of 10 N NaOH and 15.9 ml of water are added dropwise in succession. It is then filtered off with suction, washed thoroughly with ether and the filtrate is evaporated in vacuo. The syrupy residue is dissolved in 50 ml of ether and allowed to crystallize in the cold, 7.4 g or 36% of theory. Colorless prisms after recrystallization from acetonitrile; M.p. 1200C.

Example 36 Analogously to Example 35, 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid methyl ester was obtained by reduction with LiAlH4 in THF 4- (2-chlorophenyl) -1,4- dihydro-2,3,6-trimethyl-pyridine-5-carboxylic acid methyl ester of melting point 1640C (acetonitrile).

Yield 30% of theory.

Example 37 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid isopropyl (2,2,2-trichloroethyl) ester A solution of 30.2 g (0.2 mol) of 3-nitrobenzaldehyde, 46.6 g (0.2 mol) of acetoacetic acid (2,2,2-trichloroethyl) ester and 28.6 g (0.2 mol ) Isopropyl 3-aminocrotonate in 200 ml of ethanol was heated to boiling under nitrogen for 12 hours. The solvent was concentrated in vacuo and the solid residue was recrystallized from ethanol. M.p .: 1920C; Yield: 46 g (47% of theory).

Example 38 1,4-Dihydro-2 6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid (n) -hexylisopropyl ester Was prepared analogously to Example 32 from 0.2 mol of 3-nitrobenzaldehyde, 0.2 mol of (n-hexyl) acetoacetate and 0.2 mol of isopropyl 3-aminocrotonate.

M.p .: OC; Yield: Example 39 1,4-Dihydro-2,6-dimethyl-4- (pyridyl-3) -pyridine-3,5-dicarboxylic acid monoethyl ester Manufactured according to DE-OS 2,847,237 (example no. 14).

M.p .: 2050C (dec.); Yield: 32% of theory.

Example 40 3-Cyano-1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -pyridine-5-carboxylic acid methyl ester Manufactured according to DE-OS 2 658 804 (example no. 17).

M.p .: 1710C; Yield: 42% of theory.

Example 41 Diethyl 2,6-di- (4-natrophenyl) -4- (4-ethoxycarbonylmethoxy) -1-methyl-1,4-dihydropyridine-3,5-dicarboxylate 100 mmol of 4- (ethoxycarbonylmethoxy) benzaldehyde were heated to 100 ° C. for 5 hours with 200 mmol of 4-nitrobenzoyl acetic ester, 100 mmol of methylamine hydrochloride in 60 ml of pyridine. It was poured onto ice water and filtered off with suction.

Yield: 11% of theory; M.p .: 1360C.

Example 42 2,6-Dimethyl-4- (2-trifluoromethylphenyl) -1-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diallyl ester 100 mmol of 2-trifluoromethylbenzaldehyde, 200 mmol of allyl acetoacetate and 120 mmol of methylamine hydrochloride were heated to 110 ° C. in 50 ml of pyridine for 5 hours, poured into water and filtered off with suction.

Yield; 5% of theory; Fp .: 90 to 910C.

Example 43 2,6-Diphenyl-3,5-di (phenylcarbonyl3-1-methyl-4- (3-pyridyl) -1,4-dihydropyridine 1.3 ml of pyridine-3-aldehyde, 6 g of dibenzoylmethane and 1 g of methylamine hydrochloride are heated to 10 ° C. overnight in 10 ml of pyridine, then poured onto ice water, filtered off with suction and recrystallized from methanol.

Yield: 15% of theory; M.p .: 2380C.

Example 44 Bis-L7,6-dimethyl-5-ethoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid 1,6-hexanediyl ester 25 mmol of bis (3-aminocrotonic acid) -1,6-hexanediyl ester are refluxed for 14 hours together with 50 mmol of ethyl 3-nitrobenzylidene acetoacetate in 100 ml of ethanol. After cooling, the solvent is distilled off in vacuo and taken up with 50% strength aqueous ethanol. The semi-solid residue was recrystallized from methanol.

