CH660480A5 - D-2- (6-METHOXY-2-NAFTIL) PROPIONIC DERIVATIVES WITH THERAPEUTIC ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to derivatives of d-2 (6 - methoxy-2-naphthyl) -propionic acid, also known by the name of Naproxen, and more precisely the derivatives with p-amino-benzoic acid, having general formula:

where X represents hydrogen, a radical of a non-toxic and pharmaceutically acceptable organic or inorganic base, an amine group or the radical of a basic amino acid.

The anti-inflammatory properties of Naproxen are known. However, like other drugs with anti-inflammatory activity, it has some unfavorable side effects, such as low gastric tolerability and non-negligible toxicity. It is evident that these effects assume importance in the case of prolonged therapies.

The derivatives of the present invention, on the other hand, maintaining the anti-inflammatory properties of Naproxen unaltered, have been shown to have less toxicity and better activity, especially in terms of the duration of the therapeutic effect over time.

As mentioned above, in addition to the starch derivative, (wherein X = H in the previous formula), the present invention also provides the non-toxic and pharmacologically acceptable salts of the same amide, in accordance with the meanings of X indicated above.

Another aspect of the present invention relates to the process for the preparation of the aforementioned derivatives, a process which is characterized by the following stages:

a) preparation of a reactive functional derivative of d-2 (6-methoxy-2-naphthyl) -propionic acid;

b) reaction of said reactive derivative with p-amino-benzoic acid and c) possible salification with a suitable organic or inorganic base, an organic friend or a basic amino acid, according to the desired derivative.

As regards the step a) above, said reactive derivative of d-2 (6-methoxy-2-naphthyl) -propionic acid is preferably selected from the chloride, prepared by reaction with an appropriate chlorinating agent (thionyl chloride, pentachloride of phosphorus, phosgene and the like) and mixed anhydride with ethyl chloroformate, or appropriate reactive alkyl carbonates.

In turn, step b) preferably provides that the reaction is carried out in a binary mixture of solvents, such as for example water and chloroform; furthermore, the reaction medium must be made alkaline or it is preferred to use a salt with an alkaline metal of p-amino benzoic acid.

The following example illustrates the method according to the invention without any limiting intent.

Example a) Preparation of the chloride of d-2 (6-methoxy-2-naf-tyl) -propionic acid

117.4 g (0.51 moles) of d-2- (6-methoxy-2-naphthyl) -propionic acid are loaded in a 1 liter flask, equipped with a stirrer, coolant and gas trap. ml of chloroform and 150 ml of thionyl chloride.

The reaction mixture is heated in a bain-marie to the reflux temperature and is maintained at this temperature until the gas development ceases.

The reaction mixture is concentrated under reduced pressure, obtaining a solid product, brown in color and pungent odor, with a yield equal to 98% of the theoretical.

b) Preparation of the anide with p-amino benzoic acid of d-2- (6-methoxy-2-naphthyl) -propionic acid

To a solution of 97 g (0.61 moles) of solid p-amino benzoate in 500 ml of water, under a stirring, at a temperature of 10 ° C, a solution of 126 g (0.51 moles) of the chloride of d-2- (6-methoxy-2-naphthyl) -propionic acid prepared in the previous stage in 700 ml of chloroform.

A very fine cream-colored precipitate is formed, which is left to itself for 4 hours, after which it is acidified with 10 ml of 37% hydrochloric acid and is kept under stirring for 30 minutes.

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It is filtered under reduced pressure and, after drying, 150 g of product are recovered, which on the chromatographic examination is almost pure.

The product is recrystallized from a mixture of dioxane and water, obtaining 85 g of chromatographically pure dry product, i.e. 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide, having a melting point of 228-230 ° C, with yield 47%.

The product comes in the form of a microcrystalline, white powder, insoluble in water and hot soluble in alcohol, dioxane and acetone. Spectographic surveys were carried out on this product, obtaining the IR, UV and NMR spectra shown respectively in figures 1, 2 and 3 attached.

The compounds of the present invention have been subject to toxicological and pharmacological investigations.

Below are the results relating to the amide with p-aminobenzoic acid of d-2- (6-methoxy-2-naphthyl) -propionic (A) acid, in comparison with the latter (B) (i symbols A and B being used for simplicity).

Preliminary toxicological and pharmacological data

Researches on A have been carried out in comparison with equimolar doses of B and the following doses are expressed in mg of this last compound.

1) Acute toxicity

Compound A was less toxic than compound B in the mouse and rat both orally and parenterally

Composed

Species

Via di somm.

LD50 (mg / kg)

TO

oral mouse

3050

B

oral mouse

700

TO

intraperitoneal mouse

720

B

intraperitoneal mouse

440

TO

oral rat

1600

B

oral rat

440

TO

intraperitoneal rat

450

B

intraperitoneal rat

310

2) Ulcerogenic activity

It was evaluated in the rat after oral administration of A and B for 5 consecutive days at 4 different dose levels. Both compounds exhibited a dose-dependent but significantly lower gastrolesive action for A at a dose of 30 mg / kg.

660 480

Compound Average of scores for gastric lesions at:

1 mg / kg 3 mg / kg 10 mg / kg 30 mg / kg

1.88 2.88 2.88 5.50 1.50 3.00 3.50 7.75

3) Subacute toxicity

It was studied in the rat by administering A by mouth for 30 consecutive days at doses of 5 and 15 mg / kg. These doses both appeared well tolerated based on the general state and weight gain of the animals and the results of the various hematological, blood chemistry, urinary, autopsy and histological tests.

4) Anti-inflammatory activity

With the test of carrageenan edema in the rat, the anti-inflammatory activity of A was similar in intensity and duration to that of compound B.

Composed

Doses (mg / kg)

Via di somm.

DE50 (mg / kg)

at the 3rd hour

TO

1,5-3-6

oral

2.60

B

1,5-3-6

oral

2.45

5) Antipyretic activity

With the test of beer yeast hyperthermia in the rat, the antipyretic activity of A was similar in intensity and duration to that of compound B.

Composed

Dose

Street

Thermal decrease

(Mg / kg)

of somm.

medium (° C) in 4 hours

TO

5

oral

-1.23

B

5

oral

-1.14

With the derivatives according to the invention, the pharmaceutical compositions already known and in use for the d-2- (6-methoxy-2-naphthyl) -propionic acid and with equivalent dosages can be prepared.

The methods already known for Naproxen also apply to the methods of administration.

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3 drawings sheets

Claims (12)

660 480 2. 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide according to claim 1. 2 CLAIMS 1. Derivatives of the acid d-2-6 (6-methoxy-2-naphthyl) -propionic with p-amino benzoic acid having formula: ch3 ° wherein X represents hydrogen, a radical of an organic or inorganic base, non-toxic and pharmaceutically acceptable, a residue of an organic amine or a radical of a basic amino acid. 3. Process for the preparation of the derivatives of claim 1, characterized by the steps of: a) preparation of a reactive functional derivative of d-2- (6-methoxy-2-naphthyl) -propionic acid; b) reaction of said reactive derivative with p-amino benzoic acid; c) possible reaction with an organic or inorganic base, non-toxic and pharmaceutically acceptable. 4. Process according to claim 3, characterized in that said reactive derivative is chloride or anhydride mixed with ethyl chloroformate. 5. Process according to claim 4, characterized in that said chloride is prepared by reaction with thionyl chloride. 6. Process according to claim 3, characterized in that said step b) is carried out in a binary solvent mixture. 7. Process according to claim 6, characterized in that said solvent mixture consists of water and chloroform. 8. Process according to claim 3, characterized in that said derivative of p-amino benzoic acid is a salt thereof with an alkaline metal. 9. Process according to claim 3, characterized in that said step b) is carried out by initially adding an alkali metal hydrate to the reaction mixture. 10. Process for the preparation of the derivatives of claim 1 wherein X represents a radical of an organic amine or an amino acid, characterized by the steps a) - b) according to claim 3 and by the step of e) reaction with a organic amine or a basic amino acid. 11. Pharmaceutical composition and anti-inflammatory activity, characterized by comprising, as an active ingredient, a derivative according to claim 1, together with the excipients and vehicles. 12. Pharmaceutical composition according to claim 11, characterized in that said active ingredient 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide.