CA1337865C - 1,4-dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions containing same - Google Patents

Abstract

1,4-Dihydropyridine derivatives of the formula (I):

Description

1 3~57865 T I T L E

1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESSES
FOR THEIR PREPARATIOM AND PHA~lACEUTICAL
COMPOSITIONS CONTAINING SAME

FIErlD OF THE IMVENTION
The present invention relates to new compounds having valuable vasodilating and blood pressure lowering effects, etc., to processes for their preparation and to their use as vasodilating and antihypertensive agents.

BACKGROUND OF THE INVENTION
1,4-Dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diethyl ester is known to obtain by reacting 2-benzylideneacetoacetic acid ethyl ester, ~-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia, as reported in Ber. Deutsch Chem. ~æs.
31, 743(1971). DOS 2117517 and 2117573 disclose that similar compounds can be used as coronary arteriodilating and antihypertensive agents, and inter alia 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid dimethyl ester disclosed therein has been used extensively under the name of Nifedipine. Since commercial success of Nifedipine, a large number of compounds having similar chemical structure have been developed and these ~ 337865 compounds are disclosed in US Patents 3,574,843;
4,264,611; 3,79~,934; 4,239,893; 4,317,768; 4,044,141 and 4,258,042; EPO Appln. 0012180; and French Patent 2,182,983. Further, there are reported in ~O 84/02132 the compounds wherein a heterocyclic group is linked to an alkylene group through an amide bond in an ester moiety at the 3-position of 1,4-dihydro-2,6-dimethyl-4-phenyl pyridine-3,5-dicarboxylic acid diesters. Known 1,4-dihydropyridine derivatives including Nifedipine inhibit calcium influx into the cells and they have been used as remedy for cardiac diseases of angina pectoris, etc., cerebrovascular diseases of cerebral infarction, etc., and hypertension.
However, it has been reported that these derivatives have the disadvantages such as short-lasting activity and tachycardia.
The present invention results from efforts to develop new compounds with more improved pharmacological effects and lesser side effects than known 1,4-dihydro-pyridine derivatives.

DISCLOSURE OF THE INVENTION
According to the present invention, there areprovided compounds of the formula I

~R3 R 4 0C ~ C0 ( C z ) n 1 ( I ) H3C ~ CH3 wherein Rl represents a 5- or~6-membered heterocyclic group having in the ring one or two hetero atoms selected from nitrogen, oxygen and sulfur atoms, said heterocyclic 5 group may be substituted with halogen atom, haloalkyl, amino, acylamino, lower alkoxy, aryloxy, lower alkoxy-carbonyl or lower alkyl, and said heterocyclic group may be fused with a carbocyclic ring which may be substituted with lower alkyl or lower alkoxy; R2 and R3 both represent 10 halogen atoms, or one of R2 and R3 represents a nitro or trifluoromethyl group and the other represents a hydrogen atom; R4 represents a straight- or branched-chain alkyl or alkoxyalkyl group, and n represents 2 or 3, and the pharmaceutically acceptable acid addition salts thereof.
By the term "pharmaceutically acceptable acid addition salt" is meant a salt, the anion of which is relatively innocuous to the animal organism when used in therapeutic doses, so that the beneficial properties of the cation are not vitiated by side-effects ascribable to 20 the anion.
In the present specification, wherever reference -1 33786~

is made to compounds of formula I, it is intended to refer also to the said acid addition salts, where the context so permits.
In an embodiment of the present invention, the 5 compounds of the formula I wherein one of R2 and R3 represents a nitro group and the other represents a hydrogen atom are of the follpwing formula:

O ~ O O
R40C ,,~1~ ~ CO (CH2 )n-O-C-R

wherein Rl, R4 and n are as defined above. In another 10 embodiment, the compounds of the formula I wherein one of R2 and R3 represents a trifluoromethyl and the other represents a hydrogen atom are of the following formula:

~ CF3 O O O
Il 11 ~1 4 C--1~ C0 ( CH2 ) n~~C-Rl wherein Rl, R4 and n are as defined above. In further 15 embodiment, the compounds of the formula I wherein R2 and R3 both represent halogen atom are of the following formula:

~ 337~
~}Cl R40C ~' ( 2 ) n H 3 C J' I CH 3 wherein R1, R4 and n are as defined above.
As is evident from the above formula I, the compounds of the present invention are those wherein R1 is linked to an alkylene group through an ester bond (carbonyloxy group), which are different from the compounds wherein the heterocyclic group is linked to an alkylene group through an amide bond in an ester moiety at 3-position of 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diesters as disclosed in the above-cited prior art W0 84/02132. The compounds of the present invention are characterized by marked pharma-cological effects as compared with the prior art compounds.
Examples of the heterocyclic groups represented by R1 include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl, and the like.

Substituents for such heterocyclic groups inclu*e fluorine, chlorine, bromine, iodine, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, p'nenoxy, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl, and the like. One or more such substituents are substituted on the carbon atom of the above heterocyclic groups.
Examples of the groups formed by fusion of the heterocyclic groups with a carbocyclic rin~ include 2-quinolyl, 3-quinolyl, 4-quinolyl, l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolyl, 4-quinazolyl and quinoxalyl and the like. Examples of substituents on the carbocyclic ring of these groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy and propoxy and the like.
Groups represented by R4 of the above formula I
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, ~ sec-butyl, tert-hutyl, methoxyethyl, ethoxyethyl ethoxy-ethoxymethyl and the like.
Examples of preferred compounds are recitedbelow.

l) 2,6-dimethyl-4-(2-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-25 5-methyl ester;

-1 337~6~

2) 2,6,-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-methyl ester;
3) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-picolinoyloxyethyl)ester-5-methyl ester;

4) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-isonicotinoyloxyethyl)ester-5-methyl ester;
10 5) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(2-chloronicotinoyloxy)-ethyl]ester-5-methyl ester;

6) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-pyrazinoyloxyethyl)ester-5-methyl ester;

7) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]ester-5-methyl ester;

8) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-nicotinoyloxypropyl)ester-~ 5-methyl ester;

9) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-thiophencarboxy)ethyl]ester-5-methyl ester;

10) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-furancarboxy)ethyl] ester-_ 8 -1 337~65 5-methyl ester;

11) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-chloronicotinoyloxy)ethyl]-- ester-5-methyl ester;
5 12) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]-ester-5-methyl ester;
13) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyl-10 oxyethyl)ester-5-methyl ester;
14) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-chloro-nicotinoyloxy)ethyl]ester-5-methyl ester;
15) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinoline-carboxy)ethyl]ester-5-methyl ester;
16) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-methyl ester;
17) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methylnicotinoyloxy)ethyl]-ester-5-methyl ester;
18) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-aminonicotinoyloxy)ethyl]-ester-5-methyl ester;
1~) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-1 337~365 3,5-dicarboxylic acid 3-[2-(6-acetamidonicotinoyloxy)-ethyl]ester-5-methyl ester;
20) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-benzamidonicotinoyloxy)-5 ethyl]ester-5-methyl ester;
21) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(5-chloronicotinoyloxy)ethyl]-ester-5-methyl ester;
22) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-10 dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-nicotinoyloxy)ethyl]ester-5-methyl ester;
23) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)-ester-5-methoxyethyl ester;
15 24) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-trichloromethylnicotinoyl-oxy)ethyl]ester-5-methyl ester;
25) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-~2-(6-iodonicotinoyloxy)ethyl]-20 ester-5-methyl ester;
26) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxynicotinoyloxy)ethyl]-ester-5-methyl ester;
27) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-25 3,5-dicarboxylic acid 3-[2-(6-methoxycarbonylnicotinoyl-oxy)ethyl]ester-5-methyl ester;

28) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-t2-(6-phenoxynicotinoyloxy)ethyl]-ester-5-methyl ester;
29) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-5 3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-ethyl ester;
30) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-isopropyl ester;
10 31) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-isobutyl ester;
32) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)ester-5-15 methoxyethyl ester;33) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-nicotinoyloxy)ethyl]ester-5-methyl ester;
,34) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-20 dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyl-oxyethyl)ester-5-isobutyl ester;
35) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-~2-(3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;
25 36) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methyl--~ 337865 3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;
37) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]-ester-5-methoxyethyl ester;
5 38) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-guinolinecarboxy)ethyl]ester-5-methoxyethyl ester;
3~) 2,6-dimethyl-4-(2-nitrophenyl)-1 4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)-10 ethyl]ester-5-methyl ester;
40) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methyl-3-quinolinecarboxy)-ethyl]ester-5-methyl ester;
41) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-15 3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]-ester-5-isobutyl ester;
42) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dlhydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;
20 43) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
44) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methyl-3 25 quinolinecarboxy)ethyl]ester-5-methyl ester;
45) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)-ethyl]ester-5-isopropyl ester;
46) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloronicotinoyloxy)ethyl]-5 ester-5-methyl ester.

The compounds of the present invention can be prepared by reacting a compound of the formula ~ CHO (II) wherein R2 and R3 are as defined above, a compound of the formula H2N - C = C - COOR4 (III) wherein R4 is as defined above, and a compound of the formula O O O
Il 11 11 CH3 - C - CH2 - C~ (C 2)n l (IV) wherein Rl and n are as defined above.
~ he reaction is preferably conducted using reactants of the formulae II, III and IV in about equal mole amount to each other. However, the proportions of the reactants used may be varied depending on the reaction conditions.
Examples of the compounds represented by the formula II include 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-trifluoromethylbenzaldehyde, 3-trifluoromethylbenz-aldehyde, 2,3-dichlorobenzaldehyde, and the like.
Examples of the compounds represented by the formula III include methyl 3-amino crotonate, ethyl 3-aminocrotonate, n-propyl 3-aminocrotonate, i-propyl 3-aminocrotonate, n-butyl 3-aminocrotonate, i-butyl 3-aminocrotonate, tert-butyl 3-aminocrotonate, methoxy-methyl 3-aminocrotonate, méthoxyethyl 3-aminocrotonate, methoxypropyl 3-aminocrotonate, ethoxymethyl 3-amino-crotonate, ethoxyethyl 3-aminocrotonate, ethoxypropyl 3-aminocrotonate, propoxymethyl 3-aminocrotonate, propoxy-ethyl 3-aminocrotonate, propoxypropyl 3-aminocrotonate, and the like.
Examples of the compounds represented by the formula IV include those wherein n is 2 or 3, Rl is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrroyl, 3-pyrroyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl, or these heterocyclic groups may be substituted with one or more substituents selected from fluorine, chlorine, bronine, iodine, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, phenoxy, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl; and also Rl is 2-quinolyl, 3-quinolyl, 4-quinolyl, l-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolyl, 4-quinazolyl and quinoxalyl, and further benzene ring forming these groups may be substituted with one or more substituents selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy and propoxy.
The reaction can be effected using an organic solvent as`a reaction medium. Preferred solvents include an alcohol such as methanol, ethanol, i-propanol or n-butanol;
a lower dialkyl ether, e.g., diethylether; a cyclic ether such as tetrahydrofuran or dioxane; a lower dialkylformamide, e.g., dimethylformamide; dimethylsulfoxide; and a liquid heterocyclic 'oase, e.g., pyridine.
The reaction may also be carried out in the absence of a reaction medium.
The reaction temperature can be from about 20C
to 150C, preferably from 50C to 100C.
The reaction can be effected at a temperature at which the reaction medium is boiling. The reaction can be carried out at atmospheric pressure, optionally under elevated pressure. The reaction is usually completed under the above reaction conditions during the time from 45 minutes to 10 hours.
Further, the compounds of the present invention can be prepared by reacting a compound of the formu~a _ 16 _ 0 ~0 R40C \ ~ CO(CH2~n X (V) H3C ~ CH3 wherein R2, R3, R4 and n are as defined above, and X
represents a halo~en atom, a mesyloxy group, a benzene-sulfonyloxy group or a tosyloxy group, and a compound of 5 the formula l Rl - C - 0 - M (VI) wherein Rl is as defined abo~e and M represents an alkali metal or an alkaline earth metal.
Examples of the compounds represented by the 10 formula V include those wherein n is 2 or 3; R2 is hydrogen when R3 is nitro or trifluoromethyl; or R2 is nitro or trifluoromethyl when R3 is hydrogen; or both R2 and R3 are chlorine; and further R4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, 15 methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl or propoxypropyl; and further X is chlorine, bromine, iodine, mesyloxy, benzenesulfonyloxy or tosyloxy.
Examples of the compounds represented by the formula VI include those wherein R1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 5 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl; or these heterocyclic groups may be substituted with one or more substituents selected from fluorine, chlorine, bromine, 10 iodine, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, phenoxy, methoxy-carbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl; and also R1 is 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolyl, 4-quinazolyl and quinoxalyl, and further benzene ring forming these groups may be substituted with one or more substituents selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy and propoxy, and M is sodium, 20 potassium, magnesium or calcium.
The reaction can be carried out preferably in the presence of an inert organic solvent. Suitable solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexamethyl phosphoamide, dioxane, acetonitrile, N-methylmorpholine, 1,2-dimethoxyethane, and the like. The reaction temperature is suitably from -~ 1 337865 80C to 160C. Under the above conditions, the reaction is usually completed in a few hours.
Pharmaceutically acceptable acid addition salts of the compounds of the formula I according to the present invention may be prepared by the application or adaptation of kno~m methods for the preparation of salts of organic bases, for example, by reacting the compounds of the formula I with the appropriate acid in a suitable solvent.
Examples of addition salts include salts derived from inorganic and organic acids such as, without limitation, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, sorbic acid, salicyclic acid, phthalic acid, and the like.
The new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or racemate.
The racemates obtained can be separated according to known methods, e.g., by means of microorganisms, or by 20 a reaction with optically active acids forming salts of the compound, and separating the salts thus obtained, e.g., by means of the different solubility of the diastereomeric salts, from which the antipodes may be set free by the action of a suitable agent. Suitably useable 25 optically active acids are e.g., the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, 1~ --mandelic acid, camphorsulfonic acid or quinic acid.
Preferably the more active part of the two antipodes is isolated.
The compounds of the present invention have marked inhibiting activity of calcium influx into cells as will be evident from the below-mentioned pharmacological test results, with the result of the use as vasodilator and antihypertensive agents. Thus, the compounds of the present invention can be used for treatment of a variety of diseases including hypertension, angina pectoris and acute heart failure.
In clinical use the compounds of the invention are usually administered orally, or parenterally in the form of a pharmaceutical preparation, which contains the active ingredient as free base in combination with pharma-ceutically acceptable additives.
Thus the mentioning of the new compounds of the invention is here related to the free amine base even if the compounds are generally or specifically described, provided that the context in which such expressions are used, e.g., in Example l, with this broad meaning should not correspond. The additives may be a solid, semisolid or liquid diluent or a capsule. These pharmaceutical preparations are a further object of the invention.
Usually the amount of active ingredient is between O.l and 99% by weight of the preparation, suitably between 0.5 and 20~ by weight in preparations for in~ection and between 2 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form 5 o~ dosage units for oral administration the compound may be mixed with a solid, pulverulent additives, e.g., with lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatine, as well as with an lubricant such 10 as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets. If coated tablets are wanted, the above prepared core may be coated with concentrated solution of sugar, which solution may contain, e.g., gum arabicum, gelatine, talc, titandioxide 15 or the like.
In the preparation of soft gelatine capsules which consist of gelatine and, e.g., glycerine, or in the preparation of similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatine capsules may 20 contain granules of the active compound in combination with a solid, pulverulent additives as lactose, saccharose, sorbitol, mannitol, starch (as, e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active ingredient in a mixture with a neutral fat base, or -' ~37865 they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present in the form of sirups or suspensions, e.g., solutions containing from about 0.01% by weight to about 0.1% by weight of the active ingredient described, glycerol and propylene glycol.
The preparation of pharmaceutical tablets for peroral use is carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle size. The binding agent is homogenized and suspended in a certain amount of solvent.
The therapeutic compound and necessary auxiliary agents are mixed with continuous and constant mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without over-moistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real granulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during lO hours and has to be standardized carefully as the damp degree of the granulate is of outmost importance for the following process and for the feature of the tablets. Drying in a fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a container having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so called final mixture, disintegrating, lubricant and excipient are added. After this mixture the mass shall have its right composition for the tabletting step.
Many tablets, especially those which are rough or bitter, are coated with a coating. This means that they are coated with a layer of sugar or some other suitable coating.
The daily dose of the active ingredient varies and is dependent on the type of administration, but as a general rule it is l to lO0 mg/day of active ingredient at peroral administration.