Yield: 37% of theory; M.p .: 177-179 ° C.

Example 45 Bis-ER, 6-dimethyl-5-ethoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid 1,12-dodecanediyl ester Representation analogous to Example 44 with bis- (3-aminocrotonic acid) -1,12-dodecanediyl ester instead of bis- (3-aminocrotonic acid) -1,6-hexanediyl ester.

Yield: 10% of theory; M.p .: 103 to 1200C.

Claims (13)

Claims 1) Use of 1t4-dihydropyridines of the general formula (I) in which n stands for 0, 1 or 2, R1 a) stands for hydrogen, a straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical which optionally contains 1 to 3 identical or different hetero-chain members from group 0, CO, SOm (m. = O, 1 or 2), = N-, NRI or SiRIIRIII and where this hydrocarbon radical is optionally substituted by halogen, NO2, CN, N3, hydroxy, aryl or heteroaryl or b) is an aryl or heteroaryl radical , these radicals optionally having 1 to 5 identical or different substituents from the group consisting of aryl, alkyl, alkenyl, alkynyl, alkenoxy, alkynoxy, aralkyl, acyl, alkylene, dioxyalkylene, halogen, CF, OCF, SCF3, NO, NO, CN, N3 , CORIV, COORV, I, NRI or NRVIIRVIII, where the alkyl, alkoxy and aryl radicals of the abovementioned substituents can in turn be substituted by halogen, COORV or NRVIIRVIII or c) represents the radical NRVIIRI RI, and where the under away) and c) said radicals R, RII, gIII RIV RV, RVI, RVII and RVIII have the meaning given below, R a) stands for one of the substituents given under R¹ but does not have to be identical with this, or b) for the radicals NHRI or stands, where R1, RIX and RX have the meaning given below, or the substituents R1 and R2 together form a 5- to 8-membered, saturated or unsaturated ring which optionally contains 1, 2 or 3 identical or different ring members from group 0 , S, NR or CO and which optionally contains 1 to 3 identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy, aryl or aryl or aryl groups where only one of the two substituents R2 or R3 is alkoxy, alkylthio or NHRI, R4 a) is hydrogen> NO2, NO, CN, SO RXI (m = 0, m 1 or 2), halogen, stands, where R1 RVII VIII RXI and RXIII have the meaning given below R., R, or b) represents a branched or unbranched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical which is optionally substituted by halogen, OH, CN, alkoxy, Alkylthio, aryloxy, COORV or where RV, RVII and RVIII have the meaning given below, or c) for an aromatic hydrocarbon radical or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 4 identical or different hetero members from the group 0, S, -N =, NRI, where this hetero ring is linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom, and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 to 3 identical or different substituents from the group consisting of halogen, OH, CN, CF3, OCF3, SCF3 , NO2, alkyl, alkoxy, aryl and wear, or -. X d) is the radical CY-R¹, where X is oxygen, sulfur or NRI and Y is a single bond, O, S or NRI, and R8 has the meaning given for R¹ and with the substituent R¹ being the same or different from this is different, or e) for the "remainder stands, 1 1 1 1 1 where n ', R¹, R², R³, R5, R6 and R7 have the meanings given for n, R¹, R², R³, R5, R6 and R7 and are identical to or different from these are, and R4 @ and R4 @ are identical or different and each represent a radical, reduced by one hydrogen, of the substituents specified for R4 under a) to d), or R² and R4 together represent a branched, unbranched, saturated or unsaturated 5- to 8-membered ring, which optionally has 1, 2 or 3 identical or different ring members from group 0, CO, CS, C = NRI, = N-, NRI, sOm (m = 0, 1 or 2) or SiRII R111 contains, and which is optionally substituted by halogen, hydroxy, alkoxy, aryl, aralkyl, or is disubstituted by a straight-chain or branched alkylene chain having 3 to 8 carbon atoms, it being possible for this common ring of R2 and R4.auch to be fused directly to the common ring of R1 and R2, the radicals RI, RII, RIII, RVII, RVIII as below R5 has the meaning given for R4 and is identical to or different from R4, or R5 and R3 together form a ring which is identical to or different from the ring formed by R² and R4, R6 is hydrogen, Alkyl or haloalkyl, and R7 a) is a saturated, unsaturated, cyclic, straight-chain or branched aliphatic hydrocarbon radical which is optionally substituted by halogen, aryl or heteroaryl, or b) is an aryl or heteroaryl radical which is optionally 1 to 5 identical or different substituents from the group N02, CN, N3, NO, CF3, halogen, CORIV, COORV, ORVI SOmRXI (m = 0, 1 or 2), Contains alkyl, aryl, alkenyl, alkynyl, alkenoxy, alkynoxy, aralkyl, acyl, alkylene, or dioxyalkylene, the aforementioned alkyl and aryl substituents in turn being replaced by halogen, COORV or may be substituted, and where in the aforementioned definitions of the substituents R1 to R8 RI stands for hydrogen, alkyl, aryl, aralkyl, heteroaryl or acyl, RII and RIII are identical or different and each stand for alkyl, aryl, aralkyl or heteroaryl, RV , R and RVI and stand for hydrogen, alkyl, aryl, aralkyl or heteroaryl, RVII and RVIII are each identical or different and stand for hydrogen, aryl or aralkyl or stand for alkyl which is optionally interrupted by 0, S or NRI or together with the nitrogen atom form a 5- to 7-membered ring which can contain 1 or 2 identical or different hetero ring members from group 0, S or NRI or where one of the radicals RVII or RVII: for an aliphatic acyl group with up to 6 carbon atoms RIX, RX, RXI, RXII and RXIII are each identical or different and are alkyl, aryl or aralkyl, where the alkyl, Ar mentioned under R¹ to R8 and under RI to RXIII yl, aralkyl, heteroaryl and acyl radicals and the hetero ring formed with RVII and RVIII are in turn optionally substituted by OH, CF3, OCF3, CN, NO2, halogen, lower alkyl, lower alkoxy, aryl or aralkyl, and the following as heteroaryl Substituents that may be mentioned are: thienyl, furyl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, pyridazinyl, quinazolyl, quinoxalyl, benzothienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxydiazolyl, pyrazolyl, indrazinyl, oxydiazolyl, pyrazolyl, indrazinyl Benzofuranyl, indazolyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benz-thiazolyl, benztriazolyl, benzoxadiazolyl, cinnolinyl, phthalazinyl, naphthyridinyl or benzotriazinyl, in the form of isomers, isomeric mixtures, pharmaceuticals positive, as well as their pharmaceutically positive, racemic and optical antipodes inotropic effect. 2) Use of compounds of the general formula (I) according to claim 1 in medicinal products with cardiotonic effects. 3) Use of compounds of the general formula (I) according to Claim 1, in which n is 0, 1 or 2, R1 a) is hydrogen, a straight-chain, branched cyclic saturated or unsaturated aliphatic hydrocarbon radical having up to 10 carbon atoms the optionally 1 or 2 identical or different hetero chain members from the group 0, CO, S, SO2, = N- or NRI and where this hydrocarbon radical is optionally substituted by halogen, NO2, CN, W3, hydroxy, with 1 to 4 C atoms, phenyl, naphthyl or heteroaryl or b) represents a phenyl, naphthyl or heteroaryl radical, these radicals optionally having 1 to 3 identical or different substituents from the group consisting of phenyl, alkyl, alkenyl, alkynyl, alkenoxy, alkynoxy each with up to 4 carbon atoms, aralkyl with 7 to 14 carbon atoms, acyl with up to 6 carbon atoms, alkylene, dioxyalkylene with up to 4 carbon atoms in the alkylene chain, halogen, CF3, OCF3, SCF3, NO2, CN, N3 , CORIV, COORV, OR, NR or NRVIIRVIII, where the alkyl, alkoxy and aryl radicals of the above-mentioned substituents can in turn be substituted by halogen, COORV or NRVIIRVIII, or c) stands for the radical NUR WIR, and the under a), b) and c) mentioned radicals RI, RIII, RIII, RIV RV, RVI, RVII and RVIII have the meaning given below, R² is a) for one of the substituents given under R¹ but does not have to be identical with these or b) for the