# Patent

## Title
Thiazolyl methyl)-2-2'-Bi-1H-imidazoles and use as hypertensive agents

## Abstract

and salts thereof. The Y can be hydrolyzed off. The other radicals on the dihydropyridine moiety can also be varied.

## Background
The present invention relates to new dihydropyridine derivatives and processes for their preparation via new intermediates in their use in the medical field.

It has already been disclosed that dihydropyridinecarboxylic acids can be prepared from the corresponding dihydropyridinecarboxylic acid .beta.-cyanoethyl esters cf. DOS (German Published Specification) No. 3,929,545.

The invention relates to dihydropyridine derivatives of the formula (I) ##STR3## in which R.sup.1 stands for straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by halogen, hydroxyl, C.sub.1 -C.sub.8 -alkoxy, carboxyl, C.sub.1 -C.sub.8 -alkoxycarbonyl or phenyl, or disubstituted or trisubstituted by identical or different nitro, cyano, C.sub.1 -C.sub.6 -halogenoalkyl, halogen, C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -alkoxycarbonyl, or by C.sub.1 -C.sub.6 -halogenoalkoxy, C.sub.1 -C.sub.4 -halogenoalkylthio, carbamoyl, dialkylcarbamoyl having up to 6 carbon atoms per alkyl group, or C.sub.2 -C.sub.8 -alkenyl which can optionally be substituted by C.sub.1 -C.sub.6 -alkoxycarbonyl, or by phenylsulphonyloxy which is optionally substituted by C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, nitro, halogen, cyano, C.sub.1 -C.sub.4 -halogenoalkyl or C.sub.1 -C.sub.4 -halogenoalkoxy, or by C.sub.1 -C.sub.8 -alkylamino or dialkylamino each having up to 6 carbon atoms per alkyl group, or C.sub.1 -C.sub.8 -acylamino, or by C.sub.1 -C.sub.8 -alkoxy or C.sub.1 -C.sub.8 -alkylthio, each of which can optionally be substituted by cyclohexyl or phenyl which, in turn, can be substituted by halogen, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, nitro, C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.2 -alkoxycarbonyl, cyano or C.sub.1 -C.sub.4 -halogenoalkoxy, or which can contain up to 3 hetero atoms from the group N, O or S and which can be substituted by C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy or trifluoromethylthio, ##STR4## wherein R.sub.5 stands for hydrogen, or hydrocarbon radical having up to 12 C atoms which can be interrupted by an oxygen or sulphur atom and which can be substituted by N.sub.3, hydroxyl, nitro, halogen, C.sub.1 -C.sub.6 -acyloxy, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, CN or C.sub.1 -C.sub.8 -acyl, or by phenyl or phenoxy which are optionally substituted by halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.2 -halogenoalkyl, or ##STR5## stands for a group of the formula ##STR6## wherein R.sup.10 and R.sup.11 are identical or different and carbon atoms and which can be substituted by halogen, hydroxyl, alkoxy having up to 6 carbon atoms, carboxyl or alkoxycarbonyl having up to 10 carbon atoms, or by phenyl which is optionally substituted by trifluoromethyl, trifluoromethoxy, alkyl having up to 6 carbon atoms, halogen or alkoxy having up to 6 carbon atoms, or halogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino, alkylamino having up to 8 carbon atoms or dialkylamino in each case having up to 8 carbon atoms per alkyl group, 7-membered saturated or unsaturated heterocyclic ring which can contain an oxygen atom, a sulphur atom or a nitrogen atom as an additional hetero atom which can optionally be substituted by a radical R.sup.12,

wherein unsaturated alkyl group having up to 4 carbon atoms which can be substituted by phenyl which, in turn, is substituted by halogen, alkyl having up to 4 C atoms, alkoxy having up to 4 C atoms, nitro and halogenoalkyl having up to 4 C atoms, or stands for phenyl which is optionally substituted by halogen, cyano, nitro, alkyl having up to 4 C atoms or halogenoalkyl having up to 4 C atoms, and having up to 10 C atoms, and atoms, form a 5-membered ring via an ethylene bridge, and atoms, or ##STR7## or stands for the group ##STR8## wherein R.sup.10 and R.sup.11 have the abovementioned meaning, and atoms, or having up to 2 carbon atoms, alkoxy having up to 2 carbon atoms, trifluoromethyl, trifluoromethoxy or difluoromethoxy, and carbon atoms which is optionally substituted by hydroxyl, cyano, phenyl, halogeno or aminoethoxy, or 7-membered ring which can optionally contain up to 3 identical or different ring members from the group comprising .dbd.CH--, --CH.sub.2 --, O, CO, CS, S or --N.dbd., and 12 carbon atoms and which can optionally be substituted by halogen, hydroxyl, C.sub.1 -C.sub.6 -alkoxy, trifluoromethyl, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl or phenyl which can be substituted by nitro, halogen, C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.4 -alkoxy, trifluoromethyl or trifluoromethoxy, or C.sub.1 -C.sub.2 -alkyl or C.sub.1 -C.sub.4 -alkoxy, and ##STR9## wherein A stands for hydrogen or methyl,

and --NH--COO--, --NH--SO.sub.2 -- or --NH--CO--NH-- or --NH--CS--NH--, and which can be substituted by halogen, hydroxyl, carboxyl, cyano, C.sub.1 -C.sub.8 -alkoxycarbonyl, carbonyl, alkylamino or dialkylamino having up to 8 carbon atoms, carbamoyl, C.sub.1 -C.sub.6 -alkoxy or phenyl which can be substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen, C.sub.1 -C.sub.6 -alkoxy or C.sub.1 -C.sub.2 -alkyl, or -alkyl, C.sub.1 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3 -halogenoalkyl or C.sub.1 -C.sub.3 -halogenoalkoxy, carbon atoms and which can be substituted by halogen, hydroxyl, C.sub.1 -C.sub.8 -alkoxy, nitro, cyano, C.sub.1 -C.sub.8 -alkylthio, carboxyl, C.sub.1 -C.sub.8 -alkoxycarbonyl or phenyl which can be substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.8 -alkyl, halogen or C.sub.1 -C.sub.8 -alkoxy, or to pentasubstituted by identical or different nitro, cyano, halogen, C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, C.sub.1 -C.sub.8 -alkylthio, carbamoyl or dialkylcarbamoyl in each case having up to 6 carbon atoms per alkyl group, carboxyl, C.sub.1 -C.sub.8 -alkoxycarbonyl, C.sub.1 -C.sub.6 -halogenoalkyl, C.sub.1 -C.sub.6 -halogenoalkoxy, C.sub.1 -C.sub.6 -halogenoalkylthio, C.sub.1 -C.sub.6 -alkylsulphonyl, C.sub.1 -C.sub.6 -alkylsulphamoyl, amino, C.sub.1 -C.sub.8 -alkylamino or dialkylamino in each case having up to 8 carbon atoms per alkyl group or C.sub.1 -C.sub.8 -acylamino, or which can contain one to three oxygen, sulphur and/or nitrogen atoms as hetero atoms,

and their physiologically acceptable salts.

The compounds according to the invention exist in stereoisomeric forms which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and the racemic forms and also the mixture of diastereomers. The racemic forms can be resolved, just like the diastereomers, into the stereoisomerically uniform constituents in a known manner (cf. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids or bases. Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid or benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid and salts with bases such as, for example, sodium hydroxide, potassium hydroxide, barium hydroxide or ammonium salts, or salts with organic bases such as pyridine or triethylamine are preferred.

Preferred compounds of the general formula (I) are those in which atoms which can optionally be substituted by phenyl, C.sub.1 -C.sub.2 -alkoxycarbonyl or carboxyl, or trisubstituted by identical or different nitro, cyano, C.sub.1 -C.sub.4 -halogenoalkyl, halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.1 -C.sub.2 -halogenoalkoxy, C.sub.1 -C.sub.2 -halogenoalkylthio or C.sub.1 -C.sub.4 -alkoxycarbonyl, or by phenylsulphonyloxy which is optionally substituted by C.sub.1 -C.sub.2 -alkyl or halogen, or by C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkylthio, each of which can be substituted by cyclohexyl or phenyl which can optionally be substituted by halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, nitro, C.sub.1 -C.sub.4 -halogenoalkyl, cyano or C.sub.1 -C.sub.4 -halogenoalkoxy, or to 3 hetero atoms from the group comprising N, O or S, and which can optionally be substituted by C.sub.1 -C.sub.3 -alkylthio, and C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.2 -alkoxy or trifluoromethyl, or ##STR10## wherein R.sup.5 stands for hydrogen, or hydrocarbon radical having up to 8 carbon atoms and which can be interrupted by an oxygen or sulphur atom and which can be substituted by hydroxyl, nitro, halogen, C.sub.1 -C.sub.6 -alkoxycarbonyl or carboxyl, or by phenyl or phenoxy which are optionally substituted by halogen or C.sub.1 -C.sub.2 -alkyl or C.sub.1 -C.sub.2 -alkoxy, or ##STR11## wherein R.sup.10 and R.sup.11 are identical or different and which can be substituted by hydroxyl, alkoxy having up to 4 carbon atoms, carboxyl or alkoxycarbonyl having up to 8 carbon atoms, or by phenyl which is optionally substituted by trifluoromethyl, trifluoromethoxy, alkyl having up to 4 carbon atoms, halogen or alkoxy having up to 4 carbon atoms, or carbon atoms, alkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy or difluoromethoxy, 7-membered saturated heterocyclic ring which can contain an oxygen atom, a sulphur atom or a nitrogen atom as an additional hetero atom, which can be substituted by a radical R.sup.12,

