DE2032687A1 - Cardiovascular 2-aminoalkylamino-thienopyrimidines - and 4-morpholino derivatives from 4-diethanolamino-compounds by intramolecular cyclisa - Google Patents

Abstract

2-Aminoalkylamino-thienopyrimidines (I): and their acid addition salts; (where R1, R2 = H, alkyl, but esp. heterocycle, pref. morpholino; R3, R4 = H, 1-6C alkyl; A = straight or branched 2-10C alkylene), inhibit thrombocyte aggregation and have cardiovascular and/or sedative activity. Prepd. from the corresp. 4-diethanolamine-cpds., by intramolecular cyclisation with acid condensings agents e.g., conc. H2SO4 at 0-175 degrees. In an example, 1.98 g. (54%) 2-(2-aminoethylamino)-7-methyl-4-morpholino-thieno- 3,2-d pyrimid- ine.2HCl (from MeOH, m.pt. 335 degrees) is obtd. from 3.84g. 2-(2-aminoethylamino)-4-diethanolamino-7-methyl-thienopyrimidine.- HCl and 50 ml. conc. H2SO4, standing at 20 degrees for 3 days.

Description

New 2-aminoalkylamino-thieno- [3,2-d] pyrimidines [2. . Addition to DBP (patent application P 19 40 572.2) and 1st addition to DBP (patent application for the same Applicant of the same day with the title "Process for the preparation of new 2-aminoalkylamino-thieno- [3,2-d] pyrimidines", internal designation Case 5/470, 1st addition to P 19 40 572.2.

In the DBP (file number P 19 40 572.2) new 2-aminoalkylamino-thieno- [3,2-d] pyrimidines of the general formula I, in which R1 and R2J, which can be identical or different from each other, hydrogen atoms or straight-chain or branched alkyl radicals with 1-6 carbon atoms, whereby the radicals R1 and R2 together with the nitrogen atom in between can also form a saturated 5- to 7-membered mcnocyclic, heterocyclic ring , which can optionally be interrupted by an oxygen atom or another nitrogen atom and / or substituted by an alkyl radical or a hydroxyl group, R3 and R4, which can be the same or different, hydrogen atoms or straight-chain or branched alkyl radicals with 1-6 carbon atoms and A a straight-chain or branched alkylene chain with 2 to 10 carbon atoms, and their physiologically acceptable acid addition salts and processes for their preparation are described.

The compounds of general formula I have valuable pharmacological properties Properties, some of them have a cardiovascular and / or sedative effect, in particular however, they have an inhibitory effect on platelet aggregation.

It has now been found that other new compounds, which under the above general formula fall, but in the DBP ..........

(File number P 19 40 572.2) cannot be described, the same possess valuable pharmacological properties and conform to the procedures of the DBP (file number P 19 40 572.2) and the DBP (internal name Case 5/470, 1. Addition to P 19 40 572.2).

The invention thus relates to new compounds of the general formula I, which can be prepared by the following processes: a) By reacting a compound of the general formula in which R1, R2 and R4 have the meanings given above and Z denotes a halogen atom, a substituted mercapto group or an alkylsulfonyl radical, with a diamine of the general types in which R3 and A are as defined at the outset and X denotes a hydrogen atom or an easily cleavable protective group such as the atyl, benzoyl or p-toluolaultonyl group, and optionally cleavage of a protective radical X.

If the radical Z is a halogen atom, then the presence is one Hydrogen-binding agent required.

The reaction is carried out at temperatures between 20 and 20,000, preferably in the presence of an organic solvent. As a hydrogen halide binding agent an inorganic or tertiary organic base can be used; However, it can also an at least molar excess of the diamine of the formula III used as acid binding agent can be used. in further excess of this diamine can can also be used as solvents. If X means a protective residue, this becomes subsequently split off, for example by means of hydrolysis.

b) By reacting a compound of the general formula in which the radicals R3, R 4, X, among others, have the meanings given above and the radical Z 'denotes a halogen atom, a free or substituted mercapto group or an alkylsulfonyl group, with an amine of the formula where R and R2 are defined as mentioned above and optionally splitting off of a protective radical X.

if Z 'is a halogen atom, the presence of one is required for the reaction Hydrogen-binding agent required.

The reaction takes place at temperatures between 20 and 200 ° C, preferably in the equivalent of an organic solvent. As a hydrogen halide binding agent an inorganic or tertiary organic base can be used; it k m however also an at least molar excess of the amine used as acid-binding agent Means, a further excess of this amine can also be used as a solvent. If X is a protective radical, this is subsequently split off, for example by means of hydrolysis.

c) By reacting a compound of the general formula in which the radicals R1 to R4 and A are defined as mentioned above and Z ″ denotes a halogen atom, with ammonia or with any desired carboxamide or carboximide or

With their metal salts and subsequent cleavage of the acid residue from the resulting carboxylic acid derivative.

The reaction is carried out at temperatures between 20 and 20,000, preferably in the presence of an organic solvent.

When reacted with ammonia, this is advantageously in excess used and the reaction carried out in a closed vessel.

The bsw when using a carboxamide. zimids originated Carboxylic acid derivative is cleaved with acids or bases. Particularly suitable bases are Hydrazine and hydroxyl amine.

d) By catalytic reduction of a nitrile of the general formula in which the radicals R1, R2, R3 and R4 are defined as mentioned above and the radical A 'has the meaning of the radical A, but shortened by a methylene group.

The reduction is advantageously carried out by means of in the presence of Raney nickel, * PaDadium or platinum activated hydrogen at elevated temperatures and increased pressure. In general, temperatures between 30 and 1000C are sufficient a pressure between 20 and 150 atmospheres.

e) For the preparation of compounds of the general formula I in which R1 and R2 together with the intermediate nitrogen atom denote a morpholine ring optionally substituted by an alkyl radical, by intramolecular cyclization of a compound of the general formula in which the radicals X, R3, R4 and A are as defined at the outset and the radicals R5 and R6 represent hydrogen atoms or one of the radicals R5 or R6 is an alkyl radical and the other of the radicals R5 or R6 is a hydrogen atom, in the presence of an acidic condensing agent and if necessary splitting off of a protective residue X.

