DE2003714B - 2-Piperazino-4-morpholino-thieno square bracket on 3.2-square bracket to pyrimidine and its acid addition salts - Google Patents

Description

and its phannacologically acceptable acid addition salts with inorganic or organic acids.

2. Medicinal preparations which consist of a compound according to Claim 1 and customary carriers or auxiliaries.

The invention relates to I-piperazino- ^ morpholinothieno [3,2-d] pyrimidine of formula I.

(D

35

its pharmacologically acceptable acid addition salts with inorganic or organic acids as well as pharmaceutical preparations containing one of these compounds contain.

2 - piperazino - 4 - morpholino - thieno [3,2 - d] pyrimidine, which counteracts the aggregation of platelets in human blood very well although in the broadest sense under the general formula of German Offenlegungsschrift 1 470 356, but is not even described therein.

The 2-piperazino-4-morpholino-thieno [3,2-d] pyrimidine is obtained by reacting a compound of the general formula II

50

(H)

in which A is a halogen atom or a mercapto group which is free or substituted by a low molecular weight alkyl radical means with piperazine or more advantageously with a piperazine derivative of the general Formula III

55

60

R-N

NH

(ITI)

in which R is a group which can be split off by treatment with acids or alkalis, such as, for. B. denotes the carbethoxy or formyl radical, the radical R being split off again after the reaction has taken place.
The reaction takes place at temperatures between

0 and 200 ° C; if the radical A to be exchanged is a halogen atom, then the presence of one is Hydrogen halide binding agent advantageous. As such, it can be inorganic or tertiary organic Base can be used, but you can also use an at least 1 molar excess of the piperazine use as an acid binding agent. A further excess of the piperazine can also be used as a solvent be used. If the reaction is carried out in the presence of a solvent, so alcohols such as ethanol, ethers such as dioxane, higher-boiling ketones or dimethylformamide are suitable for this. The use of a solvent is not absolutely necessary because the reaction runs just as well in the absence of solvents. The reaction temperature depends on the reactivity the reactant from. In general, the exchange of a halogen atom takes place faster and at lower temperatures than the exchange of a mercapto group. Will be in the implementation If a compound is obtained which still bears the radical R on the piperazine ring, the cleavage takes place this residue expediently by boiling with a strong inorganic acid, in particular with concentrated hydrochloric acid. From the resulting salt of 2-piperazino-4-morpholino-thieno [3,2-d] pyrimidine the free base is then set free by means of an aqueous alkali. Of course the residue R can also be split off by boiling with a lye 2-piperazino-4-morpholino-thieno [3,2-d] pyrimidine can optionally subsequently in a manner known per se in a physiologically compatible manner Acid addition salts are converted with inorganic or organic acids. As such For example, hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, tartaric acid, citric acid, Maleic acid or fumaric acid in question.

The production of the starting materials of the general Funnel II is described in the German Offenlegungsschrift

1 470 356.

The starting substance of the general formula II, in which A denotes a halogen atom, can be expediently z. B. produce as follows: the ring closure reaction of urea with a 3-aminothiophene-2-carboxylic acid ester 2,4-dihydroxy-thieno [3 2-d] pyrimidine is obtained with a phosphorus oxyhalide converted to 2,4 - dihalo - thieno [3,2-d] pyrimidine and the latter reacted with the calculated amount of morpholine (cf. Examples A to C). The reaction with thiourea instead of urea leads to compounds with a free mercapto group in 2-pitch, which if desired also subsequently by means of Alkyl halides can be alkylated.

2 - piperazino - 4 - morpholino - thieno [3,2 - d] pyrimidine prevents the aggregation of platelets in human blood even at a concentration of less than 10 ~ ⁵ mol / l blood. The platelet aggregation-inhibiting effect was determined by the method of K. B reddi (cf. Switzerland. Med. Wschr., 95 [1965], pp. 655 to 660). Human blood plasma rich in platelets is slowly rotated in a water bath after the active substance has been added. A silicone-coated slide is coated with the plasma treated in this way and washed.

fixed and stained The degree of platelet aggregation is determined microscopically

Another method for determining the inhibitory effect on the aggregation of platelets comes from Born and Cross (cf. J. PhysioL, 170 [1964], p. 397). The aggregation was measured in platelet-rich plasma from healthy test subjects. For this, the course of the decrease was the optical density of the platelet suspension on addition of adenosine diphosphate (10 ^-5 mol / l) measured photometrically, and registers the active substance was in each case 10 minutes before the adenosine diphosphate added is added The aggregation of the thrombocytes was further by the method of Morris (see.!. International Symposium on Metabolism and Membrane Permeability of Erythrocytes and Thrombocytes, Vienna 1968, E. Deutsch, E. Gerlach, K. M o ser; Georg Thieme Verlag, Stuttgart). Human citrate blood was brought into contact with 1 g of glass beads for 30 seconds. After contact, the blood was allowed to stand for 1 hour to allow the reversible aggregates to disaggregate. The platelets in the supernatant platelet-rich plasma were counted microscopically before and after contact with the glass beads.

