NO854021L - 1,4-DIHYDROPYRIDINE HYDROXYAMINES AND PROCEDURES FOR PREPARING THEREOF. - Google Patents

Abstract

1. Compounds of the general formula (I) see diagramm : EP0179386,P26,F3 in which R represents phenyl, pyridyl or the benzoxadiazolyl radical, the phenyl radical containing 1 or 2 identical or different substituents from the group comprising nitro, trifluoromethyl, fluorine, chlorine and cyano, R**1 and R**3 are identical of different and each represent alkyl with 1 to 4 carbon atoms, or one of the substituents R**1 or R**3 represents hydroxymethyl, amino or cyano, R**2 represents hydrogen or alkyl with 1 or 2 carbon atoms, A either represents an alkylene group which has up to 12 carbon atoms and is substituted by methyl, ethyl or propyl, and which is optionally substituted or interrupted by a phenyl group and/or is optionally interrupted by an oxygen or sulphur atom or a grouping of the formula -NR**6 , or A represents a straight-chain or branched alkylene group which has up to 12 carbon atoms and is optionally interrupted by an oxygen or sulphur atom or a grouping of the formula -NR**6 when a) R**4 represents phenyl, benzyl, CO-R**6 , CO2 -R**6' , CO-NR**6 R**7 , SO2 R6 or -CH2 -CHOH-CH2 -OR**8 , or b) R represents pyridyl or benzoxadiazolyl, or c) R**5 represents indolyl, or d) the alkylene chain is interrupted by a sulphur atom or the group -NR**6 or e) X represents COR**9 , wherein R**6 und R**7 are identical or different and each represent hydrogen, alkyl with up to 4 C atoms, benzyl or phenyl and wherein R**8 has the meaning given for R**5 and can be identical or different from this radical wherein R**9 represents alkyl which has 1 to 7 C atoms and is optionally substituted by halogen, cyano, alkoxy or dialkylamino with in each case 1-4 C atoms, or denotes phenyl, naphthyl, phenylalkyl or anilino or an amino, monoalkylamino or dialkylamino group with in each case 1 to 4 C atoms, the alkyl groups optionally forming, with the nitrogen atom a 5-membered to 7-membered ring which can contain an oxygen atom as a further hetero-atom and wherein R**6' has the meaning of R**6 , but does not denote hydrogen, R**4 represents hydrogen, or represents straight-chain or branched alkyl with 1 to 3 carbon atoms, or represents phenyl or benzyl, or represents a radical of the formula CO-R**6 , CO2 -R**6' , CO-NR**6 R**7 , SO2 -R**6 or -CH2 -CHOH-CH2 -OR**8 , wherein R**6 , R**6' , R**7 , R**8 und R**9 have the abovementioned meaning, R**5 represents phenyl, naphthyl or indolyl, the phenyl radical optionally being substituted by 1 or 2 identical or different substituents from the group comprising fluorine, chlorine, nitro, cyano, alkyl with 1 or 2 C atoms, NR**6 , R**7 , NR**6 COR**7 , the group CH2 -CO-NH2 or acetyl and X represents the group COOR**10 , wherein R**10 represents a straight-chain, branched or cyclic alkyl radical which has up to 12 C atoms and is optionally interrupted in the chain by an oxygen atom and/or is optionally substituted by fluorine, chlorine, hydroxyl, pyridyl, phenyl or amino, or represents the group COR**9 , wherein R**9 has the abovementioned meaning, and pharmaceutically acceptable acid addition salts thereof.

Description

The present invention relates to new 1,4-dihydropyridine-hydroxyamines, a method for their production and the use of the compounds as pharmaceuticals, especially in agents that affect the circulation.

It is already known that 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylic acid diethyl ether is obtained when 2-benzylideneacetoacetic acid ethyl ester is reacted with B-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (E. Knoevenagel , Ber. dtsch. chem. Ges. 3_1, 743 (1898)).

Furthermore, certain 1,4-dihydropyridines are known to exhibit interesting pharmacological properties (F. Bossert, W. Vater, Naturwissenschaften _58, 578 (1971)).

Furthermore, it is known from German explanatory documents 28 47 236 and 22 18 644 that dihydropyridine esters can be used as coronary agents and as blood pressure lowering agents.

The present invention relates to 1,4-dihydropyridine with substituted carboxylic acid functions of general formula I

where

R stands for aryl or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyradazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where the aryl residue is as well as the heterocyclic parts contain 1-2 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, polyfluoro alkoxy, nitro, cyano, azido or SOm~alkyl (m = 0-3),

13

R and R are the same or different and stand for hydrogen, straight-chain or branched alkyl, aryl or aralkyl,

or one of the substituents R<1> or R<3> stands for hydroxyalkyl, acetoxymethyl, amino or cyano,

R stands for hydrogen or straight-chain or branched alkyl, which may optionally be interrupted by one or two oxygen atoms in the alkyl chain, or stands for aryl or aralkyl,

A stands for a straight-chain, branched or cyclic alkylene group with up to 20 carbon atoms, which may be substituted or interrupted by an optionally halogen, cyano, dialkylamino, alkyl, alkoxy, trifluoromethyl or nitro substituted phenyl group and/or which may optionally be interrupted by one or more oxygen atoms, sulfur atoms or groupings

6 7

of the formula -NR - or -CO-NR -, where

R 6 and R 7 are the same or different and stand for a hydrogen atom, a lower hydrocarbon residue, aryl or aralkyl,

R<4> stands for hydrogen, for straight-chain or branched alkyl, for aryl, aralkyl or for a residue of the formula CO-R , C02-R<6>', CO-NR<6>R<7>, SO2R<6 >', -CH2-CH-CH2-OR<8>,

where OH

R 6 , R 7 have the meanings given above,

R 6 1 has the same meaning as R 6 , but does not stand for hydrogen, R 8 has the meaning given for R 5 and may be the same or different from this,

R 5 stands for aryl or heteroaryl, where the aryls as well as the hetero-aryls can contain 1-3 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, cycloalkyl, morpholinyl, halogen, polyflourolkoxy, 6 6 6 7 nitro, cyano , azido, SO -R , -NR -SO (m = 0-2), NR R ,

6 7 sts

NR COR and acyl of the formula CO-R, and where the alkyl residues may again optionally be interrupted by one or two oxygen atoms, sulfur atoms or the groupings of the formula -NR -,

-CONR7- or -NCO„- and/or be substituted with halogen,

and where R 6 and R 7 can be the same or different and have the meanings stated above, and

o 9 9

X stands for the group -COR, where R is optionally substituted alkyl, aryl, aralkyl or anilino or an amino-, monoalkylamino- or dialkylamino group-, - where optionally the alkyl group together with the nitrogen atom forms a 5- to 7-membered ring, which as additional heteroatom may contain an oxygen or sulfur atom,

or stands for the group -COOR"*"^, where R^~ ® is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue, which may optionally be interrupted in the chain by an oxygen or a sulfur atom, and/or which is optionally substituted with halogen, cyan, hydroxy, acyloxy, pyridyl or with a phenyl, phenoxy,•phenylthio or phenylsulfonyl group,

where the aryl residue can again be substituted with halogen,

cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro,

or which can optionally be substituted with an amino group, where this amino group contains two identical or different substituents from the group alkyl, alkoxy, aryl and aralkyl and where these substituents optionally form a 5- to 7-membered ring with the nitrogen atom, which as an additional heteroatom contains an oxygen or sulfur atom or an N-alkyl group,

as well as pharmaceutically acceptable acid addition salts thereof.

