CS241038B2 - Method of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxyl acid's 3-methyl-5-ethyl-ester production - Google Patents

Abstract

The solution concerns the production of a new 3-methyl- -5-ethyl ester of 2,6-dimethyl-4- (2,3- -dichlorophenyl) -1,4-dihydropyridine-3,5- -dicarboxylic acids. It is carried out by reacting the compound of formula IV with compounds of general formula Formulas V and III. Said new compound is antihypertensive drug with specific muscle relaxation peripheral vascular effect system.

Description

The present invention relates to a process for the preparation of 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydro-pyridin-3-3-methyl-1-ethyl-ethyl ester; 5-di-carboxylic acid, which is a novel compound with valuable antihypertensive properties, for which it is suitable for reducing blood vessels in mammals, including humans, and for the manufacture of pharmaceutical preparations for this purpose. This new compound has the formula I, which is set forth below.

It is an object of the present invention to provide novel antihypertensive agents that lower blood pressure in peripheral blood vessels at lower doses than lowering blood pressure in heart blood vessels by selective dilatation of peripheral blood vessels.

It is known that compounds of the general formula

H 2 COOC

COOCI-L wherein _ _ _.

R represents a nitro or trifluoromethyl group at the 2 or 3 position, having a cerebral dilatation effect, an anti-angina effect or a blood pressure lowering effect.

A substance that relaxes vascular smooth muscle can be used to treat arterial hypertension because such patients suffer from increased peripheral resistance to blood flow. Compounds that interfere with vascular smooth muscle activity have been used clinically for several years. However, their applicability has often been limited due to lack of efficacy and / or adverse effects. Side effects (outside the cardiovascular system) have often been associated with substance properties not related to the relaxant effect on smooth muscle. Vasodilators often also have a negative effect on the contractility of the heart.

It is understood that the development of specific smooth muscle relaxants free of adverse effects may have advantages in the treatment of arterial hypertension and in the treatment of ischemic heart disease and acute heart failure. Furthermore, such agents are also useful in the treatment of other conditions with over-activation of the visceral-type smooth muscle.

It has now surprisingly been found that the compound of formula I

.CHjOjOCx Ti i] £ 1 X> COOCH _Z CH 11 * J 1 H t 1 1

(.1) has a specific muscle-relaxing effect on the peripheral vascular system, which compound is devoid of adverse effects.

The substance is intended for oral or parerrteral administration in the acute and chronic treatment of the above cardiovascular disorders.

The biological effects of the novel compounds have been evaluated and the various tests performed will be reported and explained below:

New compound of formula I

is obtained by reacting a compound of formula IV

(iv j with compounds of formulas V and

O OR ⁵ \ /

C — CH2 — C / \

H3C o

III (A)

WITH

H2N O \ Z

C = CH — C / \

H3C OR ⁶ (III) wherein

R ⁵ is methyl or ethyl;

R ⁶ is methyl or ethyl, provided that R ⁶ is methyl when R ^{5 is} ethyl, and R ⁶ is ethyl when R ^{5 is} methyl, when two compounds of formula V wherein R ^{5 is used} is methyl and ethyl, the reaction is carried out in the presence of ammonia to give a compound of formula I.

The invention also relates to any embodiment of the process according to the invention starting from any compound obtained as an intermediate in any step of the process according to the invention and carrying out the missing step of the process according to the invention, or interrupting the process at any step or reaction conditions or in which a reactant in the form of a salt is potentially present.

Said novel compound may be present in the form of optical antipodes or racemates depending on the choice of the starting materials and the method of manufacture, or if it contains at least two asymmetric carbon atoms, it may be present in the form of a mixture of isomers (a mixture of racemates).

The resulting mixtures of isomers (mixtures of racemates) can be separated, depending on the physicochemical differences of the components, into two stereoisomeric (diastereomeric) pure racemates, for example by chromatography and / or fractional crystallization.

The racemates obtained can be separated by known methods, for example, by recrystallization from an optically active solvent, by microorganisms or by reaction with optically active acid-forming salts with the compound and separation of the salts thus obtained, e.g. Suitable optically active acids are, for example, the L- and D-forms of tartaric, di-o-toluyltartaric, malic, mandelic, camphorsulfonic or quinic acids. Preferably, the active portion is isolated from both antipodes.

