CS200500B2 - Process for preparing isobutylestere of 2,6-dimethyl-3-methoxycarbonyl-4-/2'-nitrophenyl/-1,4-dihydropyridin-5-carboxylic acid - Google Patents

Description

(54) A process for preparing 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester

The present invention relates to a process for the preparation of a novel 2,6-dimethyl-3-methoxycarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester. This novel compound has valuable pharmacological properties and is useful as a coronary therapeutic.

It has been known that 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester can be obtained by reacting ethyl benzylideneacetic acid ethyl ester with beta-aminocrotonic acid ethyl ester or ethyl acetate with acetone acetone with ammonia (Knoevenegel, Ber.) . dtsch. Chem. 743 (1898)}. It is further known that certain 1,4-dihydropyridines have interesting pharmacological properties [L. Bossert, W. Vater, Die Naturwissenschaften 58, 578 (1971) 3.

It is further known from DOS Nos. 2,117,571 and 2,117,573 that similar dihydropyridines can be used as coronary agents. The newly established intensive and long-lasting coronary effect of the compound of the invention could not be expected from the prior art.

It has now been found that the new 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester of formula I

has a very strong and long-lasting coronary effect.

The new active substance of formula I by - / finding obtained by replacing 2 '-nitrobenzylidenaeetoctové acid of formula II' NO ₂ (Ji) N / C ^ / COOCHj

I c / ^Cx CH ₃ is reacted with isobutyl .beta.-aminocrotonate of the formula III

HaC

HC-HoC-OOC H)

HjC C

and.

H, C NH, optionally in the presence of water or an inert solvent.

Surprisingly, the compound of the formula I according to the invention shows a particularly strong coronary effect.

In a variety of 1,4-dihydropyridine derivatives, which are similar compounds and known in the art, such a strong and long lasting coronary effect, especially after enteral administration, could not be demonstrated. In addition, the compound of the invention is less light-labile than the corresponding dihydropyridines known in the art. This compound represents a pharmaceutical enrichment in these special properties.

The compound of the invention has a center of chirality and can exist in stereoisomeric forms which behave as mirror image and mirror image (enantiomers, antipodes). Again, these compounds may exist in various configurations. Both the racemic form and the antipodes are the subject of the invention.

The synthesis of a compound of the invention can be illustrated by the following reaction scheme:

H ₃ C \

HC - CH _{2 -} OOC H

Z γ h ₃ c nh ₂ (ll)

(III) h ₃ C 1 H ₃ c 2 ch ₂ cooc

₃ cooch ₃

The compounds of formulas II and III used as starting materials are known in the literature or can be prepared according to methods known in the literature: Org. Reactions XV, 204 et al. (1967); A.C. COPE, J. Amer. Chem. Soc. 67, 1017 (1945); and Houben-Weyl, Methoden der Organ. Chemie VII / 4, 230 et al. (1968)].

In carrying out the process according to the invention, the substances involved in the reaction are always used in approximately molar amounts.

Suitable diluents are water and all inert organic solvents. These preferably include alcohols such as ethanol, methanol, ethers such as dioxane, diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

The reaction temperatures can be varied within a wide range. Generally the reaction is carried out at temperatures between about 20 and 200 ° C, preferably at 50 to 120 ⁰ and particularly at the boiling point of the solvent.

The reaction can be carried out at atmospheric pressure but also at elevated pressure. Generally, the process is carried out at atmospheric pressure.

The compound of the invention is a substance useful as a medicament. This compound causes a significant and long-lasting increase in myocardial blood flow when administered enterally or parenterally and can therefore be used for the prophylaxis and treatment of ischemic heart diseases, especially when these diseases are combined with high blood pressure.

The new active ingredient can be converted in a known manner into the customary formulations such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic pharmaceutically acceptable carriers or solvents. In this context, the therapeutically active compound should always be present in a concentration of from about 0.5 to 90 percent by weight of the total weight of the composition, i.e. in amounts sufficient to achieve the stated dosage ranges.

These preparations are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with emulsifiers and / or dispersants, for example in the case of using water as a diluent, for example, organic solvents can be used as auxiliary solvents.