The preparation of the compounds of general formula (I)

according to the invention takes place by

reacts dihydropyridinamines of general formula II

12 3

R, R , R , R , X and A have the meaning indicated above, and

R 4 1 stands for hydrogen, alkyl, aryl or aralkyl,

with epoxides of general formula III

where

R has the above meaning,

possibly in the presence of inert organic solvents.

The preparation of compounds of general formula (I) wherein

4

R stands for the rest

where R and R are different, preferably takes place by stepwise reaction of primary dihydropyridinamines first with an epoxide with the substituent R^ (Illa) and then

g

with another epoxide with the substituent R (Illb).

The preparation of compounds of general formula (I) where R<4> stands for the residues CO-R<6>, C02R<6>', CO-NR6R7 or SO2R<6>', takes place by reacting the compounds (I) where R4 = hydrogen with acylating or sulfonylating agents such as R<6>C02H,R<6->C0C1, (R6'CO) 0, R<60>9CC1,R<6>R<7>N-C0C1, R<6- >NC0, R<6>S0?C1, where R 6 , R 6 1 and R 7 have the meanings given above.

The method according to the invention can be clarified by the examples given in the following reaction schemes.

Of particular interest are the compounds of general formula I according to the invention

where

R stands for phenyl, naphthyl or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where the mentioned ring systems can in each case be substituted with 1 or 2 identical or different substituents from the group phenyl, straight-chain or branched alkyl with up to 8 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkoxy with 1-4 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano, azido or SOm-alkyl where

m is a number from 0-2 and alkyl preferably contains 1-4 carbon atoms,

13

R and R are the same or different and stand for hydrogen,

a straight-chain or branched alkyl radical with up to 4 carbon atoms, a phenyl radical or a benzyl radical, or one of the substituents R 1 or R 3 stands for a hydroxymethyl, acetoxymethyl, amino or cyano group,

R stands for hydrogen, for straight-chain or branched, optionally interrupted by an oxygen atom alkyl with up to 6 carbon atoms, for phenyl or benzyl,

A stands for a straight-chain, branched or cyclic alkylene group with up to 20 carbon atoms, which may optionally be substituted or interrupted by a phenyl group which in turn may be substituted with halogen, cyano, dialkylamino, alkyl, alkoxy with 1-4 C atoms, trifluoromethyl or nitro, and/or which is optionally interrupted by one or two oxygen atoms, sulfur atoms or groups of the formula -NR<6-> or -CO-NR<7->, where

R 6 and R 7 are the same or different and stand for hydrogen or a hydrocarbon residue with 1-6 carbon atoms, phenyl or benzyl,

4

R stands for hydrogen,

for straight-chain or branched alkyl with up to 6 C atoms, for phenyl, benzyl or

for a residue of the formula CO-R6, CO-R6, CO-NR6R7, SO-R6,

-CH2-CH-CH2-OR

OH

where

"6 7

R , R has the above meaning,

R 6 ' ' has the same meaning as R 6 , but does not stand for hydrogen, R 8 has the meaning given for R 5 and can be equal or

different from this,

R 5 stands for phenyl, naphthyl or for furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzthia-diazolyl, quinolyl, isoquinolyl, quinazolyl , quinoxazolyl or carbazolyl, where the mentioned ring systems may optionally contain 1-2 identical or different substituents from the group phenyl, alkyl (1-8 C atoms), cycloalkyl (5-7 C atoms), morpholinyl, alkoxy C atoms), the alkylene

(2-4 C-atoms), dioxyalkylene (1-3 C-atoms), halogen, polyfluoroalkoxy (1-4 C-atoms), nitro, cyano, azido,

SO -R6, -NR6-SO (m = 0 or 2), NR<6>R<7>, NR<6>COR<7> and acyl

of the formula CO-R, where the alkyl substituent may optionally be interrupted by one or two oxygen atoms, sulfur atoms or groups of the formula -NR 6 -, -CONR 7- or -NCO--, and/or may be substituted with halogen, and H

6 7

where R and R have the meanings given above,

X stands for the group -COR 9 , where R 9 stands for alkyl with 1-7 C atoms substituted, phenyl, naphthyl, phenylalkyl or anilino or an amino- , monoalkylamino or dialkylamino group with 1-4 C atoms, where optionally the alkyl group together with the nitrogen atom forms a 5- to 7-membered ring, which as an additional heteroatom may contain an oxygen or sulfur atom,

or stands for the group -COOR-^, where R"^ stands for a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue with up to 16 C atoms, which is optionally interrupted in the chain by an oxygen or a sulfur atom, and/or which is optionally substituted with fluorine, chlorine, bromine, cyano, hydroxy, pyridyl, acyloxy with up to 4 C atoms or with a phenyl, phenoxy, phenylthio or phenylsulfonyl group, which in turn may be substituted with fluorine, chlorine,

bromine, cyano, dialkylamino (1-4 C atoms), alkoxy (1-4 C atoms), alkyl (1-4 C atoms), trifluoromethyl or nitro,

or which is optionally substituted with an amino group, where this amino group contains two identical or different substituents from the group alkyl (1-4 C atoms), alkoxyalkyl (up to 8 C atoms), phenyl, naphthyl or phenylalkyl with 1-4 C -atoms in the alkyl residue and where these substituents optionally form a 5- to 7-membered ring with the nitrogen atom, which: as an additional heteroatom contains an oxygen or sulfur atom or an N-alkyl group with 1-4 C atoms,

as well. pharmaceutically acceptable acid addition salts thereof.

Salts can preferably be mentioned as acid addition salts

with organic acids such as maleic acid, fumaric acid or tartaric acid, or with inorganic acids such as e.g. hydrogen halides or sulfuric acid.

