CH628321A5 - Process for the preparation of derivatives of isobutyramide and medical composition containing these derivatives - Google Patents

Description

The present invention relates to a new process for the preparation of isobutyramide derivatives, represented by the following general formula (I):

V * h at the same temperature, then treated with 60 g of carbon black and filtered; 1.61 dioxane is added to the filtrate and, after slowly adding 101 of demineralized water, stirring is continued for 2 h; the reaction mixture is left to stand for 12 h; after separation of the precipitate, washing with water, then drying at 40 ° C., 1380 g of a beige product are obtained which, after recrystallization from a mixture of isopropanol and water, gives 1001 g (yield 73% ) a white crystallized product, melting at 71 ° C., the analysis of which shows an excellent correspondence with the crude formula C13H1502N2C1.

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Example 2:

N-cyanoethylp'fluorophenoxyisobutyramide

The same method is used as that described in Example 1, but replacing p-chlorophenoxyisobutyramide with p-15 fluorophenoxyisobutyramide. A white crystallized product, melting at 75 ° C., the analysis of which shows a good correspondence with the crude formula Ci3H1502N2F, is obtained with a yield of 64%.

20 Example 3:

N-cyanobutyl p-chlorophenoxyisobutyramide

The same method of Example 1 is also used, but replacing acrylonitrile with pentylenonitrile. A white crystallized product melting at 88 ° C, and whose analysis shows a good correspondence with the crude formula C! sHj 9N202C1, is obtained with a yield of 77%.

The compounds of formula (I) have been subjected to toxicological, pharmacological and clinical experiments, the results of which, reported below, demonstrate the advantage of their use in medicinal compositions, in particular with lipid-lowering, hypotriglyceridemic and cholesterol-lowering actions, in combination with an excipient suitable for the mode of administration.

o-

35

- - NH-fCH-K CN

(I)

TOXICITY

wherein Ri is a halogen atom and n is an integer from 2 to 6. This invention also relates to a drug composition containing at least one compound of formula (I), obtained by this method.

Other processes for preparing the compounds of formula (I) have already been described in Swiss patents Nos. 598201 and 598202 in the name of the same holder.

The new process which is the subject of this invention is characterized in that the substituted phenoxyisobutyramide of formula:

> - 'T

with N-cyanoalkylene of formula CH2 = CH - (CH2) p — CN, in which p is an integer from 0 to 4, in the presence of a basic agent and at a temperature between 50 and 65 ° C.

The present invention will be illustrated by means of the following examples.

Example 1:

N-cyanoethyl p-chlorophenoxyisobutyramide

In a reactor of 51 equipped with heating, cooling and stirring means, a solution of 1220 g (5.71 mol) of p-chlorophenoxyisobutyramide in 1.81 of dioxane is prepared. 23 g of soda powder are then added, then slowly (over 15 min) with stirring and maintaining the temperature between 50 and 65 ° C, 394 ml of acrylonitrile. The reaction mixture is then stirred for

Acute toxicity was measured orally in mice and rats using standard techniques.

The LD50 values found for the compound of Example 1 are 40 respectively 1 g / kg for the mouse and greater than 2.4 g / kg for the rat; for the compounds of Examples 2 and 3, the same LD50 of 1.2 g / kg was found for both on the mouse and values greater than 2.5 g / kg on the rat.

The subacute toxicity sought on the compound of Example 1, on 45 of the rats, at doses of 40, 80 and 160 mg / kg orally, did not allow any difference to be observed between the treated animals and the animals witnesses.

PHARMACOLOGY (newt test)

n / a Experimental hyperlipemia and hypercholesterolemia are caused in adult male rats by intraperitoneal injection of newt at a dose of 5 ml / kg; these rats are immediately treated orally, either with the product of Example 1, or with the ethyl ester of (4-chloro-phenoxy) -2 methyl-2-propa-55 noic acid, or also with nicotinic acid at the same doses (3 lots of 10 animals each, plus a lot of 10 control animals).

The most important cholesterol-lowering activity was found for the compound of formula (I), as well as for the first reference compound, while the most important hypotriglyceridemic action was found for the second reference compound as well as for the compound of formula (I).

CLINICAL

Twenty patients were treated comparatively with the following 65 successive treatments:

A first treatment with ethyl ester of (4-chloro-phenoxy) -2-methyl-2-propanoic acid - reference compound - (30 d at a dose of 2 g / d orally); after a period of 15 d, during

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628321

from which the patients received no treatment, they were treated again, but this time with the compound of Example 1 for 30 d at a dose of 2 g / d, orally; the average values for each group of figures found for the initial and final triglyceride levels of total cholesterol and total lipids in the blood are given in g / 1 in the following table:

Reference compound

Compound of formula (I)

Triglycerides

Initial

Final

Decrease

1.611 (± 0.098) 1.137 (± 0.085) 0.474 (± 0.102)

1.59 (± 0.155) 1.082 (± 0.101) 0.507 (± 0.088)

Total cholesterol

Initial

Final

Decrease

3.31 (± 0.121) 2.85 (± 0.170) 0.46 (± 0.107)

3.17 (± 0.151) 2.70 (± 0.169) 0.47 (± 0.058)

Total fat

Initial

Final

Decrease

9.985 (± 0.342) 8.775 (± 0.491) 1.210 (± 0.244)

9.94 (± 0.454) 8.367 (± 0.431) 1.572 (± 0.198)

The activity of the compounds of formula (I) appears similar to that of the reference compound with regard to the development of the total cholesterol level, but more favorable with regard to the triglyceride and total lipid levels.

PRESENTA TION- DOSAGE

The compounds of formula (I) can be presented in any form allowing use in human therapy. For example, there may be mentioned, as a form for oral administration, capsules containing:

- compound of formula (I) 0.500 g

- silicic acid 0.018 g

- talc 0.042 g

0.560 g

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Regarding the dosage, it is of course variable depending on the patient, but is generally between 0.5 and 4 g / d.

Claims (2)

628321 2 CLAIMS 1. Process for the preparation of an isobutyramide derivative represented by the general formula (I), CH „ "■ - <3- ° C ■ CO —NH - (CH2) n -CN CH, (I) in which R, is a halogen atom and n is an integer from 2 to 6, characterized in that reacted, in dioxane, the substituted phenoxyisobutyramide of formula: with N-cyanoalkylene of formula CH2 = CH— (CH2) p — CN, in which p is an integer from 0 to 4, in the presence of a basic agent and at a temperature between 50 and 65 ° C. 2. Drug composition, in particular with hypolipê-miante, hypotriglycéridémiante and hypocholesterolémiante actions, characterized in that it contains as active substance at least one isobutyramide of formula (I) obtained by the process according to claim 1, or one of its pharmaceutically acceptable salts, as well as an excipient suitable for the mode of administration.