BEST MODE OF CARRYING OUT THE INVENTION
The following examples will serve to further typify the nature of the present invention without being a limitation on the scope thereof, the scope being defined solely by the appended claims.
EXA~IPLE 1 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)-ester-5-methyl ester (~LNO2 H 3 C O C ,X'--C O C H 2 C H 2 C--A solution of 1.3 g of 2-nitrobenzaldehyde, 1.0 g of methyl 3-aminocrotonate and 2.2 g of 2-nicotinoyl-oxyethyl acetoacetate in 3 ml of isopropyl alcohol was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, an oily residue was subjected to silica gel column chromatography with ethyl acetate as an eluent. Recrystallization from acetone gave the title compound. Yield 1.1 g (27%), m.p. 1~0-161C.

2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)-ester-5-methyl ester ~r NO2 H3COC ~COCH2CH2-O-C~

H3C iNH CH3 A mixture of 1.0 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-chloroethyl)ester-5-methyl ester and 0.55 g of sodium nicotinate in 7 ml of N,N-dimethylformamide was stirred at 120-130C in an argon stream for 4 hours. The reaction product was suction filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel colum chromatography with ethyl acetate-n-hexane (a volume ratio 5 : 1) as an eluent, whereby the title compound was prepared as crystal. Yield 1.1 g (90~), m.p. 135-136C.

Following the same procedure as described in Example 2, compounds of the undermentioned general formula were prepared as shown in Table 1 below.

~'?~ N02 H 3 COC ~ CO- ( CH2 ) n -O-C- R

Example Position n R1 Yield Melting point of NO~

3 3 2 ~ 73% 175-176C

4 3 2 ~ N 70~ 1.53-154C

3 2 ~ 58% 136-138C

6 3 2 _~ ~ 67% 152-153C

7 3 2 ~ ~ 57% 197.5-198.5C

8 2 3 - ~ 43% 171-173C

2,6-Di~ethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3- 2-(3-thiophenecarboxy)-ethyl ester-5-methyl ester ~3L NO 2 O l O O
Il l 11 11 ~3 ~ C~3 A mixture of 1.2 g of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-chloroethyl)ester-5-methyl ester and 0.5 g of sodium 3-thiophenecarboxylate in 10 ml of N,N-dimethylformamide was stirred at 120-130C in an argon stream for 2 hours.
To the reaction product was added ethyl acetate insolubles were removed by suction filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-n-hexane (a volume ratio 1 : 1) as an eluent, whereby the title compound was prepared as non-crystalline powder. Yield 0.8 g (54%).
This compound as prepared was measured for NMRo The results are shown below.
H NMR (CDC13) ~: 2.29 (s, 3H), 2.36 (s, 3H), 3.55 (s, 3H), 4.34-4.40 (m, 4H), 5.78 (s, lH), 6.03 (s, lH), 7.11-7.70 (m, 6H), 8.00 (d-d, lH) Following the same procedure as described in Example 9, there were prepared the compounds as shown in Table 2 below.

~LNO2 O o o Il 11 11 H3COC~ ~ COcH2CH2OC-R

-Example Rl Yield Physical properties ~ ~ 53% Non-crystalline powder H NMR (CDC13) ~: 2.29(s, 3H), 2,36(s, 3H), 3.56(s, 3H), 4.22-4.43(m, 4H), 5.77(s, lH), 6.11(s, lH), 6.68(d-d, lH), 7.12-7.66(m, 5H), 7.91(d-d, lH).

11 r~ 69% Non-crystalline powder, H NMR (CDC13)~: 2.30(s,3H), 2.37(s, 3H), 3.55(s, 3H), 4.34-4.49(m, 4H), 5.76(s, lH), 5.97(s, lH), 7.12-7.66(m, 5H), 8.18(d-d, lH), 8.85(d,1H).

15 12 ~ ~ ~ 49~ rl.p. 159-160C.
N

2,6-Di~ethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoyl-oxyethyl)ester-5-methyl ester I ~ CF3 3coc~ ~, COCH2CH2OC

A mixture of 1.4 g of 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-c~loroethyl)ester-5-methyl ester and 0.8 g of sodium nicotinate in 8 ml of N,N-dimethylformamide was stirred at 120-130C in an argon stream for 5 hours. To the reaction product was added ethyl acetate, insolubles were remove-l by suc~ion filtr~tion and the filtrate was concentrated under reduced pressure. The residue was suh~ected to silica gel column chromatography with ethyl acetate as an eluent, ~ereby the title compound was prepared as crystals. Yield 0.8 ~ (47~), m.p. about 139C
(end point).
This compoud as prepared was measured for NMR.
The results are shown below.
H NMR (CDC13) ~: 2.29 (s, 3H), 2.33 (s, 3H), 3.56 (s, 3H), 4.2~-4.47 (m, 4H), 5.56 (s, lH), 5.98 (s, lH), 7.11-7.54 (m, 5H), 8.22 (d-t, lH), 8.78 (d-d, lH), 9.10 (d, 1~).

Following the same procedure as described in Example 13, there were prepared the compounds as shown in Table 3 below.

- 1 337~

o o o Il A r ll 11 H3COC~COCH2CH20C R

H3C ~ CH3 H

Wherein Ar = ~ R2 Example Ar Rl Yield Physical properties 14 ~ ~ Cl 66% Non-crystalline powder, CF3 H NMR (CDCl3) ~ :
2.29(s, 3H), 2.33(s, 3H), 3.57(s, 3H), 4.26-4.49(m, 4H), 5.55(s, lH), 5.90 (s, lH), 7.16-7.54 (m, 5H), 8.15(d-d, lH), 8.86(d-d, lH).

~ ~ 65% M.P. 160-161C
CF3 (end point) _ 30 _ -1 33786~

H NMR (CDC13) ~ :
2.28(s, 3H), 2.34(s, 3H), 3.52(s, 3H), 4.37-4.56(m, 4H), 5.57 (s, lH), 5.96(s, lH), 7.08(t, lH), 7.27-7.36 (m, 2H), 7.52(d, lH), 7.64(d-d, lH), 7.85 (t, lH), 7.94(d, lH), 8.18(d, lH), 8.77 (d, lH), 9.35(d, lH).