wherein which is optionally substituted by phenyl which, in turn, can be substituted by halogen, C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.2 -alkoxy or C.sub.1 -C.sub.2 -halegenoalkyl, or -C.sub.2 -alkyl or C.sub.1 -C.sub.2 -halogenoalkyl, having up to 8 C atoms, and atoms, or ##STR12## wherein R.sup.10 and R.sup.11 have the abovementioned meaning, and atoms, or -alkyl, C.sub.1 -C.sub.2 -alkoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy, and carbon atoms which can be substituted by hydroxyl or aminoethoxy, or 7-membered ring which can optionally contain up to 3 different ring members from the group comprising .dbd.CH--, --CH.sub.2 --, O, CO, CS, --N.dbd. or S, and atoms which can be substituted by halogen, hydroxyl, carboxyl or C.sub.1 -C.sub.4 -alkoxycarbonyl, or can be substituted by phenyl which, in turn, can be substituted by halogen, C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.2 -alkoxy, trifluoromethyl or trifluoromethoxy, or -C.sub.2 -alkyl or C.sub.1 -C.sub.2 -alkoxy and ##STR13## wherein A stands for hydrogen or methyl and --NH--SO.sub.2 -- or --NH--CO--NH-- and which can be substituted by halogen, hydroxyl, C.sub.1 -C.sub.3 -alkoxy, trifluoromethyl, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl or phenyl which, in turn, can be substituted by trifluoromethyl, trifluoromethoxy, halogen, C.sub.1 -C.sub.3 -alkoxy or C.sub.1 -C.sub.2 -alkyl, or -alkyl or C.sub.1 -C.sub.2 -alkoxy, and carbon atoms and which can be substituted by halogen, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, cyano, C.sub.1 -C.sub.4 -alkylthio, carboxyl, C.sub.1 -C.sub.4 -alkoxycarbonyl or phenyl which, in turn, can be substituted by trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.4 -alkyl, halogen or C.sub.1 -C.sub.4 -alkoxy, or identical or different nitro, cyano, halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, carbamoyl, dialkylcarbamoyl having up to 4 carbon atoms per alkyl group, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, C.sub.1 -C.sub.3 -halogenoalkyl, C.sub.1 -C.sub.3 -halogenoalkoxy, C.sub.1 -C.sub.3 -halogenoalkylthio, C.sub.1 -C.sub.3 -alkylsulphonyl, C.sub.1 -C.sub.3 -alkylsulphamoyl, amino, C.sub.1 -C.sub.4 -alkylamino or dialkylamino in each case having up to 4 carbon atoms per alkyl group or C.sub.1 -C.sub.4 -acylamino, or stands for a 5- to 6-membered unsaturated heterocyclic ring which can contain a nitrogen atom as a hetero atom,

and their salts.

In the case in which R.sup.2 and R.sup.3 jointly form a saturated or unsaturated 5- to 7-membered ring which can optionally contain up to 3 different ring members from the group O, .dbd.CH--, --CH.sub.2 --, CO, CS, S, --NR.sup.3' -- or --N.dbd., where R.sup.3' has the meaning of R.sup.3, the radicals shown below are of particular interest ##STR14##

Particularly preferred compounds of the general formula (I) are those

in which atoms, or identical or different nitro, cyano, trifluoromethyl, fluorine, chlorine, methyl, methoxy, trifluoromethoxy, difluoromethoxy or phenylsulphonyloxy which is optionally substituted by methyl, fluorine or chlorine, or by C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkylthio which can each be substituted by cyclohexyl or phenyl which, in turn, can be substituted by methyl, fluorine, chlorine or methoxy, or ##STR15## wherein R.sup.5 stands for hydrogen or C.sub.1 -C.sub.6 -alkyl which can optionally be interrupted by oxygen or sulphur and which can optionally be substituted by hydroxyl, C.sub.1 -C.sub.4 -alkoxycarbonyl or carboxyl, or by phenyl or phenoxy which is optionally substituted by fluorine, chlorine, methyl or methoxy, or ##STR16## wherein R.sup.10 and R.sup.11 are identical or different and each carbon atoms and which can be substituted by fluorine, chlorine, hydroxyl, ethoxy, methoxy, carboxyl or C.sub.1 -C.sub.4 -alkoxycarbonyl, or by phenyl which, in turn, can be substituted by trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.2 -alkyl, fluorine, chlorine or C.sub.1 -C.sub.2 -alkoxy, or -C.sub.2 -alkyl, C.sub.1 -C.sub.2 -alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino or C.sub.1 -C.sub.2 -alkylamino, or methyl-piperazinyl or N-benzylpiperazinyl, and having up to 6 C atoms and atoms, or ##STR17## wherein R.sup.10 and R.sup.11 have the abovementioned meaning, and carbon atoms, or ##STR18## and R.sup.4 stands for straight-chain or branched alkyl having up to 4 carbon atoms, or ##STR19## wherein A stands for hydrogen or methyl, and --NH--SO.sub.2 -- or --NH--CO--NH--, and atoms which can be substituted by hydroxyl, methoxy or phenyl, and which can be substituted by hydroxyl or C.sub.1 -C.sub.2 -alkoxycarbonyl, or by phenyl which, in turn, can be substituted by methyl, trifluoromethyl, fluorine or chlorine, or identical or different nitro, cyano, fluorine, chlorine, C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.2 -alkylthio, carbamoyl, carboxyl, C.sub.1 -C.sub.4 -alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.2 -alkylsulphamoyl or C.sub.1 -C.sub.2 -alkylamino, or

and their salts.

The compounds according to the invention are new and possess useful pharmacological properties. They influence the contractility of the heart and may therefore be used for the control of cardiovascular disorders. Owing to the possibility of preparing pure enantiomers, the desired pharmacological properties of the compounds can be expressed in different directions.

The compounds according to the invention of the general formula (I) ##STR20## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Y have the abovementioned meaning,

are obtained by means of the intermediates of the general formula (II) ##STR21## in which R.sup.4 and Y have the abovementioned meanings, one hydrogen in (IIb),

wherein

by a process in which

[A] aldehydes of the general formula (III) ##STR22## in which R.sup.1 has the abovementioned meaning,

and the compounds of the formula (II) ##STR23## in which R.sup.4 and Y have the abovementioned meanings,

directly or optionally after isolation of the obtained benzylidene derivatives are reacted with aminocrotonic acid derivatives of the general formula (IV) ##STR24## in which R.sup.2 and R.sup.2 have the abovementioned meanings,

or by a process in which

[B] aldehydes of the general formula (III) ##STR25## in which R.sup.1 has the abovementioned meaning,

are reacted with compounds of the general formula (V) ##STR26## in which R.sup.2 and R.sup.3 have the abovementioned meanings,

directly or after isolation of the obtained benzylidene derivatives of the general formula (VI) ##STR27## in which R.sup.1, R.sup.2 and R.sup.3 have the abovementioned meanings,

are reacted with compounds of the general formula (II) ##STR28## in which R.sup.4 and Y have the abovementioned meanings,

Depending on the type of starting materials used, the synthesis variants for the compounds according to the invention can be represented by the following equations: ##STR29## Suitable solvents for the process variants A and B are water and all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulphoxide, acetonitrile or pyridine, and hydrocarbons such as toluene, xylene or benzene.