The reaction is carried out in the presence of an acidic condensing agent and optionally in a solvent at temperatures between 0 and 1750C carried out. Acids such as sulfuric acid, phosphoric acid, Perchloric acid, hydrochloric acid, hydrobromic acid, toluenesulfonic acid or anhydrous Metal salts such as zinc chloride or a cation exchanger are possible. As a solvent can higher hydrocarbons such as tetralin or those used as condensing agents Acid such as sulfuric acid or phosphoric acid can be used. The implementation can however, can also be carried out in the melt; it can also be beneficial if the cyclization is carried out under protective gas. A protective radical X is optionally then split off, for example by means of hydrolysis.

The compounds of the general formula I can optionally be added subsequently in a manner known per se into their acid addition salts with physiologically compatible ones inorganic or organic acids are converted. As such come for example Hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, vartic acid, citric acid, Maleic acid or fumaric acid in question.

The preparation of the compounds of general formula II used as starting materials is described in German Offenlegungsschrift No. 1470356. It is produced by reacting a 3-aminothiophene-2-carboxylic acid of the general formula or a reactive derivative thereof with urea or thiourea or cyano or thiocyanic acid. Particularly suitable reactive derivatives of 3-aminothiophene-2-carboxylic acid are its esters and amides. This creates compounds of the general formula in which the radical R4 has the meanings mentioned at the outset and B denotes a free hydroxyl or mercapto group. If urea or cyanic acid is reacted with a compound of the formula IX, a compound of the formula X in which B is a free hydroxyl group is formed. If thiourea or thiocyanic acid is used, a compound of the formula Xvr in which B is the free mercapto group is obtained. These reactions are generally carried out at elevated temperatures, preferably at temperatures between 20 and 2000 ° C. and optionally in the presence of water if cyanic or thiocyanic acid is reacted, or in the presence of an inert, high-boiling solvent such as toluene, xylene or tetrahydronaphthalene.

To prepare compounds of the general formula II in which Z is a halogen atom, compounds of the general formula X in which B is a free hydroxyl group are first converted into a compound of the general formula by known methods, for example by heating with a phosphorus halide in which Hal is a halogen atom. These compounds are reacted with compounds of the formula V at room temperature or at slightly elevated temperatures in a solvent, for example in ethanol. This gives rise to the starting compounds of the formula II in which the radicals R1, R2 and R4 are defined as mentioned above and Z denotes a halogen atom.

To prepare compounds of the formula II in which Z represents an alkyl mercapto or alkylsulfonyl group, compounds of the formula X in which B is a free mercapto group are treated with alkylating agents, such as dialkyl sulfates or alkyl halides, according to methods known per se, converted into the corresponding 2-alkylmercapto-4-hydroxy-thienoj3, 2-d7pyrimidines. These compounds are converted into compounds of the general formula by known methods, for example by heating with a phosphorus halide in which alkyl is any alkyl radical and Hal is a halogen atom. These compounds are then reacted with compounds of Table V at room temperature or at slightly elevated temperatures in a solvent, for example in ethanol. The result is the exit connecting cars of the formula II, in which the radicals R1, R2 and R4 are defined as mentioned above and Z denotes an alkyl mercapto group.

These compounds of the formula II obtained in this way can, if desired then with the help of oxidizing agents such as chlorine or potassium permanganate, be converted into compounds of the formula II in which Z is the alkylsulfonyl radical means.

Compounds of the general formula III in which X is a protective group such as, for example, MeAcetyl, benzoyl or p-toluenesulfonyl group produced by methods known from the literature (see. Houben / Weyl Volume XI / 1, page 26 ff).

The compounds of the formula IV are prepared, for example, as follows: By reacting a 3-amino-thiophene-2-carboxylic acid of the general formula IX or a reactive derivative thereof with thiourea or thiocyanic acid; as reactive derivatives of 3-amino-thiophene-2-carboxylic acid, their esters and amides are particularly suitable. This gives 2-mercapto-4-oxithieno [3,2-d] pyrimidines, the free mercapto group of which is then alkylated by means of alkyl halides. The 2-alkylmercapto-4-oxi-thieno [3,2-d] -pyrimidines thus obtained are treated with diamines of the formula III in which R3, I and A are defined as mentioned at the outset, converted to the corresponding 2-aminoalkylamino-4-oxy-thieno, 2-pyrimidines, optionally after cleavage of the radical X, and these then, for example by means of phosphorus oxyhalides, to the starting compounds of the formula IV, in which Z 'is a halogen atom, halogenated or converted, for example by means of diphosphorus pentasulfide, into the corresponding starting compounds of the formula IV which have a mercapto group in the 4-position. A starting compound of the formula IV obtained in this way can, if desired, then be alkylated by means of alkyl halides by methods customary per se, a compound of the formula IV being formed in which Z 'denotes an alkyl mercapto group. These compounds can easily be oxidized to compounds of the formula IV in which Z 'denotes an alkylsulfonyl radical. The oxidation is preferably carried out by means of chlorine or talium permanganate.

The starting compounds of the general formula VI are obtained by reacting 2-hydroxyalkylamino-4-aminothieno [3,2-d] pyrimidines of the general formula XIII in which the radicals R1 to R4 and A are defined as mentioned above, with halogenating agents such as, for example, thionyl chloride.

The reaction can be carried out in an inert solvent. The compounds of the formula XIII are described in German Offenlegungsschrift 14 70 356 known or can be based on the methods described there produce.

The starting compounds of the general formula VII are obtained by reacting amino nitriles of the general formula XIV in which R3 is defined as mentioned above and A 'has the meaning of the radical A, but shortened by a methylene group, with compounds of the general formula II. Some of the aminonitriles of the formula XIV are known from the literature or can be prepared on the basis of methods known from the literature (Houben / Weyl, Volume XI / 1, page 272 ff).

The starting compounds of the general formula VIII can be omitted a 2,4-dichloro-thieno [3,2-d] pyrimidine of the general formula XI by reaction with a corresponding diethanolamine and subsequent reaction with an amine of the general formula III, if X represents a protective radical, this can are then split off hydrolytically.

The compounds of the formula I have valuable pharmacological properties Properties, some of them have a cardiovascular and / or sedative effect, in particular however, they inhibit platelet aggregation.

The platelet aggregation-inhibiting effect was determined according to the method by K. Breddin, Switzerland. Med. Wschr. 95, 655-660 (1965). Platelet rich After the active substance has been added, human blood plasma is slowly poured into a water bath rotates.

A silicone coated slide is treated with the 80 Plasma coated, washed, fixed and stained. The degree of platelet aggregation is determined microscopically.

Another method of determining the inhibitory effect on the Platelet aggregation is from Born and Cross (J.