radicals NHRI or stands, where RI, RIX and RX have the meaning given below, or the substituents R¹ and R² together form a 5- to 7-membered saturated or unsaturated ring, which optionally contains one or two identical or different ring members from the group 0, S, Contains NR1 or CO and which optionally contains one to three identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy each having 1 to 4 carbon atoms, phenyl, naphthyl or aralkyl having 7 to 14 carbon atoms, R³ for one of the under R² and is the same or different from this, with only one of the two substituents R2 or R3 each being alkoxy, alkylthio, or NHRI, R4 a) being hydrogen, NO2, NO, CN, SO ,, RIX (m = 0 or 2), halogen, stands, where RI, R, RVIII, RXI and RXIII have the meaning given below, or b) stands for a branched or unbranched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally substituted by halogen, OH, CN, alkoxy, alkylthio each with 1 to 4 carbon atoms, phenyloxy, naphthoxy, COORV or where RV RVII and RVIII have the meaning given below, or c) for an aromatic hydrocarbon radical with 6 to 10 carbon atoms or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 3 identical or different hetero members from group 0 , S, -N =, NR, where this hetero ring is linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom, and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 to 3 identical or different substituents from the group consisting of halogen, OH, CN, CF3, OCF3, SCF3, NO2, alkyl, alkoxy each with 1 to 4 carbon atoms, phenyl, naphthyl and or X d) is the radical CY-R8, where X is oxygen, sulfur or NRI and Y is a single bond, O, S or NRI, and R8 has the meaning given for R1 and with the substituent R1 is the same or is different from this, or e) for the rest where n ', R11, R21, R31, R51, R6' and R71 have the meanings given for n, R¹, R², R³, R5, R6 and R7 and are identical to or different from these, and 4 * R and R are identical or different and each represent a radical of the substituents specified for R under a) to d), which is reduced by one hydrogen, or R2 and R4 together form a branched, unbranched, saturated or unsaturated 5- to 7-membered ring , which optionally contains 1, 2 or 3 identical or different ring members from the group 0, CO, CS, C = NR11 = N-, NRI or SOm (m = O or 2) and which is optionally substituted by halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 14 carbon atoms, or is disubstituted by a straight-chain or branched alkylene chain having 3 to 8 carbon atoms, this common ring of R² and R4 also being fused directly to the common ring of R1 and R2, the radicals RI, RII, R1111, RVII, RVIII having the meaning given below have, 4 R5 has the meaning given for R- and is identical to or different from R4, R6 is hydrogen, alkyl or haloalkyl each having 1 to 4 carbon atoms and R7 a) is a saturated, unsaturated cyclic, straight-chain or branched aliphatic hydrocarbon radical with up to 10 carbon atoms, which is optionally substituted by halogen, phenyl, naphthyl or heteroaryl or b) a phenyl, naphthyl or heteroaryl radical which optionally has 1 to 3 identical or different substituents from the group N02 , Halogen, CN, N3, NO, CF3, CORIV, COORV, ORVI, SOmR I (m = 0, 1 or 2), Alkyl with 1 to 4 carbon atoms, phenyl, naphthyl, alkenyl, alkynyl, alkenoxy, alkynoxy with up to 4 carbon atoms each, aralkyl with 7 to 14 carbon atoms, acyl with 1 to 4 carbon atoms, alkylene or dioxyalkylene each containing up to 4 carbon atoms, the aforementioned alkyl and aryl substituents in turn by halogen, COORV or can be substituted, and where in the above definitions of the substituents R to R7 RI stands for hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms, heteroaryl or acyl with up to 7 carbon atoms Atoms, II III are identical or different and each represent alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms or heteroaryl, R, RV and RVI are each identical or different and represent hydrogen , Alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, aralkyl