The starting materials are either known or, if novel, can be obtained by methods known per se.

The compound produced according to the present invention is used clinically usually orally or rectally in the form of a pharmaceutical composition which contains the active ingredient as the free base in combination with a pharmaceutically acceptable carrier.

Thus, reference to the novel compound of the present invention refers to the free amine base, although the compound is generally or specifically described, provided that the context in which the term is used, for example in the examples, does not correspond to this broad meaning. The carrier can be a solid, semi-solid or liquid diluent or capsule (s). These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1 and 99% by weight. % of the composition, suitably between 0.5 and 20 wt. for an injectable preparation and between 2 and 50% by weight, for preparations for oral administration.

In the manufacture of pharmaceutical compositions containing the compound of the invention in the form of dosage units for oral administration, the compound may be admixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch, amylopectin, cellulose derivatives; gelatin as well as a glidant such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like and compressed into tablets. If coated tablets are required, the above-prepared core may be coated with a concentrated sugar solution, which solution may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. Further, the tablets may be coated with a varnish dissolved in a slightly volatile organic solvent or solvent mixture. A colorant can be added to this coating to make tablets with different active compounds or different amounts of active compound present readily distinguishable.

In the manufacture of soft gelatin capsules (bead-shaped closed capsules), which consist of gelatin and, for example, glycerol, or in the manufacture of similar closed capsules, the active compound is mixed with vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, powdered carrier, for example lactose, sucrose, sorbitol, mannitol, starch (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient in admixture with a neutral fat base or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 wt. up to about 20 wt. the active ingredients described, glycerin and propylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saline and carboxymethylcellulose as a thickening agent.

The preparation of pharmaceutical tablets for oral use is carried out as follows.

The solids are ground or sieved to a particular particle size. The binder is homogenized and suspended in a certain amount of solvent. The drug substance and the necessary auxiliaries are mixed with continuous and constant mixing with the binder solution and the wetter so that the solution is uniformly distributed in the meat without any part being wetted too much. The amount of solvent is usually adjusted such that a mass of snow-like consistency is obtained. The wetting of the powder mixture with the binder causes the particles to some extent to form aggregates and the actual granulation process is carried out in such a way that the mass is forced through a stainless steel mesh screen of about 1 mm. The mass is then placed in the form of a thin layer on a bowl in which it is dried in an oven. Drying is carried out for 10 hours and must be carefully standardized because the degree of moisture of the granulate is of particular importance for the following process and the appearance of the tablets. The drying may optionally be carried out by a fluid process. In this case, the meat is not placed in a bowl but poured into a net-bottom tray.

After drying, the granules are sieved to obtain the desired particle size. In certain circumstances, dust must be removed.

To the so-called final mixtures are added disintegrating, anti-friction and anti-adhesive agents. After this treatment, the mixture must have the correct composition for the tabletting step.

The cleaned press is provided with a set of punches and dies, and the appropriate adjustment to the tablet weight is tested and the compression pressure: The tablet weight is decisive for the dose size in each tablet and calculated by starting from the amount of drug in the granules. The compression pressure affects the size of the tablets, their strength and the ability to disintegrate in water. Especially with regard to the last two characteristics, the choice of compression pressure (0.5 to 5 tonnes) represents a partial compromise. When the correct setting is selected, the production of tablets starts at a rate of 20,000 to 200,000 tablets per hour. depends on batch size.

The tablets are de-dusted in a special device and stored in sealed packages before shipping.

Many tablets, especially those that are rugged or bitter in taste, are coated. Tp means that they are coated with a layer of sugar or another suitable coating.

Tablets are usually packaged on machines with electronic counting equipment. Different types of packaging are glass or plastic containers, but also boxes, tubes and specially adapted dispensing packages.

The daily dose of the active ingredient varies and is dependent on the mode of administration; however, it is usually 100 to 1000 mg / day of active ingredient when administered orally.