Physiol. 170, 597 E196J4). The aggregation was in this case in platelet-rich Plasma measured from healthy subjects.

For this purpose, the course of the decrease in the optical density of the platelet suspension was monitored photometrically measured and registered on the addition of adenosine diphosphate (10-5 M / l). The active ingredients were 10 minutes each time adenosine diphosphate is added added. The aggregation of platelets was also determined by the method of Morris (1st International Symposium on Metabolism and Membrane Permeability of Erythrocytes and Thrombozyten, Vienna 1968, E. Deutsch, E. Gerlach, K. Moser; Georg Thieme publishing house Stuttgart) measured. Human citrate blood was spiked for 30 seconds with 1 g glass beads brought in contact. After the contact, the blood was allowed to stand for 1 hour to enable the disaggregation of the reversible aggregates. The platelets in the protruding Platelet-rich plasmas were microscopic before and after contact with the glass beads counted out.

After these 3 test methods, for example, show the following substances a good inhibiting effect already in concentrations of approx. 10 5 mol / l: 2 - [(5-aminopentyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride 2 - [(5-aminopentyl) methyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride 2 - [(3-aminopropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride 2 - [(2-Aminoethyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride The following examples are intended to explain the invention in more detail; EXAMPLES for the preparation of the starting materials: Example A 2,4-dioxy-6-methyl-thieno [3,2-d] pyrimidine 1.7 g (0.01 mol) 3-aminothiophene-6-methyl-2-carboxylic acid methyl ester and 3 g (0.05 mol) urea are intimately mixed and heated to 2000C for 2 hours. It arises a clear brown melt that solidifies on cooling. One dissolves in warm sodium hydroxide solution, decolorized with charcoal and acidified with 2N hydrochloric acid.

The precipitated crystalline product is filtered off with suction and extracted from water recrystallized.

F .:> 3200C Yield: 1.4 g (77% of theory) C7H6N202S (182.21) Calc .: C 46.14 H 3.32 N 15.38 Found: 46.02 3.40 15.25 In the same way, the the following compound prepared: 2,4-Dioxy-7-methyl-thieno [3,2-d] pyrimidine from 3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester and urea.

Q .:> 3000C Example B 2,4-Diochloro-6-methyl-thieno [3,2-d] pyrimidine 9.1 g (0.05 mol) of 2,4-dioxythieno [3,2-d] pyrimidine and 100 ml of phosphorus oxychloride are refluxed for 10 hours, during which a clear solution occurs.

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

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

The solid residue obtained after removal of the solvent is recrystallized from ethanol.

F .: 1500C Yield: 7.1 g (65% of theory) C7H4Cl2N2S (219.11) Calc .: C 38.37 H 1.84 Cl. 32.36 Found: 38.44 1.89 32.17 In the same manner, became the following Connection made: 2,4-dichloro-7-methyl-thieno? 2-dzpyrimidine from 2, 4-dioxy-7-methyl-thieno, 5,2-d7 pyrimidine and phosphorus oxychloride.

F .: 1860C (ethanol) Example C 2 -chloro-4-piperidino-thieno [3,2-d] pyrimidine 5.1 g (0.025 mol) of 2,4-dichlorothienoL3,2-d7pyrimidine are mixed with 200 ml of absolute Ethanol added. With vigorous stirring, and are added to the suspension obtained Cool to 200C 4.7 g (0.055 mol) piperidine. A clear solution emerges from a crystalline compound separates out after a short time.

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

The product is filtered off with suction, washed with water and ethanol and crystallized from ethanol.

F .: 127-1280C Yield: 5.2 g (82% of theory) C11H12ClN3S (253.76) 3rd: C 52.07 H 4.77 Cl 13.97 Found: 51.98 4.82 14.09 In the same way, the the following compounds prepared: a) 2-chloro-4-dimethylamino-thieno [3,2-d] pyrimidine from 2,4-dichloro-thieno [3,2-d] pyrimidine and dimethylamine.

F. 1630C (acetone) b) 2-Chloro-4-methylamino-thieno [3,2-d] pyrimidine from 2,4-dichloro-thieno [3,2-d] pyrimidine and methylamine F .: 2530C (acetone / ethanol 1: 1) c) 2-Chloro-4n-propyllamino-thieno [3,2-d] pyrimidine from 2,4-dichloro-thieno [3,2-d] pyrimidine and n-propylamine F .: 960C (petroleum ether / ethyl acetate 10: 1) d) 2-chloro-4-diethanolamino-thieno [3,2-d] pyrimidine from 2,4-dichloro-thieno [3,2-d] pyramidine and diethanolamine F .: 143 - 1440C (ethyl acetate / ethanol 2: 1) e) 2-Chloro-7-methyl-4-morpholino-thieno [3,2-d] pyrimidine from 2,4-dichloro-4-methyl-thieno [3,2-d] pyrimidine and Morpholine F .: 1280C (ethanol) Example 2 - [(3-Hydroxypropyl) -methyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine hydrochloride 5.1 g (0.02 mol) of 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 20 ml of 3-methylamino-1-propanol are heated to 120 ° C. for 4 hours.

After cooling, the clear solution is poured into water, whereby separates an oil. This is dissolved in ethanol and im Staggered excess.

When acetone is added, the hydrochloride precipitates in the form of white crystals the end.

It is filtered off with suction and recrystallized from ethanol / acetone (2: 1): Yield: 5.8 g (85% of theory F .: 203 ° C C14H21C1N4 02S (344.88) Calc .: C 48.75 H 6.13 N 16.24 Cl 10.27 Found: 48.75 6.34 216.15 10.33 In the same way, the following Compounds prepared: a) 2 - [(3-Hydroxypropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 3-ethylamino-1-propanol.

F. of the hydrochloride: 2350C (ethanol / acetone 2: 1) b) 2- [4-hydroxybutyl) methyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-4-morpholino-thieno [3, pyrimidine and 4-methylamino-1-butanol.

F .: of the hydrochloride: 217 ° C. (ethanol / acetone 2: 1) c) 2- [4-hydroxybutyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine.

from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 4-ethylamino-1 -butanol.

F. of the hydrochloride: 226-2270C (ethanol / acetone 2: 1) d) 2- [4-Hydroxybutyl) -n-propyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 4-n-propylamino-1-butanol.

F. of the hydrochloride: 160-1630C (ethanol / acetone 2: 1) a) 2- [4-hydroxybutyl) -n-butyl-amino] -4-morpholinothieno- [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 4-n-butyiamino-1-butanol.

