DERIVATIVES OF D-2-(6-METHOXY-2-NAPHTHYL)-PROPIONIC ACID HAVING THERAPEUTICAL ACTIVITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Derivatives of d-2-(6-methoxy-2-naphtyl)-propionic acid with therapeutical activity having general formula: wherein X is selected in the group comprising H, and a radical selected among the radicals of organic or inorganic, non toxic and pharmaceutically acceptable bases, the radicals of basis aminoacids and the radicals of basic antibiotics. The invention relates also to the process for obtaining said therapeutically active derivatives and the pharmaceutical compositions con­ taining them for anti-inflammatory, analgesic, antipyretic and mucolithic use.

Description: The present invention relates to derivatives of d-2-(6-methoxy-2-naphtyl)- prop ironic acid having therapeutical activity, the process for their preparation and the pharmaceutical compositions containing them. The invention particularly relates to derivatives of d-2-(6-methoxy-naphtyl) prop ironic acid having general formula: EMI1.1 wherein X is selected in the group comprising H, and a radical selected among the radicals of organic or inorganic, non toxic and pharmaceutically acceptable bases, the radicals of basic aminoacids and the radicals of basic antibiotics. As it is known, the d-2-(6-methoxy-2-naphtyl)-propionic acid (Naproxen) is endowed with anti-inflammatory, analgesic and antipyretic, pharmacologically well demonstrated properties and, as such, this acid found clinical use in the therapy of rheumatoid artritis and of other degenerative forms having a phlogistic feature. The alpha-mercaptopropionylglycine is in turn a compound known as well, possessing, besides some anti-inflammatory activity, a relevant mucolithic activity. The main purpose of the present invention is that of providing novel derivatives of d-2-(6-methoxy-2-napthyl)-propionic acid, which, in comparison with the starting compounds, are endowed with an improved anti-inflammatory, analgesic, antipyretic and mucolithic activity. Another purpose of the present invention is that of providing a process for the preparation of these derivatives. A further purpose of the present invention is that of providing pharmaceutical compositions particularly useful for the therapeutical indications in MhfcfistzeJ aforesaid properties are particularly advantageous. The invention relates particularly to derivatives of d-2-(6-methoxy-2-naphtyl)- prop ironic acid permitting the above mentioned purposes to be attained, having the general formula: EMI2.1 wherein X is selected in the group comprising H, and a radical selected among the radicals of organic or inorganic, non toxic and pharmaceutically acceptable bases, the radicals of basic aminoacids and the radicals of basic antibiotics. The process according to the invention does essentially comprise the following steps: a) preparation of a reactive derivative. particularly chloride or mixed anhydride with ethyl chloroformiate, of the d-2-(6-methoxy-2-naphtyl)-propionic acid; b) reaction of said reactive derivative of the d-2-(6-methoxy-2-napthyl)- prop ironic acid with an alkaline salt of alpha-mercaptopropionylglycine; c) isolation of the pure DL form of the thio-derivative obtained in the preceding step; and d) possible salification of the pure DLderivative. Among the organic bases useful for the purposes of the present invention there can be included: primary and secondary amines, such as for instance diethylamine, and the primary, secondary and tertiary aminoalcohols, such as for example diethanolamine. Among the inorganic bases suitable for the invention there are contemplated sodium hydroxide. potassium hydroxide and silver hydroxide. Examples of basic aminoacids useful for the invention are arginine, lysine and histidine, whereas examples of basic antibiotics useful for the purposes to the invention are represented by erythromycin. propionylerytrhomycin, mechlocycline, clindomycine and iosamycine. Among the derivatives of the invention there are for example included: Sodium salt of DL-2-(6-methoxy-2-napthyl'-alpha-thio-propionylglycine; Potassium salt of DL-2-(6-methoxy-2 -napthyl!-alpha-th io-propionylg]icine ine; Silver salt of DL-2-(6-methoxy-2-naphthyl)-alpha-thio-propionylglicine; Lysine salt of DL-2-(6-methoxy-2-naphtyl)-alpha-thio-propionylglycine; Arginine salt of nL-2 -(6-methoxy-2-napthy i)-alpha-thio-prop ionylglycine; Histidine salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-propionylglycine; Erythromycin salt of DL-?