The reaction temperatures can be varied within a relatively large range. In general, the reaction is carried out between +10.degree. C. and +150.degree. C., preferably between +20.degree. C. and +100.degree. C., in particular at the boiling point of the respective solvent.

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

When carrying out the process variants A and B according to the invention, the ratio of the substances participating in the reaction is arbitrary. However, in general the reaction is carried out using molar amounts of the reactants. The isolation and purification of the substances according to the invention is preferably carried out in such a way that the solvent is distilled off in vacuo and the residue, which may initially be obtained crystalline only after ice cooling, is recrystallized from a suitable solvent. In some cases, it may be necessary to purify the compounds according to the invention by chromatography.

The compounds of the general formula (II) are new. Only L-(2-benzyloxycarbonyl-2-tert.-butoxy-carbonyl-1-methyl)-ethyl 3-oxobutanoate is employed as a protecting group in the synthesis of amino acids [cf. Bull. Chem. Soc. Jpn. 52 (16), 3111-3112].

The invention therefore also relates to the starting materials of the general formula (II), in which R.sup.4, Y, D and E have the abovementioned meanings, with the proviso that Y cannot be tert.-butyl if R.sup.4 denotes methyl, D denotes oxygen and E denotes two hydrogen atoms. The new compounds of the formula (II) can be obtained by various processes. For example compounds in which

can be prepared by a process in which

[A] compounds of the general formula (VIII)

in which

are reacted with diketene of the general formula (IX) ##STR30##

The compounds of the formula (II) in which

can alternatively be prepared by a process in which

[B] compounds of the formula (VIII) are reacted with compounds of the general formula (X) ##STR31## in which R.sup.4 has the abovementioned meaning.

The compounds of the general formula (II) in which

are obtained by a process in which

[C] compounds of the general formula (II)

in which

are reacted with ammonia.

[D] Compounds of the general formula (II)

in which

are obtained by a process in which

in which R.sup.1 has the abovementioned meaning, are reacted with compounds of the general formula (II) in which

The aldehydes of the general formula (III) employed as starting materials are known or can be prepared by known methods [DOS (German Published Specification) Nos. 2,165,260; 2,401,665; T. D. Harris, G. P. Roth, J. Org. Chem. 44, 2004 (1979); W. J. Dale, H. E. Hennis, J. Am. Chem. Soc. 78, 2543 (1956); Chem. Abstr. 59, 13929 (1963)].

The enamines of the general formula (IV) employed as starting materials are known or can be prepared by known methods [DOS (German Published Specification) No. 2,228,377; F. A. Glickman, A. C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].

The ylidene-.beta.-ketocarboxylic acid derivatives of the general formula (VI) employed as starting materials are known or can be prepared by known methods [G. Jones "The Knoevenagel Condensation" in Organic Reactions Vol. XV, 204 (1967)].

The starting materials of the formula (VIII) are in some cases known or can be prepared by known methods [cf. Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15, part 1, E. Wunsch, page 46 et seq.].

The compound of the formula (IX) and its reactions are known [cf. R. J. Clemens, Chem. Rev. 88, 241 (1986)].

The compounds of the formula (X) are known in some cases or can be prepared by customary methods [cf. J. Org. Chem. 43, 1087 (1978)].

The compounds of the general formula (I) can exist both as mixtures of diastereomers and as pure diastereomers. If pure L- or D-compounds are employed as starting materials of the formula (VIII), in the end pairs of diastereomers of the formula (I) are obtained from these, which, if desired, surprisingly can be easily resolved into the pure diastereomers by known methods such as column chromatography, fractional crystallization or Craig partition. [For Craig partition see, for example, "Verteilungsverfahren im Laboratorium ("Partition Methods in the Laboratory"), E. Hecker, Verlag Chemie GmbH, Weinheim, Bergstrasse (1955)].

This invention in addition relates to the use of compounds of the general formula (I) for the preparation of dihydropyridinecarboxylic acids of the general formula (XI) ##STR32## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the abovementioned meaning,

and their use as intermediates to make enantiomers of dihydropyridines, because surprisingly it has been found that the radical Y of the compounds of the formula (I) can be eliminated exceedingly easily compared to the customary known dihydropyridine esters. If pure diastereomers of the formula (I) are employed, pure enantiomeric carboxylic acids of the formula (XI) are obtained, which can be transformed by usual methods into esters, amides, nitriles, lactones etc. Hereby the pure enantiomeres of dihydropyridines can be easily obtained.

(1R,2S)-[1-Methyl-2-methoxycarbonyl-2-(4-tolyl-sulphamoyl)]-ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylate ##STR33##

725 mg (3.8 mmol) of benzylidenenitroacetone are boiled for 3 hours with 1.4 g (3.8 mmol) of (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-tolylsulphamoyl)]-ethyl .beta.-aminocrotonate in 7 ml of ethanol. The mixture is concentrated and the two diastereomers are separated by column chromatography.