F. of the hydrochloride: 162-1650C (ethanol / acetone 2: 1) f) 2- [5-hydroxypentyl) -ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 5-ethylamino-1 -pentanol.

F. of the hydrochloride: 115-1200C (ethanol) g) 2- [6-hydroxyhexyl) methylamino] -4-morpholino-thieno [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 6-methylamino-1-hexanol.

F. of the hydrochloride: 1150C (ethanol) h) 2- [6-hydroxypentyl) -ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 6-ethylamino-1-hexanol RF: 0.5; Silica gel G from Merck, (petroleum ether / ethyl acetate 1: 1) 1) 2- [5-hydroxypentyl) -n-butyl-amino] -4-morpholinothieno [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 5-n-butylamino-1-pentanol.

F. of the hydrochloride: 900C (isopropanol / petroleum ether) Example E 2- [2-chloropropyl) -methyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine hydrochloride 15.4 g (0.05 mol) of 2- [3-hydroxypropyl) methyl-amino] -4-morpholinothienoL3,2-d7-pyrimidine 30 ml of thionyl chloride are added and the mixture is left to stand at room temperature overnight calmly. Then the excess thionyl chloride is stripped off in vacuo and the Acetone or ether added to the residue. The colorless crystalline precipitate is filtered off with suction, dried and recrystallized from ethanol / acetone (1: 1).

F .: 1800C Yield: 17.6 g (97% of theory) C14H20Cl2N40S (363.32) Ber. C 46.25 H 5.54 N 15.43 Cl 19.53 Found: 46.00 5.62 15.37 19.55 In the same way the following compounds were prepared: a) 2- [4-chlorobutyl) methylamino] -4-morpholino-thieno [3,2-d] pyrimidine hydrochloride from 2- [2-hydroxybutyl) methylamino] -4-morpholinothieno- [3,2-d] pyrimidine and thionyl chloride.

F .: 205 - 208 ° C (ethanol / Aveton 1: 1) b) 2- / r4-chlorobutyl) ethyl amine ° 7-4-morPholino-thieno , 2-d7-pyrimidine hydrochloride from 2- [4-hydroxybutyl) ethyl-amino] -4-morpholino-thienog , 2-d7pyrimidine and thionyl chloride.

F .: 1650C (ethanol / acetone 1: 1) c) 2- [4-chlorobutyl) -n-propyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine hydrochloride from 2- [4-hydroxypentyl) -n-propyl-amino] -4-morpholino-thieno- [3,2-d] pyrimidine and thionyl chloride M.p .: 195 ° C (ethanol / acetone 1: 1) d) 2- [4-chlorobutyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine hydrochloride from 2- [4-hydroxybutyl) -n-butyl-amino] -4-morpholino-thieno- [3,2-d] pyrimidine and thionyl chloride.

F .: 187-1880C (ethanol / acetone 1 t 1) e) 2- [5-chloropentyl) -ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine hydrochloride from 2- [5-hydroxypentyl) ethyl-amino] -4-morpholino-thieno-L3, 2-d7pyrimidine and thionyl chloride.

F .: 183 - 1850C (ethanol / acetone 1: 1) f) 2- [4-chloropentyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine from 2- [5-hydroxypentyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and thionyl chloride.

Oil, RF = 0.8 silica gel G from Merck, petroleum ether / ethyl acetate 1 : 1 g) 2- [6-chlorohexyl) methylamino] -4-morpholino-thieno [3,2-d] pyrimidine from 2- [6-hydroxyhexyl) methylamino] -4-morpholino-thieno [3,2-d] pyrimidine and thionyl chloride.

oil, RF = 0.8 silica gel G from Merck, petroleum ether / ethyl acetate 1: 1 h) 2- (6-chlorohexyl) -ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine 2- [6-Hydroxyhexyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and thionyl chloride.

oil, RF = 0.8 silica gel G from Merck, petroleum ether / ethyl acetate 1 : 1 Example F 2-Methylmercapto-4-morpholino-thieno [3,2-d] pyrimidine 2.16 g (0.01 mol) 2-methylmercapto-4-chloro-thieno [3,2-d] pyrimidine (prepared from 2-methylmercapto-4-oxy-thieno [3,2-d] pyrimidine and phosphorus oxychloride, melting point: 71-73 ° C) are mixed with 30 ml of absolute ethanol. The suspension obtained is added with vigorous stirring and cooling to 200.degree 1.74 g (0.02 mol) of morpholine.

The reaction mixture is stirred for three hours at room temperature.

It is filtered off with suction, washed with water and ethanol and crystallized out Ethanol.

F .: 138-140 ° C Yield: 2.05 g (77% of theory) C11H13N30S2 (267.38) Calc .: C 49.44 H 4.90 N 15.72 Found: 49.21 4.95 15.84 Example G $ 2-Methylsulfonyl-4-morpholinothieno [3,2-d] pyrimidine To a solution of 2.67 g (0.01 mol) of 2-methylmercapto-4-morpholino-thieno [3,2-d] pyrimidine in 25 ml of glacial acetic acid at 250C within 15 minutes 3.5 g (0.022 mol) of potassium permanganate, dissolved in 25 ml of water, added dropwise.

The reaction mixture is then stirred at 250 ° C. for 2 3/4 hours.

It is decolorized with sodium bisulfite solution, and sodium hydroxide solution is added until alkaline and extracted several times with methylene chloride.

The combined extracts are washed with water over sodium sulfate dried and evaporated in vacuo.

The remaining residue is recrystallized from ethanol.

F .: 191-1930C Yield: 1.84 g (62% of theory) C11H13N3O3S2 (299.38) Calc .: C 44.12 H 4.38 N 14.03 Found: 44.19 4.45 13.90 Example H 2- (2-Amino-ethylamino) -4-mercapto-thieno [3,2-d] pyrimidine 2.1 g (0.01 mol) 2- (2-Amino-ethylamino) -4-oxy-thieno [3 , 2-d] pyrimidine and 2.5 g (0.011 mol) of phosphorus pentasulfide are in 25 ml of absolute pyridine for 4 hours heated to reflux.

The clear solution is evaporated to dryness in vacuo. One relocates with 20 ml of water, heated to boiling for one hour and cooled to 50C.

A pH value of 12 is set by adding 2N sodium hydroxide solution, the resulting solution filtered through activated charcoal and the 2- (2-amino-ethylamino) -4-mercapto-thieno [3,2-d] pyrimidine precipitated by means of glacial acetic acid.