-(t;-methoxy -2-napthyl)-alpha-thio-prop ionyiglycine; ; Propionylerytrhomye in salt of DL-2 -(6-me thoxy-2 -nap thy l)-a lpha-th of DL-2-(-methoxy-2-napthyl)-alpha-thio-prop iony- Iglycine; Mechlocycline salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-propionylglycine; Clindomycine salt of DL-2-(6-methoxy -2-napthyl)-alpha-th io-propiony Iglycine; Iosamycine salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-propionylglycine; According to a preferred embodiment of the process of the present invention the chlorination of the d-2-(6-methoxy-2-napthyl)-propionic acid is carried out with thenoyl chloride in the presence of a solvent (preferably chloroform). From the chlorination step crystals of chloride are obtained which are used as such for the subsequent step. According to the invention an alkaline solution of the sodium salt of alpha mercaptopropionylglycine is prepared,which is slowly added (preferably over about 4 hours) with a solution of the chloride of d-2-(6-methoxy-2-napthyl) prop ironic acid as prepared in the preceding step. This solution is preferably obtained by dissolving the chloride crystal into dioxane. The reaction is carried out at temperatures of between 0 and 5 C and through acidification (preferably with HCI) a precipitate of d-2-(6-methoxy-2-naphtyl) propionyl-alpha-thio-propionylglycine acid is obtained. The isolation of the pure DL form of the thio-derivative obtained as above described is carried out, according to the invention, by dissolving the thio-ester in a suitable solvent, for example ethylacetate and by subsequent slow crystallization. The process of the invention lastly comprises the possible salification of the DL-2 -(6-methoxy-2 -n ap thy l!-prop ionyl-alpha-thio -prop iony Iglye ine as obtained from the proceding crystallization step. Such a salification can be obtained through the reaction of the pure DL-thioderivative with an organic or inorganic base, a basic arninoacid or with a basic antibiotic, such as of the previously said type , in the presence of a solvent. Suitable solvents are for instance water, alcohols (e.g. ethanol) and ketones (e.g. acetone). The salification reaction is normally carried out by stirring the reactants and then through cold precipitation of the desired salt. The following example has the purpose of better illustrating the invention, without however limiting the scope thereof. EXAMPLE a) Chlorination of the d-2-(6-methoxv-2 -napthyl)prop ionic acid The chlorination is carried out by putting 50 g of d-2-(6-methoxy-2-napthyl) prop ironic acid in 2O0 ml of chloroform with 100 ml of thenoyl chloride. The mixture is heated to reflux until the development of hydrogen chloride and of sulfurous anhydride ceases. Upon the gas development ceases. the mixture is cooled and then concentrated under vacuum to dryness. The product is taken with the minimum amount of chloroform and then the chloride of the d-2-(6-methoxy-2-napthyl)-propionic acid is crystallized, filtered and dried. It is used as such for the next step. b) Preparation of d-2 -(6-methoxv-2-napthyl)-prop ionyl-alpha-th io sropionylqly- cin ic acid A 2000 ml flask is charged with 230 g of alpha-mercaptopropionylglycine dissolved in one liter of water. This solution is added with 56 g of NaOH in form of flakes and then the solution is cooled to a temperature of between OOC and 150C.r Upon the solution is obtained, it is made alkaline by adding another amount of NaOH as above used. Then the addition is started of a dioxane solution in which the chloride of d-2 (6-methoxy-2-napthyl!-propionic acid is dissolved. Such an addition takes place slowly over about 4 hours at temperatures of between 0 and 5 C. Upon the addition is completed, the mixture is maintained under stirring for more than 10 hours. Thereafter the whole mixture is treated with 37% HCI until completely acidic. A white product precipitates which is filtered and washed with H2O and then dried. A yield of about 80% of the theoretical value is obtained of a white product, having melting point 135-138 C, with a chromatographic purity, as evaluated using chloroform/acetic acid/water (85/15/1) as eluent and Merk 5735 plates, corresponding to an Rf value of 0.61. c) Separation with ethyl acetate through crystallization of an optical DD form from the DL form obtained in the preparation of the d-2-(6-methoxy-2-napthyl)prop ionyl-alpha-thio-prop ionv Iglycinic acid. The product obtained in the step (b) is charged as such (400 g) in a flask provided with a stirred and is treated with ethyl acetate by heating the solution to reflux, using 850 ml of solvent. The mixture is then slowly crystallized for 24 hours and there are obtained 120 g of a white crystalline product, corresponding to DL-2-(6-methoxy-2-napthyl) propionyl-alpha-thio-propionylglcyine, having melting point 175-1770C, and a rotatory index [alpha]D20 = 0 d 1) Preparation of L(+)lysine salt of DL-2 -(6-me thoxy-2-napthy 1)-prop iony I- alpha-thio-prop iony Iglycine acid. It is obtained in ethanol from 11.3 g of DL-2(6-methoxy-2-napthyl)-alpha-thio- propionyl glycinic acid and 4.59 of crystals of-lysine base. The ethanolic solution is heated to reflux and then cooled and there are obtained 12.5 g of L(+)-lysine salt of the DL-2-(6-methoxy-2-napthyl)-alpha- thio-propionyl glycinic acid, having melting point 175-1800C and which is perfectly soluble in water. d2) Preparation of the erythromycin salt of DL-2-(6-methoxy-2-naphtyl)-alpha- thiopropionylglycinic acid. The reaction takes well place in aqueous ace tonic medium by charging in the flask under stirring 1 mole of DL-2-(6-methuxy-2-napthyl5-alpha-thio-propionyl- glycinic acid and then adding 1 mole of pure erytrhomvcin base. The whole is maintained under stirring and by cooling to a temperature of between 0 and 10n e the salt precipitates, with a yield of 75% of the theoretical value. The product is filtered, well washed with a 50% acetone/water solution and then dried. By the same process as in the