16 ~ ~ 64% M.P. 144-145C.

Cl Cl EX~IPLES 17-38 Following the same procedure as described in Example 13, there were prepared the compounds as shown in Table 4 below.

~ - R3 ~ R 2 4 ( 2 2 . .

` - 1 337865 R2 R4 R1 Yield Ph~sical pro~erties 17 N02 CH3 ~ CH3 25% Non-crystalline yellow powder 1H NMR(CDCl )~:
2.28(s,3H),32.36(s,3H), 2.64(s,3H), 3.53(s,3H), 4.30-4.60(m,4H), 5.78 (s,1H), 7.13(t,1H), 7.25(d,1H) 7.40(t,1H), 7.55(d~,2H~, 8.10~-d, 1H), 8.98(d,1H) 18 N2 CH3 ~ NH2 19,b Non-crystalline yellow N powder 1H NMR(CDCl )~:
2.28(s,3H),32.35(s,3H), 3.55(s,3H), 4.38(br.s, 4H), 5.30(br.s,2H), 5 1758~tS~d11H~ 67.33_7.6 (m,4H), 7.90(d-d,1H), 8.58(d,1H) 19 N02 CH3 ~ NHCOCH3 41,b Non-crystalline yellow 1H NMR(CDCl )~:
2.28(s,3H),32.30(s,3H), 2.35(s,3H~, 3.54(s,3H), 4.30-4.60(m,4H), 5.78 (s,1H), 6.70(s,1H), 7.15(t,1H), 7.30-7.60 (m,3H), 8.10-8.30(m,2H), 8,80(~d,1H), 9.15(br.s, 1H) N02 CH3 ~ NHC0 ~ 12% Non-crystalline yellow 1H NMR(CDCl )~:
2.28(s,3H),32.35(s,3H), 3.54(s,3H), 4.30-4.50 (m,4H), 5.78(s,1H), 6.40(br.s,1H), 7.15 -TABLE 4 (Continued) ~x. R2 R4 R1 Yield Physical pro~erties (t_d,1H), 7.40(t,1H), 7.45-7.65(m,5H), 7.95 (d-d,2H), 8.20~-d 1H), - 7.43~d,1H), 8.75~d,1H), ,Cl 9.14(br.s,1H) 21 N2 CH3 ~ 20% Non-crystalline yellow powder 1H NMR(CDCl )~ :
2.30~s,3H),32.37(s,3H), 3.54(s,3H), 4.35-4.56 (m,4H), 5.77(s,1H), 6.10(br.s,1H), 7.15 ~d,1H), 7.35-7.60(m, 3H), 8.18(t,1H), 8.74 (d,1H), 8.95~d,1H) 22 CF CH ~ CH 62% Non-crystalline pale 3 3 3 yellow white powder 1H NMR(CDC1 )~ :
2.26(s,3H),32.30(s,3H), 2.65(s,3H), 3.56(s,3H), 4.25-4.50(m,4H), 5.55 (s,1H), 6.66(br.s,1H), 7.10-7.45(m,4H), 7.55 (d,1H), 8.10(d-d,1H), 9.00(d,1H) 23 CF3 CH2CH2CH3 ~ 75% Crystalline white powder m.p. 123-124C
1H~R(CDCl ) ~ :
2.25(s,3H),3 2.31(s,3H), 3.30(s,3H), 3.45-3.65 (m,2H), 3.94-4.10(m,1H), 4.22-4.50(m,5H), 5.58 (s,1H), 6.20(br.s,1H), 7.24(t,1H), 7.30-7.60 (m,4H), 8.20(d,1H), 8.78(d,1H), 9.10(s,1H) 24 N02 CH3 ~ Cl3 28% Non-crystalline yellow 1H NMR(CDC13)~ :

TABLE 4 (Continued) Ex. R2 R4 R1 Yield Physical ~ro~erties 2.29(s,3H), 2.37(s,3H), 3.54(s,3H), 4.30-4.65 (m,4H), 5.77(s,1H), 6.69~r,1H), 7.07-7.20 (m 1H), 7.32-7.58(m, 3H5, 8.09(d-d,1H), 8.38 (d~,1H), 9.09(d-d,1H) N02 CH3 ~ I 29% Non-crystalline yellow powder 1H NMR(CDCl ) ~:
2.30(s,3H),32.36(s,3H), - 3.55(s,3H), 4.25-4.58 (m,4H), 5.75(s,1H), 5.96(br,1H), 7.10-7.22 (m 1H), 7.32-7.60(m, 3H5, 7.82(d,2H), 8.77 (~d,1H) 25 N2 CH3 ~ OCH3 powder 1H NMR(CDCl ) ~:
2.30(s,3H),32.37(s,3H), 3.55(s,3H), 4.00(s,3H), 4.25-4.53(m,4H), 5.78 (s,1H), 5.97(br,1H), 6.74(d,1H), 7.10-7.22 (m 1H), 7.35-7.61(m, 3H5, 8.05(~d,1H), 8.70 (d,1H) 27 N2 CH3 ~ powder 1H NMR(CDCl ) ~:
2.30(s,3H),32.36(s,3H), 3,53(s,3H), 4.05(s,3H), 4.30-4.60(m,4H), 5.77 (s,1H), 6.29(br1H), 7.08-7.20(m,1H~, 7.32-7.50~m,3H) 8.19(d,1H) 8.38(d~,1H5, 9.18(d,1H5 TABLE 4 (Continued) Ex. R2 R4 R1 Yield Physical pro~erties 28 N2 CH3 -~ ~ - ~ 57% Non-crystalline yellow 1H NMR(cDc~
2.28(s,3H),32.34(s,3H), 3.53(s,3H), 4.25-4.58 (m,4H), 5.76(s,1H), 6.13 ~r,1H), 6.91(d,1H), 7.07-7.70(m,9H), 8.19 (d~,1H), 8.67(d,1H) 29 N02 C2H5 ~ 46% Non-crystalline yellow H NMR(CDCl ) ~: 1.12(t,3H) 2.31(s,3H),32.34(s,3H), 3.98(q,1H), 4. 08(q,1H), 4.30-4.53(m,4H), 5.83 (s,1H), 5.93(br,1H), 7.09-7.20(m,1H), 7.35-7.62(m,4H), 8.25(d-d-d, 1H), 8.77(d~,1H), 9-09(d-d,1H) N02 i-C3H7 ~ 59,~ Yellow oily product H ~R(CDCl ) ~:
0.95(d,3H),31.16(d,3H), 2.29(s,3H), 2.32(s,3H), 4.30-4.55(m,4H), 4.92 (sep,1H), 5.87(s,1H), 6.08(b,1H), 7.10-7.22 (m 1H), 7.34-7.70(m, 4H~, 8.31(d-d-d,1H), 8.77~d-d,1H), 9.12(d,1H) 31 N02 i-C4H9 ~ 550/~ Yellow oily product H MMR(CDCl ) ~:
0.73(d,3H),30.76(d,3H), 1.82(n,1H), 2.33(s,5H), 3.65-3.90(m,2H), 4.27-4.53(m,4H), 5.80~r,1H), 5.82(s,1H), 7.10-7.22 (m,1H), 7.35-7.55(m,4H), __ .