It is filtered off with suction, washed with water and crystallized from dimethyl formamide around.

F .: 249-250 ° C (decomp.) Yield: 0.9 g (40% of theory) C8H10N4S2 (226.33) Calc .: C 42.46 H 4.45 N 24.76 Found: 42.33 4.47 24.57 Example I 2- (2-Amino-ethylamino) -4-methylmercapto-thieno [ 3,2-d] pyrimidine 2.26 g (0.01 mol) of 2- (2-amino-ethylamino) -4-mercapto-thieno-2-d7-pyrimidine dissolved in 40 ml of 0p25 n potassium hydroxide solution.

The mixture is cooled to 0 ° C. and 1.42 g (0.01 mol) of methyl iodide are added dropwise, stirring to. After a short time, an oil separates out.

The reaction mixture is stirred for a total of 2 hours at 0 ° C and then extracted several times with chloroform. The combined extracts are washed with Water, dry over sodium sulfate, evaporate the solvent and crystallize the residue from ether.

F .: 750C (dec.) Yield: 1.9 g (79% of theory) CgH12N4S2 (240.36) Calc .: C 4h, 96 H 5.03 N 23.31 Found: 45.13 5.10 23.18 Example J 2 [(2-cyanoethyl) -n-butyl-amino) -4-morpholino-thieno [ 3,2-d] pyrimidine 5.2 g (0.02 mol) of 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine and 20 ml of 3-n-butylamino-propionitrile are heated to 1500C for 10 hours. The excess 3-n-butylamino-propionitrile is then distilled off in vacuo, the residue is poured into water and extracted several times with methylene chloride. The methylene chloride phase is dried with sodium sulfate and evaporated to dryness. Column chromatography (silica gel, petroleum ether / ethyl acetate 2: 1) is used to recover after distilling off the eluent, the desired product as a yellow oil. This is precipitated by adding methanolic hydrochloric acid and adding acetone crystalline hydrochloride.

F .: 182 - 1850C (isopropanol) Yield: 5.0 g (65.4 56 of theory) C <24ClN50S (381.96) Calc .: C 53.45 H 6.33 N 18.33 Cl 9.27 S 8.38 Found: 53.50 6.59 18.45 9.02 8.33 In the same way, the following compounds were made prepared: a) 2 - [(2-cyanoethyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine hydrochloride from 2-chloro-4-morpholino-thienog 2-d] pyrimidine and 3-ethylamino-propionitrile.

F .: 1800C (isopropanol) b) 2 - [(2-cyanoethyl) methylamino] -4-morpholino-thieno [3,2-d] pyrimidine from 2-chloro-4-morpholino-thieno [3,2-d] pyramidine and 3-methylamino-propionitrile.

Q .: 100-1010C (isopropanol).

Examples for the preparation of the end products: Example 1 2- (2-Amino-ethylamino ) -4-ieridino-thieno '2-d7-pyrimidine dihydrochloride 5.1 g (0.02 mol) of 2-chloro-4-piperidino-thieno [3,2-d] pyramidine and 20 ml of 1,2-diaminoethane are heated to 1200C for 30 minutes.

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

The combined extracts are washed with water and dried over sodium sulfate and evaporates. The non-crystalline residue is purified by column chromatography (Sorbent: silica gel for column chromatography, 0.2-0.5 mm, Merck; mobile phase: Acetone / methanol = 7: 3).

The uniform fractions are evaporated.

The remaining, non-crystalline 2- (2-amino-ethylamino) -4-piperidino-thieno [3,2-d] pyrimidine is dissolved in absolute ether and the dihydrochloride precipitates with ethereal hydrochloric acid. This is suction filtered, washed with ether and recrystallized from absolute ethanol.

F .: 275-2770C (dec.) Yield: 3.9 g (56% of theory) C13H21C12N5S (350.32) Calc .: C 44.60 H 6.04 N 20.00 Cl 20.23 Found: 44.40 6.21 19.80 20.45 on the following compounds were prepared in the same manner: a) 2- (4-Aminobutylamino) -4-piperidino-thieno [3,2-d] pyrimidine from 2-chloro-4-piperidino-thieno [3,2-d] pyrimidine and 1,4-diamino-butem.

F. of the dihydrochloride: 2190C (ethanol / acetone 1: 5) b) 2- (6-amino-hexylamino) -4-piperidino-thieno [3,2-d] pyrimidine from 2-chloro-4-piperidino-thieno [3,2-d] pyrimidine and 1,6-diamino-hexane.

F. of the dihydrochloride: 281-2830C (ethanol / acetone 1: 5) c) 2- (3-amino-propylamino) -4-dimethylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-dimethylamino-thleno 2-d] pyrimidine and 1,3-diamino-propane.

F. of the dihydrochloride: 269-271 ° C (methanol) d) 2- (4-Aminobutylamino) -4-dimethylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-dimethylamino-thieno [3,2-d] pyrimidine and 1,4-diamino-butane.

F, of the dihydrochloride: 280 ° C (ethanol) e) 2- (6-Amino-hexylamino) -4-dimethylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-dimethylamino-thieno [3,2-d] pyrimidine and 1,6-diamino-hexane.

F. of the dihydrochloride: 265 - 2660C (ethanol / acetone) f) 2- (4-Amino-butylamino) -6-methyl-4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-6-methyl-4-morpholino-thieno [3,2-d] pyramidine and 1,4-diamino-butane.

F. of the dihydrochloride: 315-316 ° C (ethanol) g) 2- (5-amino-pentylamino) -6-methyl-4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-6-methyl-4-morpholino-thieno [3. 2-d7pyrimidine and 1,5-diamino-pentane.

F. of the dihydrochloride: 302-3050C (ethanol) h) 2- (2-amino-ethylamino) -7-methyl-4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-7-methyl-4-morpholino-thieno [3,2-d] pyrimidine and 1,2-diamino-ethane F. of the dihydrochloride: 2900'C (dec.) (methanol) 1) 2- (5-Amino-pentylamino) -7-methyl-4-morpholino-thieno [3,2-d] -pyrimidine from 2-chloro-7-methyl-4-morpholino-thieno [3,2-d] pyrimidine and 1,5-diamino-pentane.

F. of the dihydrochloride: 2500C (ethanol) j) 2- (2-amino-ethylamino) -4-methylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-methylamino-thieno [3,2-d] pyrimidine and 1,2-diamino-ethane.