preceding example the salt with base DL-lysine or with arginine can be obtained (step d 1); the arginine crystalline product obtained in that step is soluble in water with pH= 7.3 and has a definite melting point of 178-179 C. By a like process (step d2), the salt with propionylerythromycin can be obtained in form of crystals with a melting point 11I-113nC. The compounds of the present invention have been subjected to preliminary pharmacological tests, and those relating to the propionylerytrhomycin salt of DL-2-(6-methoxy -9 - lapthyl)-propiony l-alpha-th io -prop iony Glycine (hereinfater shortly indicated with the abbreviation NXTP) are hereinafter reported. A) Acute toxicitv The acute toxicit! both in the mouse and the rat was evaluated per os and by intraperitoneal route, the following results being obtained: 1) in the mouse: per os LD501,500 mg/kg i.p. Lid50= 405 mg/kg 2) in the rat: per os LD58 > 1,500 mg/kg 50 i.p. LD50 > 1,500 mglkg B) Anti-inflammatorv activity This activity has been evaluated for the NXTP compound by the carrageenin induced oedema test, carried out in the manner known in the literature, in Sprague-Dawaley male rats, having a body weight of 180-200 g, the NXTP being administered to groups of 3 animals each at the dosages of 50, 100, 200 and 400 mg/kg, the results being evalutaed in comparison with a control group. The volume increase of the paw in the group of control rats was on the average 60.30% and it was ohserved that the tested compound causes the oedema to be inhibited proportionally to the administered dose. Since in no caso an inhibition rate of 50% was attained, the value of ED33 was calculated, it being 759 mg/kg (0,651 mM/kg). c) Analgesic activity This test was carried out in Swiss male albine mice, having a body weight of 30-40 g through the "stretching or writhing" inhibition test, as induced by acetic acid, the test being carried out in a manner per se known from the literature. It was found that the NXTP caused an inhibition of the number of contorsions induced by acetic acid in a rate proportional to the administered doses (50,100 and 200 mg/kg as injected by subcutaneous route). The ED50 of NXTP was 400 mg/kg. D) Antipyretic activity This test has been carried out in the manner known from the literature in Sprague Dawley male rats, having a body weight of 190-2209, which were selected according to the rectal temperature which was of between 37.0 and 37.7 C. The hyperpyrexy was induced by subcutaneous injection of 2.0 ml of a 7.5% suspension of yeast as prepared at the moment. The tested dosages were 100, 200 and 400 mg/kg and the found ED33 value was 802 mg/kg. E) Mucolithic activity This test was carried out, in the manner known from the literature, in 13 ml samples of expectorate collected from hospitalized patients, and stored in a freezer at -200C until the testing time. The viscosity of the expectorate added with 1 ml of physiological solution was at the beginning 15.5 and after one hour incubation at 370C showed a 13% reduction (value of the viscosity at t= 1 h equal to 13.5). At the tested concentration of the compound undergoing the experiment (0.05M) a viscosity reduction of 16% (29% to 13%) was found. As above stated, the invention also relates to the pharmaceutical compositions containing as the active principle the above descried derivatives, in admixture with solid, liquid or semiliquid, phvsiologically compatible excipients, which can be administered bv parenteral. oral, topical or rectal route. The compositions which can be normally administered bv oral route include tables, pills, gastroresistant tablets,pawders for the prompt preparation of syrups and lastly granulates. As the excipients those normally used in the related art are contemplated, such as for instance talc, starch, lactose. These compositions for oral use can be obviously also admixed with lubricating agents, such as magnesium stearate. Among the compositions of liquid type for oral administration, syrups, emusions, - suspensions and elixirs, duly sweetened and flavoured are meant. As the liquid vehicles water, paraffine and hydro-alcoholic solutions can be used. Furthermore for the oral administration also capsules with a solid or semiliquid content are foreseen. For the administration by parenteral route, as the vehicle distilled water and propilene glycol, polyethylene glycol, vegetal oils and their organic esters, such as for instance ethyl oleate, are meant. All these injectable formulations can be sterilized by means of filtering membranes or sterilizing agents, both of chemical and of physical nature. For the administration by rectal route the normal suppositories or absorbable capsules are meant, having as the vehicle cacao butter, stearates and waxes. As regards the therapeutical administration of the compositions of the present invention, dosages equivalent to those normally used for the starting acid, namely of d-2-(6-methoxy-2-napthvl)-propionic acid , are contemplated, with the advantages deriving for instance from the addition of the anti-inflammatory and mucolithic activity specific of the alpha-mercaptopropionylglycine, as well as of the possible specific activity of the antibiotic when the latter is used for the salification.

