Antithrombotics derived from coumarin and process for obtaining them.

Abstract: New antitrombotic derivatives of coumarin and procedures for obtaining them. Said derivatives respond to the formula (I) wherein Z and R are as indicated in the description. The compounds are prepared by acylation of 4-hydroxycoumarin with an acid chloride of formula (II). The compounds obtained are useful as antitrombotic agents for the prevention and the treatment of coronary and trombolitical diseases.

Description: This invention relates to new derivatives of hydroxy-4-coumarin, of the general formula wherein Z can be -(CH 2 ) n -O-, wherein n is 1 or 2 and R' is H, CH 3 or C 2 H 5 , and R can be H, CH 3 , C 2 H 5 , Cl, Br, F, NO 2 , CF 3 . The position of R is preferably para or meta. These derivatives are resultant of the acylation in the 3-position of the hydroxy-4-coumarin. JP-A-50 046 666 describes coumarin derivatives of the formula: wherein R 1 is -(CH=CH) n - R or -(CH 2 ) 2n R wherein R is an aromatic group and n is 1-2. Said coumarins have antibacterial, hypotensive and antiinflammatory activities. CS-B- 200796 describes coumarin derivatives of the formula: which have rodenticide activity. US-A-2 427 578 describes anticoagulant coumarin derivatives of the formula: wherein R can be (i.a.) a phenyl group. GB-A- 1 175 808 describes anticoagulant coumarin derivatives of the formula: wherein R is a phenyl or alpha-naphthyl radical, or a phenyl or alpha-naphthyl radical substituted with at least one alcoxy group having from 1 to 5 carbon atoms. GB-A- 2 055 831 describes rodenticide coumarin derivatives of the formula: wherein R 1 is -CO-Y or The general preparation procedure of this invention consists in effecting the acylation with an acid chloride according to the following scheme: The reaction is preferably effected in pyridine, in the presence of piperidine. The products according to the invention possess a potent anticoagulant and antithrombotic activity that has been evidenced in both the rat and in the rabbit. These products can be used as antithrombotic agents for the prevention and treatment of tromboembolic and coronary diseases. The invention will be further described by the following examples with reference to the attached drawings in which: Figure 1 shows the IR spectrum of the compound obtained according to the example 1. Figure 2 shows the NMR spectrum of the compound obtained according to the example 2. Figure 3 is a graph that shows the anticoagulant activity in the rat of the compounds according to this invention, in ordinates being showed the degree of prothrombin and in abscises being showed the ingestion time in hours. Figure 4 is a graph that shows the anticoagulant activity in the rabbit of the compounds according to this invention, in ordinates being showed the degree of prothrombin and in abscises being showed the ingestion time in hours. The following examples illustrate the invention without limiting its extent. EXAMPLE 1 3-(4-methyl phenoxy isopropionyl)-4-hydroxy coumarin Preparation In 110 ml of anhydrous pyridine, introduce 12 drops of piperidine, 13,5 gr of 4-hydroxy coumarin and 23,3 g of 2-(4-methyl phenoxy)-propionyl chloride. Heat during 3 hours at 95 º 5 º C. Once same returns to room temperature, slowly pour the reactional mixture into 700 ml of HCl 2N and 350 g of ice. A brown precipitate becomes generated which is isolated by filtration. The product is crystallized in absolute ethanol (330 ml) in presence of active coal. Accordingly, 10.6 g of a beige product is obtained. Analysis Melting point: 155-156 º C Analysis: IR Spectrum at 200 MHz: see figure 1 EXAMPLE 2 Preparation The method of preparation is identical to that of example 1. By causing the 2-(4-chloro phenoxy)-propionyl chloride to react with hydroxy-4-coumarin, a beige product with a yield of 51% is obtained after crystallization in butanol. Analysis Melting point: 179.180 º C Titratable chloride: 10.42% (theory:10.3) NMR Spectrum at 200 MHz: see the figure 2 Anticoagulant Activity The measurements were made in the rat and the rabbit working on a homogeneous bath of 6 animals. The product has been administrated by mixing same with corn starch, in suspension in an Arabic gum mucilage. Blood from the anesthetized animal is taken and the Quick time is then determined in the plasm, according to the customary technique. A previous calibration, effected in a control plasma, enables one to evaluate the degree of prothrombin, and for a given dose, the curve indicating the decrease in the degree of prothrombin can be plotted againts a time interval. This hypothrombinat action characterizes the antivitamin K activity of the products according to the invention. The curves obtained show the great activity of these products for an active dose of 2 mg/kg in the rat and of 0.2 mg/kg in the rabbit (figures 3 and 4).

Claims: Acylated derivatives of the hydroxy-4-coumarin of the general formula (I) wherein z can be =(CH 2 ) n -O-, wherein n is 1 or 2 and R' is H, CH 3 or C 2 H 5 , and R can be H, CH 3 , C 2 H 5 , Cl, Br, F, NO 2 , CF 3 , endowed with anticoagulant and antithrombotic properties. 3-(4-methyl phenoxy isopropionyl)-4-hydroxy coumarin. 3-(4-chloro phenoxy isopropionyl)-4-hydroxy coumarin. Procedure for the preparation of the new acylated derivatives of hydroxy-4-coumarin of the general formula (I) indicated in the claim 1, characterized in that it comprises acylating hydroxy-4-coumarin with an acid chloride of the formula wherein Z and R are defined as mentioned in claim 1, preferably in pyridine, and in the presence of piperidine. Medicines bases on the active principle of the general formula (I), useable as antithrombotic agents for the prevention and treatment of arterial and venous thrombosis. Medicines that contain as their active principle 3-(4-methyl phenoxy isopropionyl)-4-hydroxy coumarin. Medicines that contain as their active principle 3-(4-chloro phenoxy isopropionyl)-4-hydroxy-coumarin.

Inventors: LOPEZ BELMONTE LORENZO, LOPEZ BELMONTE, LORENZO
Applicants: ROVI LAB FARMACEUT SA, LABORATORIOS FARMACEUTICOS ROVI, S.A.
Application year: 1992
Main classification: C07D311
IPC codes: C07D311