F. of the dihydrochloride: 2800C (dec.) (Ethanol / acetone 1: 3) k) 2- (4-amino-butylamino) -4-methylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-methylamino-thieno [3,2-d] pyrimidine and 1,4-diamino-butane.

F. of the dihydrochloride: 3000 (dec.) (Ethanol / acetone) 2- (6-Am ~ ino-hexvlamino) -4-methylamino-ienone, e-dZpyrimidine from 2-chloro-4-methylamino-thieno [3,2-d] pyrimidine and 1,6-diamino-hexane.

F. of the dihydrochloride: 241 0C (ethanol / acetone) m) 2- (2-amino-ethylamino) -4-n-propylamino-thieno [3,2-d] pyrimidine from 2-chloro-4-n-propylamino-thieno [3,2-d] pyrimidine and 1,2-diamino-ethane.

F. of the dihydrochloride: 246-2470C (ethanol / acetone 1: 3) n) 2- (4-amino-butylamino) -4-n-propylamino-thieno [3,2-d] pyramidine from chloro-4-n-propylamino-thieno [3. 2-d7pyrimidine and 1,4-diamino-butane.

F. of the dihydrochloride: 216-2170C (ethanol / acetone 1: 3) Example 2 2 - [(4-aminobutyl) methyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride 9.5 g (0.025 mol) of 2 - [(4-chlorobutyl) methyl-amino) -4-morpholinothieno [3,2-d] pyrimidine hydrochloride are together with 10.0 g (0.054 mol) of phthalimide potassium in 75 ml of dimethylformamide Heated to 145 ° C. for 44 hours. After cooling, the reaction mixture is added with water and extracted with chloroform. The chloroform phase is made with sodium sulfate dried and the solvent removed. The residue is recrystallized from isopropanol.

F .: 1400C Yield: 5.5 g (49% of theory) 1.75 g (0.025 mol) of hydroxylamine hydrochloride are dissolved in 100 ml of ethanol and mixed with 12.5 ml of 4 normal methanolic sodium methylate solution (0.05 mol) are added. To After filtering off the precipitated sodium chloride, 3.0 g (0.0066 mol) of the phthalimido compound in 20 ml of ethanol and the mixture is stirred for two hours at room temperature. After suctioning off the gelatinous precipitate (sodium salt of the N-hydroxy-phthalimide) the filtrate is mixed with methanolic hydrochloric acid and a bit narrowed. The precipitated crystalline product is filtered off with suction and removed Recrystallized ethanol / acetone.

F .: 2600C Yield: 1.35 g (51.5 5 'of theory) C15H25Cl2N50S (394.38) Calc .: C 45.70 H 6.40 N 17.76 S 8.12 Found: 45.70 6.47 17.90 8.17 In the same way the following compounds were prepared: a) 2- [4-aminobutyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride from 2 - [(4-chlorobutyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine and phthalimide-potassium and hydroxylamine.

F .: 259-2610C (ethanol / acetone) b) 2- / t4-aminobutyl) -n-proyl -amino7-4-rnorpholino-thienq-2-d7-PYrimid - dihvdyochlorid from 2 - [(4-chlorobutyl) -n-propyl-amino] -4-morpholino-thieno-3,2-d7-pyrimidine and phthalimide-potassium and hydroxylamine.

F: 1850C (ethanol / acetone) c) 2 - [(4-aminobutyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2 - [(4-chlorobutyl) -n-butyl-amino] -4-morpholino-thieno- [3,2-d] pyrimidine and phthalimide-potassium and hydroxylamine.

M.p .: 280 ° C (ethanol / acetone) d) 2 - [(5-aminopentyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2 - [(5-chloropentyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and phthalimide-potassium and hydroxylamine.

F.s 236-238Q C <ethyl acetate / methanol 3: 1) e) 2 - [(6-Aminohexyl) -methyl-amino] -4-morpholino-thieno [3,2-d] -pvrimidine-dihyrochloride from 2 - [(6-chlorohexyl) methylamino] -4-morpholinothieno- [3,2-d] pyrimidine and phthalimide-kaline and hydroxylamine.

F .: 227-2280C (ethanol) f) 2 - [(6-Aminohexyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine from 2 - [(6-chlorohexyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and phthalimide-potassium and hydroxylamine.

Yellow oil (RF = 0.5, silica gel, methanol / ammonia 9 s 1) example 3 2- (2-Amino-ethvlamino) -4-diethanolamino-7-methyl-thieno, 2-d7-pyrimidine dihydrochloride 2.87 g (0.01 mol) of 2-chloro-4-diethanolamino-7-methyl-thieno [3,2-d] pyrimidine (shown from 2,4-dichloro-7-methyl-thieno-, 2-d7pyrimidine and diethanolamine) and 10 ml of 1,2-diaminoethane are heated to 120 ° C. for Z hours. The excess amine is then distilled off in vacuo and the residue is purified by column chromatography (sorbent: silica gel for column chromatography; 0.2-0.5 mm, Merck; Mobile phase: methanol / conc.

Ammonia. = 9: 1).

The uniform fractions are evaporated. The remaining non-crystalline 2- (2-amino-ethylamino) -4-diethanolamino-7-methyl-thieno [3,2-d] pyrimidine is dissolved in excess ethanolic hydrochloric acid, evaporated to dryness and the residue was recrystallized from methanol / ethanol (3: 1).

F .: 2350C (dec.) Yield; : 2.6 g (68% of theory) C13H2DCl2N502S (384.34) Calc .: C 40.62 H 6.03 N 18.22 Found: 40.45 6.18 18.11 2- (2-Amino-ethylamino) -7-methyl-4-morpholino- thieno [3,2-d] -pvrimidine dihydrochloride 3.84 g (0.01 mol) of 2- (2-amino-ethylamino) -4-diethanolamino-7-methyl-thieno [3,2-d] pyrimidine dihydrochloride are dissolved in 50 ml of concentrated sulfuric acid and with exclusion of moisture Left to stand at 200C for 3 days.

The reaction mixture is poured onto ice water * and 40% sodium hydroxide solution strongly alkaline and extracted several times with methylene chloride.

The combined extracts are washed with water over sodium sulfate dried and mixed with essential hydrochloric acid.

The dihydrochloride of 2- (2-amino-ethylamino) -7-methyl-4-morpholino-thieno [3,2-d] pyrimidine is precipitated from, which is suction filtered, washed with ether and recrystallized from methanol will.