1 33786~

TABLE 4 (Continued) E R2 R4 R1 Yield Physical pro~erties - 8.28(d-d-d,1H), 8.77 (d-d,1H), 9.10(d-d,1H) 32 NO CH OCH CH -~ O ~ 47% Crystalline yellow 2 3 2 2 ~ ~ powder m.p. 137-139C
1H NMR(cDc~
2.28(s,3H),32.35(s,3H), 3.27(s,3H), 3.37-3.65 (m 2H), 3.93-4.60(m, - 4H5, 5.84(s,1H), 6.07 (br1H), 7.07-7.20(m 1H~, 7.30-7.66(m,4H~, - 8.23(d-d-d,1H) 8.77 ~d-d,1H), 9.08~d,1H) 33 CF CH ~ OCH3 73b Non-crystalline color-3 3 less powder 1H NMR(cDc~
2.30(s,3H),32.33(s, 3H), 3.57(s,3H), 4.00 (s 3H), 4.20-4.50(m, 4H~, 5.57(~r,1H), 5.79 (s,1H), 6.74(d 1H), 7.10-7.22(m,1H5, 7.29-7.57(m,3H), 8.06(d-d, 1H), 8.74(d,1H) 34 CF3 i-C4H9 ~ 443b Colorless oily product H ~R(CDCl ) ~:
0.77(d,5H),31.86(n,1H), 2.29(s,3H) 2.31(s,3H), 3.69~,1H~, 3.88(d-d, 1H), 4.27-4.60(m,4H), 5.~7(s,1H), 5.83(br,1H), 7.08-7.21'm,1H), 7.28-7.60(m,4H , 8.24(d-d-d, 1H), 8.78~d-d,1H), 9.11~-d,1H) 35 CF3 i-C4Hg ~ ~ 36% Colorless oily product N 1H NMR(CDCl3) ~:

~_ -36-TABLE 4 (Continued) _ R2 R4 R1 Yield Physical pro~erties 0.72(d,6H), 1.79(n,1H), 2.28~s,3H) 2.32(s,3H), 3.67(d-d,1H5, 3.84(~d, 1H), 4.30-4.60(m,4H), 5.59(s,1H), 5.81~r,1H), 7.03-7.15(m,1H), 7.30-8.20(m,7H), 8.79(d,1H), 9.35(d,1H) 36 CF3 i-C4H9 ~ ~ 33% Non-crystalline color-N less powder CH3 1H NMR(CDCl ) ~:
0.72(d,5H),31.83(n,1H), 2.29(s,3H), 2.33(s,3H), 2.85(s,3H), 3.67(d-d, 1H), 3.84(d~,1H), 4.27-4.60(m,4H), 5.58(s, 1H), 5.64~r,1H), 7.03-7.15(m,1H), 7.25-7.82 (m,6H), 8.75(d,1H), 9.38(d,1H) 37 2 3 2 H2 ~ 53% Crystalline yellow N powder m.p. 100-102C
1H N~(CDCl ) ~:
2.27(s,3H),32.36(s,3H), 3.22(s,3H), 3.37-3.65 (m12H), 3.83-4.67(m, 5H , 5.85(s,1H), 6.13 (br1H), 6.97-7.10(m 1H~, 7.27-8.20(m,7H~, 8.82(d,1H), 9.33(d,1H) 38 CF3 CH30CH2CH2 -~ ~ 80% Crystalline pale yellow N powder m.p. 74-76 C
1H NMR(cDc~
2.24(s,3H),32.33(s,3H), 3.24(s,3H), 3.41-3.57 (m 2H), 3.94-4.05(m 1H~, 4.22-4.52(m,5H~, 5.60(s,1H), 6.17(s, 1H), 7.03-7.10(m,1H), 7.27-8.20(m,7H), 8.77 (d,1H), 9.35(d,1H) .~

1 3378b~

TABLE 4 (Continued) Ex. R2 R4 R1 Yield Physical ~ro~erties 39 N2 CH3 ~ OCH3 49% Non-crystalline yellow `N ~ powder H NMR(CDCl ) ~:
2.29(s,3H),32.39(s,3H), 3.51(s,3H), 3.98(s,3H), 4.37-4.56(m,4H), 5.79 (s,1H), 5.92(br?1H), 6.98-7.10(m,1H), 7.18-7.55(m,5H), 8.06(d,1H), 8.72(d,1H), 9.15(s,1H) N02 CH3 ~ 57% Non-crystalline yellow N powder CH3 1H NMR(CDCl ) ~:
2.30(s,3H),32.39(s,3H), 2.85(s,3H), 3.51(s,3H), 4.34-4.67(m,4H), 5.79 (s,1H), 5.83~r1H), 6.96-7.08'm,1H~, 7.27-7.83(m,6H , 8.75(d, 1H), 9.33~d,1H) 41 N02 i-C4Hg ~ ~ powder 1H NMR(CDCl )~:
0.68(d,3H),30.71(d,3H), 1.81(n,1H), 2.31(s,3H) 2.33(s,3H) 3.70~,1H~, 3.78(d~,1H~, 4.30-4.64(m,4H), 5.84(s,1H), 6.25~r,1H), 7.00-8.20 (m,8H), 8.85(d,1H), 9.35(d,1H) 42 CF3 i-C4Hg ~ OCH3 less powder 1H N~(CDCl )~:
0.72(d,6H),31.83(n, 1H), 2.27(s,3H), 2.31 (s,3H), 3.68~-d,1H), 3.83(d~,1H), 3.96(s 3H), 4.28-4.62(m,4H~, _ TABL3 4 (Continued) R R R
E 2 4 1 Yield Physical ~ro~erties 5.59(s,1H), 6.10(br,1H), 7.03-7.60(m,6H), 8.06 (d,1H), 8.70(d,1H), 9.20(d,1H) 3 3 3 ~ 3 71% Non-crystalline color-less powder 1H NMR(cDc~
2.29(s,3H),32.34(s,3H?, 3.52(s,3H), 3.97(s,3H), 4.28-4.56(m,4H), 5.56 (s,1H), 5.82~r 1H), 7.02-7.54(m,5H~, 8.06 (d,1H), 8.68(d,1H), 9.19(d,1H) 44 CF3 CH3 ~ ~ 54,~0 Non-crystalline color-N-~y~ less powder CH3 1H NMR(cDc~
2.30(s,3H),32.35(s,3H), 2.84(s,3H), 3.52(s,3H), 4.25-4.55(m,4H), 5.57(s,1H), 5.58(br,1H), 7.02-7.80(m,7H), 8.72 (d,1H), 9.37(d,1H) N02 i-53H7 ~ 3 62,~ Non-crystalline yellow 1H NMR(CDCl ) ~:
0.93(d,3H),31.13(d,3H), 2.31(s,6H), 3.97(s,3H), 4.32-4.59(m,4H), 4.84-4.96(m,1H), 5.89(s, 1H), 5.99~r,1H), 7.05-7.65(m,6H), 8.05(d,1H), 8.75(d,1H), 9.20(d,1H) .--TABLE 4 (Continued) 3x. R2 R4 R1 Yield Physical ~ro~erties Cl 46 N02 CH3 ~ 47% Non-crystalline yellow 1H N~(CDCl ) ~:
2.30(s,3H),32.38(s, 3H), 3.55(s,3H), 4.36 -4.53(m,4H), 5.78(s, 1H), 6.09(s,1H), 7.10-7.18(m,1H), 7.35-7.59 (m,4H), 8.59(d,1H), 8.91(s,1H) The novel compounds as prepared in the above-mentioned examples were individually measured for Ca-blocking potency thereof in accordance with the method of M. Fiol de Cureo et al. (Arch. int. Pharmacodyn., 263, 28-39, 1983). This method is to evaluate each compound to be tested with respect to Ca-blocking potency on the basis of 50% inhibiting concentration of a spontaneous contraction of an isolated rat portal vein. The results are shown in terms of a relative activity to Nifedipine (Nifedipine=l) ~C~