0.6 g of a yellow-coloured diastereomer of R.sub.f =0.18 and 0.4 g of a diastereomer of R.sub.f =0.146 are obtained.

TLC: silica gel aluminium roll, silica gel 60, F 254, layer thickness 0.2 mm (Merck)

Mobile phase: methylene chloride/ethyl acetate in the volume ratio 20:1.

Methyl (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-tolylsulphamoyl)]-ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate ##STR34##

5 g (20 mmol) of methyl 2-(3-nitrobenzylidene)-3-oxo-butyrate are boiled for 5 hours with 7.4 g (20 mmol) of (1R,2S)-[1-methyl-2-methoxy-2-(4-tolylsulphamoyl)]-ethyl .beta.-aminocrotonate in 40 ml of isopropanol. The mixture is cooled, and the deposited crystals are filtered off with suction and washed with isopropanol. 4.8 g (39.9% of theory) of a pure diastereomer of melting point: 157.degree.-159.degree. C. are obtained (see Example 4). [.alpha.].sub.589.sup.20 =+49.3.degree. (c=1.0:DMF). 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenyl-pyridine-5-carboxylate ##STR35##

0.37 g (1.95 mmol) of benzylidene-nitroacetone are boiled in 4 ml of ethanol for 3 hours with 0.6 g (1.95 mmol) of (1R,2S)-(1-methyl-2-methoxycarbonyl-2-phenyl-carbamoyl)-ethyl .beta.-aminocrotonate. The mixture is concentrated and the mixture of diastereomers is purified over a silica gel column using toluene/ethyl acetate. 0.7 g of a reddish yellow oil of R.sub.f 0.1 are obtained (mobile phase: methylene chloride/ethyl acetate 20:1).

Methyl (1R,2S)-1-methyl-2-methoxy-carbonyl-2-(p-tolylsulphamoyl)-ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate

3.6 g (29.9% of theory) of the other diastereomer are obtained from the mother liquor of the compound from Example 2 as an oil by column chromatography. R.sub.f : 0.38 Mobile phase: toluene/acetone (4:1)

1,4-Dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-car boxylic acid ##STR36##

1.22 ml (8.15 mmol) of diaza-bicyclo-undecane are added to 2 g (3.33 mmol) of the compound from Example 2 in 18 ml of methanol and the mixture is stirred at room temperature for 3 hours. It is concentrated, water is added to the residue from the evaporation and the mixture is rendered acidic with 10% strength hydrochloric acid added dropwise with stirring. The deposited solid product is filtered off with suction, washed with water and then with ether. 1.02 g (88.5% of theory) of a colourless product of melting point 181.degree.-182.degree. C. with decomposition are obtained.

[.alpha.].sub.589.sup.20 =-21.degree. (c=0.711, acetone) (exceed of enantiomeres (ee)>99%).

The compounds shown in the table below were obtained analogously to Examples 1 to 4. ##STR37## Example No. R.sup.1 R.sup.2 Y M.p. [.degree.C.] R.sub.f (Mobile phase)         6 ##STR38## NO.sub.2 ##STR39## (*1)0.43/0.49 7 ##STR40## NO.sub.2 ##STR41## oil175-178 (*1)0.42 8 ##STR42## NO.sub.2 ##STR43## 115-118 (*2)0.56 9 ##STR44## NO.sub.2 ##STR45## oil (*2)0.46 10 ##STR46## NO.sub.2 ##STR47## foam (*2)0.36/0.41 11 ##STR48## H.sub.3 COOC ##STR49## oil (*2)0.2/0.24(*1)0.54/0.59 12 ##STR50## H.sub.3 COOC ##STR51## 158-160 (*2)0.38/0.41(*1)0.53/0.59 13 ##STR52## NO.sub.2 ##STR53## foam (*2)0.02/0.04(*3)0.31 14 ##STR54## NO.sub.2 ##STR55## 178 (*4)0.16/0.21 15 ##STR56## NO.sub.2 ##STR57## oil (*4)0.16/0.19 16 ##STR58## NO.sub.2 ##STR59## oil (*4)0.09 17 ##STR60## NO.sub.2 ##STR61## oil (*4) 0.29/0.36 18 ##STR62## NO.sub.2 ##STR63## 178-182 (*4)0.22/0.92(*1)0.22/0.29 19 ##STR64## H.sub.3 COOC ##STR65## oil (*2)0.24/0.29(*1)0.56/0.62 20 ##STR66## H.sub.3 COOC ##STR67## foam (*2)0.394/0.44(*1)0.54/0.59 21 ##STR68## H.sub.3 COOC ##STR69## oil (*2)(*1)0.07/0.21 22 ##STR70## H.sub.3 COOC ##STR71## oil (*1)0.63/0.66(*2)0.4 23 ##STR72## NO.sub.2 ##STR73## 199-202 (*1)0.55 24 ##STR74## H.sub.3 COOC ##STR75## oil (*5)0.53/0.59(*1)0.89 25 ##STR76## H.sub.3 COOC ##STR77## oil (*1)0.44(*2)0.18 26 ##STR78## H.sub.3 COOC ##STR79## oil (*1)0.43(*2)0.18/0.23 27 ##STR80## H.sub.3 COOC ##STR81## oil (*1)0.17/0.22(*3)0.27/0.32 28 ##STR82## H.sub.3 COOC ##STR83## oil (*6)0.42/0.46 29 ##STR84## H.sub.3 COOC ##STR85## oil (*6)0.32/0.36 30 ##STR86## ##STR87## ##STR88## oil (*3)0.46/0.32 31 ##STR89## ##STR90## ##STR91## foam (*7)0.44/0.5(*3)0.35/0.4 32 ##STR92## ##STR93## ##STR94## foam (*7)0.59/0.65(*3)0.49/0.55 33 ##STR95## NO.sub.2 ##STR96## 194-197 (*2)0.45 34 ##STR97## ##STR98## ##STR99## foam (*2)0.02(*3)0.42 35 ##STR100## NO.sub.2 ##STR101## foam (*1)0.39 36 ##STR102## NO.sub.2 ##STR103## 180 (*2)0.55 37 ##STR104## NO.sub.2 ##STR105## oil (*1)0.26 38 ##STR106## H.sub.3 COOC ##STR107## 157-159 (*1)0.29/0.33(*8)0.39/0.47 39 ##STR108## H.sub.3 COOC ##STR109## foam (*4)0.37/0.41 40 ##STR110## H.sub.3 COOC ##STR111## foam (*1)0.67(*9)0.18 41 ##STR112## H.sub.3 COOC ##STR113## foam (*2)0.76/0.82 42 ##STR114## ##STR115## ##STR116## 155-157 (*3)0.58/0.64(*10)0.47/0.52 43 ##STR117## H.sub.5 C.sub.2HNOC ##STR118## 118-122 (*2)0.05(*3)0.71 44 ##STR119## H.sub.5 C.sub.2HNOC ##STR120## (*7)0.43/0.5(*3)0.46/0.52 45 ##STR121## NO.sub.2 ##STR122## 178 (*9) 0.48 46 ##STR123## NO.sub.2 ##STR124## 186-188 (*2)0.56 47 ##STR125## ##STR126## ##STR127## >270 48 ##STR128## COOCH.sub.3 ##STR129## oil (*2)0.130.17 49 ##STR130## COOCH.sub.3 ##STR131## oil (*1)0.35 50 ##STR132## ##STR133## ##STR134## oil (*1)0.54 51 ##STR135## ##STR136## ##STR137## oil (*1)0.33 52 ##STR138## ##STR139## ##STR140## oil (*1)0.16 53 ##STR141## COOCH.sub.2CH.sub.2OCH.sub.3 ##STR142## oil (*1)0.38/0.42 54 ##STR143## NO.sub.2 ##STR144## oil 0.56/0.6 (a = R, S; b = S, R) acetoacetate ##STR145##

(a) Preparation of methyl (2S,3R)-2-amino-3-hydroxybutyrate

109 ml (1.5 mol) of thionyl chloride are added dropwise at 0.degree. C. with strong cooling to 240 ml of methanol. 60 g (0.5 mol) of L-threonine are then added and the mixture is stirred at room temperature for 2 days, a clear solution resulting. After concentration, 85 g of a colorless oil are obtained.

(b) Preparation of methyl (2S,3R)-2-benzyloxycarbonylamino-3-hydroxybutyrate

34.1 g (0.201 mol) of methyl (2S,3R)-2-amino-3-hydroxybutyrate are mixed in 300 ml of ethyl acetate with a solution of 40 g of potassium carbonate in 200 ml of water. 33 ml (0.215 mol) of 90% strength benzyloxy-carbonyl chloride are then added dropwise at 0.degree. C. The mixture is stirred at 0.degree.-5.degree. C. for 2 hours and separated, and the ethyl acetate phase is washed twice with water, dried and concentrated. Hexane is added to the crystals obtained and filtered off with suction. 42.2 g (78.6%) of colorless crystals of melting point 96.degree. C. are obtained.

0.2 ml of triethylamine is added to 35 g (0.13 mol) of methyl (2S,3R)-2-benzyloxycarbonylamino-3-hydroxy-butyrate in 75 ml of absolute toluene. 9.8 ml (0.13 mmol) of diketene, dissolved in 10 ml of absolute toluene, are added dropwise at 90.degree. C., the temperature being kept between 90.degree. C. and 98.degree. C. The mixture is subsequently stirred at 95.degree. C. for 2 hours, cooled, shaken once with water, dried and concentrated. 44.3 g (96.6% of theory) of a brown-colored oil are obtained. 3-imino-acetoacetate or (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-nitrophenylsulphamoyl)]-ethyl .beta.-aminocrotonate ##STR146##

200 mg of p-toluenesulphonic acid are added to 39.2 g (97.5 mmol) of (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-nitrophenylsulphamoyl)]-ethyl acetoacetate in 370 ml of toluene and the mixture is boiled in a water separator for 4 hours, ammonia being introduced at the same time. The mixture is cooled, shaken twice with water, dried and concentrated. The crystals obtained are stirred with a little ethanol, filtered off with suction and washed with ethanol and ether. 20.2 g of beige-colored crystals of melting point 155.degree.-156.degree. C. are obtained. 2-(2-benzyloxybenzylidene)-3-oxo-butyrate ##STR147##

100 g (243.5 mmol) of (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(3,5-dinitrophenylcarbamoyl)]-ethyl acetoacetate are stirred in 300 ml of isopropanol with 51.3 g (243.5 mmol) of 2-benzyloxybenzaldehyde. A freshly prepared solution of 1.5 ml of piperidine and 0.75 ml of acetic acid in 12 ml of isopropanol is added to this suspension. The mixture is stirred at 40.degree.-45.degree. C. for 4 hours, a non-crystalline magma being formed initially and crystallization then occurring. The crystals are filtered with suction and washed with isopropanol and ether. 123.6 g (83.9% of theory) of a pale brown product of melting point 143.degree.-146.degree. C. are obtained.