Excipients include, for example: water, nontoxic organic solvents such as paraffinic hydrocarbons (such as petroleum fractions), vegetable oils (such as peanut and sesame oil), alcohols (such as ethyl alcohol, glycerin), glycols (such as propylene glycol, polyethylene glycol) solid carriers such as natural stone meal (e.g. kaolins, clays, talc, chalk), synthetic stone meal (e.g. highly disperse silicic acid, silicate), sugars (e.g. cane sugar, milk sugar, and grape sugar); emulsifiers such as non-ionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, fatty alcohol polyoxyethylene ethers, alkylsulfonates and arylsulfonates), dispersants (e.g. lignin, sulfite waste liquors, methylcellulose, polyvinylpyrrolidone starches) and lubricants (e.g. stearic acid, stearic acid) and sodium lauryl sulfate).

Administration is carried out in a conventional manner, preferably enterally or parenterally, in particular perlingually or intravenously.

For enteral administration, the tablets may of course also contain, in addition to the shared carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starches, preferably potato starch, gelatin and the like. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used concurrently in the manufacture of tablets. In the case of aqueous suspensions and / or elixirs which are intended for oral administration, various flavor enhancers or colorants may be added to the active ingredients in addition to the aforementioned excipients.

For parenteral administration, solutions of the active compounds using suitable liquid carriers can be used.

In general, it has proven advantageous to administer an amount of from about 0.0001 1 mg / kg, preferably about 0.0005 to 0.01 mg / kg of body weight per day for intravenous administration, to achieve effective results and for enteral administration a dosage of about 0.0005 to 10 mg / kg, preferably 0.001 to 0.1 mg / kg body weight / day.

Nevertheless, it may be necessary to deviate from these amounts, depending on the body weight of the test animal or the mode of administration, but also on the basis of the type of animal and its individual behavior towards the medicament or the interval at which it is administered. Thus, in some cases it may be sufficient to use less than the minimum amount mentioned above, while in other cases the above-mentioned upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide this into several individual doses over the day. For administration in human medicine, the same dose ranges are contemplated.

Accordingly, the above rules also apply.

To demonstrate the effect of stimulating cardiac blood flow, the present invention was administered to dogs and myocardial blood flow was measured using an electromagnetic flow meter.

The compound of the invention increases the blood flow to the heart after intravenous and enteral administration. A particular advantage is its rapid and complete resorption after perlingual administration, so that even in this mode of administration, the compound of the invention is effective at very low doses and has a long-lasting effect.

The results of the experiments on the dog after sublingual administration are shown in the following table:

dose mg / kg increased blood flow to the heart muscle reduction blood sublingually pressure % 0% half-life in min. 0.003. 23 100 ALIGN! 0 0.01 46 133 5 0, ’ 142 184 13

From the results it can be seen that the compound of the invention increases in dependence on the doses of cardiac blood supply, and the effective doses are surprisingly very low. The effect of the compound according to the invention takes place after a few minutes after sublingual administration and lasts for a dose of 2 to 6 hours, depending on the dose (the half-life is given as a more precise measure of duration of action). At the same time, it induces a mild and long-lasting decrease in blood pressure, which is usually an additional advantage in the treatment of coronary diseases.

The compound of the invention is therefore suitable for the prophylaxis and treatment of acute and chronic ischemic heart diseases in the broadest sense. It can be used as a means to prevent and treat angina-related problems and to treat conditions following a heart attack. Particularly suitable is a compound of the invention for the treatment of cases in which any of the aforementioned heart diseases are combined with high blood pressure.

Example illustrating a process for the manufacture of an active ingredient

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

H ₃ C ₁ H ₂ O - H ₃ C - OOC

NOj cooch ₃

H ₃ C ^H 3 ^C S ^CH 3

H

12.5 g (50 mmol) of 2'-nitrobenzylideneaceto-acetic acid methyl ester are heated together with 7.85 g (50 mmol) of beta-aminocrotonic acid isobutyl ester in 80 ml of ethanol for 20 hours at reflux. After cooling the reaction mixture, the solvent was distilled off in vacuo, the solid residue was triturated with ether, filtered off and recrystallized from ethanol. Melting point 140-142 ° C, yield: 14.5 g (74%).

Claims (1)

PLEASE MEET THE INVENTION A process for preparing 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester of formula I, H ₃ C hc-h ₃ c-00c no ₂ cooch ₃ (i), h ₃ ch ₃ c ^{/ x} n ch ₃ H, characterized in that 2'-nitrobenzylideneaceto-acetic acid methyl ester of formula II (II) is reacted with isobutyl beta-aminocrotonic acid ester of formula III H ₃ C (III) optionally in the presence of water or an inert solvent.