FR2528425A1 - 1,4-DIHYDROPYRIDINES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Abstract

The present invention relates to the use of 1,4-dihydropyridines, some of which are known, of the general formula I in which R<1> and R<2> are identical or different and each represent alkyl or alkoxyalkyl having up to 12 C atoms, where the alkyl radical is optionally substituted by fluorine or chlorine, and R<3> represents one or two identical or different substituents from the group consisting of nitro, trifluoromethyl, halogen and cyano, for use in the control of arteriosclerosis.

Description

The present invention relates to the use of i, 4-dihydropyridines partly known for combating atherosclerotic modifications of the vessels in the form of fibromusculo-elastic plaques, antiarteriosclerosis compositions containing these compounds and their preparation. The compounds intended for use according to the invention and their vasodilatory, hypoglycemic and coronary action are in part known (see patent applications of the Federal Republic of Germany DE-OS NO 2 117 571; DE-OS NO 1 670 827; DE-OS NO 2,117,573;
DE-OS NO 2 549 568 and DE-OS NO 2 841 667).

It is also known that the compound called nifedipine (see the patent application of the Republic
Federal of Germany DE-OS NO 7 670 827) and other calcium antagonists inhibit the introduction of calcium into smooth muscle cells. With regard to nifedipine, it has also meanwhile been found to suppress an accumulation of cholesterol in the vessel walls in cholesterol-absorbing rabbits (see PD Henry and KI Bentley
J. Clin. Invest. 68, 1366-9, 1981).

The use of the dihydropyridines in accordance with the invention as anti-arteriosclerotics which inhibit the formation, caused by an alteration of the vessel wall, of fibromusculo-elastic plaques which are formed by the proliferation of an internal tunica, n! is not yet known.

Heart and circulatory diseases, which are statistically recognized as the cause of more than 50% of fatal cases in industrialized countries, very often result from arteriosclerotic changes in the arterial part of the vascular system. In the etiology of atherogenesis, internal tunica proliferations are considered important preliminary stages. Such arteriosclerotic changes, which can lead to partial or total blockage of the vessel, cause tissue damage and can lead to local tissue death, i.e. infarction, for example in the heart and in the brain.

dans laquelle
R1 et R2 sont égaux ou différents et représentent chacun
un reste alkyle ou alkoxyalkyle ayant jusqu'à
12 atomes de carbone, le reste alkyle étant
éventuellement substitué par du fluor ou du
chlore, et
R3 désigne un ou deux substituants égaux ou diffé
rents choisis dans le groupe des substituants
nitro, trifluorométhyle, halogéno ou cyano, destinées à être utilisées pour combattre l'artériosclérose.The present invention relates to 1,4-dihydropyridines of general formula (I)

in which
R1 and R2 are equal or different and each represents
an alkyl or alkoxyalkyl residue having up to
12 carbon atoms, the alkyl residue being
optionally substituted with fluorine or
chlorine, and
R3 denotes one or two equal or different substituents
annuities selected from the group of substituents
nitro, trifluoromethyl, halo or cyano, intended for use in combating arteriosclerosis.

Particularly preferred are compounds of general formula (I), in which
R1 and R2 are equal or different and each represents
an alkyl residue having 1 to 4 carbon atoms
or an alkoxyalkyl residue having up to 6 atoms
carbon, and
R3 denotes one or two substituents in position
ortho or meta, chosen from the group of substi
nitro, chloro or trifluoromethyl killers.

Mention should be made very particularly of compounds of general formula (I), in which
R1 and R2 represent alkyl radicals having 1 to 4 ato
my carbon and
R3 is a nitro group.

In view of the state of the art, it could not be expected that the compounds which can be used in accordance with the invention exert such an advantageous antiarteriosclerotic action.

Arteriosclerosis is a complex disease, the onset of which can often be influenced or caused by the following processes
a) alteration of the vessel wall with
subsequent proliferation of muscle cells
smooth leaves and lesion formation
fibromusculo-elastic,
b) accumulation of lipids in this lesion,
and
c) formation of a mural thrombus and its insertion
tion in the vessel wall.

The following examples illustrate the advantageous specific action of inhibiting the proliferation of the compounds to be used in accordance with the invention.

Test method
Inner lining proliferations are induced in rats by lesion of the vessels. By refitting the carotid artery (2 minutes; 110 ° C), partial or total exfoliation of the endothelium is achieved in a locally delimited region. Inner lining proliferations appear after a short period of about 10 days and largely correspond to the early stages of arteriosclerotic plaques in humans.

The proliferation zones are detached and weighed. The wet weight in the cooled segment measuring 7 cm is about 200-300 Ag. In addition, the animals are fed a diet rich in fat (3% king cholesterol).

Fat deposits are stained with Sudan IV, a fat soluble dye, and can be identified as an additional parameter (see F. Seuter et al., Experimentally induced thromboathero scierosis. Folia angiologica 28, 85 (1980)).

It is surprising to find that the compounds indicated by way of example in the following table exert an anti-arteriosclerotic action even after oral administration, since the proliferation of the inner shell is significantly inhibited.

BOARD
Substance Daily Dose Proliferation Reduction
dienne (mg / kg) * (shot) (%)
Witness - 309
Example 3 30 '' 159 49
10 '' 270 13
Example 1 100 in 73 44
30 in 109 16
Control - 130 * In two takes
Besides cytostatics and alkylating glucocorticoids, which inhibit cell proliferation in a non-specific manner, only heparin has so far been shown to be active in this model after parenteral administration. Lipid lowering substances such as lacholestyramine, neomycin and nicotinic acid have been shown to be inactive. The action, depending on the dose, of heparin, which in this case serves as a reference standard, is already known (see R.Sitt et al., Suppression by Heparin of intima proliferation in the injured carotid artery (rat ), Arch.

Pharmacol., Suppl. 311, Abstr. 188, 1980).

Heparin has the essential drawback of parenteral administration. After oral administration, practically no effect is observed. The oral activity of the compounds according to the invention is surprising and it was unexpected on the basis of the knowledge of the prior art.

Preparation examples
Dihydropyridine derivatives as anti-atherosclerotic agents
Example 1 4- (2 '-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy-1, 4-dihydropyridine

45 g of 2-nitrobenzaldehyde, 80 ml of acetylacetic acid methyl ester, 75 ml of methanol and 32 ml of ammonia are heated for several hours at reflux, filtered, cooled and, after filtration with suction, the mixture is heated. obtains 75 g of yellow crystals melting at 172-1740C.

Example 2 4- (3'-nitrophenyl) -2,6-dimethyl-3,5-di- (2-propoxyethyl) -1, 4-dihydropyridine carboxylate

7.5 g of 3-nitrobenzaldehyde, 19 g of 2-propoxyethyl ester of acetylacetic acid and 5.5 ml of ammonia are heated in 40 ml of alcohol for 6 to 8 hours at reflux and after cooling 21 is obtained. g of yellow crystals which are recrystallized from ligrolne to which a little benzene has been added. Melting point 83-860C.

Example 3
2,6-Dimethyl-4 - ('nitro-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl-5-ethyl ester

After boiling for 10 hours a solution of 13.4 g of 3'-nitrobenzylideneacetylacetic acid ethyl ester and 5.8 g of ss-aminocrotonic acid methyl ester in 50 ml of ethanol, there is Obtained the 3-methyl and 5-ethyl ester of 2,6-dimethyl-4- (3'nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, melting at 1580C (ethanol). Yield: 67% of theory.

Example 4
1,4-Dihydro-2,6-dimdthyl- 4- (2-nitrophdnyl) -pyridine-3,5-dicarboxylic acid decylethyl ester

A solution of 263 g (1 mole) of 2- (3-nitrobenzylidene) -acetylacetic acid ethyl ester and 241 g (1 mole) of S-aminocrotonic acid decyl ester in 2.4 liters of Absolute ethanol was heated to boiling under a nitrogen atmosphere for 18 hours. Then, the solution was filtered while hot and concentrated to about half its volume in vacuo. The concentrated solution was cooled with ice, which precipitated a thick crystalline magma. This magma was filtered off with suction, recrystallized from ethanol and dried at 600 ° C. in a vacuum oven after washing with 0.5 liter of n-hexane.

Melting point 106-1080C, yield: 337 g (69.5%).

Example 5
2,6-Dimethyl-3-methoxycarbonyl- 4- (2 '-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid isobutyl ester

14.6 g (50 mmol) of 2'-nitrobenzylidene-acetylacetic acid isobutyl ester was heated under reflux for 20 hours with 5.8 g (50 mmol) of S-aminocrotonic acid methyl ester in 80 ml of ethanol.

After cooling the reaction mixture, the solvent was distilled off in vacuo and the oily residue was mixed with a little ethanol. The product crystallized in a short time, it was filtered off with suction and recrystallized from ethanol. Melting point 151-1520C, yield: 15.2 g (78%).

Claims (6)

1.14-dihydropyridines of general formula (I)

in which R1 and R2 are equal or different and each represents an alkyl or alkoxyalkyl residue having up to 12 carbon atoms, the alkyl residue being optionally substituted with fluorine or chlorine, and R3 denotes one or two equal or different substituents annuities selected from the group of substituents nitro, trifluoromethyl, halo or cyano, intended for use in combating arteriosclerosis. 2. 1,4-dihydropyridines according to claim 1, characterized in that R1 and R2 are equal or different and each represents an alkyl residue having 1 to 4 carbon atoms or an alkoxyalkyl residue having up to 6 atoms carbon, and R3 denotes one or two substituents in position ortho or meta, chosen from the group of substi nitro, chloro or trifluoromethyl killers. 3. 1,4-dihydropyridines according to claim 1, characterized in that R1 and R2 represent alkyl groups having 1 to 4 carbon atoms and R3 is the nitro group. 4. The 2,6-dimethyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester of the formula

intended for use in combating arteriosclerosis. 5. Pharmaceutical composition intended for the fight against arteriosclerosis, characterized in that it consists of or in that it contains 1,4dihydropyridines of general formula I according to claim 1. 6. Composition according to claim 5, characterized in that it further contains adjuvants and conventional pharmaceutically acceptable carriers.