The intermediates shown in the table below were obtained analogously to the directions for intermediates No. 1 to 3. Intermediate Example                                      M.p.: Configuration No.    B          R.sup.13         R.sup.14  R.sub.f : (*1) (1); __________________________________________________________________________ (2) ##STR148## 4      NHCOO      CH.sub.3         C(CH.sub.3).sub.3 oil, 0.6 R,S 5      NHCOO      CH(CH.sub.3).sub.2 C(CH.sub.3).sub.3 oil, 0.62 R,S 6      NHCOO      CH(CH.sub.3).sub.2 ##STR149## oil, 0.7 R,S 7      NHSO.sub.2 CH.sub.3 ##STR150## 85.degree. R,S 8      NHCO       CH(CH.sub.3).sub.2 ##STR151## oil, 0.61 R,S 9      NHCO       CH.sub.3 ##STR152## oil, 0.5 R,S 10     NHSO.sub.2 CH.sub.3 ##STR153## at 78.degree. C. R,S 11     NHCO       CH.sub.3 ##STR154## at 84.degree. C. R,S 12     NHCOO      CH.sub.3         CH.sub.3  70-72.degree. C. R,S 13     NHSO.sub.2 CH.sub.3         CH.sub.3  oil, 0.29 R,S 14     NHCO       CH3              CH.sub.3  oil, 0.31 R,S 15     NHSO.sub.2 CH.sub.3 ##STR155## 95-96.degree. C. R,S 16     NHSO.sub.2 CH.sub.3 ##STR156## 105-106.degree. C. R,S 17     NHCO       CH.sub.3 ##STR157## 79-84.degree. C. R,S 18     NHSO.sub.2 CH(CH.sub.3).sub.2 ##STR158## 100.degree. C. R,S 19     NHCO       CH(CH.sub.3).sub.2 ##STR159## 162-165.degree. C. R,S 20     NHSO.sub. 2 CH.sub.3 ##STR160## 99-100.degree. C. S,R 21     NHCO       CH.sub.3 ##STR161## 83.degree. C. S,R 22     NHSO.sub.2 CH(CH.sub.3).sub.2 ##STR162##     R,S 22a    NHCONH     CH.sub.3 ##STR163##     R,S ##STR164## 23     NHCOO      CH.sub.3 ##STR165## oil, 0.61 R,S 24     NHCOO      CH.sub.3         C(CH.sub.3).sub.3 0.6   R,S 25     NHSO.sub.2 CH.sub.3 ##STR166## 94-96.degree. C. R,S 26     NHCOO      CH(CH.sub.3).sub.2 ##STR167## oil, 0.69 R,S 27     NHCOO      CH(CH.sub.3).sub.2 C(CH.sub.3).sub.3 93-95.degree. C. R,S 28     NHCO       CH(CH.sub.3).sub.2 ##STR168## oil, 0.59 R,S 29     NHCO       CH.sub.3 ##STR169## oil, 0.5 R,S 30     NHSO.sub.2 CH.sub.3 ##STR170## 114-115.degree. C. S,R 31     NHSO.sub.2 CH.sub.3 ##STR171## 152-155.degree. C. R,S 32     NHCO       CH.sub.3 ##STR172## 102-103.degree. C. R,S 33     NHCOO      CH.sub.3         CH.sub.3  oil, 0.32 R,S 34     NHSO.sub.2 CH.sub.3         CH.sub.3  oil, 0.28 R,S 35     NHCO       CH.sub.3         CH.sub.3        R,S 36     NHSO.sub.2 CH.sub.3 ##STR173## 82-86.degree. C. R,S 37     NH SO.sub.2 CH.sub.3 ##STR174## 120.degree. C. R,S 38     NHCO       CH.sub.3 ##STR175## 161-164.degree. C. R,S 39     NHSO.sub.2 CH(CH.sub.3).sub.2 ##STR176## 153-156.degree. C. R,S 40     NHSO.sub.2 CH(CH.sub.3).sub.2 ##STR177## 180-182.degree. C. R,S 41     NHCO       CH(CH.sub.3).sub.2 ##STR178## 155-159.degree. C. R,S __________________________________________________________________________ Intermediate Example                                      M.p.: Configuration No.    B          E                R.sup.14  R.sub.f.: (1); __________________________________________________________________________ (2) ##STR179## 42     NHSO.sub.2 ##STR180## ##STR181## oil, 0.8 R,S 43     NHCO ##STR182## ##STR183## 141.degree. C. S,R 44     NHSO.sub.2 ##STR184## ##STR185## oil   R,S 45     NHCONH ##STR186## ##STR187##     R,S 46     NHSO.sub.2 ##STR188## ##STR189## oil, 0 8 S,R __________________________________________________________________________ Explanation of symbols for the tables (*1) Toluene/ethyl acetate 1:1 (*2) Methylene chloride/ethyl acetate 9:1 (*3) Methylene chloride/ethyl acetate 1:4 (*4) Methylene chloride/ethyl acetate 20:1 (*5) Chloroform/ethyl acetate 9:1 (*6) Toluene/ethyl acetate 2:1 (*7) Ethyl acetate (*8) Toluene/methyl isobutyl ketone 3:1 (*9) Toluene/ethyl acetate 4:1 (*10) Toluene/ethyl acetate 1:5

It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.