Example R2 R4 RlS c f c 1 NO2 3 ~ 3.1 9 NO2 3 ~ 5 9 N2 ~ )~

11 NO2 3 ~ Cl 40.6 12 NO2 3 ~ 40.6 13 CF3 CH3 ~ O~ 14.4 14 CF3 3 ~ Cl 29.5 CF3 3 ~ 7 4 16 Cl CH3 ~ 6.8 17 No2 CH3 < ~ CH3 15.5 18 No2 CH3 ~ ~ NH2 1.9 19 No2 CH3 ~ ~ NHCOCH31.4 NO2 3 ~ NHCO ~ 2.0 21 2 3 ~ Cl 16.7 22 CF3 3 ~ CH3 9.2 23 CF3(CH2)2cH3 ~ 135.4 TABLE 5 (Continued) Specific Example R2 R4 Rl potency 24 NO2 3 ~ CC13 3.1 25 NO2 3 ~ I 17.1 26 NO2 3 ~ 3 27 NO2 3 ~ COOCH3 4.6 28 2 3 ~ ~ 3.6 29 No2 C2H5 ~ 31.0 30 NO2 3 7 ~ 130.0 31 NO2 4 9 ~ ~ 103.2 32 2 ( 2)2 3 ~ 5 33 CF3 3 ~ OCH3 12.3 34 CF3 4 9 ~ 8.2 35 CF3 4 9 ~ 8.0 36 CF3 4 9 ~ 17.6 37 NO2 (CH2)2cH3 ~ 135.4 38 CF3 (CH2)2cH3 ~ 26.0 39 NO2 3 ~ CH3 10.3 ~ 337865 TABLE 5 (Continued) Specific Example R2 R4 Rl potency NO2CH3 ~ 5.4 41 N2 4 9 ~ 3 15.9 42 CF3 4 9 ~ OCH3 3.8 43 CF3 3 ~ OCH3 2.1 44 CF3CH3 ~ 9.0 NO2 i-C3H7 [ ~,, 10.8 46 N2 CH3 -~O >

Remarks: R3 is Cl in Example 16, but R3 is H in other examples.

- ~ 33~865 A syrup containing 0.5~ (weight per volume) of active ingredient was prepared from the following ingredients-Active ingredient 0.5 g D-sorbitol 70 W/V ~ 25 g Sugar 30 g Methyl p-oxybenzoate 0.03 g Glycerine 0.15 g Propyl p-oxybenzoate 0.015 g Flavouring agent 0.2 g ~6% Ethanol 0.5 g Distilled water ad 100.0 ml Sugar, d-sorbitol and the active ingredient were dissolved in 60 g of warm water. After cooling, glycerine and 15 solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml.
The above named active ingredient may be replaced by other therapeutically active ingredients of the invention.

An active ingredient (50 mg) was mixed with lactose (50 mg), potato starch (20 mg) and colloidal silicic acid (9.5 mg). The mixture was moistened with a 10~ solution of gelatine and was granulated through a 25 12-mesh sieve. After drying potato starch (10 mg), talc (0.75 mg) and magnesium stearate (0.75 mg) were admixed .~.

and the mixture thus obtained was pressed into tablets, each containing 50 mg of active ingredient. These tablets are coated with a 10~ alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2~). After the first five coatings talc and powdered sugar were used for powdering. The priming coat was then coated with a 66~ sugar syrup and polished with a 10 carnauba wax solution in carbon tetrachloride.
ExArlpLE 4~
Granu]es were prepared from active ingredient (50 mg), lactose (250 mg), potato starch (150 mg) and an alcoholic solution of polyvinylpyrrolidone (50 mg). After the drying step the granules were sieved through a 12 x 60 mesh sieve to prepare granules, each containing 50 mg of active ingredient.

_ 46 -SUPPLEMENTARY DISCLOSURE

Further examples of preferred compounds according to the invention, having the formula (I) as defined in theprincipal disclosure, are listed below:
1) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-6-methyl-3-quinoline carboxy)ethyl]ester-5-methyl ester;
2) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
3) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
4) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
5) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
6) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;

7) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(7-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
8) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(7-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
9) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
10) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
11) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
12) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(5,8-dimethoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;
13) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-(7,8-benzoquinoline)carboxy )ethyl ]ester-5-methyl ester;
14) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(5,8-dimethyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

- 4~ --The following additional examples further illustrate the invention:

2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihy-dropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester H3~CH2CH20C~CH3 A mixture of 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-chlo-roethyl)ester-5-methylester (1.00 g) and sodium 4-chloro-6-methyl-3-quinolinecarbonate (0.64 g) was heated and stirred in N,N-dimethylformamide (10 ml) under an argon stream at 120-130C for 4 hours. After the reaction was complete, ethylacetate (20 ml) was added to the reaction mixture, filtered with suction and the filtrate was distilled under reduced pressure.
Silicagel column chromatography of the residue eluting with ethyl acetate/n-hexane (1:1 volume ratio) gave the title compound (1.14 g, 79% yield) as non-crystal-line colorless powder. This compound was measured for NMR with the following results.

, . . .

lH NMR(CDC~3)~ 2.28(s,3H), 2.33(s,3H),2.61(s,3H), 3.55(s,3H), 4.26~ 4.65(m,4H), 5.58(s, lH), 5.99 (b, lH), 7.01~ 7.15(m, lH), 7.25~ 7.75 (m, 4H), 8.09 (d, lH), 8.10~ 8.21(m,1H), 9.04(s, lH) In accordance with the same procedure as described in Example 50, there were prepared the compounds as shown in Table 6.

~ Rl R200C ~COOCH2CH20C-R3 H

~i .~, .

Example 1 R2 R3 Physical properties & Yield 51 2-CF3 Me C~ Non-crystalline colorless powder ~ lH NMR (CDCQ3) ~ 2.30 (s, 3H), N 1 2.35(s,3H), 2.83(s, 3H), Me 3.56(s, 3H),-4.25~ 4.60(m, 4H), 5.58(s, lH), 5.67(b, lH), 7.02 -7.14(m, lH), 7.27- 7.75 (m,5H), 8.27(d, lH), 9.13(s, lH), yield 44%
52 2-NO2 Me Crystalline yellow powder m.p. 171~ 174 C, H NMR
(CDC Q3) OMe 2.30(s, 3H), 2.37(s, 3H), 3.51(s, 3H), 4.12(s, 3H), 4.35 ~4.64(m, 4H), 5.78(s, lH), 5.84(b, lH), 6.95~ 7.06(m, lH), 7.14 -7.58(m, 6H), 8.75(d, lH), 9.32(d, lH), yield 37%
53 2-CF3 Me Crystalline colorless powder m.p. 197~ 198C lN NMR(CDCQ3) 2.30(s, 3H), 2.34(s, 3H), OMe 3.52(s, 3H), 4.12(s, lH), 4.25 ~4.57(m, 4H), 5.56(s, lH), 5.69(b, lH), 7.00~ 7.60(m, 7H), 8.72(s, lH), 9.35(s, lH), yield 44%

TABLE 6 ( continued ) Example Rl R2 R3 Physical properties & yield 54 2-NO2 Me Non-crystalline yellow powder Me lH ~qR (CDC~3) ~

N~ 2.29(s, 3H), 2.38(s, 3H), 2.58(s, 3H), 3.51 (s, 3H), 4.33 - 4.68(m, 4H), 5.79(s, lH), 6.03(b, lH), 6.95 ~ 7.07(m, lH), 7 . 27 ~ 7 . 40 (m, lH ) , 7 . 40 ~ 7 . 60 (m, 2H), 7.60 ~ 7.80(m, 2H), 8.05(d, lH), 8.70(d, lH), 9.23(d, lP), yield 46%
2-CF3 Me Crystalline colorless powder Me 1H NMR (CDCQ3) ~

2.29(s, 3H), 2.34(s, 3H), 2.58(s, 3H), 3.53(s, 3H), 4.30 ~ 4.65(m, 4H), 5.57(s, lH), * m.p. 146-148 C 5.93(b, lH), 7.00~ 7.14(m, lH), 7.25~ 7.40(m, 2H), 7.47~ 7.55 (m, lH) 7.60~ 7.73(m, 2H), 8.06(d, lH), 8.69(d, lH), 9.27(d, lH), yield 69%

TABLE 6 (continued) ExamPle Rl R2 ~3 Physical properties &yield 56 2-NO2 Non-crystalline yellow powder H NMR (CDCQ3) N~` OMe 2.29(s, 3H), 2.38(s, 3H), 3.51(s, 3H), 3.99(s, 3H), 4.35 ~4.62(m, 4H), 5.79(s, lH), 5.88(b, lH), 7.04(m, lH), 7.23 ~7.57(m, 5H), 7.82(d, lH) 8.68(d, lH), 9.24(d, lH), yield 24%
57 2-CF3 Me Non-crystalline colorless powder _ H NMR (CDCQ3) ~
N ~ OMe 2.29(s, 3H), 2.34(s, 3H), 3.53(s, 3H), 3.99 (s, 3H), 4.25 ~ 4.60(m, 4H), 5.58(s, lH), 6.01(b, lH), 7.00- 7.15(m, lH), 7.23 ~ 7.58(m, 5H), 7.80(d, lH), 8.66(d, lH), 9.27(d, lH), Yield 34%
20 58 2-NO2 Me CQ Crystalline yellow powder m p 2;9C (dec ) lH NMR

OMe 2.30(s, 3H), 2.37(s, 3H), 3.53(s, 3H), 4.12(s, 3H), 4.36 ~4.65(m, 4H), 5.78(s, 2H), 6.95 -7.07(m, lH), 7.17~ 7.40 (m, 2H), 7.43 ~7.56(m, 2H), 7.64(t, lH), 7.97 (d, lH), . _ TABLE 6 ( continued ) Example ~1 R2 3 - - Physical properties & yield 9.08(s, lH), yield 48%
59 2-CF3 Me CQ Crystalline colorless powder ~ m.p. 189 C tdec. ), H NMR
N ~~ ( CDCQ 3) OMe 2.30(s, 3H), 2.33(s, 3H), 3.55(s, 3H), 4.12(s, 3H), 4.26 ~ 4.65(m, 4H), 5.58(s, lH), 10 5.84 (b, lH), 7.02 ~ 7.16 (m, lH), 7.16~ 7.56(m, lH), 7.64(t, lH), 7.98(d, lH), 9.11 (s, lH) yield 60%
2-NO2 Me C~ Non-crystalline yellow powder ~ Me 1H NMR (CDCQ3) ~

N 2.30(s, 3H), 2.39(s, 3H), 2.62(s, 3H), 3.54(s, 3H), 4.36 4.63 (m, 4H), 5.79 (s, lH), 5.87(b, lH), 6.95 ~ 7.06(m, lH), 7.26~ 7.40(m, lH), 7.40 ~7.56 (m, 2H), 7.64~ 7. (m, lH), 8.04 (d, lH), 8.13 ~8.20(m, lH), 9.02 ( s , lH ) yield 46%

TABLE 6 ( cont inued ) Example Rl R2 R3 Physical properties & yield 61 2-CF3 Me OMe Cristalline pale greenish blue powder, lH ~R (CDCQ3)~
N~
OMe 2.29(s, 3H), 2.32(s, 3H), 3.51(s, 3H), 4.00(s, 3H), 4.06(s, 3H), 4.28- 4.56(m, 4H), 5.55(s, lH), 5.87(s, lH), 6.83(d, lH), 7.00~ 7.12(m, lH), 7.08(d, lH), 7.25~ 7.53(m, 3H), 9.16 (d, lH), 9.36 (d, lH) Yield 85%
62 2-CF3 Me Non-crystalline colorless ~ powder, lH ~R ( CDCQ 3) N~ 2.28(s, 3H), 2.34(s, 3H), 3.53(s, 3H), 4.30~ 4 65 (m, 4H), 5.58(s, lH), 5.82(b, lH), 7.00~7.13(m, lH), 7.23 ~7.54 (m, 4H), 7.65 ~ 8.00(m, 4H), 8.73 (d, lH), 9.24~ 9.35(m, lH), 9.43(d, lH), yield 85%
63 2-CF3 ~e Me Non-crystalline colorless ~ powder, lH ~R ( CDCQ3) r 2.30(s, 3H), 2.34(s, 3H), Me 2.70(s, 3H), 2.79(s, 3H), 3.52(s, 3H), 4.27~ 4.60(m, 4H), ,, ~ . ~

TABLE 6 (continued) Example Rl R2 R3 Physical properties & ~ield 63 (continued) 5.58(s, lH), 5.71(b, lH), 7.02^~7.12(m, lH), 7.24~ 7.58 (m, 5H), 8.93(d, lH), 9.37(d, lH) yield 7196 Ca-blocking potency of 1,4-dihydropyridine derivatives Example Rl R2 3 Specific potency 10 50 2-CF3 Me ~ 21.7 \~e 51 2-CF3 Me C~ 3.1 52 2-No2 Me ~ 1.9 Me 53 2-CF3 Me ~ 3.6 Me 54 2-N02 Me ~) 10.8 15 55 2-CF3 Me ~/Me 9.6 56 2-NO2 Me ~ Me 3.6 57 2-CF3 Me ~ OMe 8.8 ; - 56 -~ ~31~65 T~ & (continued) Exemple Rl R2 R3 specific potency 59 2-CF3 Me C~ 1.8 2-NO2 Me ~ 28.3 2-CF3 Me ~ Me 61 2-CF3 Me ~
Me 62 ~ ~

63 2-CF3 Me Me 2.4 ,~
e

Claims (46)

1. A compound of the formula I:

(I) wherein:
R1 represents furyl, thienyl, pyridyl, pyrazinyl or quinolyl, optionally substituted by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trichloro-methyl, trifluoromethyl, amino, acetylamino, benzoylamino,(C1-C4)alkoxy carbonyl or phenyloxy;
R2 and R3 are both halogen, or one of R2 and R3 represents nitro or trifluoromethyl and the other represents hydrogen;
R4 represents a straight- or branched-(C1-C4)alkyl, methoxyethyl or ethoxyethoxymethyl; and n represents 2 or 3.

2. A compound according to claim 1, wherein R1 is selected from the group consisting of 3-furyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl and 3-quinolyl.

3. A compound according to claim 1, wherein R1 represents a 3-furyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl or 3-quinolyl group containing at least one substituent selected from the group consisting of fluorine, chlorine, bromine, iodine, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, phenoxy, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl.

4. A compound according to claim 1, wherein R1 represents a 3-quinolyl group optionally substituted by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy or propoxy.

5. A compound according to claim 2, wherein one of R2 and R3 represents a nitro group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxy ethyl, ethoxyethyl and ethoxyethoxymethyl.

6. A compound according to claim 3, wherein one of R2 and R3 represents a nitro group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxyethoxymethyl.

7. A compound according to claim 4, wherein one of R2 and R3 represents a nitro group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxyethoxymethyl.