Claims: CLAIMS 1. Therapeutically active derivatives of d-2-(6-methoxy-2-napthyl)-propionic acid having general formula: EMI9.1 wherein X is selected in the groups comprising H, and a radical selected among the radicals of organic or inorganic, non toxic and pharmaceutically acceptable bases, the radicals of basic aminoacids and the radicals of basic antibiotics. 2. Therapeutically active derivatives according to claim 1, characterized in that said organic bases are selected among primary and secondary amines and among primary, secondary and tertiary aminoalchols. 3. Therapeutically active derivatives according to claim 2, characterized in that said organic bases are selected among diethanolamine and diethylamine. 4. Therapeutically active derivatives according to claim 1. characterized in that said inorganic bases are selected among sodium, potassium and silver hydroxides. 5. Therapeutically active derivatives according to claim 1, characterized in that said basic aminoacids are selected among arginine, lysine and histidine. 6. Therapeutically active derivatives according to claim 1, characterized in that said basic antibiotics ere selected among erythromye in, prop iony lery thromye in, nechlocycline, chinolomycine and iosaycine. 7. Sodium salt of DL-2-(6-methoxy-2-naphtyl)-alpha-thio-prop ionylglycinic acid according to claim 1. 8. Potassium salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-propionylglycinic acid according to claim 7. 9. Silver salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-prop iony lglcyinic acid according to claim 1. 10. Lysine salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio-propionylglycinic acid according to claim 1. 11. Arginine salt of DL-2-(6-methoxv-2 -napthy I:-aIpha-thio-prop ionylglycinic acid according to claim 1. 12. Histidine salt of li)L-2-(6-methoxy-2-napthyl5-alpha-thio-propionylglycinic acid according to claim I. 13. Erythromycin salt of DL-2-(6methoxy-2-naphtyl)-alpha-thiopropionylglycinic acid according to claim 1. 14. Prop ionylerythro mycin salt of DL-2-(6-methoxy-2-napthyl)-alpha-thio- propionylglycinic acid according to claim 1. 15. Mechlocycline salt of DL-2-(6-methoxy-2 -napthyl)-alpha-thio-prop ionylglycinic acid according to claim 1. 16. Clindomycine salt of DL-2-(6-methoxy-2-napthyl)-alpha-thiopropionylglycinic acid according to claim 1. 17. Iosamycine salt of DL-2-(6-methoxy-2 -napthyl'-alpha-thiopropionylglycinic acid according to claim 1. 18. A process for the Dreparation of the derivatives according to the preceding claims characterized by comprising the steps of: al preparation of a reactive derivative of d-2-(6-methoxy-2-napthyl)-propionic acid; b' reaction of said reactive derivative with an alkaline salt of alpha-mercaptopro pionylglycine; c isolation of the pure DL form of the thus obtained thio-derivative; and d) possible salification of the DL-thio-derivative. 19. A process according to claim 18, characterized in that said reactive derivative is selected among the chloride and the mixed anhydride, e.g. with ethyl chloroformate, of the d-2-(6-methoxy-2-napthyl)-propionic acid, and in that said alkaline salt is the sodium salt of alpha-mercaptopropionylglycine. 20. A process according to claim 19, characterized in that the chlorination of the d 2-(6-methoxy-2napthyl)-propionic acid is carried out by adding thenoyl chloride, in the presence of a solvent. 21. A process according to claim 20, characterized in that the reaction of the chloride of d-2 -(6-me thoxy-2 -nap thyl)-prop ionic acid with the sodium salt of alphamercaptopropionylglycine is carried out in aqueous medium at a temperature of between 0 C and + 50C. 22. Pharmaceutical composition for parenteral, oral, rectal or topical use, containing a therapeutically active amount of a derivative according to any of claims ] to 5.

Inventors: FRANCHINA, ANTONINO
Applicants: RESA FARMA
Application year: 1984
Main classification: C07C153
IPC codes: C07C51, C07H17