DE3241333C2 - - Google Patents

Description

The present invention relates to a thiazolo pyrimidine derivative with vasodilator effect, hypoten sive effect, inhibitory effect on the platelet Aggregation and reducing effect on cholesterol contained in the blood.

Cardiovascular diseases, e.g. B. ischemic heart disease diseases, cerebrovascular diseases, arteriosclerosis and High blood pressure, together with malignant tumors the main causes of death. It is believed that cardiovasku diseases, ischemic heart diseases and insuf efficiency of the cerebral or peripheral circulation in the general due to a lack of nutrients and acid Material supply caused, this deficiency insufficient blood flow due to arterial thrombus bus formation or arteriosclerosis. Des half are medicinal in the treatment of these diseases medium effective, which affects the blood flow of the affected organ due to a vasodilatory effect in ischemic Area, such as B. improve the coronary arteries. It It is also believed that these tion of the pathogenesis of diseases are effective by they the platelet formation the one cause of the arteri represents all thrombus formation, inhibit. this is also valid for medicines that cause the increased serum cholesterol reduce what arteriosclerosis is caused.

Vasodilators (vasodilators), e.g. B. hydralazine, have an antihypertensive effect and have been common used in the treatment of hypertension. Lately vasodilators have also been used in the treatment  heart failure successfully used what is on their effect of reducing peripheral vascular resistance ren, based; Kai Itoh et al. (Nippon Rinshon, 36 (11) 51 (1978)) and by Shinobu Matsui et al. (Abstract No. 165, The 43rd Annual Congress of the Japanese Circulation Society).

DE-OS 22 48 792 and DE-OS 21 55 963 are thiazolo [5,4-d] pyrimidines with hypotensive and antithrombo known effect, these compounds great have polar morpholino and thiomorpholino residues. It was not expected to be replaced by these residues a methyl group in the 5-position and a diethylamino group in the 7-position the antihypertensive and anti thrombotic effect of thiazolo [5,4-d] pyrimidine remains.

The inventors recognized that cardiovascular diseases, as mentioned above, together in Be stand and that the optimal treatment of this Diseases represents such treatment that too leads to a comprehensive improvement of these diseases. As a result, this search for a connection that fulfilling this requirement, the inventors have the verb 7-Diethylamino-5-methylthiazolo [5,4-d] pyrimidine found that a vasodilator, a hypotensive Effect, an inhibitory effect on the platelets Chen aggregation and a lowering effect on the chole contains sterol in the blood.

The present invention therefore relates to the compound 7-diethylamino-5-methylthiazolo [5,4-d] pyrimidine, which can be prepared as follows:
4-Diethylamino-6-mercapto-2-methyl-5-nitropyrimidine is reduced according to known methods in order to convert the nitro group in the 5-position to the amino group. The aminopyrimidine derivative obtained in this way is cyclized directly using formic acid, a thiazolopyrimidine derivative being obtained.

The compound according to the invention as he above can become a pharmacologically acceptable salt be converted, such as B. an acid adduct with anorga African acids, e.g. B. hydrochloric acid, hydrobromic acid, iodine hydrochloric acid, sulfuric acid, nitric acid or phosphorus acid, or with organic acids, e.g. B. acetic acid, malein acid, citric acid, tartaric acid, oxalic acid or amber acid.

The compound of the invention has as a therapeutic Properties advantageous, in particular as a vasodilator, since this has a strong vasodilatory effect, a hypo tensive effect, an inhibitory effect on the platelets aggregation and a reducing effect on blood cholesterol has ring content and is also soluble in water. The A compound according to the present invention or its Acid adducts can be formulated into products that the find therapeutic use, alone or together with other pharmacologically active compounds, after a any conventional method, where appropriate pharmaceutically acceptable binders, fillers or flavoring fabrics used.

The following is an example of the manufacturing process specified the compound of the invention.

Example 1 7-diethylamino-5-methylthiazolo [5,4-d] pyrimidine

7.3 g of 4-chloro-6-diethylamino-2-methyl-5-nitropyrimidine were in 100 ml of a mixture of methanol-water (9: 1) dissolves and 4.7 g of 70% sodium hydroxide are slowly added. The reaction mixture was at room temperature for 30 minutes long stirred and the solvent under reduced pressure distilled off and the pH of the residue by adding  5N hydrochloric acid adjusted to 5 to 6. The fancy yellow ones Crystals were filtered off by filtration. The crystals were extracted from a mixture of chloroform and n-hexane installed, with purified 4-diethylamino-6-mercapto-2- methyl-5-nitropyrimidine was obtained (5.2 g, melting point 181.3∼183.3 ° C).

5 g of the 4-diethylamino-6-mercapto-2-methyl-5-nitropyrimidine Crystals and 7.0 g of metallic tin worked well together mixed and 50 ml of concentrated hydrochloric acid slowly with cooling added to the mixture. After the addition, that was Reaction mixture stirred at room temperature for 3 hours. Then a 3N sodium hydroxide solution was added to the mixture while cooling with ice, and the pH of the mixture set to 8 to 9 to obtain an oily substance has been. The oily substance was extra with 200 ml of ethyl acetate hiert and the organic layer over magnesium sulfate anhydride dried. Then the solvent was reduced Distilled off pressure and the residue from a mixture of Chloroform and n-hexane recrystallized, with 5-amino-4- diethylamino-6-mercapto-2-methylpyrimidine crystals (3.9 g) were obtained.

3 g of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine were dissolved in 50 ml of 90% formic acid and refluxed for 2 hours held. After the reaction was complete, the formic acid distilled off under reduced pressure. The backlog were 30 ml of water are added and this is neutralized with ammonium hydroxide lized. This aqueous solution was mixed with 200 ml of ethyl acetate extracted and the organic layer over sodium sulfate hydride dried. Then the solvent was reduced Distilled off pressure and the residue by column chromatography topography on a silica gel column, 7-diethyl amino-5-methylthiazolo [5,4-d] pyrimidine (1.6 g) obtained has been.  

Melting point: 41.6-43 ° C.
Mass spectrum: M⁺ 222.

Elemental analysis C₁₀H₁₅N₄S:
Calculated: C 54.05%, H 6.37%, N 25.23% Found: C 54.11%, H 6.32%, N 25.29%

NMR (δ ppm, CDCL₃) 8.48 1 H s , 3.91 4 H q (7 Hz), 2.49 3 H s , 1.36 6 H t (7 Hz).

In the following, comparative experiments will show that the compound of the invention compared to be knew compounds such as diltiazem, dipyridamole, nitro glycerin and aspirin are significant vasodilators Effect, a reinforcing effect on the coronary blood electricity and an antihypertensive effect as well as an inhi effect on platelet agglutination and a reducing effect on serum cholesterol owns.

Comparative Trials (Submitted March 4, 1986) Experimental example 1 Vasodilator effect

Isolated hearts of guinea pigs were made using the method perfused by Langendorff. The effect of the test connection to the outflowing volume of the perfusate was investigated by adding the appropriate compound to the Perfusate was added.

The test compound was in each case in physiological cook saline solution and dissolved at the perfusate inlet admitted.

The vasodilation was calculated as the ratio of the outflowing volume after administration of the test compound addition to that before administration of the same.  

The results are shown in Table 1 together with the ver results of diltiazem, dipyridamole and nitro glycerin compiled.

Table 1

It was observed that the invention Compound 7-diethylamino-5-methylthiazole- [5,4-d] pyrimidine has a strong vasodilatory effect.

Experimental example 2 Reinforcing effect on the coronary blood flow and hypotensive effect.

Male dogs with Pento were used as experimental animals were barbitally anesthetized. With the help of an electro magnetic ammeter was changing the blood flow in the left anterior descending coronary ramus intravenous administration of the test compound was measured.

At the same time, blood pressure was measured.

The increase in the flow rate of the coronary blood was calculated as the ratio of blood flow after administration of the Test compound calculated prior to administration. The hypotensive effect was expressed as Ver Ratio of blood pressure after administration of the test ver binding to that before administration of the same.  

The results obtained are shown in Table 2 together with those of the comparison compound dipyridamole listed.

Table 2

The experiment showed that 7-diethylamino-5-methyl-thiazole [5,4-d] pyrimidine has a coronary enhancing effect Blood flow and an antihypertensive effect. The increase in coronary blood flow was special pronounced.

Experimental example 3 Inhibitory effect on the Platelet agglutination

According to the method of Ohnishi et al. (Folia Pharmacologica Jajonica, 76, 495 [1980]) became a platelet-rich plasma from a blood of guinea pigs treated with citrate produced; 2 µl of a solution containing the test compound contained 180 µl of the platelet-rich plasma admitted. One minute after the addition, 20 ul of a solution, which contained 5 µl / ml adenosine diphosphate (ADP), added to the mixture to effect the test compound on the secondary platelet agglutination as they go through ADP is caused to investigate.

The results with the compound of the invention and with dipyridamole and aspirin as comparison compounds were summarized in Table 3.  

Table 3

As can be seen from the table above, 7-diethylamino-5-methylthiazole- [5,4-d] pyrimidine a significant inhibitory effect on platelet agglu tination.

Experimental example 4 Reducing effect on the Serum cholesterol content

According to the method of Ohnishi et al. (Folia Pharmacologica Japonica, 76, 495 [1980]), were groups of three Quails on a high-fat diet (one Food consisting of 9.7 g of quail food, available from Yamako, 0.2 g cholesterol and 0.05 g sodium deoxycholate), in an amount of 10 g / quail / day for a total 7 days. The test compounds were taken orally twice a day Administered for 7 days; the serum cholesterol content was 8th day determined.

The results are summarized in Table 4.  

Table 4

As shown in the table above, decreased 7-diethylamino-5-methylthiazole [5,4-d] pyrimidine the serum Cholesterol content.

Experimental example 5 acute toxicity

Groups of 10 male mice each (ddY strain) with a weight of 75 g was orally 10 ml / kg of the test compound dung, suspended in 5% gum arabic solution enough. A solution of the test network was separated solution in 0.1 N HCl saline intravenously into the Tail vein administered. The LD₅₀ value of the Test compound was made for each test according to the method of Wilcoxon-Litchfield calculated based on the number of dead animals 7 days after administration.

The results are shown in Table 5.

Table 5

Claims (1)

Thiazolopyrimidine derivative, characterized in that it is 7-diethylamino-5-methylthiazolo [5,4-d] pyrimidine.