In all experiments, the platelet aggregation-inhibiting effect of the closest to the 2 - piperazino - 4 - morpholine) - thieno [3,2 - d] pyrimidine = A, in the French The substances described in patent specification 4321 M are 2-diethanolamino-4-morpholino-thieno [3,2-d] pyrimidine = B and 2- (4-methylpiperazino) -4-morpholino-thieno [3.2 * d] pyrimidine = C determined. The following table contains the values found and shows the clear superiority of substance A according to the invention:

substance

Inhibitory effect according to the method of

Born and

Cross

Minor

Morris

Minor

3.10 " ⁶
1.10- *

ι.ίο- ⁵

5.10 " ⁶
1.10 " ⁴
3.10

-5

Breddin Minor

5.10 " ⁶
1.10- *
5.10

-5

LD ₅₀ mg / kg mouse po

200
710

350

The acute toxicity was determined by oral administration in groups of 10 mice per dose and active substance. _{The LD 50 was} calculated from the values found.

The following examples are intended to explain the invention in more detail:

Examples for the production of the starting materials

Example A.
2,4-dihydroxy-thieno [3,2-d] pyrimidine

1.6 g (0,01MoI) 3-aminothiophene-2-oarbonsäuremethylester and 3 g (0.05 mol) of urea are mixed intimately and heated for 2 hours at 200 ⁰ C. The result is a clear, brown melt that solidifies on cooling. It is dissolved in warm 1 η sodium hydroxide solution, decolorized with charcoal and acidified with 2 η hydrochloric acid.

The precipitated crystalline product is filtered off with suction and recrystallized from water. F.> 300 ⁰ C.

Yield: 1.2 g (72% of theory).
C ₆ H ₄ N ₂ O ₂ S (168.8):

Calculated ... C42.84, H2.40, N 16.66%;
found .... C 42.75, H 2.57, N 16.82%.

Example B.
2,4-dichloro-thieno [3 ^ -d] pyrimidine

8.4 g (0.05 mol) 2,4-dihydroxythieno [3,2-d] pyrimidine and 100 ml of phosphorus oxychloride are refluxed for 10 hours, with complete Solution occurs

The excess phosphorus oxychloride is stripped off in vacuo, the remaining UI with ice water decomposed and extracted with chloroform.

The organic phase is washed neutral with water and dried over sodium sulfate

The solid residue obtained after the solvent has been stripped off is recrystallized from ethanol. M.p. 141 to 142 ° C.

Yield: 1.6 g (74% of theory).

C ₆ H ₂ Cl ₂ N ₂ S (205.08):

Calculated ... C 35.13, H 0.98, Cl 34.58%;
found .... C 35.25, H 1.02, Cl 34.68%.

Example C
2-chloro-4-morpholmo-thieno [3,2-d] pyrimidine

5.1 g (0.025 mol) of 2,4-dichlorothieno [3,2-d] pyrimidine are mixed with 200 ml of absolute ethanol. 4.8 g (0.055 mol) of morpholine are added to the suspension obtained with vigorous stirring and cooling to 20 ^{° C.} A clear solution results from which a crystalline compound separates out after a short time.

The reaction mixture is stirred for a further 2 hours at room temperature.

The product is filtered off with suction, washed with water and ethanol and recrystallized from methyl ethyl ketone. F. 196 to 198 ° C.

Yield: 5.75 g (90% of theory).

C ₁₀ H ₁₀ ClN ₃ OS (255.74):
Calculated ... C 46.97, H 3.95, N 16.44%;
found .... C 47.10, H 4.03, N 16.30%.

Examples for the manufacture of the end product
example 1

10.2g (0.04MoI) 2-chloro-4-morpholino-thieno- [3,2-d] pyrimidine, 15.6 g (0.08 mol) of piperazine hexa-

hydrate and 100 ml of absolute ethanol are heated ^{to 120 ° C. in a bomb for 3 hours.} After cooling, the ethanol is removed in vacuo and the residue is dissolved in water.

The pH of the solution is adjusted to 6 by adding 2η hydrochloric acid and the mixture is extracted three times Chloroform. Then 30% sodium hydroxide solution is added to the aqueous phase up to pH 12 and extracted three times with methylene chloride.

The combined extracts are dried over sodium sulfate, evaporated and the non-crystalline one is purified Residue by column chromatography (sorbent: silica gel for column chromatography, 0.2 to 0.5 mm, Merck; Mobile phase: benzene / acetone = 7: 3).

The uniform fractions are combined and evaporated, the remaining non-crystalline 2 - Piperazino - 4 - morpholino - thieno [3,2 - d] pyrimjdin dissolved in absolute ethanol and treated with ethereal hydrochloric acid precipitated as dihydrochloride.

It is filtered off with suction, rewashed with ether and recrystallized from absolute ethanol. F. Decomposition from 175 ° C.
Yield: $ 2 g (19% of theory).

Q ₄ H ₁₉ N ₅ OS- 2HCl (378.34):

Calculated. C 44.44, H 5.60, N 18.51, Cl 18.75%; found ... C 44.15, H 5.71, N 18.30, C! 18.51%.

Example 2

a) 2.6 g (0.01 mol) of 2-ChloΓ-4-moφholino-thieno-3,2-d] pyrimidine and 6.3 g (0.04 mol) of 1-Carbäthoxypiperazin be 3 hours at 120 ⁰ C. heated.

After cooling, the reaction solution is poured into ice water, with 2- (4-Carbäihoxy-piperazino) - 4 - morpholine - thieno [3.2 - d] pyrimidine in in a greasy form. This greasy product crystallizes when rubbed. The crystals will be suction filtered and recrystallized from ethanol. F. 139 up to 141 ° C.

Yield: 3.2 g (86% of theory).

b) 1.9 g (0.005 mol) 2- (4-carbethoxy-piperazino) -4-morpholino-thieno [3,2-d] pyrimidine and 20 ml of concentrated hydrochloric acid are refluxed for 10 hours.

After cooling, the reaction solution is poured onto ice and made strongly alkaline with 30% strength sodium hydroxide solution and extracted several times with methylene chloride.

The combined extracts are dried over sodium sulfate and evaporated, the non-crystalline residue is taken up in absolute ethanol and converted into dihydrochloride by adding ethereal hydrochloric acid like.

It is filtered off with suction, washed with ether and recrystallized from absolute methanol. Decomposition from 175 ° C.
Yield: 1.2 g (63% of theory).

Example 3

a) 2.7 g (0.01 mol) of 2-methylmercapto-4-morpholinothieno [3,2-d] pyrimidine (melting point 138 to 139 ° C) and 11.4 g (0.1 mol) of 1-formyl -piperaziD are heated 10 hours at 150 ⁰ C.

ίο The cooled reaction solution is poured into water, wherein 2- (4-formyl-piperazino) -4-morpholinothieno [3,2-d] pyriinidine precipitates in a greasy form.

The compound can be obtained in crystalline form by rubbing with a glass rod. It is made from ethanol J5 recrystallized. Mp 139 ° C (decomposition).

Yield: 1.8 g (54% of theory).

b) 1.6 g (0.005 mol) of 2- (4-formyl-piperazino) -4-morpholino-thieno [3 ^ -d] pyrimidine and 20 ml of concentrated hydrochloric acid are refluxed for 9 hours.

The cooled reaction solution is poured onto ice, made alkaline with 30% sodium hydroxide solution and extracted several times with methylene chloride. The combined extracts are dried over sodium sulfate and distilled the solvent is removed in vacuo, the non-crystalline residue is taken up in absolute ethanol and the reaction product falls as a dihydrochloride with essential hydrochloric acid. This is suction filtered, washed with ether and recrystallized from ethanol. Decomposition from 175 ° C.

Yield: 1.35 g (71% of theory).

2 - piperazino - 4 - morpholino - thieno [3,2 - d] pyrimidine and its acid addition salts can be converted into customary pharmaceuticals by methods known per se Incorporate preparations.

Claims (1)

Patent claims: 1. 2- Piperazmo-4-inorphoIino-thieno [3,2-d] -pyrimidine of formula I. H-N N- /, N _n N I A S ^