Example 1

Preparation of 3-methyl-5-ethyl ester

2,6-Dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid

100.0 g of 2,3-dichlorobenzaldehyde, 71.8 g of ethyl 3-aminocrotonate, 66.1 g of methyl acetoacetate and 900 ml of 95% ethanol are heated at reflux overnight. The reaction mixture was poured into water. After removal of the water, the oily residue was triturated with a light petroleum fraction (40-60 ^° C). The resulting crystalline product is then recrystallized from diisopropyl ether to give 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridin-3, 13-methyl-5-ethyl ester, 5-dicarboxylic acid, mp 145 ° C, 47% yield,

Example 1 a d .2

Preparation of 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester

10.0 g of 2,3-dichlorobenzaldehyde, 7.4 g of ethyl acetoacetate, 8.5 g of 25% ammonia and 20.0 ml of 95% ethanol are heated under reflux for 24 hours. The reaction mixture was poured into water. After removal of the water, the oily residue was triturated with a light petroleum fraction. (40 - 60-C). The resulting semicrystalline product is purified by silica gel column chromatography and then recrystallized from diisopropyl ether to give 2,6-dimethyl-4- (2,3-dichlorophenyl) -1-methyl-5-ethyl-ethyl ester, m.p. 4-dihydro-pyridine-3,5-dicarboxylic acid, m.p. 145 DEG C. in a yield of 20%.

Example 3

A syrup containing 2% (w / v) of active ingredient was prepared from the following ingredients:

5-Ethyl 5-ethyl ester 3-methyl ester

2,6-dimethyl-4- (2,3-dichlorophenyl) -

-1,4-dihydropyridine-3,5- -dicarboxylové 2,0 g saccharin -0.6 g sugar .30.0 g glycerol 5.0 g flavoring agent , 0.1 g ethanol 96% 10,0 g distilled water to 1Q0; O .ml

The sugar, saccharin and active ingredient were dissolved in 60 g of warm distilled water. After cooling, glycerol and a solution of the automation reagents dissolved in ethanol were added. The mixture was then filled to 100 ml with distilled water.

Biological tests

The antihypertensive effect of the compound was tested in the watchful free-moving spontaneously hypertensive rats (SHK) of the Okamoto strain. Animals were prepared by prior implantation of a catheter inserted into the rectal aorta by the femoral arteries. Mean arterial blood pressure (STKT) and heart rate were continuously evaluated. After a two-hour control, the test compound was administered by oral intubation at two-hour intervals suspended in a methocel solution (5 ml / kg body weight). The cumulated doses were 1, 5 and 24 µmol per kg body weight. Antihypertensive reactions, i.e. lowering of blood pressure Single dose, was expressed as a percentage of the initial blood pressure control and plotted against the dose on a logarithmic scale. The dose that should provide a 20% reduction in blood pressure was then determined by interpolation. The results are shown in the table at the end of the text.

The specific effect on smooth muscle relaxation was evaluated as follows: an isolated portal vein preparation of Wistar rats was placed in an organ bath, along with an electrically stimulated isolated papillary heart muscle preparation of the same animal. They were evaluated; integrated contraction activity of portal vein smooth muscle and maximal contraction strength of papillary myocardial preparation. The respective activities during the 30 minute control period were taken as 100% and the following activities under the influence of the test substance were expressed as a percentage. The compound was administered at 10 minute intervals and the extent of vasodilatation (—log ED50 of portal vein) and mycardial depression (—log ED50 of papillary muscle) was determined by interpolation of the concentration-effect relationship determined in each experiment. The value of the "separation" of the individual compound was determined by averaging the difference between the loglog ED 50 in the experiments. The logarithmic separation value was expressed numerically and shown in the following table.

The compound of the invention was compared to Nifedipine [2,6-dimethyl-4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-dimethyl ester].

Table

Compound Rats with spontaneous hypertension Heart rate ratio.

EDso μΐηοΐ / kg body. % by weight of Example 1 Nifedipine

Claims (1)

SUBJECT A process for the preparation of 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester, characterized in that it is reacted the compound of formula IV of the invention with compounds of formulas V and III O OR ⁵ / C- / -CH 2 —C OF HsC O (IN) HzN O '\ of C = = CH-C / \ H.; C OR ⁶ (III) in which R ⁵ represents methyl or ethyl and ^R is methyl or ethyl, with the proviso that R ⁶ is methyl, zname- NA-R ⁵ where ethyl, and ^R represents ethyl, zname- NA-methyl when ^R, wherein when used, two compounds of formula V wherein R ⁵ represents methyl and ethyl, the reaction is carried out in the presence of ammonia.