PHARMACOLOGICALLY ACTIVE SALT DERIVATIVES OF 1,2,3,6-TETRAHYDRO-1,3-DIMETHYL-2,6 DIOXOPURINE-7-ACETIC ACID

Abstract: The present invention relates to a new pharmacological­ ly active salt derivative, constituted by 4-(1-pirrolidinyl)-1-­ (2,4,6-trimethoxyphenyl)-1-butanone 1,2,3,6-tetrahydro-1,3-­ dimethyl-2,6-dioxopurine-7-acetate, to the process for the production thereof, and to the related pharmaceutical com­ positions. Said salt derivative is produced by means of the reaction of 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid with 4-(1-pirrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-­ butanone in an organic solvent, followed by crystallization. Said salt derivative exerts a particularly important pharmacological action as coronarodilator, peripheral vaso­ dilator and cardial stimulator.

Description: The present invention relates to a new pharmacologically active salt derivative, and precisely to 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetate, having the following structural formula: The present invention relates moreover to the process for the production of the salt derivative (I) and to the related pharmaceutical compositions. The salt derivative (I) is obtained by means of the salification of 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid with 4-(1-pirrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone. The pharmacological activity of the two starting products is known. It is known in particular that 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid (theophyllineacetic acid) exerts a coronary vasodilator and stimulating action on the cardial circulation, and the pharmacological activity is further known of 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy-phenyl)-1-butanone hydrochloride (Buflomedil) on the cerebral circulation, for the treatment of the consciousness diseases, of states consequent to cerebral traumata, and moreover its peripheral vasodilator property. The salt derivative (I) according to the present invention has, in the clinical field, an important application in the treatment of senility, thanks to its stimulating activity of the respiratory function, to its peripheral vasodilator activity, to its diuretic, antithrombotic, cardial stimulating and coronarodilator activity. All these activities are associated in the salt derivative (I) according to the present invention, which displays moreover a high water solubility, which favours its bioavailability and allows its administration also by the parenteral and rectal way. The salt derivative (I) according to the present invention is prepared by means of a process characterized in that 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid is reacted with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy-phenyl)-1-butanone in a reaction medium constituted by an organic solvent wherein (I) is highly soluble, and that the reaction product (I) is crystallized from an organic solvent wherein it has a low solubility. The characteristics and advantages of the salt derivative (I) and of the related production process shall be better evidenced by the following disclosure, which is referred to a preferred embodiment. For the preparation of the salt derivative (I), 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid is dissolved in an organic solvent, and the solution is heated at a temperature comprised within the range of from 40°C to the boiling temperature of the solvent, and, preferably, of from 45 to 55°C. The solvent is preferably an alifatic alcohol containing from 1 to 4 carbon atoms. To the so-obtained alcoholic solution, 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy-phenyl)-1-butanone is added, a complete solution being obtained. The two reactants, which are present in the stoichiometric molar ratio, or in a ratio close to the stoichiometric one, give rise to a reaction in solution. The solution is cooled and concentrated in vacuo and to the residue ethyl acetate anhydrous and preheated to a temperature comprised within the range of from 50 to 70°C is then added. By cooling at a temperature comprised within the range of from 0 to 25°C, the salt derivative (I) crystallizes, which is filtered, washed with ethyl acetate and then dried in vacuo at 35 - 45°C. The yield of the raw product is of about 80 - 85% of the theoretical value. The salt derivative (I) obtained has the appearance of a white crystalline powder, very soluble in water, alifatic alcohols and chloroform, whilst it is insoluble in ethyl acetate. The crystallization of the raw product is carried out from a mixture of alifatic alcohols and ethyl acetate, until the required purity degree is obtained. The yield of each crystallization is of about 90%. The characterization of said product is carried out by: X-ray diffractometry, I.R, U.V. and N.M.R. spectrography and by means of the determination of the melting temperature and of pH. The crystallographic analysis by X-ray diffractometry shows that the product is a single substance deriving from the formation of a ionic bond between the two reactants. In the following Table 1 the characteristic peaks (diffraction angles ϑ and interplanar distances of λ Cu = 1.5418 A ° and the intensity on relative scale I rel , for the salt derivative (I) according to the invention, and, to comparative purposes, for the two reactants (Buflomedil and theophyllineacetic acid) are reported. It results from this table than no one of the characteristic peaks of the reactants is present in the salt derivative (I) and vice-versa; in the salification of the reactants a new crystalline phase has been hence obtained. The U.V. spectrum shows an absorption maximum at 275 ± 1 nm. The melting temperature, as determined on Kofler block, is well defined at the value of 108 - 111°C. pH, as determined in an aqueous solution at 2%, is of 7.4. As for the pharmaceutical compositions in which the salt derivative (I) according to the invention may enter as the active principle, it may be observed that, thanks to its high solubility in water, with it all pharmaceutical forms can be prepared, both for oral and rectal administering, and for the injectable or topic way, in association with the usual conventional pharmaceutical excipients and media. To illustrative, but not limitative purpose of the process according to the present invention, the following Example is reported. Example 1 Fourty grams of 1,2,3,6-tetrahydro-1,3-dimetyl-2,6-dioxopurine-7-acetic acid (C₉H₁₀N₄O₄, M.W. = 238.2) are dissolved in 100 ml of absolute ethanol, and the solution is heated at 50°C. In it, 51.7 g of 4-(pyrrolidinyl)-1-(2,4,6-trimethoxy-phenyl)-1-butanone (C₁₇H₂₅NO₄,M.W. = 307) are introduced. The solution obtained is cooled, is concentrated in vacuo to a low volume, and is poured into 450 ml of anhydrous ethyl acetate preheated at 60°C. The salt then precipitates by cooling to a temperature comprised within the range of from 0° to 25°C, and is filtered, washed with ethyl acetate and dried in vacuo at 40°C. Seventy-six grams of 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetate (C₂₆H₃₅N₅O₈, M.W. = 545.2) are obtained, having after two crystallizations from absolute ethanol / ethyl acetate 1 : 2 the following chemical-physical characteristics: Melting point: 108 - 111°C U.V. absorption maximum at 275 ± 1 nm Titer in 1,2,3,6-tetrahydro-2,3-dimethyl-2,6-dioxopurine-7-acetic acid: 42.92 Titer in N-4-(pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone: 57.08 pH of a 10% aqueous solution: 7.4.