with 7 to 12 carbon atoms or heteroaryl, RVII and RVIII are each identical or different and are hydrogen, phenyl, naphthyl or aralkyl with 7 to 12 carbon atoms are or are alkyl with 1 to 6 carbon atoms, which is optionally interrupted by O, S or NRI, or together with the nitrogen atom form a 5- to 7-membered ring containing 1 or 2 identical or different hetero ring members from the group May contain 0, S or NRI or where one the radicals RVII and RVIII are an aliphatic acyl group with up to 6 carbon atoms, RIX RX and RXIII RXII are each identical or different and represent alkyl with 1 to 6 carbon atoms, phenyl, naphthyl or aralkyl with 7 to 12 carbon atoms, where the alkyl, aryl, aralkyl, heteroaryl and acyl radicals mentioned under R1 to R8 and under RI to RVIII and the hetero ring formed with R6 and R7 are on the other hand optionally substituted by OH, CF3, OCF3, CN, NO2, halogen, Alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, phenyl or benzyl and the following substituents being mentioned as heteroaryl: thienyl, aryl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, pyridazinyl, quinazolyl, quinoxalyl, Benzothienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxydiazolyl, pyrazinyl, oxazinyl, thiazinyl, indolizinyl, indolyl, benzofuranyl, indazolyl benzothienyl, benzimidazolyl, benzoxazolyl, benzistroxazolyl, benzistroxazolyl yl, cinnolinyl, phthalazinyl, naphthyridinyl or benzotriazinyl, in the form of isomers, isomer mixtures, racemates and optical antipodes as well as their pharmaceutically acceptable salts, in drugs with positive inotropic effects. 4) Use of compounds of general formula (I) according to claim 1, in which n is 0 or 1, R¹ a) is hydrogen, a straight-chain, branched cyclic saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms, which optionally by one or two identical or different hetero chain members from group 0, CO, S, = N- or NRI, and this hydrocarbon radical is optionally substituted by F, Cl, Br, NO2r CN, OH, phenyl or pyridyl or b) for a phenyl, naphthyl or pyridyl radical, these radicals optionally having 1 or 2 identical or different substituents from the group consisting of phenyl, alkyl, alkenyl, alkoxy, alkenoxy each with up to 4 carbon atoms, benzyl, acetyl, alkylene, dioxyalkylene Carry 2 to 4 carbon atoms, fluorine, chlorine, bromine, CF3, OCF3, SCF3, NO CN, COORV, ORVI, NRI or NRVIIRVIII, the alkyl, alkoxy and aryl radicals of the above-mentioned substituents in turn being substituted by halogen or c) stands for the radical NR R, and where the radicals RI to RVIII mentioned under a), b) and c) have the meaning given below, but R2 a) stands for one of the substituents given under R1 need not be identical to these or b) for the residues NHRI or stands, where R1, RIX and RX have the meaning given below or the substituents R1 and R2 together form a 5- to 7-membered saturated or unsaturated ring, which optionally contains 1 or 2 identical or different ring members from group 0, S, Contains NRI or CO and which optionally contains 1 or 2 identical or different substituents from the group consisting of halogen, hydroxy, alkyl, alkoxy, each with 1 to 4 carbon atoms, phenyl or benzyl, R3 stands for one of the substituents specified under R2 and with this is the same or different from this, where only one of the two substituents R2 or R3 each represents alkoxy, alkylthio or NHRI, R4 a) represents hydrogen, NO2, CN, SR I, SO2RXI, stands, where R, RVI, RVII, RVIII and RIX have the meaning given below, b) stands for a branched or unbranched alkyl or cycloalkyl radical with up to 8 carbon atoms, which is optionally substituted by halogen, hydroxy, cyano, alkoxy with 1 to 4 carbon atoms, phenyloxy, COORV or where RV, RVII and RVIII have the meaning given below or c) for an aromatic hydrocarbon radical with 6 to 10 carbon atoms or for a 5- to 7-membered saturated or unsaturated hetero ring with 1 to 3 identical or different hetero members from group 0 , S, = N-, NRI, where this hetero ring is linked to the dihydropyridine ring either via a carbon atom or a nitrogen atom and where the aromatic hydrocarbon radical and the hetero rings optionally have 1 or 2 identical or different substituents from the group consisting of halogen, hydroxy, cyano, CF3 , NO2, phenyl, alkyl and alkoxy with 1 to 4 carbon atoms each, or X # d) stands for the radical CY-R8, where X stands for oxygen or NRI and Y stands for a single bond, oxygen or NRI and R stands for has the meaning given for R¹ and is identical to or different from the substituent, or e) for the remainder where n ', R¹', R² ', R³', R5 ', R6' and R7 'have the meanings given for n, R¹, R², R³, R5, R6 and R7 and are identical to or different from these , and R4 * and R4 are identical or different and each represent a radical of the substituents specified for R4 under a) to d), which is reduced by one hydrogen, or R2 and R4 together represent a branched unbranched, saturated or unsaturated 5- to 7- form a membered ring which optionally contains 1 or 2 identical or different ring members from group 0, CO, CS, C = NR1, = N- or NRI and which is optionally substituted by halogen or hydroxy, where R¹ has the meaning given below , R5 has the meaning given for R4 and is identical to or different from R4 or R5 and R3 together form a ring as defined for R2 and R4 and is identical to or different from this, R6 is hydrogen or alkyl with 1 to 4 carbon atoms, which may be you rch fluorine, chlorine or bromine is substituted and R7 a) stands for a saturated, unsaturated cyclic, straight-chain or branched aliphatic hydrocarbon radical with up to 8 carbon atoms, which is optionally substituted by halogen, or b) stands for a phenyl or heteroaryl radical , which optionally contains 1 to 3 identical or different substituents from the group N02, CN, N31 CF3, halogen, CORIV, CORV, ORVI, SRXI, Contains phenyl, alkyl with 1 to 4 carbon atoms, benzyl or acyl with 1 to 4 carbon atoms, where in the aforementioned definitions of the substituents R1 to R8 RI stands for hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, Benzyl, phenethyl, heteroaryl or acyl with up to 4 carbon atoms, RII and R111 are identical or different and each represent alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, benzyl or heteroaryl, RIV V, Rv and RVI are each identical or different and represent hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, naphthyl, benzyl or heteroaryl, RVII and RVIII, which are each the same or different and represent hydrogen, phenyl or benzyl or represent alkyl with 1 to 6 carbon atoms, which is optionally interrupted by 0 or NRI, or together with the nitrogen atom form a 5- to 7-membered ring which can contain 1 or 2 identical different hetero ring members from the group 0, S or NRI, or where one of the residues RVII or RV III stands for an aliphatic acyl group with up to 6 carbon atoms and RIX. RX, RXI, RXII and RXIII are each identical or different and represent alkyl with 1 to 6 carbon atoms, phenyl or benzyl, the following substituents being mentioned as heteroaryl: thienyl, furyl, pyryl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, Pyridazinyl, quinazolyl, quinoxalyl, benzothienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxydiazolyl, pyrazinyl, oxazinyl, thiazinyl, indolyl, benzofuranyl, indazolyl, benzothienyl, benzoxthoxazolyl or benzoxthoxazolyl, benzoxthoxazolyl, benzoxthoxazolyl, benzoxthazolyl, benzimidoxazolyl, benzoxazolyl, oxazolyl, 5) Use of compounds of the general formula (I) according to claim 1, in which n is 0, R1 a) is hydrogen, an aliphatic hydrocarbon radical having up to 6 carbon atoms, which may optionally be a hetero chain member from group 0, CO, = Contains N- or NRI and which is optionally substituted. by halogen, nitro, hydroxy or phenyl or b) represents a phenyl or pyridyl radical, which are optionally substituted by halogen, NO2, CF3, OCF3, CN, COORV or NRVIIRVIII, R² represents one of the substituents given under R¹, but not must be identical to this or stand for one of the radicals NHRI or N = CRXRXI, R3 stands for one of the substituents specified under R2 and is identical to or different from this, R4 a) stands for hydrogen, NO2, NRVIIRVIII or halogen, or b) represents an alkyl radical with 1 to 4 carbon atoms which is optionally substituted by halogen, OH, CN, alkoxy with 1 to 4 carbon atoms, COORV or NRVII RVIIZ or c) represents phenyl, pyridyl or thienyl, which are optionally substituted by halogen, OH, CN, alkyl or alkoxy each having 1 to 4 carbon atoms or by NRVIIRVIII or for the remainder stands, where X is oxygen and Y is a simple one. Bond, oxygen or NRI and R8 has the meaning given for R1 and with the substituent R1 is the same or. is different from this or for the rest where n ', R1', R2 ', R3', R5 ', R6', and R7 'have the meanings given for n, R¹, R², R3, R5, R6 and R7 and are identical to or different from these are, and R and R are identical or different and each stand for a radical reduced by one hydrogen of the substituents specified for R4 under a) to d), or R2 and R4 together form a 5- to 7-membered ring which optionally has 1 or 2 different ring members from group 0, CO, CS or C = NRI and which is optionally substituted by halogen, R5 has the meaning given for R4 and is identical to or different from R4, R6 is hydrogen or alkyl with 1 to 4 carbon atoms and R7 has the meaning given above, the substituents RI to RVIII in the above-mentioned definitions having the meaning given above. 6) Use of compounds of the general formula (I) according to claim 1, in which at least one of the substituents R4 and R5 is NO2 and / or in which R2 and R4 together or R3 and R5 together form a lactone ring. 7) compounds according to preparation examples 1 to 10, 19 to'23, 26, 28 to 32, 35 to 38, 41, 42, 43 and 45. 8) Process for the preparation of new compounds of the general formula (I) according to claim 1, characterized in that 1. carbonyl compounds of the general formula (II) in which R6 and R7 have the meaning given above, with ketones of the formula (III) and (IV) in which R2, R3, R4 and R5 have the meaning given above, and primary amines of the formula (V) H2N- (CO) nR1 (V) in which n = 0 and R1 has the meaning given above, optionally in the presence of inert ones Converts solvents, or 2. carbonyl compounds of the formula (II) in which R6 and R7 have the meaning given above, with enamines of the formula (VI) in which R1, R2, R4 and n have the meaning given above and ketones of the formula (IV) R3 -CO-CH2-R5 (IV) in which R3 and R5 have the meaning given above, optionally in the presence of inert solvents or 3. enamines of the formula (VI) in which R1, R2, R4 and n have the meaning given above with ylidene compounds of the formula (VIII) in which R3, R5, R6 and R7 have the meaning given above, optionally reacts in the presence of inert solvents, or one or more functional groups of dihydropyridines by customary methods of hydrolysis, esterification, transesterification, lactonization, rondensation, acylation, reduction or cyclization with suitable reaction partners or intramolecularly prepares new compounds of the general formula (I). 9) Use of compounds of the general formula (I) according to claim 1 in medicinal products with a positive inotropic effect. 10) Use of compounds of the general formula (I) according to claim 1 in drugs with the effect of increasing the Ca influx into the cell. 11) Medicinal products with positive inotropic effects containing at least a compound of the general formula (I) according to claim 1. 12) Medicines with the effect of increasing the influx of Ca into the cell containing at least one compound of the general formula (I) according to claim 1. 13) Process for the production of pharmaceuticals, characterized in that that at least one compound of the general formula (I) according to Claim 1, if appropriate using inert auxiliaries and carriers in a suitable application form convicted.