HU182708B - Process for preparing moroxydine-phenoxy-izobutyric acid derivatives - Google Patents

Abstract

Moroxydine phenoxyisobutyrates of formula (I) are new (where R is Cl or P-chlorobenzoyl). Medicaments contg. p-R- phenoxyisobutyric acid (II) and moroxydine (III) in a (II):(III) molar ratio of 0.1-10:1 are also new. Compared with (II) and (III) alone, (I) and combinations of (II) and (III) have synergistically increased activity w.r.t. lowering blood cholesterol and fibrinogen levels and inhibiting platelet aggregation. They have low toxicity and are free of hypoglycaemic side-effects. They can be used in the treatment of atherosclerosis, coronary disorders, thrombosis, etc. (I) are prepd. by reacting a salt of (II) with a salt of (III), in an aq. medium at elevated temp. The salt of (II) is pref. a Na, K, NH4 or amine salt and the salt of (III) is pref. the HCl, HBr, HNO3 or H2SO4 salt. Alternatively, (II) can be reacted with (III) as free base, obtd. by passage of a salt over an ion exchange resin.

Description

EXTRACT

The present invention relates to moroxidine-phenoxyisobutyrate derivatives.

According to the invention, an equivalent amount of phenoxyisobutyric acid and moroxidine is reacted and the resulting salt of formula (I) - in formula (I) - is R or chlorine (wherein a)

R 'represents a chlorine atom isolated.

The pharmaceutical compositions of the present invention have antiplatelet and antihypertensive effects.

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-1182.708

THE "; This invention relates to novel phenoxyisobutyric acid salts. The pharmacological properties of phenoxyisobutyric acid derivatives, in particular p-chlorophenoxyisobutyric acid (clofibrinic acid), homologues thereof, 4- (4-chlorobenzoyl) -phenoxylisobutyric acid are known. These acids and their derivatives are effective in inhibiting cholesterol synthesis, which is associated with lowering cholesterol levels in the body, preventing the production of higher than normal blood levels of uric acid and blood fibrins, and inhibiting anti-atheroma and platelet aggregation ...... ..... ..............-....... ............

However, administration of higher amounts of these compounds, especially in individuals with low protein levels, results in muscle cramps, which is accompanied by an increase in SGOT and OPK. In these cases, the appearance of immuno-allergic diseases such as plaque, dermatitis, leukopenia, and kidney stones, in particular the application of 4- / 4'-chlorobenzoyl / phenoxyisobutyric acid on the brush, has been observed. The above phenomena are known to all known clofibrate derivatives and homologues thereof, such as aluminum clofibrate, hydroxyaluminium chloroformate, magnesium clofibrate, ethyl clofibrinic acid, 4- / 4 ^, 4-chlorobenzoyl / phenoxy, and the like. -isobutyric acid isopropyl ester - even when used. Other derivatives, such as methorphine clofibrate, have very potent blood glucose lowering properties and this determines the suitability of the salt.

It is therefore an object of the present invention to provide novel phenoxyisobutyric acid derivatives which are more effective, need less to be used and have less adverse side effects.

The novel phenoxy-isobutyric acid salts of the present invention are moroxidine-phenoxy-isobutyric acid derivatives represented by the general formula (I). In formula (I), R is chlorine or in formula (a), wherein R 'is chlorine.

Moroxidine, i. , the latter will be significantly improved, its α-hypolipaemic properties and thus more effective in preventing and treating atheroma and coronary artery disease as well as in the treatment of superficial and intravenous thromboses.

According to the invention, the moxidine salts are prepared by reacting the stoichiometric amount of clofibrinic acid or 4- (4-chlorobenzoyl) -phenoxyisobutyric acid with moroxidine and isolating the resulting salt by crystallization.

Since the moroxldine base is difficult to handle and not commercially available, it is preferable to start with a moxidine salt such as 'morphoine hydrochloride'. ........ .......... *

Preferably, according to the invention, an equimolecular amount of the molexidine salt is added to the clofibrate or 4- (4-chlorobenzoyl) -phenoxyisobutyric acid in a suitable solvent.

In another preferred process of the invention, an equimolar amount of moroxidine base is added to the phenoxyisobutyric acid solution, which is prepared by passage through an ion exchange resin.

-2182.708

Surprisingly, it has been found * that moxidine clofibrate forms a dihydrate, which is poorly soluble in water below 50 ° C. Thus, this product can be readily prepared in equimolar amounts of the moroxide II salt of formula 11 and the clofibrin acid salt of formula 11 in the formulas 11 and 11.

A 'and B represent an anion or cation and such that the resulting aqueous solution of salt A' B * in water is very soluble in hot water at less than 0 ° C and the crystalline moroxidine clofibrate dihydrate is separated from the reaction mixture.

According to the invention, the moxidine clofibrate dihydrate is preferably dried to give an anhydrous salt.

The AA anion according to the invention is preferably a chloride, bromide, nitrate, sulfate anion and the B ⁺ cation is preferably a cation derived from sodium, potassium, ammonium or organic amines.

The moroxidine-phenoxyisobutyrate derivatives of the present invention are useful in pharmaceutical compositions.

In some cases, it is desirable to balance the constituents of the active ingredients of the compositions and thus to provide compositions wherein the gold of the two components is different from the 1: 1 ratio. In these drugs, one component is used in excess of the other component. For example, to increase the hypolipidemic effect of a drug, the amount of phenoxyisobutyric acid is increased.

The pharmaceutical compositions of the present invention contain phenoxyisobutyric acid (PBA) and moroxidine / MCR (0.1: 1 and 1: 0.1).

According to the invention, the excess phenoxyisobutyric acid used is preferably in the form of a pharmaceutically acceptable salt of an inorganic and / or organic acid.