## Claims

1. A dihydropyridine compound of the formula ##STR190## in which R.sup.1 represents aryl having 6 to 10 carbon atoms which is monosubstituted, disubstituted or trisubstituted by identical or different nitro, cyano, C.sub.1 -C.sub.6 -halogenoalkyl, halogen, C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -alkoxycarbonyl, or by C.sub.1 -C.sub.6 halogenoalkoxy, C.sub.1 -C.sub.4 -halogenoalkylthio, carbamoyl, dialkyl carbamoyl having up to 6 carbon atoms per alkyl group, or C.sub.2 -C.sub.8 -alkenyl which can optionally be substituted by C.sub.1 -C.sub.6 -alkoxycarbonyl or by phenylsulphonyloxy which is optionally substituted by C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, nitro, halogen, cyano, C.sub.1 -C.sub.4 -halogenoalkyl or C.sub.1 -C.sub.4 -halogenoalkoxy, or by C.sub.1 -C.sub.8 -alkyl-amino or dialkylamino each having up to 6 carbon atoms per alkyl group, or C.sub.1 -C.sub.8 -alkyl-amino or dialkylamino each having up to 6 carbon atoms per alkyl group, or C.sub.1 -C.sub.8 -acylamino, or by C.sub.1 -C.sub.8 -alkoxy or C.sub.1 -C.sub.8 -alkylthio, each of which can optionally be substituted by cyclohexyl or phenyl which, in turn, can be substituted by cyclohexyl or phenyl which, in turn, can be substituted by halogen, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, nitro, C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.2 -alkoxycarbonyl, cyano or C.sub.1 -C.sub.4 -halogenoalkoxy, wherein cyclic, saturated or unsaturated hydrocarbon radical having up to 12 C atoms which can be interrupted by an oxygen or sulphur atom and which can be substituted by NO.sub.3, hydroxyl, nitro, halogen, C.sub.1 -C.sub.6 -acyloxy, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl, CN or C.sub.1 -C.sub.8 -acyl, or by phenyl or phenoxy which are optionally substituted by halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.2 -halogenoalkyl, having up to 10 C atoms, carbon atoms which is optionally substituted by hydroxyl, cyano, phenyl, halogeno or aminoethoxy, 12 carbon atoms and which can optionally be substituted by halogen, hydroxyl, C.sub.1 -C.sub.6 -alkoxy, trifluoromethyl, carboxyl, C.sub.1 -C.sub.6 -alkoxycarbonyl or phenyl which can be substituted by nitro, halogen, C.sub.1 -C.sub.2 -alkyl, C.sub.1 -C.sub.4 -alkoxy, trifluoromethyl or trifluoromethoxy, ##STR191## wherein A represents hydrogen or methyl, --NH--COO--, --NH--SO.sub.2 -- or --NH--CO--NH-- or --NH--CS--NH, and which can be substituted by halogen, hydroxyl, carboxy, cyano, C.sub.1 -C.sub.8 -alkoxycarbonyl, carbonyl, alkylamino or dialkylamino having up to 8 carbon atoms, carbamoyl, C.sub.1 -C.sub.6 -alkoxy or phenyl which can be substituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen, C.sub.1 -C.sub.6 -alkyl, and carbon atoms and which can be substituted by halogen, hydroxyl, C.sub.1 -C.sub.8 -alkoxy, nitro, cyano, C.sub.1 -C.sub.8 -alkylthio, carboxyl, C.sub.1 -C.sub.8 -alkoxycarbonyl or phenyl which can be substituted by nitro, cyano, trifluoromethyl, trigluoromethoxy, C.sub.1 -C.sub.8 -alkyl, halogen or C.sub.1 -C.sub.8 -alkoxy or pentasubstituted by identical or different nitro, cyano, halogen, C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, C.sub.1 -C.sub.8 -alkylthio, carbamoyl or dialkylcarbamoyl in each case having up to 6 carbon atoms per alkyl group, carboxyl, C.sub.1 -C.sub.8 -alkoxycarbonyl, C.sub.1 -C.sub.6 -halogenoalkylthio, C.sub.1 -C.sub.6 -halogenoalkoxy, C.sub.1 -C.sub.6 -halogenoalkylthio, C.sub.1 -C.sub.6 -halogenoalkoxy, C.sub.1 -C.sub.6 -halogenoalkylthio, C.sub.1 -C.sub.6 -alkylsulphonyl, C.sub.1 -C.sub.6 -alkylsulphamoyl, amino, C.sub.1 -C.sub.8 -alkylamino or dialkylamino in each case having up to 8 carbon atoms per alkyl group or C.sub.1 -C.sub.8 -acylamino, or a physiologically acceptable salt thereof.

2. A compound according to claim 1, wherein such compound is methyl [1-methyl-2-methoxycarbonyl-2-(4-tolyl-sulphamoyl)]-ethyl 1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate of the formula ##STR192## or a physiologically acceptable salt thereof.

3. A cardioactive composition comprising a cardioactive amount of a compound or salt thereof according to claim 1 and a pharmaceutically acceptable diluent.

4. A unit dose of a composition according to claim 3 in the form of a tablet, capsule or ampule.

5. A method of modifying the contractility of the heart of a patient in need thereof which comprises administering to such patient an amount effective therefor of a cardioactive amount of a compound or a salt thereof according to claim 1.

6. The method according to claim 5, wherein such compound is 1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate, 1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate, or 1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate.