JPS61137861A - 1,4-dihydropyridine-hydroxyamines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is filed in Continuing-in-Part No. 6 dated October 26, 1984.
No. 64.904.

The present invention relates to new 1,4-dihydropyridine-hydroxyamines, a process for their preparation and their use as medicaments, in particular as medicaments affecting the circulatory system.

When ethyl 2-benzylideneacetoacetate is reacted with ethyl β-aminocrotonate or ethyl acetoacetate and ammonia, 1,4-dihydro-2,6-diif-4-phenylhyricine-3,5-dicarvone is produced. It has already been disclosed that diethyl acid can be obtained [Fi, Knoevenagel, IJ
Hite f7 Teutchen Hemitsien Gesellschaft (Ber.

dtsch, Chem, Ges, ) 31.743 (
1898)].

Another class of 1,4-dihydropyridines is known to have useful pharmacological properties [F.
F., Bossert), W. Vater (W.
, Vater), Naturbitsensha7ty (N
53.
578 (1971)).

Also, German patent publication details $@2,847,236
It is also known from No. 1 and No. Z218.644 that dihydropyridine esters can be used as coronary and antihypertensive agents.

The invention has a general formula I R'' having a substituted carboxylic acid function, where R represents aryl or chenyl, furyl, pyryl, pyrazolyl, imidazolyl, oxasilyl, inxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, Pyrazinyl, indolyl, benzimidazolyl, penzoyasazolyl, benzinxazolyl, penzosadiazolyl, quinolyl, isoquinolyl,
Φ represents nazolyl or noxalyl, and the aryl and heterocyclic groups are optionally phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, polJyfluoroalkoxy, nitro, cyano, azide and SOm- may contain one or two identical or different substituents from the group consisting of alkyl (m=O~3), B and RsFi are the same or different;
each represents hydrogen, straight-chain or branched alkyl, aryl-spanning aralkyl, or one of the substituents R1 or R3 represents hydroxyalkyl, acetoxymethyl, amino or cyano, and R2 is hydrogen or optionally an alkyl chain represents a straight-chain or branched alkyl which may contain one or two oxygen atoms in the chain, or represents an aryl or aralkyl; represents a branched or cyclic alkylene group, some of which can be substituted by phenyl, optionally substituted by halogen, cyano, dialkylamino, alkyl, alkoxy, trifluoromethyl or nitro; or in between, and/or optionally one or more oxygen atoms, sulfur atoms or groups of the formula -NFL'- or -Co-NR'-, R6 and R7 are the same or different and each represents hydrogen, a lower hydrocarbon group, aryl or aralkyl; R4 represents hydrogen, straight-chain or branched alkyl, or aryl or aralkyl; or represents a group of formula % or -CH, -CH-CH, -OR'',
H Here, R6 and H, t have the above meanings, R.6' has the meaning of R6, but does not represent hydrogen, Bs has the meaning indicated for R5, and R.6 represents aryl or heteroaryl, and the aryl and heteroaryl groups optionally represent phenyl, alkyl, cycloalkyl, morpholinoyl, alkoxy, alkylene, dioxyalkylene. , halogen, polyfluoroalkoxy, nitro, cyano, azide, S OR'
, NR' 80m (m = 0 to 2), NR'R, N86COR and formula co-R
' may contain from 1 to 3 identical or different substituents from the group consisting of acyls of the formula -NR'- may contain a 1-CONR- or -NGO,- group, and /'j! f, = may be substituted with halogen, where Ba and R7 are in each case the same or different and have the meanings given above, and X represents the group -COR,11, where Bo represents an optionally substituted alkyl, aryl, aralkyl, anilino, or amino, monoalkylamino or dialkylamino group, and the alkyl group optionally joins with a nitrogen atom to form a 5- to 7-membered ring. the chain may further contain oxygen or sulfur atoms as heteroatoms, or X represents the group -COORIO, where RIG represents a linear, branched or cyclic saturated or represents an unsaturated hydrocarbon group, optionally in the chain (optionally containing oxygen or sulfur atoms), rogene, cyano, hydroxyl, acyloxypyridyl, or phenyl, may be substituted with phenoxy, phenyl, tertiary L<H phenylsulfonyl group, and the aryl group may be further substituted with halogen, cyano, dialkylamino, alkoyas, alkyl, trifluoromethyl or nitro, or Optionally substituted with an amino group, this amino group carries two identical or different substituents from the group consisting of alkyl, alkoxyalkyl, aryl and aralkyl, and these substituents are optionally substituted with a nitrogen atom. 1,4-dihydropyridines and preparations thereof, which may be taken together to form a 5- to 7-membered ring, and the chain ring may further contain an oxygen or sulfur atom or an N-alkyl group as a heteroatom. The above invention relates to acceptable acid addition salts.

The compound of the general formula H according to the present invention is a compound of the general formula (1) in which 几, R1, R1, R, 3, X and 人 have the above meanings,
and R1'' represents hydrogen, alkyl, aryl or aralkyl, are reacted with an epoxide of the general formula I, where R' has the meaning given above, if appropriate in the presence of an inert organic solvent. manufactured by the method.

[41 is different from Bs], where the compound [41 is different from Bs] is first prepared by a stepwise reaction of primary dihydropyridine amines to form the epoxide (Ia) having the substituent 5.
, then other epoxides with substituted i&B s (Wb)
Manufactured by reaction with

General formula m, provided that R4 is a group ('O-R, 6, CO, fL
8'.

Co-NR'R' or 80. The compound representing R.6' is the compound (■), where R4=hydrogen, and is an acylating agent or monosulfonylating agent, such as 36CO, HSR.''
! OC1.

(Re/Co), O1R' O, CC1, R6R7N-
CQCl, R6-NC0 or BS! 30. CI, provided that R', R16' and R7 have the above meanings,
It is produced by reacting with

The process according to the invention can be illustrated by the example shown in the following reaction scheme.

Compounds according to the invention of particular interest are those of the general formula II in which R represents phenyl or naphthyl; represents pyrazinyl, indolyl, benzimidazolyl, benzoxasilyl, benzisoxazolyl, benzoxadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, preferably the ring system mentioned in each case is phenyl, has 8 carbon atoms straight-chain or branched alkyl having from 3 to 7 carbon atoms, alkoxy having from 1 to 4 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, halogen, tri- Fluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano,
azide and SOm-alkyl (where m represents the number of O~2 and alkyl preferably has 1~2 carbon atoms)
R, l and R3 are the same or different, each containing hydrogen, 4 carbon atoms, represents a straight-chain or branched alkyl group, phenyl group or benzyl group having up to fI! one of the substituents R1 or R3 represents a hydroxymethyl, acetoxymethyl, amino or cyano group, R2 represents hydrogen or has up to 6 carbon atoms, optionally containing an intermediate oxygen atom; represents a straight-chain or branched alkyl group which may have up to 20 carbon atoms, or phenyl or benzyl; , the layer may optionally be substituted with phenyl groups or may contain intermediates, in particular the phenyl groups may be halogens, cyanogens, dialkylaminos, alkyls having from 1 to 4 carbon atoms in each case. Maybe! d can be substituted with alkoxy, trifluoromethyl or nitro, and or optionally the intermediate V
C 1 or 2 oxygen atoms, length across the Kiyo atom - NR
6-or -CO-NR? -, where R6 and R.7 are the same or different and each represents hydrogen or a hydrocarbon group having 1 to 6 carbon atoms, phenyl or benzyl; represents a straight-chain or branched alkyl having up to 6 carbon atoms, represents phenyl or benzyl, or has the formula GO-46, Cotl
(6/.

Co-NR6R, γ, 80. R6' or -CH, -C
'H-CH, represents a group of -0R8, where H represents R6 and f4. , T has the above meaning, R6/ is R6
However, hydrogen is not represented, R' has the meaning shown in H, s, and is the same as this group! %, R5 represents phenyl or naphthyl, or furyl, chenyl, pyryl, pyrazolyl, imidazolyl, oxasilyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzoxacylyl, benzoxadiazolyl, benzthiadiazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl or carbazolyl, the ring system being optionally phenyl, alkyl (from 1 to 41 carbon atoms);
1, fullkylene (2 to 4 carbon atoms), dioxyalkylene (1 to 3 carbon atoms), halogen, polyfluoroalkoxy (1 to 4 carbon atoms), nitro, cyano,
Azide, 80m-R, 6, N & 6-80m (m = □ i take 2), N86Rγ, NR”COR? and formula (FO-R,
h may carry one or two identical or different substituents from the group consisting of 6 acyls, and the alkyl substituent may optionally have one or two intermediate (vA oxygen atoms, sulfur atoms or formula -NR' -1-CONR?-Moshikke-N
may contain a GO,- group and may be substituted with WII by a halogen, where R6 and R.
T has the abovementioned meaning in each case;
cyano, in each case alkyl optionally substituted by alkoxy or dialkylamino having 1 to 4 carbon atoms, or phenyl, naphthyl, phenylalkyl or anili/or amino, in each case carbon It represents a monoalkylamino or dialkylamino group having 1 to 4 atoms, and the alkyl group may optionally be combined with a nitrogen atom to form a 5- to 7-membered ring, and the pattern further includes oxygen as a hetero atom. or may contain a sulfur atom, or X represents a group ('?0ORIO, where R, 1111
represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group, a nuclear group (having up to 16 carbon atoms,
and may optionally contain oxygen or sulfur in the chain and/or when I+flt fluorine, chlorine, bromine, cyano, hydroxyl, pyridyl, acyl oyster, or phenyl, phenoxy, phenylthiomosil, having up to 4 carbon atoms. Kuhaphenylsulfonyl group +'A
San Deitete 4 (= 2 phenyl, phenol, phenyl) r"tf, -1t"i phenylsulfonyl group kit, fluorine, chlorine, bromine, cyanide, dialkylamino (carbon atoms 1 to 4 #I) ), alkyl (carbon atoms -7-1 to 4@), alkyl (1 to 4 carbon atoms), trifluoromethyl or di) a, or optionally substituted with amino The amino group may be a group consisting of alkyl (1 to 4 carbon atoms), alkoxyalkyl (up to 8 carbon atoms), phenyl, naphthyl, phenylalkyl having 1 to 4 carbon atoms in the alkyl group. Alternatively, it may be A with two different substituents, and these substituents can be combined with a nitrogen atom to form a 5- to 7-membered A, and mathematically, an oxygen or sulfur atom can be added as a heteroatom. or a N-alkyl group having up to 4 carbon atoms, and their pharmaceutically acceptable acid addition salts.

Preferred acid addition salts which may be mentioned are salts with organic acids, such as maleic acid, fumaric acid or tartaric acid, or with inorganic acids, such as hydrohalic acid or sulfuric acid.

Compounds of particular interest have the general formula m, with the proviso that Rdi phenyl, chenyl, furyl, phenyl, or benzoxadiazuryl, and the phenyl radicals are kenitro, trifluoromethyl, fluorine, chlorine, cyano, and dioxymethylene. containing one or two identical or different transmuting groups from the group consisting of, R.1 and R.1 are the same or mutually exclusive, and each represents an alkyl having 1 to 4 carbon atoms, or #i Substituent R1″!TakeBs
one of which represents hydroxymethyl, aminocyano, Bt represents hydrogen or alkyl having 1 or 2 carbon atoms, and A represents linear, branched or represents a cyclic alkylene radical, which may optionally be replaced by phenyl or contain an intermediate phenyl group, and/or optionally contain an oxygen atom or a group of the formula -N
A group of Ra- or -〇〇NB'- may be included in the middle, and R6 and R? are the same or different and each represents hydrogen, alkyl having 4 carbon atoms, phenyl or benzyl; R4 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; or dream of benzyl, or the formula % Formula % Fill and R7 have the above meanings, Re/ has the meaning of 几6, but does not represent hydrogen, ■ (=8 is 1 %5 (has the meaning indicated for tc and can be identical or different from this radical and represents phenyl, naphthyl or indolyl, the phenyl radical optionally containing fluorine, chlorine, nitro, cyano,
Alkyl having 1 or 2 carbon atoms, NR'R'
, NR6 ("OR?" may also be substituted with acetyl, and X represents the group -COOR'°, where Bto is a straight-chain, branched or cyclic Representing an alkyl group of the formula 12, the group may optionally contain an oxygen atom in the chain and/or be substituted with fluorine, chlorine, hydroxyl, pyridyl, phenyl or amino, and its pharmaceutically acceptable acid addition salts.

The dihydropyridine amines of the general formula (Ill) used as starting materials are those known from the literature or have been published in the literature, and for the most part
zsch) can be prepared by a method based on pyridine synthesis (European Patent Application No. 88-276-A
(see issue).

Examples that can be used are: isopropyl 2-aminoethyl 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, methyl 3-aminopropyl 1,4-dihydro-2,6-dimethyl-4
-(2-nitrophenyl)-? 'IJ Shin-3,5
-dicarboxylate, 2-cyanoethyl 11-aminoundecyl 1゜4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, neopentyl 6-aminehexyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-cycarboxylate, isobutyl 5-aminopentyl 1,4-dihydro-
2,6-dimethyl-4-1-(3-nitrophenyl)-
Pyridine-3,5-dicarboxylate, methoxyethyl 5-amino-2,2-dimethylpentyl 1,4-
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3゜5-dicarboxylate, ethyl 2-N-methylaminoethyl 1,4-dihydro-2,6-dimethyl-4-(3- Nitrophenyl)-
Pyridine-3,5-dicarboxylate, isopropyl 3-aminopropyl 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)
-Pyridine-3,5-dicarboxylate, methyl 2-N-benzylaminoethyl 1-ethyl-
], 4-dihydro-2,6-dimethyl-4-(2,3-
dichlorophenyl)-pyridine-3゜5-dicarboxylate, methyl 4-aminobutyl 1,4-dihydro 2.6
-Simethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate, cyclopentyl
4-aminobutyl 1,4-dihydro-2,6-dimethyl-4-(2-)lifluoromethylphenyl)-pyridine-3,5-dicarboxylate, 2.2.2-17fluoroethyl 5-aminopentyl 1,4-dihydro-2,6-dimethyl-4-(3-pyridyl)-pyridine-3,5-dicarboxylate, methyl 2-aminoethyl 1,4-dihydro-2,6
-Simethyl-4-(4-benzoxadeazolyl)-pyridine-3,5-dicarboxylate, 2-hydroxyethyl 3-aminopropyl 1゜4-
Dihydro-2,6-dimethyl-4-(3-cyanethyl)-pyridine-3,5-dicarboxylate, isopropyl 5-aminopentyl 1,4-dihydro-2,6-dimethyl-4-(2-penzyl phenyl)-pyridine-3,5-dicarboxylate, neopentyl 4-aminobutyl 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-pyricin-3,5-dicarboxylate, ethoxyethyl
6-ami/hexyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyricin-3,5-dicarboxylate, allyl 2-aminoinpropyl 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, methyl 4-amino-4-methyl-butyl 1°4-dihydro-2,6-
Cymethyl-4-(3-methoxyphenyl)-pyridine-
3,5-dicarboxylate.

The epoxides of general formula (1) used as starting materials are those known from the literature or can be prepared by methods known from the literature. and L.
L, H, Gnuth, Journal of Medicinal Chemistry (J.

See Med, Chem, 11.1009 (1968)].

Possible examples are: 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, ]-(2-allyloxyphenoxy)-2,3-epoxy-propane, 1-(4-carbazoyloyac)-2,3- epoxypropane 1-(4-methoxyethylphenoxy)-2,3-epoxy-propane, 1-(4-indolyloxypropane)-2,3-dipoxy-propane, 1-(1-naphthyloxy)- 2,3-epoΦ di-propane 1-(4-allyl-3-methoxyphenoxy)-2,3
-Epoxy-propane, 1-(2-cyanophenol)-2,3-epoxy-propane, 1-(5-allyl-2-ethoxyphenoxy)-2,3
-Epoxy-propane, 1-(4-7minocarbonylmethyl-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 All inert organic solvents can be used for the process according to the invention. These solvents preferably include lower alcohols such as ethanol, methanol, propatool or impropatol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, and chlorinated hydrocarbons such as chloride. methylene, chloroform and 1,2-
Dichloroethane, as well as mixtures of these solvents are included.

The reaction temperature can be varied within a substantial range. Generally, the reaction is carried out between 10 and 150°C, preferably between 20 and 130°C, especially at the boiling point of the particular solvent.

This reaction can be carried out under normal pressure, but also under elevated pressure. Generally, this reaction is carried out under normal pressure.

To synthesize compounds of formula (1) where R+4 is hydrogen, the corresponding amines of formula (II) are used in 1 to 2 times the molar amount.

R4 is a group -CH! -CH-C)4-OR' (
For the reaction of 1) to produce the H compound, the corresponding epoxide of formula (1) is used in a molar amount of 1 to 3 times.

For annulation or sulfonylation, the reactants are used in molar proportions.

The above molding method is merely for illustrative purposes.
The preparation of compounds of formula (1) is not limited to this method; any modification of this method can be applied in a similar manner when preparing the compounds according to the invention, depending on the choice of starting materials. , the compounds according to the invention can exist in stereoisomeric forms, either as mirror images (enantiomers) or as non-mirror images (diastereomers). The present invention relates to both enantiomers and racemic forms as well as diastereomeric mixtures.

Like diastereomers, racemic forms can be resolved into stereochemically homogeneous components in known methods [eg E.L.

Eliel), Stereochemistry of Carbon Compounds (Stereoc
he-mistry of Carbon Compo
unds), McGraw Hi
ll), 1962].

In addition to the preparation examples below, the following active compounds according to the invention may also be mentioned: isopropyl[2-
C2-hydro-C3-(1-naphthyloxy)-1-
propyl]-aminoethyl) 1,4-dihydro-2,
6-Simethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate, cyclopentyl (4-[2-hydroxy-3-(4-indolyloxy)-1-propyl]-aminobutyl)
1,4-dihydro-2,6-dimethyl-4- (2-
) fluoromethylphenyl)-pyridine-3,5-
dicarboxylate, methyl (6-(2-hydroxy-
3-(4-aminocarbonylmethyl-phenoxy)-2
-propyl]-aminohexyl) 1,4-dihydro-2゜6-diethyl-4-(2,a-dichlorophenyl)-pyridiso 3,5-dicarboxylate, ethyl(11-(2-hydroxy-3-( 2-me-4-(2-
benzyloxyphenyl)-pyricine-3,5-dicarboxylate, isopropyl (5-[2-cyanophenoxy-1-propylcouamino-2,2-dimethylpentyl) 1,4
-dihydro-2,6-cymethyl-4-(3-pyridyl)
-Pyridine-3,5-dicarboxylate, ethyl (3-(2-hydroxy-3-(4-methoxyethyl-phenoxy)-1-propyl]-amitubu avir) 1,4-dihydro-2,6- Cymethyl-4-(2-
chlorophenyl)-pyricin-3,5-dicarboxylate, neopentyl (2-(2-hydroyac-3-(2-allyl-phenoxy)-1-propyl)-N-methyl-aminoethyl) 1,4-dihydro- 2゜6-dimethyl-4-(4-benzoxadiazolyl)-pyridine-3,
5-dicarboxylate, isopropyl [2-N, N-
Bis-[2-hydroxy-3-(1-naphthyloxy)
-1-7'lopyl]-7mi/ethyl) 1,4-dihydro-2゜6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate, cyclopentyl (4-N, N -bis-[2-hydro#c3-(4
-indolyloxy)-1-propyl)-aminobutyl) 114-dihydro-2,6-cymethyl-4-(2
-trifluoromethylphenyl)-pyridine-3,5-
Dicarboxylate, methyl (6-N, N-bis-[2-hydroxy-3-(
4-aminocarbonylmethyl-phenoxy)-1-7'
[ropyl]-aminohexyl)1,4-dihydro-2,6
-Simethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-/fylbosylate, ethyl(11-N,N-bis-[2-hydroxy-3-
(2-methoxyphenoxy)-1-propyltuaminoundecyl) 1,4-dihydro-2,6-dimethyl-4-(2-benzyloxyphenyl)-pyridine-3
,5-dicarboxylate, isopropyl (5-N,,N-bis-[2-hydroxy-3-(2-cyano-phenoxy)-1-propyltoamino-2,2-dimethylpentyl)1.4- Dihydro-2,6-dimethyl-4-(3-pyridyl)-pyridine-3,5-dicarboxylate, (2,2-dimethyl)-ethyl(3-N,N-bis-[
2-Hydroxy-3-(4-methoxyethylphenoxyl-1-propyl]-aminopropyl) 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)
-Pyridine-3,5-dicarboxylate, (2-cyan)-ethyl (2-N,N-bis-[2-hydroxy-3-(4-indolyloxy)-1-propyltuaminoethyl) 1 .4-dihydro-2,6-
Dimethyl-4-(3-nitrophenyl)-1:'+7dine-3,5-dicarboxylate, Impropyl (5-N,N-bis-[2-hydroxy-
3-(1-naphthyloxy)-1-7'rovyl]-aminopentyl) 1,4-dihydro-2゜6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate, ( 2-methoxy)-ethyl(4-N
, N-bis-[2-hydroxy-3-(3-methylphenocoa)-1-propyltuamino-3-methyl-butyl)1,4-dihydro-2,6-cymethyl-4-(2-
17fluoromethyl-phenyl)-pyridine-3,5-
Dicarboxylate, cyclopentyl (3-N,N-bis-[2-hydroxy-3-(4-acetamidophenoxy)-1-propyl]-aminopropyl) 1,4-dihydro-2,6-
Dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate, methyl (2-N,N-[:2-hydroac-3-(1
-naphthyloxy)-1-propyl]-N-[2-hydroxy-3-(4-indolyloxy)-1-propyl-aminoethyl) 1,4-dihydro-2,6-simethyl-4-(2- nitrophenyl)-pyridine-3,5
-dicarboxylate, isopropyl (4-N-C2
-Hydroxy-3-(4--f/)'IJ-ruoxy)-
1-Propyl]-N-[2-hydroxy-3-(4-methoxyethylphenococo)-1-propyl]-aminobutyl)1,4-dihydro-2,6-cymethyl-4-(3
-nitrophenyl)-pyridine-3,5-dicarboxylate, methyl (3-N-(2-hydroxy-3-(4-aminocarbonylmethyl-phenoxy)-1-propyl)-
N-C2-hydroxy-3-(1-naphthyloxy)-
1-propyl-aminopropyl) 1,4-dihydro-
2,6-dimethyl-4-(3-chlorophenyl)-pyridine-3,5-dicarboxylate, cyclopentyl (2-N-C2-hydroxy-3-(2
-allyloxy-phenoxy) -1,-propyl)-
N-C2-hydroxy-3-(4-indolyloxy)
-1-propyltuaminoethyl)1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, (2-cyano)-ethyl (2-C2-hydroxy-3
-(4-indolyloxy)-1-propyl]-aminoethyl) ・1,4-dihydro-2゜6-dimethyl-4
-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, isobutyl (5-(2-hydroxy-
3-(1-naphthyloxy)-1-propyl]-ami/
pentyl) 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3゜5-dicarboxylate, (2-methoxy)-ethyl (4-C2-hydro-3=( 3-methylphenoxy)-1-7"ropyl-amino-3-methylbutyl)1,4-dihydro-2,6-
(cymethyl-4-(2-)lifluoromethyl-phenyl)
-hy+)cine-3,5-dicarboxylate, cyclopentyl [3-C2-hydro-C3-(4-
Acetamidophenoxy)-1-propyl]-aminopropyl) 1,4-dihydro-2,6-cymethyl-4
-(2,3-dichlorophenyl)-pyridine-3,5-
Dicarboxylate.

The novel compounds according to the invention have a broad and varied spectrum of pharmacological action. The compound exhibits calcium-antagonistic properties and β-adreceptor blocking (adre receptor blocking) properties.
It has noreceptor-blocking) characteristics. Surprisingly, the present compound inhibits KCI- and noradrenaline-induced contractions in isolated rabbit aortas [: Experimental Design, R. Towart, Journal Op.
Cardiopathic fur-r mouth aggregation (J, C
Ardiovascular Pharma-coto
gy 4.895-902 (1982)].

In particular, the following main effects were demonstrated in animal experiments: L When administered parenterally, orally and sublingually, the compound causes a marked expansion of the coronal taste. This effect on the coronary taste is intensified by the simultaneous effect of feeling strain on the heart. The compounds inhibit pathologically increased cardiac contractility through additional antagonism on β-adrenergic receptors. This compound has a heart metabolic effect in the sense of energy conservation.
) or improve its effect.

2 Stimulus generation in the heart
-rmation) and excitatory transmission system
The exci-tability of the onconduction system is reduced, thus resulting in an anti-arrhythmia effect, which can be detected at therapeutic dosages.

λ The tone of the vascular smooth muscles is significantly reduced by the action of the present compounds. This vaso-spasmodic effect may occur in the entire vasculature or in the circumscribed vascular region (cii).
rcumseribed vascularr6gio
n) expressed more or less isolated in the central nervous system or kidneys (e.g. in the central nervous system or kidneys). The compounds are therefore particularly suitable as agents for the treatment of the brain and for the treatment of renal dysfunction.

4. This compound lowers blood pressure in catatonic and hypertonic animals, and therefore can be used as an antihypertensive agent.

5. This compound has a strong muscle-spasmodic effect, and this effect is noticeable on the smooth muscles of the stomach, intestinal tract, genitourinary tract, and respiratory system.

6. This compound reduces the 6-stroke frequency.

Based on these properties, the compounds according to the invention are useful in the broad sense of the prevention and treatment of acute and chronic ischemic heart disease, the treatment of hypertension, the treatment of disorders in the brain, kidneys and systemic circulatory system, heartbeat disorders, Pregnancy-associated hypertension, chromophilic cell tumors, hypertrophic myocardial disease, and vortex heart syndrome (h
hyperkinet 1heart syndro
It is particularly suitable for the treatment of me), cardioprotection by Fcb in cases of acute myocardial infarction and heart failure, and prevention of secondary infarction.

The compounds can also be used as an additional medication for the syndromes ffK of thyroid hyperfunction, Parkinson's syndrome, anxiety symptoms, migraines, psychosomatic disorders and glaucoma.

The nuclear novel compounds can be prepared in a known manner using inert, non-toxic, pharmaceutically suitable excipients or solvents into conventional preparations such as tablets, capsules, dragees, pills, granules, etc.
Can be converted into aerosols, syrups, emulsions, suspensions and solutions. In this case, the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie, in an amount sufficient to achieve the indicated dosage range.

this! ! Iil preparations are prepared, for example, by extending the active compound with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, e.g. when water is used as diluent, and if appropriate auxiliaries. An organic solvent can be used as the solvent.

Examples of auxiliary substances that may be mentioned are: water, non-toxic organic solvents such as paraffins (e.g. petroleum distillates), vegetable oils (e.g. peanut oil/sesame oil), alcohols (e.g. ethyl alcohol and glycerin). and glycols (e.g. demipyrene glycol and hypholyethylene glycol), solid excipients such as natural rock powders (e.g. kaolin, alumina, talc and chalk), synthetic rock powders (e.g. highly dispersed silica and silicates) and sugars. (Example I
f-nuclose, lactose and glucose), emulsifiers (
(e.g. polyoxydiethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, sulfite waste, methyl cellulose, starch and polyvinylvia IJ) and lubricants (e.g. magnesium stearate). , Merck, stearic acid and sodium lauryl sulfate).

Administration takes place in the usual manner, preferably orally or parenterally, especially sublingually or intravenously. For oral use, of course, tablets also contain, in addition to the excipients mentioned above,
Additionally, various substances may be included, such as starch, preferably smooth potato starch, gelatin, etc., as well as additives such as sodium citrate, calcium carbonate and dicalcium phosphate. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and Merck can be used together in making tablets.

In the case of aqueous suspensions and/or elixirs intended for oral use, the active compounds can be mixed, in addition to the adjuvants mentioned above, with various flavor-enhancing agents or colorants.

For parenteral administration, solutions of the active compound can be used with suitable liquid vehicles.

Generally, for effective results, for intravenous administration, a dose of about 0.001 to 5 cm/m body weight per day, preferably about 0.05 to 2 cm/m body weight per day, may be administered. It was found to be advantageous, while for oral administration the dosage was 1
Approximately 0.01 to 2 O++V/body weight per day, preferably 0
．． 1 to 10 kg/body weight.

However, it is sometimes necessary to deviate from the above amounts, in particular as a function of the body weight of the experimental animal or due to the nature of the route of administration, but also due to the species of the animal and its individual reaction to the drug or due to differences in the preparation. This will depend on the nature and the timing or interval at which the administration takes place. Thus, in some cases it may be sufficient to use less than the above-mentioned minimum amount of VC, whereas in other cases the above-mentioned upper limit may have to be exceeded. When administering a relatively large amount, it is desirable to divide it into several doses a day. Similar dosage ranges are contemplated for human pharmaceutical administration. In this regard, the same applies as above.

Specific Examples Example 1 Isopropyl (2-(2-hydroxy-·3-(tnaphthyloxy)-1-de-a-pyl]-aminoethyl) 1.4
1.0 f (5, 0 mmol) Woisodero/(Nol 1
2.5-isopropyl 2-aminoethyl 1,4-dihydro-2,6-somethyl-4-(5-nitrophenyl)-pyridine-2,3-socargoxylate 2, or (
5,0 mmol) and this mixture was stirred at room temperature for 4 hours.
Stirred for 8 hours. This was then concentrated under vacuum and the resulting residue was purified with silica (40-65 nml, 20:1
: Purified twice by column chromatography using an eluent mixture of chloroform/methanol/ammonia (system 1) in a volume ratio of 0.05. The crystalline foam obtained after concentration of the eluate was dried at 40° C. under vacuum.

Rf: 0.33 (system 1).

Yield: 1.2F (59.8chi).

Example 2 1.4-zohydroα-2,6-nomethyl-4-(5-nitrophenyll-t'ljson-3.5-socargoxylate 1-(1-naphthyloxyl-2,!l- 1.5 f (7.5 mmol: 4
Methyl 6-amitudelopyl 1°4 in Nor40#I/
-dihydro-2,6-somethyl-4-(5-nitrophenyl)-pyridine-5゜5-socalcoxylate 5.9
was added to a solution of F (15 mmol) and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent under reduced pressure, the oily residue was purified by column chromatography analogously to Example 1. The crystalline foam obtained by concentration of the eluate was dried at 40° C. under vacuum.

Rf: a, z2 (system 1).

Collection@:2. A7t (55,9 inches).

Example 5 Isopropyl (5-(2-hydroxy-6-(1-naphthyloxy-1-1-propyl)-amino-2,2-tmethyl-pentyl)1,4-sohydro-2,6-nomethyl-4- (3-nitrophenyl) + hillison-5.5-
Socargoxylate Isopropyl 5-amino-2,2-tmethyl-pentyl in tetrahydrofuran 42-1.
4-dihydro-2,6-nomethyl-4-(3-nitrophenyl-1-pyridine-6,5-socarpoxylate)5.
7P (12 mmol) and 1-(1-naphthyloxyl)
-2,3-Epoxy-Zolo/9N 1.2f (6617
mol) solution was heated to 50° C. for 18 hours. After evaporating the solvent under vacuum, the residue was purified by column chromatography as in Example 1. The crystalline foam obtained after concentration of the eluate was dried at 40°C under vacuum.

Rf: 0.17 (system 1).

Yield: 2.54f (62.8%).

Example 4 Cyclointyl (S-(2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminopropyl) 1
．． 4-dihydro-2,6-nomethyl-4-(3-nitrophenyl)-pyridine-3,5-socargexylate cyclomethyl 5-aminode a in methylene chloride 46-
Pill 1,4-nohydro-2,6-nomethyl-4-(3-
'', trophenyl)-pyridine-5,5-nocal-xylene 6, IP (13L 8 mmol) and 1-(1-naphthyloxy + -2,3-epoxy pio, J-1.58
f<6.9 mmol) was heated under reflux for 16 hours. The solvent was then evaporated and the residue purified as in Example 1 by column chromatography. The crystalline foam obtained after concentrating the eluate was heated at 40° under vacuum.
It was dried at C.

Rf'', 0.25 (system 1).

Yield: 2.04 (45.9 cm 1°) By the same method as above, the compounds of the example group shown in Table 1 below were obtained.

Example 53 Isopropyl (5-N,N-bis[2- and doxy-3
~(?-su7tyloxy)-1-propyl]-aminodea-pyl)1,4-sohydroc7-2,5-tmethyl-4-
(5-nitrophenyl)-pyrinone-3,5-socargoxylate isopropyl 5-aminopropyl 1,4-dihydro-2,6-nomethyl-4-(
3-nitrophenyl)-pyrisone-3,5-socarxylate 1.7F (4 mmol) and 1-(1-naphthyloxy l-2,3-epoxy-zologun 2.4f(
1 fit of 12 mmol) was stirred at room temperature for 48 hours.

This was then concentrated under vacuum and the resulting residue was transferred onto silica glue (40-63 am) using an eluent mixture of chloroform/methanol/ammonia (system 11) in a volume ratio of 20:1:Q, 05. The crystalline foam obtained after concentration of the eluate was dried under vacuum at 40'C.

Rf: o, sqt system 1).

Yield: 25. f (70,5%1 Example 64 Methyl (2~N,N-bis[2-hydroxy-3-(1
-naphthyloxyJ-1-propyl]-amino) 1.4
-dihydro-2,5-methyl-4-(3-nitrophenyl)-pyrinone-3,5-inoderonognol 14a
Methyl 2-aminoethyl 1,4-no in t and draw 2.
6-dimethyl-4-[3-nitrophenyl 1-pyrinone-5,5-zocargexylate 1.9F (5 mmol l
&hi 1-(1-naphthyloxy l-2,5-epoxy-
Zoro Gun 2. (1) (10 mmol lt-boiling point for 16 hours. This was then concentrated under vacuum and the resulting residue was purified by column chromatography on silica gel, as in Example 1.

The crystalline foam obtained by concentration of the eluate was dried at 40° C. under vacuum.

Rf-, α32 (system 1).

Yield i: 16.0f (6a6%).

Example 35 Cyclopentyl (5-N, N-bis[2-hydroxy-5-(1-naphthyloxy)-1-propyl]-aminopropyl)1. a-Sohydro 2゜6-dimethyl-4-(3-nitrophenyl)-pyry-non-3,5-noryl xylate cyclopentyl 5-aminopropyl 1,4-sohydro ell-2 in methylene chloride 20- ,6-
Somethyl-4-(3-nitrophenyl l-bi lJson-dicargoxylate 3.06P (6,9 mmol) and 1-(1-naphthyloxy l-2,3-epoxypropane 2.76R (13,8 mil J mole) solution to the boiling point
Heated for 0 hours. Next, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography in the same manner as in Example 1. The crystalline foam obtained after concentration of the eluate was dried at 40° C. under vacuum.

Rf', 0.42 (system 11° yield @: 3.85 f (65,7chi 1.゛Example 6
6 Methyl (11-N, #-binu[2-hydroxy-3-(
1-naphthyloxy1-1-propylquaminoundecyl)1,4-dihydro-2,6-simethyl-4-(3
-ditho-a phenyl l-virison-3,5-socargexylate methyl 11-aminoundecyl 1,4-dihydro-2,6-somethyl-4 in tetrahydrofuran 21 pnt
-(5-di-a-phenyl 1-pyrison-3,5-nocarxylate 2,712 (4,5 mmol) and 1-(
1-Naphthyloxy l-2,5-epoxide O/#7
A solution of 1.729 (a6 mmol) was heated to 50° C. for 20 hours. After evaporation of the solvent under vacuum, the resulting residue was purified analogously to Example 1 by column chromatography. The crystalline foam obtained after concentration of the eluate was dried at 40° C. under vacuum.

Rf: α45 (system 1).

Yield: 2.18F (56.3%).

By the same method as above, the compounds of Examples shown in Table 2 below were obtained.

Example 62 Methyl (24-[2-hydroxy-3(1-naphthyloxy)-1-propyl]-N-methyl-aminoethyl)
1.4-dihydro-2,6-somethyl-4-(3-nitrophenyl-3,5-socargoxylate 1-(t-naphthyloxy)-2゜5-epoxy-demipane, 1t (5.5 mmol) of isodemipanol 5
Methyl 2-N-methylaminoethyl 1.4- in 0mt
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyrinone-3,5-socaloxylate 1.95
F (5 mmol) and this mixture was stirred at room temperature for 4 hours.
Stirred for 8 hours.

After evaporation of the solvent under reduced pressure, the oily residue was purified by column chromatography analogously to Example 1. The crystalline foam obtained by concentration of the eluate was dried at 40° C. under vacuum.

Rf: 0.5BC system 11° Yield f: 2.13F (72.2%).

Example 66 Isodemivir (11-#-[1-hydroxy-5-(4
-aminocarbonylmethyl-phenoxy)-1-demipyl)-N-(2-hydroxy-5-(1-naphthyloxy)-1-de.pyr]-aminoundecyl)1. Isodemivir (11
-[2-Hydroxy-5-(1-naphthyl-1-
deapil]-aminoundecyl)1,4-dihydro-2
, 6-nomethyl-4-(3-nitrophenyl-1-pyrinone-5,5-socargyxin-) 1.0f (1,37 mmol 1 and 1-(4-aminocarzanylmethyl-phenol-2. 3-Epoxy Zoro/Gun 0.57F (
A solution of 2.74 mmol) was heated to boiling point for 18 hours.

This was then concentrated under vacuum and the resulting residue was used in Example 1.
It was purified by column chromatography on silica del. The crystalline foam obtained by concentration of the eluate was dried at 40° C. under vacuum.

Rf: 0.05 (system 1).

Yield: 0.62F (4a8chi).

Example 64 Methyl<2-N-C2-hydroxy-5-(1-naphthyloxy)-1-propyl]-N-me'! -Cargonyl-aminoethyl)1,4-&Hitomy-2,6-somethyl-4-(5-nitrophenyl)-pyrinone-3,5-
Socalgexylate 357 q (1,1 mmol) of acetic anhydride dissolved in 2 dK of sooxane were added to methyl (2-(2-hydroxy-5-[71-1-de-a-pyr in 1-naphthylo)]- in 20 m/s of so-oxane. Aminoethyl) 1゜4-dihydro-2,6-somethyl-4-(5-nitrophenyl)-monolysine-3.5-Sokarge beef shirley) 1.73F
(3.0 mmol) and triethylamine 532HI (
After the addition was complete, the mixture was stirred at room temperature for a further 5 VC hours. After concentrating the sooxane solution, the reaction mixture was taken up in methylene chloride and sequentially
Washed with dilute hydrochloric acid, sodium bicarbonate solution and water and dried the methylene chloride solution over sodium sulfate. After evaporation of the organic phase, the resulting residue was purified analogously to Example 1 by column chromatography.

Yield: 0.9f (4a6%l. Rf: 0.57 (system 1).

Example 65 Isopropyl (5-N-ethoxycarbonyl-N-[2
-hydroxy-5-(1-naphthyloxy)-1-dea
pyl]-aminopropyl)1,4-dihydro-2,6-
Cymethyl-4-(5-nitrophenyl)-pyridine-5
, 5-zocargoxylate isopropyl (3-[2-hydroxy-5-(1-naphthyloxy)-1-dea-pyl]-aminopropyl)1.
2.29 (16 mmol) of 4-dihydro-2,6-nomethyl-4-(3-nitrophenyl l-bison-5,5-dicarboxylate) was dissolved in triethylamine 40 Q
, 20 d of methylene chloride with q(・4; 0 mmol)
772 ml of methichloride and 391 to 3,6917 mol of ethyl chlorocal dissolved in K were added dropwise at 10°C. After the addition was complete, the mixture was stirred at room temperature for an additional VC1 hour and worked up as in Example 65.

Yield z: 1.7ay (7a1%l. Rf: 0.2
1(C'HtCZ!/Et o AC"=5711Example 66 Methyl(2-N-[2-YczkiV-5-(1-naphthyloxy)-1-propyl]-N-phenylaminocargo nylaminoethyl)1,4-dihydro-2,6
-Nomethyl-4-(3-nitrophenyl:-pyridine-
5,5-Nocardaxylate Phenyl incyanate a dissolved in methylene chloride 5mK
77 capes (4,0 mmol) were dissolved in methyl (2-[2-hydroxy-3-(1-naphthyloxy)-1-propyl]-aminoethyl)1,4-dihydro-2,6- in 50 d of methylene chloride. Nomethyl-a--(5-nitrophenyl)
-pyridino-6,5-calgexylate 2.5t (4,
0 mmol) solution at 10°C. After addition,
The mixture was stirred for an additional hour at room temperature and worked up as in Example 65.

Yield: 2.2! M(81,01°Rf:a,2q(t'
H, (:L, /EtOAt'=5/1J Example 6 physopropyl (2-A'-(2-hydroxy-5-(1
-naphthyloxy)-1-propyl-N-tosyl-aminozolovir)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-5,5-socardexylateinderovir (3 -(2-hydro-3-(1-naphthyloxy)-1-propyl]-aminopropyl)1,4-dihydro-2,6-somethyl-4-
(3-nitrophenyl 1-gyrinone-6,5-dicarboxylate 2.59 (4,0 mmol) and pyridino 3
50I9 (4.4 mmol) in methylene chloride 15at/
A solution of sitatoluenesulfonylchloro(lyi)'8594 (4,4 mm + 7 moles) dissolved in methylene chloride was added dropwise at 10°C. After the addition was complete, the mixture was stirred for a further 2 hours at room temperature and worked up as in Example 35.

Yield: 2. IP (6a5%+.

Rf: 0.44 ((-'HtCLt/Eto
,4. (,'',==5/11° By the same method as above, the compounds of Example Todoroki shown in Table 3 below were obtained.

The novel compound according to the present invention was administered intravenously to rats with T/c1#/
Doses of IqF were administered and blood pressure was tested before and after administration. In another attempt, isoderenaline was administered subcutaneously to stimulate the 6-beat frequency, followed by administration of a new compound and its effect on lowering the 6-beat frequency.

The compounds administered and the results obtained are shown in Table 4 below.

While the specification and examples illustrate the invention,
It will be understood, however, that other embodiments within the spirit and scope of the invention may be suggested to those skilled in the art without limitation.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R represents aryl, or thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, represents pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxaneazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, and the aryl group and heterocyclic group are optionally phenyl, alkyl, Alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, polyfluoroalkoxy, nitro, cyano, azide and SO_m-alkyl (m=0-3)
may contain one or two of the same or different electrosubstituted groups from the group consisting of, R^1 and R^3 are the same or different,
each represents hydrogen, straight-chain or branched alkyl, aryl or aralkyl, or one of the substituents R^1 or R^3 represents hydroxyalkyl, acetoxymethyl, amino or cyano, R^2 Hydrogen or optionally 1 or 2 in the alkyl chain
represents a straight-chain or branched alkyl which may contain up to 20 oxygen atoms, or represents an aryl or aralkyl; A is a straight-chain, branched or cyclic alkyl having up to 20 carbon atoms; represents an alkylene radical, which radical can be substituted or can be intermediately substituted by phenyl, optionally substituted by halogen, cyano, dialkylamino, alkyl, alkoxy, trifluoromethyl or nitro. , and/or optionally one or more oxygen atoms, sulfur atoms or the formula -NR^6- or -C
It may contain an O-NR^7- group in the middle, where R^6 and R^7 are the same or different,
each represents hydrogen, a lower hydrocarbon group, aryl or aralkyl; R^4 represents hydrogen, straight-chain or branched alkyl, aryl or aralkyl, or the formula CO-R^ 6, CO_2-R^6', CO-NR^6R
^7, SO_2R^6' or ▲ represents a group of ▼ with mathematical formulas, chemical formulas, tables, etc., where R^6 and R^7 have the above meanings, and R^6' has the meaning of R^6 with the proviso that it does not represent hydrogen, R^8 has the meaning indicated for R^5 and can be the same or different from this group, R^5 is aryl or heteroaryl and the aryl and heteroaryl groups are optionally phenyl, alkyl, cycloalkyl, morpholinoyl, alkoxy, alkylene, dioxyalkylene, halogen, polyfluoroalkoxy, nitro, cyano, azide, SO_m-R^6, -NR ^6SO_m(m=
0-2), NR^6R^7, NR^6COR^7 and acyl of formula CO-R^6, and also the alkyl The group may optionally contain one or two intermediate oxygen atoms, sulfur atoms or the formula -NR^6-, -CONR^7- or a ▲numeric formula, chemical formula, table, etc.▼ group, and/
or may be substituted with halogen, in which R^6 and R^7 are in each case the same or different and have the meanings given above, and X represents the group -COR^9; Here, R^9 represents an optionally substituted alkyl, aryl, aralkyl, anilino, amino, monoalkylamino, or dialkylamino group, and the alkyl group optionally together with a nitrogen atom represents a 5- to 7-membered group. It may form a ring, which ring may further contain oxygen or sulfur atoms as heteroatoms, or X represents the group -COOR^1^0, where R^1^0
represents a straight-chain, branched or cyclic saturated or unsaturated hydrocarbon group which may optionally contain oxygen or sulfur atoms in the chain and/or optionally contain halogen, cyano, hydroxyl. , acyloxypyridyl, or with phenyl, phenoxy, pethylthio or phenylsulfonyl groups, and the aryl group is further substituted with halogen, cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro. or optionally substituted with an amino group, which amino group has two identical or different substituents from the group consisting of alkyl, alkoxyalkyl, aryl and aralkyl, and these substituents may optionally be combined with a nitrogen atom to form a 5- to 7-membered ring, and the ring may further contain an oxygen or sulfur atom or an N-alkyl group as a heteroatom. Compounds and preparations thereof Acceptable acid addition salts. 2. R represents phenyl or naphthyl, or thienyl, furyl, pyryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl phenyl, straight-chain or branched alkyl having up to 8 carbon atoms; cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, Nitro, cyano, azide and SO_m-alkyl (where m is 0
2 and the alkyl preferably contains 1 to 4 carbon atoms), R^1 and R ^3 are the same or different,
each represents hydrogen, a straight-chain or branched alkyl group having up to 4 carbon atoms, a phenyl group or a benzyl group, or one of the substituents R^1 or R^3 is hydroxymethyl, acetoxymethyl, represents an amino or cyano group, and R^2 represents hydrogen or a straight or branched alkyl having up to 6 carbon atoms and optionally containing an oxygen atom in the middle; , or phenyl or benzyl, and A represents a straight-chain, branched or cyclic alkylene radical having up to 20 carbon atoms, which radical may optionally be substituted with a phenyl radical, or an intermediate and the phenyl group can be substituted with halogen, cyano, dialkylamino, alkyl or alkoxy having 1 to 4 carbon atoms in each case, trifluoromethyl or nitro, and or It may optionally contain one or two intermediate oxygen atoms, sulfur atoms or the formula -NR^6- or -CO-NR^7-, where R^6 and R^7 are the same or different. each represents hydrogen or a hydrocarbon group having 1 to 6 carbon atoms, phenyl or benzyl, and R^4 represents hydrogen or a straight-chain or branched alkyl group having up to 6 carbon atoms; or represents phenyl or benzyl, or has the formula CO-R^6, CO_2R^6', CO
-NR^6R^7, SO_2R^6' or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ group, where R^6 and R^7 have the above meanings, and R^6' is R has the meaning of ^6, provided that hydrogen is not represented, R^8 has the meaning indicated for R^5 and can be the same or different from this group, and R^5 represents phenyl or naphthyl, or furyl, thienyl, pyryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzthiadiazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl or carpazolyl, the ring system being optionally phenyl, alkyl (from 1 to 4 carbon atoms); ), alkylene (2 to 4 carbon atoms), dioxyalkylene (1 to 3 carbon atoms), halogen, polyfluoroalkoxy (1 to 4 carbon atoms), nitro, cyano, azide, SO_m-R^6 , -NR^6-SO_m (m=0 or 2), NR^6R^7, NR^6COR^7 and formula C
The alkyl substituent may have one or two identical or different substituents from the group consisting of O-R^6 acyl, and the alkyl substituent optionally has one or two intermediate oxygen atoms, sulfur atoms or Formula -NR^6-, -C
ONR^7- or ▲ may contain mathematical formulas, chemical formulas, tables, etc. ▼ groups and/or may be substituted with halogens, where R^6 and R^7 are in each case has the above meaning, and X represents a group -COR^9, in which R^9 has 1 to 7 carbon atoms, and optionally halogen,
cyano, in each case alkoxy or dialkylamino-substituted alkyl having 1 to 4 carbon atoms, or phenyl, naphthyl, phenylalkyl or anilino or amino, in each case 1 carbon atom It represents a monoalkylamino or dialkylamino group having ~4 atoms, and the alkyl group may optionally be combined with a nitrogen atom to form a 5- to 7-membered ring, and the ring further contains oxygen or a heteroatom. may contain a sulfur atom, or X represents a group COOR^1^0, where R^1^0 represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group; , the group has up to 16 carbon atoms and may optionally contain oxygen or sulfur atoms in the chain and/or optionally fluorine, chlorine, bromine, cyano, hydroxyl, pyridyl, 4 carbon atoms or phenyl, phenoxy, phenylthio or phenylsulfonyl groups having up to fluorine, chlorine, bromine, cyano, dialkylamino ( (1 to 4 carbon atoms), alkoxy (1 to 4 carbon atoms), alkyl (1 to 4 carbon atoms), trifluoromethyl or nitro, or optionally substituted with amino. Often, the amino group is an identical or It may have two different substituents, and these substituents can optionally be combined with a nitrogen atom to form a 5- to 7-membered ring, and the nuclear ring may further contain oxygen or sulfur as a heteroatom. Compounds according to claim 1 and their pharmaceutically acceptable acid addition salts, which may contain atoms or N-alkyl groups having up to 4 carbon atoms. 3. R represents phenyl, thienyl, furyl, pyridyl or benzoxaneazolyl, and the phenyl group is substituted with the same or different substituents from the group consisting of nitro, trifluoromethyl, fluorine, chlorine, cyano and dioxymethylene. Contains 1 or 2 groups, R^1 and R^3 are the same or different,
each represents alkyl having 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 having 1 or 2 carbon atoms, and A is linear, branched or cyclic having up to 12 carbon atoms; represents an alkylene group which may optionally be substituted with phenyl or contain an intermediate phenyl group and/or optionally contain an oxygen atom or a group of the formula -NR^6- or -CONR^7- may contain a group in the middle, R^6 and R^7 are the same or different,
each represents hydrogen, alkyl having up to 4 carbon atoms, phenyl or benzyl, R^4 represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms or represents benzyl or the formula -CO-R^6, -CO_2R^6', CO-NR^6
R^7, SO_2R^6' or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R^6 and R^7 have the above meanings, and R^6' has the meaning of R^6. with the proviso that hydrogen does not represent R^8 and R^8 has the meaning indicated for R^5 and can be the same or different from this radical, and R^5 represents phenyl, naphthyl or indolyl; , the phenyl group can optionally be fluorine, chlorine, nitro, cyano, alkyl having 1 or 2 carbon atoms, NR^6R^7, NR^6C
may be substituted with OR^7 or acetyl and X represents the group -COOR^1^0, where R^1^0
represents a straight-chain, branched or cyclic alkyl radical having up to 12 carbon atoms, which radical may optionally contain oxygen atoms in the chain and/or optionally fluorine, chlorine, hydroxyl , pyridyl, phenyl or amino, and a pharmaceutically acceptable acid addition salt thereof. 4. General formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) In the formula, R, R^1, R^2, R^3, X and A are as described in claim 1 R^4' represents hydrogen, alkyl, aryl or aralkyl, and the dihydropyridineamines of are optionally prepared in the presence of an inert organic solvent to form the general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc. ▼(III) In the formula, R^5 has the meaning described in claim 1, and the general formula (
I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R, R^1, R^2, R^3, R^4, R^5,
A and X have the meanings set forth in claim 1. A method for producing a compound and a pharmaceutically acceptable acid addition salt thereof. 5. Dilates the coronary pulse, eliminates arrhythmia, and reduces smooth muscle tone, characterized by containing an effective amount of the compound or salt according to claim 1 in combination with a diluent. Compositions for reducing and lowering blood pressure. 6. A unit dosage of the composition of claim 5 in the form of a tablet, capsule or ampoule. 7. The compound or salt according to claim 1 is administered to a patient in need of the effects, which dilates the coronary pulse in the patient, eliminates arrhythmia, and increases smooth muscle tone. and how to lower blood pressure. 8. A method for lowering blood pressure in a patient, which comprises administering to the patient an effective amount of the compound or salt according to claim 1.