Claims: Claims for the following Contracting States : CH, DE, FR, LI Pharmacologically active salt derivative constituted by 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetate, having the following structural formula: Process for the preparation of the pharmacologically active salt derivative according to claim 1 characterized in that 1,2,3,6-tetrahydro-1,3-dimethyl-2,5-dioxopurine-7-acetic acid is reacted with 4-(1-pirrolidinyl)-1-(2,4,6 -trimethoxyphenyl)-1-butanone in a reaction medium constituted by an organic solvent, wherein (I) is highly soluble, and that the reaction product (I) is crystallized from an organic solvent, wherein it is poorly soluble. Process according to claim 2, characterized in that said reaction is carried out at a temperature comprised within the range of from 40°C to the boiling temperature of the solvent under refluxing conditions, and preferably at a temperature comprised within the range of from 45 to 55°C. Process according to claim 2, characterized in that said reaction medium is constituted by an alifatic alcohol containing from 1 to 4 carbon atoms. Process according to claim 2, characterized in that the reactants are reacted in an about stoichiometric molecular ratio. Process according to claim 2, characterized in that said crystallization solvent is constituted by ethyl acetate or by mixtures of alifatic alcohols and ethyl acetate. Process according to claim 2, characterized in that said crystallization of the reaction product (I) from the solvent constituted by ethyl acetate or by mixtures of alifatic alcohols and ethyl acetate is carried out by cooling at a temperature comprised within the range of from 0° to 25°C. Claims for the following Contracting State : AT Process for the preparation of the pharmacologically active salt derivative constituted by 4-(1-pirrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetate, having the following structural formula: characterized in that 1,2,3,6-tetrahydro-1,3-dimethyl-2,5-dioxopurine-7-acetic acid is reacted with 4-(1-pirrolidinyl) -1-(2,4,6 -trimethoxyphenyl)-1-butanone in a reaction medium constituted by an organic solvent, wherein (I) is highly soluble, and that the reaction product (I) is crystallized from an organic solvent, wherein it is poorly soluble. Process according to claim 1, characterized in that said reaction is carried out at a temperature comprised within the range of from 40°C to the boiling temperature of the solvent under refluxing conditions, and preferably at a temperature comprised within the range of from 45 to 55°C. Process according to claim 1, characterized in that said reaction medium is constituted by an alifatic alcohol containing from 1 to 4 carbon atoms. Process according to claim 1, characterized in that the reactants are reacted in an about stoichiometric molecular ratio. Process according to claim 1, characterized in that said crystallization solvent is constituted by ethyl acetate or by mixtures of alifatic alcohols and ethyl acetate. Process according to claim 1, characterized in that said crystallization of the reaction product (I) from the solvent constituted by ethyl acetate or by mixtures of alifatic alchols and ethyl acetate is carried out by cooling at a temperature comprised within the range of from 0° to 25°C.

Inventors: ZAGNOLI, GIORGIO
Applicants: LABORATORIO ITALIANO BIOCHIMICO FARMACEUTICO LISAPHARMA S.P.A.
Application year: 1985
Main classification: C07D473
IPC codes: C07D295, C07D473