According to the invention, the excess moroxidine used is preferably in the form of its hydrochloride and / or sulfate and / or phosphate and / or carbonate and / or hydrobromide and / or nitrate.

The invention is further illustrated by the following examples.

Production examples

A / Preparation of equilibrium salts

Preparation of moroxidine clofibrate

1. / 450 g of clofibrinic acid are dissolved in 800 ml of water at 70 ° C containing 80 g of sodium hydroxide. This extension is added to 414 g of moroxidine hydrochloride in 800 ml of hot 70 ° C solution. The reaction mixture was stirred several times and then cooled to 5 ° C and held at this temperature for 2-4 hours. From Moroxidine Clofibar? Crystallized as 7a crystalline dihydrate / by filtration, washed with ice water (4 x 500 mL), dried for 12 hours at azo temperature and then at 80 ° C to constant weight. 44 g (84%) of anhydrous product with a melting point of 16 ° C are obtained.

Lemanalysis C H Cl N O calculated 49,% 6.27%. 9.19% 18.1% 16.8% apot 49.4% 6.17% 9.45% 18.2% 16.6% sodium chloride content less than 0.1%.

-3182.708

2 / Kulium Clofibrate is dissolved in ethanol and the resulting solution is diluted with ethanolic moroxidine hydrochloride solution. The excellent potassium chloride is removed by filtration and the ethanol is evaporated. The resulting moxidine clofibrate is crystallized from isopropyl alcohol.

B / Manufacture of products containing ingredients other than in stoichiometric ratios

1 / One serving with product production Ratio: PBA / MOR = 1: 4 mg / day mg / tablet klofibrin-ion 1200 150 moroxydine-ion 4000 5200 ..... 500 "T50-

Dosage:

tablets daily

Composition: g moroxidine clofibrate 1: 1270/1. Prepared according to example / mroxidine hydrochloride 462 starch 100 magnesium stearate 6

manufacture:

Moroxidine Clofibrate. homogeneous starch is mixed and granulated with 100 ml of water. . after all, the dry granules are in a bowl and the resulting mixture is 1000

Example 2 / B

Ratio: PBA / MOR = 10: 1 mg / day Clofibrin ion 2600 Moroxidine ion 200

2800

Dosage:

tablet daily composition:

moroxidine clofibrate 1: 1/1 was prepared as magnesium stearate of starch from the clofibrin band

manufacture:

As described in Example 1.

Pharmacological results:

the moroxidine hydrochloride and the granules obtained with the starch (25 g) are dried and mixed into a magnesium stearate tablet.

mg / tablet

650

700g

115 before /

589

100 identical 1000 tablets were made

-4182.708

The results shown in the following tables are obtained by testing 15 animals. The tests him AF Han. WPS WISTAR. It is performed on rats weighing 250 g.

In each case, the results obtained in rats with the moroxidine clofibrate of the invention are compared with those obtained with clofibrate and moroxidine separately.

The products are administered orally, 35 mg daily.

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Λ t; The sexin compounds of the invention, cloflbrate and moroxidine, show very interesting results.

The most important properties of the compounds of the invention are the inhibition of platelet aggregation and the reduction of blood flbrin. These effects are seen in both normolipid and hyperllpid rats and rabbits / although the best results are obtained with a 1: 1 stoichiometric ratio * in some cases, it may be advantageous to use an unbalanced product /.

toxicity

Intravenous LD50 value / average of 25 mice / 380 mg / kg. So the teas are non-toxic.

From the foregoing it can be seen that the phenoxy-butyric acid derivatives of the present invention have a number of advantages over the known compounds regardless of the route of administration. Thus, for example, they are more effective, do not cause side effects, are non-toxic, and do not produce hypoglycemic effects.

As will be apparent from the foregoing, the present invention is not limited to the examples provided herein, but encompasses all embodiments which would be practiced by one of ordinary skill in the art without departing from the scope of the invention.

Claims (7)

Patent claims A process for the preparation of moroxidine-phenoxyisobutyrate derivatives comprising reacting an equivalent amount of phenoxysulobutyric acid and moroxidine and yielding the salt of formula (I) - in formula (1) - ^p is chlorine or in formula (a) -, ιοί B * represents a chlorine atom. 2. The method of claim 1, wherein the moroXidine salt of formula (11) and the clofibrinic acid salt of formula (II) are the compounds of formula (II) and (III) A and B ⁺ represent an arion or cation and such that A * B ⁺ salt formed therefrom at a temperature below 30 ° C is well soluble in hot aqueous solutions and the crystalline moroxidine clofibrate dihydrate is separated from the reaction mixture. 3. The process according to claim 2, wherein the moxidine clofibrate dihydrate is dried to obtain an anhydrous salt. 4. The process of claim 2, wherein the "anion" is selected from the group consisting of chloride, bromide, nitrate and sulphate anions, cation B ⁺ , sodium or potassium or an organic amine. cation. * 5. A process according to claim 1, wherein the moxidine salt is added to the phenoxyisobutyric acid salt in a suitable solvent and the resulting moroxidine phenoxysulfuric acid and the av-s derivative are obtained. -10182,708 6. A process according to claim 1 wherein the moroxidine base obtained by passage through an ion exchange resin is reacted with phenoxyisobutyric acid. 7. A process for the manufacture of a medicament for the inhibition of platelet aggregation and for reducing the amount of fibrin in the blood, characterized in that from a compound of the general formula (I) according to claim 1, wherein E is as defined above, or moroxidine and phenoxy a mixture of isobutyric acid in a molar ratio of from 0.1: 1 to 1: 0.1 to form pharmaceutical compositions in admixture with excipients conventional in the pharmaceutical art. 1 drawing F.k .: Hlmar Zoliin Oraágot Invention Office 70 - OTH - 85.0Θ2