M.p .: 335 ° C (decomp.) Yield: 1.98 g (54% of theory) C13H21Cl2N505 to Cl2N5OS (366.33) Calc .: C 42.70 H 5.77 N 19.10 Found: 42.50 5.88 18.95 To analogous The following compounds were prepared: a) 2 - [(3-Aminiopropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2-Zv3-aminopropyl) -ethyl-amino7-4-diethanolamino-thieno- [3,2-d] pyrimdine dihydrochloride and concentrated sulfuric acid.

F .: 2800C (ethanol) b) 2 - [(5-aminopentyl) -ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2-5-aminopentyl) -ethyl-amino7-4-diethanolamino-thieno [3,2-] pyrimidine dihydrochloride and concentrated sulfuric acid.

F .: 236-2380C (ethyl acetate / methanol 3: 1) c) 2- / t6-aminohexyl) -methyl-amino7-4-morholino-thieno / ' 2-d7-pyrimidine dihydrochloride from 2 - [(6-aminohexyl) methylamino] -4-diethanolaminothieno [3,2-d] pyrimidine dihydrochloride and concentrated sulfuric acid.

F .: 227 - 2280C (ethanol) d) 2 - [[4-aminobutyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidino-dihydrochloride from 2 - [(4-aminobutyl) -n-butyl-amino] -4-diethanolamino-thieno-, 2-d7pyrimidine dihydrochloride and concentrated sulfuric acid.

M.p .: 280 ° C (ethanol / acetone) e) 2 - [(2-aminoethyl) -iso-propyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride from 2 - [(2-aminoethyl) -iso-propyl-amino] -4-diethanolaminothieno [3,2-d] pyrimidine dihydrochloride and concentrated sulfuric acid.

F .: 278-2800C (ethanol) Example 4 2 - [(3-aminopropyl) -methyl-amino] -4-morpholino-thieno [3,2-d] -kLa 10.7 g (0.035 mol) of 2 - [(2-cyanoethyl) methylamino] -4-morpholinothieno [3,2-d] pyrimidine are dissolved in 200 ml of methanolic ammonia and together with 10 g of Raney nickel in an autoclave at room temperature and a hydrogen pressure of 100 at 8 hours hydrogenated. after filtering off the catalyst and concentrating the filtrate, the Reskstand mixed with water and the solution by adding dilute hydrochloric acid adjusted to pH-6. After extraction with chloroform, the aqueous phase becomes alkaline and again extracted with chloroform. The chloroform phase is made with sodium sulfate dried and the solvent removed. The residue is taken up in isopropanol and converted into the crystalline dihydrochloride by adding ethereal hydrochloric acid.

F .: 245-248 ° C (ethanol) Yield: 5.2 g (39.1% of theory) the following compounds were prepared in the same way: a) 2 - [(3-aminopropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2 - [(2-cyanoethyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and hydrogen / Raney nickel M.p .: 280 ° C (ethanol) b) 1 - [(3-aminopropyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine hydrochloride from 2- [2-cyanoethyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and hydrogen / Raney nickel F. .: 279-281 ° (isopropanol) Example 5 2- [2- (p-toluenesulfonamido) -ethyl-ethyl-amino] -4-morpholinothieno [3,2-d] pyrimidine 2.36 g (0.01 mol) 2-chloro-4-morpholino-thieno [3.2-d] pyrimidine and 7 @@ g (0. @ mol) 2- (p-Toluolsolsulfonamido) -äthyl-ethylamine heated to 140 ° C for 8 hours. After this After cooling, the all-yellow solution is poured into water and extracted with methylene chloride @@@ Ethylene chloride phase is dried with sodium sulfate and vaporized to dryness. By column chromatography (silica gel; benzene / acetone / methanol 60:25:15 + 1% ammonia) recover the desired product in after distilling off the eluent crystalline form.

F .: 123-1250C (methanol) Yield: 4.0 g (87% of theory) Avg Treatment with methanolic hydrochloric acid gives the hydrochloride.

F .: 249-251 ° C (methanol) C21H28ClN503S2 (498.08) Calc .: C 50.64 H 5.67 N 14.06 Cl 7.12 S 12.87 Found: 50.85 5.74 13.95 7.19 12.60 2 - [(2-Aminoethyl) -ethyl-amino] -4- morpholino-thieno [3,2-d] pyrimidine dihydrochloride 4.6 (0.01 ml) 2- [2- (p-toluenesulfonamido) ethyl-ethylamino] -4-morpholino-thieno [3,2-d] pyrimidine together with 50 ml of a 40 percent solution of hydrogen bromide in glacial acetic acid and 1.8 g (0.02 mol) phenol heated to 60 ° C. for 6 hours.

Then the solvent is distilled off under reduced pressure, the residue is mixed with water and made strongly acidic by adding hydrochloric acid. After extraction with diethyl ether, the aqueous phase is treated with potassium carbonate Made alkaline cooling and extracted with methylene chloride.

The extract is dried with sodium sulfate and the solvent deducted.

The oily residue is obtained by adding methanolic hydrochloric acid converted into the crystalline dihydrochloride.

F .: 284-2850C (ethanol) Yield: 1.2 g (32% of theory) Cn4H23Cl2 N50S (380.27) Calc .: N 18.45 Cl 18.65 S 8.42 Found: 18.25 18.40 8.23 In The following compounds were prepared in the same way: a) 2- / t2-aminoethyl) methyl-amino] -6-methyl-4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride from 2- [2- (p-toluenesulfonamido) ethyl-methylamino] -6-methyl-4-morpholino-thieno [3,2-d] pyrimidine (F .: 270 - 273 ° C) and hydrogen bromide / glacial acetic acid.

Q .: 293-2950C (ethanol) b) 2 - [(2-aminoethyl) -n-propyl-amino] -4-morpholino-thieno [3,2-d] -pvrimi.ddihvdrochlorid from 2- [2- (p-toluenesulfonamido) ethyl-n-propylamino] -4-morpholino-thieno [3,2-d] pyrimidine gF .: 218 222 ° C) and hydrogen bromide / glacial acetic acid.

F .: 273-2750C (methanol) c) 2 - [(2-aminoethyl) -iso-propyl-amino] -4-morpholino-thieno- [3,2-d] pyrimidine dihydrochloride from 2- [2- (p-toluenesulfonamido) -ethyl-iso-propylamino] -4-morpholino-thieno [3,2-d] pyrimidine (F .. 228-2300C) and hydrogen bromide / glacial acetic acid.

F .: 278-2800C (ethanol) d) 2 - [(2-aminoethyl) -n-butyl-amino] -4-morpholino-thieno [3,2-d] -pyrimidine dihydrochloride from 2- [2- (p-toluenesulfoanmido) ethyl-n-butylamino] -4-morpholino-thieno [3,2-d] pyrimidine (F .: 214 "a15) and hydrogen bromide / glacial acetic acid.

F .: 271 - 2740C (ethanol) e) 2 - [(3-aminopropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine dihydrochloride from 2- [3- (p-toluenesulfonamido) propyl-ethylamino] -4-morpholino-thieno [3,2-d] pyrimidine (F .: 118-120 ° C) and hydrogen bromide / glacial acetic acid.

M.p .: 280 ° C (ethanol) f) 2 - [(3-aminopropyl) -n-propyl-amino] -4-morpholino-thieno [3,2-d] -pvrimidine dihydrochloride from 2- / 3- (p-toluenesulfonamido) propyl-n-propylamino] -4-morpholino-thieno [3,2-d] pyrimidine (F .: 111 ° C) and hydrogen bromide / glacial acetic acid.

F.s 291-2930C (ethanol) The compounds of the general formula I and their salts can also be combined by methods known per se incorporate into common pharmaceutical preparations with other active ingredients. the The single dose for adults is 5 to 100 mg, preferably 10 to 50 mg Daily dose 100 to 200 mg.

Claims (17)

P a t e n t a n s p r ü c h e 1.) new 2-aminoalkylamino-thieno [3,2-d] pyrimidines of the general formula in which R1 and R2, which can be the same or different from one another, represent hydrogen atoms or straight-chain or branched alkyl radicals with 1 to 6 carbon atoms, the radicals R1 and R2 together with the intermediate nitrogen atom also being a saturated 5- to 7 ° membered monocyclic, heterocyclic Can form a ring, which can optionally be interrupted by an oxygen atom or a further nitrogen atom and / or substituted by an alkyl radical or a hydroxyl group, R3 and R4, which can be the same or different? Hydrogen atoms or straight-chain or branched alkyl radicals with 1-6 carbon atoms and A denotes a straight-chain or branched alkylene group with 2 to 10 carbon atoms and their physiologically acceptable acid addition salts with inorganic or organic acids. 2.) 2 - [(5-aminopentyl) ethyl-amino] -4-morpholino-thiena [3,2-d] -pyrimidine and its acid addition salts. 3.) 2 - [(5-aminopentyl) methyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and its acid addition salts. 4.) 2- [§-Aminopropyl) ethyl-amino] -4-morpholino-thieno [3,2-d] pyrimidine and its acid addition salts. 5.) 2-Zt2-aminoethyl) ethyl amine -4-morpholino-thieno g, 2-d7-pyrimidine and its acid addition salts. 6.) Process for the preparation of new 2-aminoalkylaminothieno, 2-d7pyrimidines of the above general formula I and of their acid addition salts with inorganic or organic acids, characterized in that a) a compound of the general formula IIi in which R1, R2 and R4 are as defined at the outset and Z denotes a halogen atom, a substituted mercapto group or an alkylsulfonyl group, with a diamine of the general formula III, in which A and R3 as defined at the outset and X represents a hydrogen atom or a protective radical, reacted and, if appropriate, a protective radical X is then split off, or b) a compound of the general formula IV, in which A, X, R3 and R4 are as defined at the outset and Z 'denotes a halogen atom, a free or substituted mercapto group or an alkylsulfonyl group, with an amine of the general formula V, in which R1 and R2 are as defined at the outset, reacted and, if appropriate, a protective radical X is then split off or c) a compound of the general formula VI, in which A, R1, R2, R3 and R4, as defined at the outset and Z "denotes a halogen atom, is reacted with ammonia or with a carboxamide or imide or with their metal salts and in the case of a reaction with a carboxamide or - imide or with a metal salt of the carboxylic acid - imide from the resulting carboxylic acid derivative, the carboxylic acid residue is then split off with acids or bases, or d) a compound of the general formula VII, in which R1, R2, R3 and R4 are as defined at the outset and A; has the meaning of the radical A, but shortened by one methylene group, is catalytically reduced or e) for the preparation of compounds of the general formula 1 in which R1 and R2 together with the nitrogen atom in between represent a morpholine ring optionally substituted by an alkyl radical, a compound of the general formula VIII, in which A, R3, 4 and X are as defined at the outset and R5 and R6 represent hydrogen atoms or one of the radicals R5 or R6 is an alkyl radical and the other of the radicals R5 or R6 is a hydrogen atom, is cyclized intramolecularly in the presence of an acidic condensing agent and optionally thereafter a protective radical X is split off and, if desired, a compound of the general formula I obtained is then converted into its acid addition salts with inorganic or organic acids. 7 '. Method according to claims 6a and 6b, characterized in that that the implementation of a compound of the general formula II or IV, in which Z or Z 'represents a halogen atom in the presence of a hydrogen halide binding agent he follows. 8 .. Method according to claims 6a, 6b and 7, characterized in that that as a halogenated hydrogen binding agent an excess of the diamine of the general Formula III or the amine of the general formula V is used. 9 ,. Method according to Claims 6a, 6b and 6e, characterized in that that the cleavage of a protective radical X, e.g. of an acyl radical, hydrolytically in the presence of acids or bases he follows. 10. The method according to claims 6a, 6b, 6c, 7 and 8, characterized in that that the reaction takes place in a solvent and at temperatures between 20 and 2000C is carried out. 11. The method according to claim 6d., Characterized in that the Reduction activated by means of in the presence of Raney nickel, palladium or platinum Hydrogen in a solvent at temperatures between 30 and 100 0C and is carried out at pressures of 20 to 150 atmospheres. 12. The method according to claim 6e, characterized in that the condensation agent Acids, anhydrous metal salts or a cation exchanger is used. 13. The method according to claims 6e and 12, characterized in that that the reaction is carried out at temperatures between 0 and 175 ° C. 1.4. Method according to claims 6e: generally and 19, characterized in that that the reaction is carried out in a solvent. 15. The method according to claims 6-14, characterized in that when using a volatile reactant, the reaction takes place in a closed Vessel takes place. 1. Medicinal preparations, characterized by einn content of a or several compounds of the general formula I in addition to carriers and auxiliaries. 17. A method for producing pharmaceutical preparations according to claim 16 characterized in that one or more compounds of the general formula I are mixed with the carrier and auxiliary materials.