Of particular interest are compounds of the general formula (I), where

R stands for phenyl, thienyl, furyl, pyridyl or benzoxadiazolyl, where the phenyl residue contains 1 or 2 identical or different substituents from the group nitro, trifluoromethyl, fluorine, chlorine, cyano or dioxymethylene,

R"*" and R<3> are the same or different and stand for alkyl with

1-4 carbon atoms or one of the substituents R"<*>" or R<3>

stands for hydroxymethyl, amino or cyano,

R<2> stands for hydrogen or alkyl with 1-2 carbon atoms,

A stands for a straight-chain, branched or cyclic alkylene group with up to 12 carbon atoms which is optionally substituted or interrupted by a phenyl group and/or which is optionally interrupted by an oxygen atom or a group of the formula

-NR<6->or -CONR<7->,

R 6 and R 7 are the same or different and stand for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl,

R4 stands for hydrogen,

for straight-chain or branched alkyl with up to 4 C atoms, for benzyl or

where

6 7

R , R has the above meaning,

R has the same meaning as R<6>, but does not stand for hydrogen,

8 5

R has the meaning given to R and may be the same or different from this,

R 5 stands for phenyl, naphthyl or indolyl, where the phenyl residue is optionally substituted with 1 or 2 identical or different substituents from the group fluorine, chlorine, nitro, cyano, alkyl with 1-2 C atoms, NR6R7, NR<6>COR< 7> or acetyl and X stands for the group -COOR<10>, where R<10> stands for a straight-chain, branched or cyclic alkyl residue with up to 12 C atoms, which is optionally interrupted by an oxygen atom in the chain and/or which optionally substituted with fluorine, chlorine, hydroxy, pyridyl, phenyl or amino,

as well as pharmaceutically acceptable acid addition salts thereof.

The dihydropyridineamines of general formula (II) which are used as starting materials are known from the literature or can be prepared by methods known from the literature, these are essentially based on the pyridine synthesis according to Hantzsch (see European patent application 88-276-A).

As examples can be mentioned: 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-(2-aminoethyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl-(3-aminopropyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid (2-cyanoethyl)-(11-aminoundecyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid neopentyl-(6-aminohexyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid isobutyl-(5-aminopentyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methoxyethyl-(5-amino-2,2-dimethylpentyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid ethyl (2-N-methylaminoethyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid isopropyl-(3-aminopropyl)-ester,

1-ethyl-1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylic acid methyl-(2-N-benzylaminoethyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylic acid methyl-(4-aminobutyl)-ester,

1,4- dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5- dicarboxylic acid cyclopentyl-(4-aminobutyl)-ester, .1,4-dihydro-2,6-dimethyl-4-( 3-pyridyl)-pyridine-3,5-dicarboxylic acid-2,2,2-trifluoroethyl-(5-aminopentyl)-ester,

1,4- dihydro-2,6-dimethyl-4-(4-benzoxadiazolyl)-pyridine-3,5- dicarboxylic acid methyl-(2-aminoethyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-cyanoethyl)-pyridine-3,5-dicarboxylic acid-(2-hydroxyethyl)-(3-aminopropyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(2-benzyloxyphenyl)-pyridine-3,5-dicarboxylic acid isopropyl-(5-aminopentyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid neopentyl-(4-aminobutyl)-ester,

1,4- dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid ethoxyethyl-(6-aminohexyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid allyl-(2-aminoisopropyl)-ester,

1,4-dihydro-2,6-dimethyl-4-(3-methoxyphenyl)-pyridine-3,5-dicarboxylic acid methyl-(4-amino-4-methyl-butyl)-ester.

The epoxides of the general formula (III) used as starting materials are known from the literature or can be prepared by methods known from the literature (see A.F. Growther and L.H. Gnuth, J. Med. Chem. 11, 1009

(1968)).

Examples include: 1-phenoxy-2,3-epoxy-propane, 1-(4-methoxyphenoxy)-2,3-epoxy-propane, 1-(3-methoxyphenoxy)-2,3-epoxy-propane, 1 -(3-methoxyphenoxy)-2,3-epoxy-propane, 1-(2-allylphenoxy)-2,3-epoxy-propane, 1-(2-allyloxyphenoxy)-2,3-epoxy-propane, 1-( 4-carbazolyloxy)-2,3-epoxy-propane, i-(4-methoxyethylphenoxy)-2,3-epoxy-propane, 1-(4-indolyloxy)-2,3-epoxy-propane,

1-(1-naphthyloxy)-2,3-epoxy-propane,

1-(4-ally1-3-methoxyphenoxy)-2,3-epoxy-propane, 1-(2-cyanophenoxy)-2,3-epoxy-propane,

1-(5-allyl-2-ethoxyphenoxy)-2,3-epoxy-propane, 1-(4-aminocarbonylmethyl-phenoxy)-2,3-epoxy-propane, 1-(4-methylsulfonyl-N-methylamido-phenoxy )-2,3-epoxy-propane, 1-(4-methyl-carbaminoylethyl-phenoxy)-2,3-epoxy-propane, 1-(2-acetyl-4-propionamido-phenoxy)-2,3-epoxy- propane, 1-(4-acetamidophenoxy)-2,3-epoxy-propane.

For the method according to the invention, all inert organic solvents can be used. These preferably include lower alcohols such as ethanol, methanol, propanol or isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran or glycol monomethyl ether, as well as chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, as well as mixtures of these, the solvents.

The reaction temperature can be varied within a wide range. In general, one works between 10 and 150°C, preferably

between 20 and 130°C, especially at the boiling temperature of the solvent used.

The turnover can take place at normal pressure, but also at elevated pressure. In general, you work at normal pressure.

For the synthesis of the compounds of formula TD where R 4 = hydrogen, the corresponding amines of formula (II) are used in molar amounts up to twice the molar amount.

For the further reaction to compounds of formula (I),

4 o

where R stands for the remainder

they apply to-I.

corresponding to the epoxides of formula (III) in molar amounts to three times the molar amount.

For the acylation or the reactants are used in the sulfonylation

in molar amounts.

The above procedure is indicated to clarify the procedure, and the preparation of the compounds of formula (I) is not limited to this procedure, but any modification of this procedure can be used in the same way for the preparation of compounds according to the invention.

Depending on the choice of the starting materials, the compounds according to the invention can exist in stereoisomeric form, where they either relate to each other as image and mirror image (enantiomers) or do not relate to each other as image and mirror image (diastereomers). Both the antipodes as well as the racemen forms and also the diastereomer mixtures are the subject of the present invention. The racemic forms can, in the same way as the diastereomers, separate into stereoisomeric unitary components in a known manner (see, for example, E.L. Eliel, "Stereochemistry of Carbon Compounds",

McGraw Hill, 1962 ) ..

In addition to the preparation examples given below, the following active substances according to the invention can also be mentioned in particular: 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{ 2-[2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminoethyl} ester,

1,4-Dihydro-2,6-dimethyl-4-(2-trifluoromethylphenylHpyridine-3,5-dicarboxylic acid cyclopentyl-{4-[2-hydroxy-3-(4-indolyl-oxy)-1-propyl]-aminobutyl} ester ,

1,4-dihydro-2,6-dimethyl-4-(2,3-dichloropentyl)-pyridine-3,5-dicarboxylic acid-methyl-{6-[2-hydroxy-3-(4-aminocarbonylmethyl-phenoxy)- 2-propyl]-aminohexyl[residues,

1,4-dihydro-2,6-dimethyl-4-(2-benzyloxyphenyl)-pyridine-3,5-dicarboxylic acid-ethyl-{11-[2-hydroxy-3-(2-methoxy-phenoxy)-1- propyl]-aminoundecyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-pyridyl)-pyridine-3,5-dicarboxylic acid -isopropyl- {5-[2-cyanophenoxy)-1-propyl]amino-2, 2-dimethyl-pentyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid-(2,2-dimethyl)-ethyl-{3-[2-hydroxy-3- (4-Methoxyethyl-phenoxy)-1-propyl]-aminopropyl} ester,

1,4-dihydro-2,6-dimethyl-4-(4-benzoxadiazolyl)-pyridine-3,5-dicarboxylic acid-neopentyl-{2-f-[.2-hydroxy-3-(2-allyl-phenoxy ) - 1-propyl]-N-methyl-aminoethyl} ester,

1.4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{2-N,N-bis[2-hydroxy-3-(1-naphthyloxy) -1-propyl;]-aminoethyl} ester>:,

1> 4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl-{4-N,N-bis-[2-hydroxy-3-(4-indolyloxy)- 1-propyl]-aminobutyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylic acid-methyl-{6-N,N-bis[2-hydroxy-3-(4- aminocarbonyl-methylphenoxy)-1-propyl]-aminohexyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2-benzyloxyphenyl)-pyridine-3,5-dicarboxylic acid-ethyl-{11-N,N-bis[2-hydroxy-3-(2-methoxy- phenoxy)-1-propyl]-aminoundecyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-pyridyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{5-N,N-bis[2-hydroxy-3-(2- cyano-phenoxy)-1-propyl]-amino-2,2-dimethylpentyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid-(2,2-dimethyl)-ethyl-{3-N,N-bis-[ 2-hydroxy-3-(4-methoxy-ethylphenoxy)-1-propyl]-amino-propyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-(2-cyano)-ethyl-{2-N,N-bis[2-hydroxy -3-(4-indolyloxy)-1-propyl]-aminoethyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isobutyl-{5-N,N-bis[2-hydroxy-3-(1- naphthyloxy)-1-propyl]-aminopentyl} ester,

1,4- dihydro-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylic acid-(2-methoxy)-ethyl-{4-N,N-bis[2-hydroxy-3- ( 3-methylphenoxy)-1-propyl]-amino-3-methyl-butyl}-ester,

1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl-{3-N,N-bis[2-hydroxy-3-(4- acet-amidophenoxy)-1-propyl]-aminopropyl}-ester,

1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl- {2-N-[2-hydroxy-3-(1-naphthyloxy)- 1-propyl]-N-[2-hydroxy-3-(4-indolyloxy)-1-propyl]-aminoethyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl- {4-N-[2-hydroxy-3-(4-indolyloxy) -1-propyl]-N-[2-hydroxy-3-(4-methoxy-ethylphenoxy)-1-propyl]-aminobutyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-chlorophenyl)-pyridine-3,5-dicarboxylic acid-methyl- ■{ 3-N- [ 2-hydroxy-3-( 4-aminocarbonylmethyl- (phenoxy)-1-propyl]-N-[2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminopropyl} ester,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl-{2-N-[2-hydroxy-3-(2-allyloxy-phenoxy )-1-propyl]-N-[2-hydroxy-3-(4-indolyloxy)-1-propyl]-amino-ethyl}-ester, ,

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-(2-cyano)-ethyl-{2-[2-hydroxy-3-(4 -indolyloxy)-1-propyl]-aminoethyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isobutyl-{5-[2-hydroxy-3-(1-naphthyloxy)-1- propyl]-aminopentyl} ester, ;.

1,4- dihydro-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-pyridine-3,5- dicarboxylic acid-(2-methoxy)-ethyl {4-[2-hydroxy-3-(3-methyl-phenoxy) -1-propyl]-amino-3-methyl-butyl} ester,

1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl-{3-[2-hydroxy-3-(4-acetamidophen-oxy)- 1-propyl]-aminopropyl} ester.

The new compounds according to the invention have a broad and versatile spectrum of pharmacological action. They have calcium-antagonistic and β-adrenoceptor blocking properties. Surprisingly, they inhibit the KC1- or norepinephrine-induced contraction of isolated rabbit aortas (experimental device;

R. Towart, J. Cardiovascular Pharmacology 4_, 895-902 (1982)).

More specifically, the following main effects could be demonstrated in animal experiments: 1. The compounds cause an early dilation of the coronary blood vessels when administered parenterally, orally or per-lingually. This effect on the coronary blood vessels is reinforced by a simultaneous heart-relieving effect. By the antagonistic action on the 6-adrenergic receptors >.o: ;which comes in addition, the compounds inhibit a pathological increase in the contractility of the heart. They affect respectively changes cardiac metabolism in the direction of energy saving. 2. The effectiveness of the stimulus formation and irritation transmission system inside the heart is reduced, so that a detectable antiarrhythmic effect is achieved at therapeutic doses. 3. The tone of the smooth muscles in the vessels is greatly reduced by the action of the compounds. This vasospasmolytic effect can be found throughout the blood vessel system, or manifests itself more or less isolated in certain blood vessel areas (e.g. in the central nervous system or in the kidneys). The compounds are therefore particularly suitable as cerebral therapeutics and as a means of treating disturbances in kidney function. 4. The compounds lower the blood pressure of normotonic and hypertonic animals and can therefore be used as antihypertensive agents. 5. The compounds have a strong muscular-spasmolytic effect which is evident in the smooth muscles of the stomach, the intestinal tract, the urogenital tract and the respiratory system.

6. The compounds lower the heart rate.

The compounds according to the invention are suitable because of . these properties in particular for the prophylaxis and treatment of acute and chronic ischemic heart diseases in the broadest sense, for the treatment of high blood pressure, for the treatment of cerebral, renal and systemic blood circulation disorders as well as for the treatment of heart rhythm disorders, high blood pressure associated with pregnancy, adrenal medullary tumor, hypertropic cardiomyopathies , hyperkinetic heart syndrome and for cardioprotection in acute myocardial infarction and cardioplegia as well as to prevent secondary infarction.

Furthermore, the compounds can be used as additional medication

for symptomatic treatment of hyperthyroidism, parkinsonism, anxiety states, migraine, psychosomatic disorders and glaucoma.

The new active substances can be transferred in a known manner

the usual preparation forms, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic pharmaceutically suitable carriers or solvents.'The therapeutically active compound should in this context be present in a concentration of approx. 0.5-90% by weight of the total mixture, i.e. in amounts sufficient to achieve the stated dosage margin.

The preparations are produced, for example, by mixing the active substance with solvents and/or carriers,

possibly using emulsifiers and/or dispersants, where e.g. if water is used as diluent, possibly organic solvents

can be used as auxiliary solvents.

Excipients can be mentioned, for example: Water, ■ non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut/sesame oil), alcohols (e.g. ethyl alcohol, glycerin) , glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as e.g. natural stone flour (e.g. kaolin, aluminum oxide, talc, chalk), synthetic stone flour (e.g. highly dispersed silicic acid, silicate), sugar (e.g. cane, rrielke-

6g dextrose), emulsifiers (e.g. polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, alkyl sulphonates and aryl sulphonates), dispersing agents (e.g. lignin,

sulphite lye, methyl cellulose, starch and polyvinylpyrrolidone) and lubricant (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The supply takes place in the usual way, preferably orally or parenterally, especially perlingually or intravenously.

In case of oral administration, the tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like, in addition to the aforementioned carriers. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and/or elixirs intended for oral administration, the active substances, in addition to the auxiliaries mentioned above, can be mixed with various taste-improving substances or dyes.

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

In general, it has proven advantageous for intravenous use to add amounts of approx. 0.001-5 mg/kg, preferably approx. 0.05-2 mg/kg body weight per day to achieve good results, and when used orally, the dosage amounts to approx. 0.01-20 mg/kg, preferably 0.1-10 mg/kg body weight per day.

Nevertheless, it may be necessary to deviate from the amounts mentioned above, this depends on the body weight of the experimental animal or the method of administration, and also of the animal species and its individual reaction to the drug or the type of composition and the time respectively the interval at which the feed-in takes place. In some cases, it may be sufficient to use less than the amount mentioned above,

while in other cases the mentioned upper limit must be exceeded. When supplying larger quantities, there may be recommenda-

worthy of distributing this in several individual supplies during the day. For the application in human medicine, there is the same leeway for dosage. Correspondingly, the above-mentioned versions also apply here.

Execution examples

Example 1

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-(2-[2-hydroxy-3-(1-naphthyloxy)-1- propyl ]-aminoethyl.} ester..

A solution of 2.0 g (5.0 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl-(2-aminoethyl)-ester in 12.5 ml isopropanol was mixed with 1.0 g (5.0 mmol) 1-(1-naphthyloxy)-2,3-epoxy-propane and stirred for 48 hours at room temperature. 'Then' the mixture was evaporated in vacuo and the resulting residue was purified twice by column chromatography on silica gel (40-63 µm) with the eluent mixture chloroform/methanol/ammonia in the volume ratio 20:1:0.05 (system 1). The crystal foam that arose after evaporation of the eluate was dried in vacuum at 40°C.

Rf: 0.33 (system 1)

Yield: 1.2 g (39.8%)

Example 2

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarbon-

acid-methyl {3-[2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminopropyl ester.

A solution of 5.9 g (15 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl-(3-aminopropyl) ester in 40 ml of isopropanol was mixed with 1.5 g (7.5 mmol) of 1-(1-naphthyloxy)-2,3-epoxy-propane and stirred for 24 hours at room temperature. After evaporation of the solvent under reduced pressure, the oily residue was purified column chromatographically analogously to example 1. The crystal foam which arose by evaporation of the eluate was dried in vacuum at 40°C.

Rf: 0.22 (system 1)

Yield: 2.47 g (55.9%)

Example 3

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-(5-[2-hydroxy-3-(1-naphthyloxy)-1- propyl]-amino-2,2-dimethyl-pentyl} ester.

A solution of 5.7 g (12 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-(5-amino-2,2- dimethyl (pentyl) ester and 1.2 g (6 mmol) of 1-(1-naphthyloxy)-2,3-epoxy-propane in 42 ml of tetrahydrofuran were heated to 50°C for 18 hours. After evaporating the solvent in vacuum, the resulting residue was purified by column chromatography analogously to example 1. The crystalline foam obtained after evaporating the eluate was dried in vacuum at 40°C.

Rf: 0.17 (system 1)

Yield: 2.54 g (62.8%).

Example 4

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-di-carboxylic acid-cyclopentyl- {3-[2-hydroxy-3-(1-naphthyloxy)-1- propyl]-aminopropyl} ester.

A solution of 6.1 g (13.8 mmol) of 1,4-dihydro-2,6-dimethyl-Ai. 3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl-(3-aminopropyl)-ester and 1.38 g (6.9 mmol) of 1-(1-naphthyloxy)-2,3-epoxypropane in 46 ml methylene chloride was heated for 16 hours under reflux. The solvent was then evaporated and the residue was purified by column chromatography analogously to example 1. The crystal foam that arose after evaporation of the eluate was dried in vacuum at 40°C.

Rf: 0.23 (system 1)

Yield: 2.04 g (45.9%)

The other examples listed in the following table were prepared analogously to the procedures mentioned.

Example 33 1,4-dihydro-2,5-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{3-N,N-bis[2-hydroxy-3-( 1-Naphthyloxy)-1-propyl]-aminopropyl} ester

A solution of 1.7 g (4 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl-(3-aminopropyl)-ester and 2 .4 g (12 mmol) of 1-(1-naphthyloxy)-2,3-epoxy-propane in 12 ml of isopropanol was stirred for 48 hours at room temperature. The mixture was then evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (40-63 μm) with the eluent mixture chloroform/methanol/ammonia in a volume ratio of 20:1:0.05 (system 1). The crystal foam obtained after evaporation of the eluate is dried in vacuum at 40°C.

Rf: 0.39 (system 1)

Yield: 2.3 g (70.3%).

Example 34

1.4-Dihydro-2,5-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl-{2-N,N-bis[2-hydroxy-3-(1-naphthyloxy) -1-propyl]-aminoethyl} ester.

A solution of 1.9 g (5 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl-(2-amino-ethyl)-ester and 2.0 g (10 mmol) of 1-(1-naphthyloxy)-2,3-epoxy-propane in 14 mL of isopropanol was heated to boiling for 16 h. The mixture was then evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel analogously to example 17. The crystal foam obtained by evaporation of the eluate was dried in vacuo at 40°C.

Rf: 0.32 (system 1).

Yield: 2.66 g (68.6%).

Example 35

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-cyclopentyl- {3-N,N-bis[2-hydroxy-3-(1- naphthyloxy)-1-propyl]-aminopropyl} ester.

A solution of 3.06 g (6.9 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine dicarboxylic acid cyclopentyl-(3-aminopropyl) ester and 2.76 g (13.8 mmol) of 1-(1-naphthyloxy)-2,3-epoxypropane in 20 ml of methylene chloride was heated to boiling for 20 hours. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography analogously to example 17. The crystal foam obtained after evaporation of the eluate was dried in vacuum at 40°C.

Rf: 0.42 (system 1).

Yield: 3.83 g (65.7%).

Example 3 6

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl- {11-N,N-bis[2-hydroxy-3-(1- naphthyloxy)-1-propyl]-aminoundecyl ester.

A solution of 2.71 g (4.3 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl-(11-amino-undecyl) -ester and 1.72 g (8.6 mmol) of 1-(1-naphthyloxy)-2,3-epoxy-propane in 21 ml of tetrahydrofuran were heated to 50°C for 20 hours. After evaporating the solvent in vacuo, the resulting residue was purified column chromatographically analogously to example 17. The crystal foam that arose after evaporating the eluate was dried in vacuum at 40°C.

Rf: 0.45 (system 1)

Yield: 2.18 g (56.3%)

The further examples set out in the following

the table was prepared analogously to the methods previously described.

Example 62 1^4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridiri^3,5-dicarboxylic acid-methyl-{2-N-[2-hydroxy-3-(1-naphthyloxy)- 1-propyl]-N-methyl-amino} ester

A solution of 1.95 g (5 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl-(2-N-methyl-aminoethyl) -ester in 30 ml isopropanol was mixed with 1.1 g (5.5 mmol) 1-(1-naphthyloxy)-2,3-epoxy-propane and stirred for 48 hours at room temperature. After evaporation of the solvent under reduced pressure, the oily residue was purified column chromatographically analogously to example 1. The crystalline foam obtained by evaporation of the eluate was dried in vacuum at 40°C.

Rf: =.38 (system 1).

Yield: 2.13 g (72.2%).

Example 63

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{11-N-[2-hydroxy-3-(4-aminocarbonyl-methyl) -phenoxy)-1-propyl]-N-[2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminoundecyl} ester.

A solution of 1.0 g (1.37 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-riitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{11-[2-hydroxy -3-(1-naphthyloxy-1-propyl]aminoundecyl}ester and 0.57 g (2.74 mmol) of 1-(4-aminocarbonyl-methyl-phenoxy)-2,3-epoxy-propane in 20 ml of isopropanol were heated to boiling for 18 hours. The mixture was then evaporated in vacuo and the residue formed was purified by column chromatography on silica gel analogously to example 1. The crystal foam obtained by evaporation of the eluate was dried in vacuo at 40°C.

Rf: 0.05 (system 1).

Yield: 0.62 g (48.8%).

Example 64'

1.4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl- {2-N-[2-hydroxy-3-(1-naphthyloxy)-1- propyl]-N-methyl-carbonyl-aminoethyl} ester.

A solution of 1.73 g (3.0 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl-{2- [ 2- hydroxy-3-(1-naphthyloxy)-1-propyl]-aminoethyl} ester and 332 mg (3.3 mmol) of triethylamine in 20 ml of dioxane were mixed dropwise with 337 mg (1.1 mmol) of acetic anhydride dissolved in 2

ml of dioxane and after completion of the addition it was stirred for a further 3 hours at room temperature. After evaporation of the dioxa solution, the reaction mixture was taken up in methylene chloride, washed successively with dilute hydrochloric acid, hydrogen carbonate solution and water and the methylene chloride solution was dried with sodium sulfate. After evaporation of the organic phase, the residue formed was purified column-

Chromatographic Analog Example 17.

Yield: 0.9 g (48.6%)

Rf: 0.37 (system 1).

Example 65

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicar-' .• bonic acid-isopropyl-{3-N-ethoxycarbonyl-N-[ 2-hydroxy-3 -(1-naphthyloxy)-1-propyl]-aminopropyl} ester.

2.2 g (3.6 mmol) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{3-[2-hydroxy-3- (1-Naphthyloxy)-1-propyl]-aminopropyl}'-ester was dissolved together with 400 mg (4.0 mmol) of triethylamine in 20 ml of methylene chloride and at 10°C mixed dropwise with 391 mg (3.6 mmol) chlorocarbonic acid ethyl ester dissolved in 2 ml of methylene chloride. After the addition was finished, it was stirred for another hour at room temperature and then worked up analogously to example 35.

Yield: 1.74 g (70.1%)

Rf: 0.21 (CH 2 Cl 2 /EtOAc = 5/1)

Example 66

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl- {2-N- [2-hydroxy-3-(1-naphthyloxy)- 1-propyl]-N-phenylamino-carbonyl-aminoethyl} ester

A solution of 2.3 g (4.0 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-methyl-{2-[2-hydroxy -3-(1-Naphthyloxy)-1-propyl]-aminoethyl} ester in 30 ml of methylene chloride was mixed dropwise at 10°C with 477

mg (4.0 mmol) of phenyl isocyanate dissolved in 5 ml of methylene chloride. After the addition was finished, it was stirred for another hour at room temperature and worked up analogously to example 35.

Yield: 2.25 g (81.0%)

Rf: 0.29-(CH2Cl2/EtOAc = 5/1)

Example 67

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{2-N-[2-hydroxy-3-(1-naphthyloxy)- 1-propyl]-N-tosyl-aminopropyl} ester.

2.5 g (4.0 mmol) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-isopropyl-{3-[2-hydroxy- 3-(1-

naphthyloxy)-1-propyl]-aminopropyl} ester and 350 mg (4.4 mmol) pyridine were dissolved in 15 ml methylene chloride and at 10°C dropwise mixed with a solution of 839 mg (4.4 mmol) toluenesulfonyl chloride dissolved in 5 ml methylene chloride. After the addition was finished, it was stirred for a further 2 hours at room temperature and then worked up analogously to example 35.

Yield: 2.1 g (68.3%).

Rf: 0.44 (CH 2 Cl 2 /EtOAc = 5/1).

The new compounds according to the invention are administered to rats

in a dose of 1 mg/kg intravenously and the blood pressure is determined before and after the administration.

In a second experiment, the heart rate in rats is stimulated by subcutaneous administration of isoprenaline. The compounds according to the invention are then administered (1 mg/kg i.v.) and the effect on the reduction of the heart rate is measured.

Table 4 contains the results from these experiments for

a representative selection of the compounds according to the invention.

Claims (9)

1. Compounds of the general formula (I) characterized by that R stands for aryl or for thienyl. furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxazolyl, where the aryl residue and the heterocyclic parts optionally contain 1 to 2 identical or different substituents from the group of phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, polyfluoroalkyloxy, nitro, cyano, azido or SOm~ alkyl (m = 0-3), and R <3> are the same or different and stand for hydrogen, straight-chain or branched alkyl, aryl or aralkyl, or one of the substituents R 1 or R stands for hydroxyalkyl, acetoxymethyl, amino or cyano, R 2 stands for hydrogen or straight-chain or branched alkyl, ; which is optionally interrupted in the alkyl chain by one or two oxygen atoms, or stands for aryl or aralkyl, A stands for a straight-chain, branched or cyclic alkylene group with up to 20 carbon atoms, which may optionally be substituted or interrupted by a phenyl group optionally substituted with halogen, cyano, dialkylamino, alkyl, alkoxy, trifluoromethyl or nitro, and/or which is optionally interrupted by one or more oxygen atoms, sulfur atoms or groups 6 7 of formula -NR - or -CO-NR -, where R 6 and R 7 are the same or different and stand for hydrogen, a lower hydrocarbon residue, aryl or aralkyl, 4 R stands for hydrogen, for straight-chain or branched alkyl, e.g for aryl, aralkyl or for a residue of formula CO-R <6> , CO- -R <6> ', CO-NR <6> R <7> , SO„R <6> , where 6 7 R , R has the above meaning, R 6 1 has the same meaning as R 6 , but does not stand for hydrogen, 8 5 R has the meaning given for R and may be equal to or different from this, R <5> stands for aryl or heteroaryl, where the aryls as well as the hetero-aryls may possibly contain 1 to 3 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, cycloalkyl, morpholinyl, halogen, polyfluoroalkyl, nitro, cyano, azido, SO -R6, -NR6-SO:.: (m = 0-2), NR6R7, NR6COR7 2 m-'g m and acyl of the formula CO-R , and where the acyl residues in turn may optionally be interrupted by one or two oxygen atoms, sulfur atoms or groupings of the formula -NR 6 -, -CONR 7 -or -NCO-- and/or may be substituted with halogen and H where R 6 and R 7 are the same or different and have the meanings indicated above, and 9 9 X stands for the group -COR, where R is optionally substituted alkyl, aryl, aralkyl or anilino or an amino, monoalkylamino or dialkylamino group, where the alkyl group together with the nitrogen atom can optionally form a 5- to 7-membered ring, which as an additional heteroatom may contain an oxygen or sulfur atom, or stands for the group -COOR"*"^, where R"^ is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue, which is optionally interrupted by an oxygen or sulfur atom in the chain, and/or which is optionally substituted by halogen, cyan, hydroxy, acyloxy, pyridyl or by a phenyl, phenoxy, phenylthio or phenylsulfonyl group, where the acyl residue can again be substituted with halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl, or nitro, or which is optionally substituted with an amino group, where this amino group contains two identical or different substituents from the group alkyl, alkoxyalkyl, aryl or aralkyl and where these substituents optionally together with the nitrogen atom form a 5- to 7-membered ring, which as an additional heteroatom can contain an oxygen or sulfur atom or an N-alkyl group, as well as pharmaceutically acceptable acid addition salts thereof. 2. Compounds of general formula (I) according to claim 1, characterized in that R stands for phenyl, naphthyl or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl. pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where the mentioned ring systems can be substituted with 1 or 2 identical or different substituents from the group phenyl, straight-chain or branched alkyl with up to 8 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkoxy with .1-4 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano, azido or SOm~ alkyl, where m is a numbers from 0 to 2 and alkyl preferably contains 1-4 carbon atoms, 13 R and R are the same or different and stand for hydrogen, a straight-chain or branched alkyl radical with up to 4 carbon atoms, a phenyl radical or a benzyl radical, or one of the substituents R"*" or R <3> stands for a hydroxymethyl, acetoxymethyl, amino or cyano group, R 2 stands for hydrogen, straight-chain or branched, possibly with an oxygen atom interrupted alkyl with up to 6 carbon atoms, for phenyl or benzyl, A stands for a straight-chain, branched or cyclic alkylene group with up to 20 carbon atoms, which is optionally substituted or interrupted by a phenyl group which in turn can be substituted with halogen, cyano, dialkylamino, alkyl, alkoxy with 1-4 C atoms, trifluoromethyl or nitro , and/or which is optionally interrupted by one or two oxygen atoms, sulfur atoms or groups of the formula -NR 6 - or -CO-NR <7-> , where R 6 and R 7 are the same or different and stand for hydrogen or a hydrocarbon residue with 1-6 carbon atoms, phenyl or benzyl, R4 stands for hydrogen, for straight chain or branched alkyl, for aryl, aralkyl or for a residue of the formula CO-R6, CO--R6 , CO-NR6R7, SO~R6, where R 6 , R 7 have the meaning stated above, R <6> has the same meaning as R <6>, but does not stand for hydrogen, R 8 has the meaning given for R 5 and can be equal to/or different from this, R 5 stands for phenyl, naphthyl or for furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzthia-diazolyl, quinolyl, isoquinolyl, quinazolyl , quinoxazolyl, or carbazolyl, where the mentioned ring systems may optionally contain 1 to 2 identical or different substituents from the group phenyl, alkyl (1-8 C atoms), cycloalkyl (5-7 C atoms), morpholinyl, alkoxy (1- 4 C atoms), alkylene (2-4 C atoms), halogen, polyfluoroalkyl (1-4 C atoms), nitro, cyano, azido, SO -R6, -NR6-SO (m = 0 or 2), NR <6> R <7> , NR <6> COR <7> and m ' 6m acyl• of the formula CO-R , where the alkyl substituent optionally may be interrupted by one or two oxygen atoms, sulfur atoms or groups of the formula -NR <6-> , -CONR <7-> or -NCO-- and/ H or may be substituted with halogen, and where R 6 and R 7 have the above meaning, X stands for the group -COR 9 , where R 9 stands for optionally with halogen, cyano, alkoxy or dialkylamino with 1-4 C atoms substituted alkyl with 1-7 C atoms, phenyl, naphthyl, phenylalkyl or anilino or an amino -, monoalkylamino or dialkylamino group with 1-4 C atoms, where optionally the alkyl group forms a 5- to 7-membered ring with the nitrogen atom, which, as an additional heteroatom, may contain an oxygen or sulfur atom, or stands for the group -COOR"*"^, where R"^ is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue with up to 16 C atoms, which is optionally interrupted in the chain by an oxygen or a sulfur atom and/or which is optionally substituted with fluorine, chlorine, bromine, cyano, hydroxy, pyridyl, acyloxy with up to 4 C atoms or with a phenyl, phenoxy, phentylthio or phenylsulfonyl group, which in turn may be substituted with fluorine, chlorine, bromine, cyano, dialkylamino (1-4 C atoms), alkoxy (1-4 C atoms), alkyl (1-4 C atoms), trifluoromethyl or nitro, or which is optionally substituted with an amino group, where this amino group contains two identical or different substituents from the group (1-4 C atoms), alkoxyalkyl (up to 8 C atoms), phenyl, naphthyl or phenylalkyl with 1-4 C atoms in the alkyl residue, and where these substituents optionally form a 5- to 7-membered ring with the nitrogen atom, which, as an additional heteroatom, may contain an oxygen or sulfur atom or N-alkyl group with 1-4 C atoms, as well as pharmaceutically acceptable acid addition salts thereof. 3. Compounds of general formula (I) according to claim 1, characterized in that R stands for phenyl, thienyl, furyl, pyridyl or benzoxadiazolyl, where the phenyl residue contains 1 or 2 identical or different substituents from the group nitro, trifluoromethyl, fluorine, chlorine, cyano or dioxymethylene, 13 R and R are the same or different and stand for alkyl with 1 3 1-4 carbon atoms or one of the substituents R or R stands for hydroxymethyl, amino or cyano, R 2 stands for hydrogen or alkyl with 1-2 carbon atoms, A stands for a straight-chain, branched or cyclic alkylene group with up to 12 carbon atoms, which is optionally substituted or interrupted by a phenyl group and/or which is optionally interrupted by an oxygen atom or a group of the formula -NR <6-> or -CONR <7-> , R 6 and R 7 are the same or different and stand for hydrogen, alkyl with up to 4 C atoms, for benzyl or phenyl, R <4> stands for hydrogen, for straight chain or branched alkyl, for aryl, aralkyl or for a residue of the formula CO-R, C02-R6'.' ,: CO-NR <6> R <7> , S02 R <6> , where R <6> , R <7> have the meaning given above, 6 1 6 R has the same meaning as R , but does not mean hydrogen, R 8 has the meaning given for R 5 and may be the same or different from this, R^ stands for phenyl or naphthyl or indolyl, where the phenyl residue is optionally substituted with 1 or 2 identical or different substituents from the group fluorine, chlorine, nitro, cyano, alkyl with 1-2 C atoms, NR <6> R <7> , NR6COR7 or acetyl, and X stands for the group -COOR <10>, where R <10> stands for a straight-chain, branched or cyclic alkyl residue with up to 12 C atoms, which is optionally interrupted by an oxygen atom in the chain and/or is optionally substituted with fluorine, chlorine, hydroxy, pyridyl, phenyl or amino, as well as pharmaceutically acceptable acid addition salts thereof. 4. Process for the preparation of compounds of the general formula (I) where R stands for aryl or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalylyl, where the aryl residue and the heterocyclic parts optionally contain 1 to 2 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, polyfluoroalkyloxy, nitro, cyano, azido or SOm~ alkyl (m = 0-3), 13 R and R are the same or different and represent hydrogen, straight-chain or branched alkyl, aryl or aralkyl, or one of the substituents R"*" or R<3> represents hydroxyalkyl, acetoxymethyl, amino or cyano, R 2 stands for hydrogen or straight-chain or branched alkyl, which is optionally interrupted by one or two oxygen atoms in the alkyl chain, or stands for aryl or aralkyl, A stands for a straight-chain, branched or cyclic alkylene group with up to 20 carbon atoms, which may be substituted or interrupted by a phenyl group optionally substituted with halogen, cyano, dialkylamino, alkyl, alkoxy, trifluoromethyl or nitro, and/or which may optionally be interrupted by one or more oxygen atoms, sulfur atoms or groups of fi 7 formula -NR - or -CO-NR -, where R 6 and R 7 are the same or different and stand for hydrogen, a lower hydrocarbon residue, aryl or aralkyl, R4 stands for hydrogen, for straight chain or branched alkyl, for aryl, aralkyl or for a residue of the formula CO-R <6> , CO--R6 , -CO-NR <6> R <7> , S0_R <6> , where R 6 , R 7 have the meaning stated above, 6 1 6 R has the same meaning as R , but does not mean hydrogen, R 8 has the meaning given for R 5 and is equal to or different from this, stands for aryl or heteroaryl, where the aryls as well as the hetero-aryls may optionally contain 1 to 3 identical or different substituents from the group phenyl, alkyl, alkoxy,.alkylene, dioxyalkylene, halogen, polyfluoroalkylene, nitro, cyano, azido, SO -R6, -NR <6> -SO (m = 0-2), NR <6> R <7> , NR <6> COR <7> and acyl m g m of formula CO-R , and where the alkyl residues can again be interrupted by one or two oxygen atoms, sulfur atoms or groups of formula -NR 6 -, -CONR 7- or -NCO~ - and/or can be substituted H tuated with halogen, and where.R <6> and R <7> are the same or different and have the meaning indicated above, and X stands for the group -COR 9 , where R 9 is optionally substituted alkyl, aryl, aralkyl or anilino or an amino, monoalkylamino or dialkylamino group, where optionally the alkyl group together with the nitrogen atom forms a 5- to 7-membered ring, which, as additional heteroatom may contain an oxygen or sulfur atom, or stands for the group -COOR <10> , where R <10> is a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon residue, which is optionally interrupted in the chain by an oxygen or a sulfur atom, and/or which is optionally substituted with halogen, cyano, hydroxy, acyloxy, pyridyl or with a phenyl, phenoxy, phenylthio or phenylsulfonyl group, where the acyl residue can again be substituted with halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro, or which is optionally substituted with an amino group, where this amino group contains two identical or different substituents from the group alkyl, alkoxyalkyl, aryl and aralkyl, and where these substituents optionally form a 5- to 7-membered ring together with the nitrogen atom, which, as further heteroatom may contain an oxygen or sulfur atom or an N-alkyl group, as well as pharmaceutically acceptable acid addition salts thereof, characterized by reacting dihydropyridinamine of general formula (II) where 1 2 3 R, R , R , R , X and A have the meaning given above and R 4 represents hydrogen, alkyl, aryl or aralkyl, with epoxides of general formula (III) where 5 R has the above meaning, optionally in the presence of inert organic solvents at temperatures between 10 and 150°C, and then optionally converting the compound to its acid addition salt. 5. Medicine, characterized in that it contains at least one compound of the general formula (I) according to claims 1-3. 6. Compounds of general formula (I) according to claims 1-3, for combating circulatory diseases. 7. Method for the production of pharmaceuticals according to claim 5, characterized in that the active substances are transferred, possibly using common excipients and/or carriers, into a suitable delivery form. 8. Use of the compounds of general formula (I) according to claims 1-3 for the production of medicinal products. 9. Use of the compounds of general formula (I) according to claims 1-3 for the production of medicinal products which exert an effect on the circuit.