8. A compound according to claim 2, wherein one of R2 and R3 represents a trifluoromethyl group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

9. A compound according to claim 3, wherein one of R2 and R3 represents a trifluoromethyl group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

10. A compound according to claim 4, wherein one of R2 and R3 represents a trifluoromethyl group and the other represents a hydrogen atom; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

11. A compound according to claim 2, wherein R2 and R3 both represent halogen atoms; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

12. A compound according to claim 3, wherein R2 and R3 both represent halogen atoms; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

13. A compound according to claim 4, wherein R2 and R3 both represent halogen atoms; and R4 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert-butyl, methoxyethyl, ethoxyethyl and ethoxy-ethoxymethyl.

14. A compound according to claims 5, 6 or 7, wherein R2 is at the 2-position and represents a nitro group.

15. A compound according to claims 8, 9 or 10, wherein R2 is at the 2-position and represents a trifluoromethyl group.

16. A compound according to claims 11, 12 or 13, wherein R2 is at the 2-position and R3 is at the 3-position.

17. A compound according to claim 1, selected from the group consisting of:
1) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)-ester-5-methyl ester;
2) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(2-nicotinoyloxyethyl)-ester-5-methyl ester;
3) 2, 6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(2-picolinoyloxyethyl)-ester-5-methyl ester;
4) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(2-isonicotinoyloxy-ethyl)ester-5-methyl ester;

5) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(2-chloronicotin-oyloxy)ethyl]ester-5-methyl ester;
6) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(2-pyrazinoyloxyethyl)-ester-5-methyl ester;
7) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)-ethyl]ester-5-methyl ester;
8) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-(3-nicotinoyloxypropyl)-ester-5-methyl ester;
9) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(3-thiophencarboxy)-ethyl]ester-5-methyl ester;
10) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(3-furancarboxy)-ethyl]ester-5-methyl ester;
11) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-chloronicotin-oyloxy)ethyl]ester-5-methyl ester;
12) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)-ethyl]ester-5-methyl ester;
13) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotin-oyloxyethyl)ester-5-methyl ester.
14) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-chloro-nicotinoyloxy)ethyl]ester-5-methyl ester;
15) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]ester-5-methyl ester;
16) 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxy-ethyl)ester-5-methyl ester.

17) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-methylnicotinoyl-oxy)ethyl]-ester-5-methyl ester;

18) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-aminonicotinoyl-oxy)ethyl]ester-5-methyl ester;

19) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-acetamidonicotin-oyloxy)ethyl]ester-5-methyl ester;

20) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-benzamidonicotin-oyloxy)ethyl]ester-5-methyl ester;

21) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(5-chloronicotin-oyloxy)ethyl]ester-5-methyl ester;

22) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-nicotinoyloxy)ethyl]ester-5-methyl ester.

23) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotin-oyloxyethyl)ester-5-methoxyethyl ester;

24) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-trichloromethyl-nicotinoyloxy)ethyl]ester-5-methyl ester;

25) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-iodonicotinoyl-oxy)ethyl]ester-5-methyl ester;

26) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-methoxynicotinoyl-oxy)ethyl]ester-5-methyl ester;

27) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-methoxycarbonyl-nicotinoyloxy)ethyl]ester-5-methyl ester;

28) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(6-phenoxynicotinoyl-oxy)ethyl]ester-5-methyl ester;

29) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxy-ethyl)ester-5-ethyl ester.

30) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxy-ethyl)ester-5-isopropyl ester.

31) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxy-ethyl)ester-5-isobutyl ester.

32) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-nicotinoyloxy-ethyl)ester-5-methoxyethyl ester.

33) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-meth-oxynicotinoyloxy)ethyl]ester-5-methyl ester;

34) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(2-nico-tinoyloxyethyl)ester-5-isobutyl ester.

35) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;

36) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methyl-3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;

37) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]ester-5-methoxyethyl ester;

38) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-quinolinecarboxy)ethyl]ester-5-methoxyethyl ester;

39) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;

40) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(8-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;

41) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(3-quinolinecar-boxy)ethyl]ester-5-isobutyl ester;

42) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-di-hydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-isobutyl ester;

43) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-di-hydropyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester;

44) 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester;

45) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(6-methoxy-3-quinolinecarboxy)ethyl]ester-5-isopropyl ester;

46) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-[2-(4-chloronicotin-oyloxy)ethyl]ester-5-methyl ester.

18. A pharmaceutically acceptable acid addition salt of a compound as claimed in claims 1 or 17.

19. A pharmaceutically acceptable acid addition salt of a compound as claimed in claims 2, 3 or 4.

20. A process for preparing a compound of the formula (I):

(I) wherein:
R1 represents furyl, thienyl, pyridyl, pyrazinyl or quinolyl, optionally substituted by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trichloro-methyl, trifluoromethyl, amino, acetylamino, benzoylamino,(C1-C4)alkoxy carbonyl or phenyloxy;
R2 and R3 are both halogen, or one of R2 and R3 represents nitro or trifluoromethyl and the other represents hydrogen;
R4 represents a straight- or branched-(C1-C4)alkyl, methoxyethyl or ethoxyethoxymethyl; and n represents 2 or 3, which comprises reacting a compound of the formula (II) wherein R2 and R3 are as defined above, a compound of the formula (III) wherein R4 is as defined above, and a compound of the formula (IV) wherein R1 and n are as defined above.

21. A process for preparing a compound of the formula (I):

(I) wherein:
R1 represents furyl, thienyl, pyridyl, pyrazinyl or quinolyl, optionally substituted by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trichloro-methyl, trifluoromethyl, amino, acetylamino, benzoylamino,(C1-C4)alkoxy carbonyl or phenyloxy;
R2 and R3 are both halogen, or one of R2 and R3 represents nitro or trifluoromethyl and the other represents hydrogen;
R4 represents a straight- or branched-(C1-C4)alkyl, methoxyethyl or ethoxyethoxymethyl; and n represents 2 or 3, which comprises reacting a compound of the formula (V) wherein R2, R3, R4 and n are as defined above, and X
represents a halogen atom, a mesyloxy group, a benzenesulfonyloxy group or a tosyloxy group, with a compound of the formula (VI) wherein R1 is as defined above and M represents an alkali metal or an alkaline earth metal.

22. A process according to claims 20 or 21, further including the step of converting the compound of the formula (I) thus obtained into a pharmaceutically acceptable acid addition salt.

23. A pharmaceutical composition for vasodilation and lowering blood pressure, which comprises as active ingredient a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.

24. A pharmaceutical composition for vasodilation and lowering blood pressure, which comprises as active ingredient a compound as claimed in claims 5, 6 or 7, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.

25. A pharmaceutical composition for vasodilation and lowering blood pressure, which comprises as active ingredient a compound as claimed in claims 8, 9 or 10, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.

26. A pharmaceutical composition for vasodilation and lowering blood pressure, which comprises as active ingredient a compound as claimed in claims 11, 12 or 13, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.

27. A pharmaceutical composition according to claim 23, wherein the active ingredient is a compound as claimed in claim 17, or a pharmaceutically acceptable acid addition salt thereof.

CLAIMS SUPPORTED BY THE
SUPPLEMENTARY DISCLOSURE

28. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

29. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

30. 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

31. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

32. 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

33. 2-6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

34. 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(7-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

35. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(7-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

36. 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-me-thoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

37. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-8-methoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

38. 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(4-chloro-6-methyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

39. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(5,8-dimethoxy-3-quinolinecarboxy)ethyl]ester-5-methyl ester.

40. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(3-(7,8-benzoquinoline) carboxy)ethyl]ester-5-methyl ester.

41. 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(5,8-dimethyl-3-quinolinecarboxy)ethyl]ester-5-methyl ester.