DE3013930A1 - 2-Per:hydro:diazine-pyrimido-pyrimidine derivs. - with antithrombotic activity, used e.g for prophylaxis of thromboembolic and arteriosclerosis - Google Patents

Abstract

4-(R2) 8-(R1) 2-(perhydro-1,4-diazino) pyrimido (5,4-d)- pyrimidine derivs. of formula (I) and their acid addn. salts are new (R1 is OR4, SR5 or NR6R7; R4 is alkyl opt. substd. by OH, alkoxycarbonyl, Ph, alkylthiophenyl or dialkylamino, all alkyl parts having 1-3C; R5 is H, 4-8C alkyl, 5-7C cycloalkyl, phenyl, methylenedioxy- benzyl, indanyl, naphthyl-methyl; phenyl or benzyl both substd. by one or two same or different OH, NO2, NH2, CF3, 1-3C alkyl, 1-3C alkoxy and/or halogen; or as R4; R6 and R7 are each H, 1-4C alkyl (opt. substd. by OH, 1-3C alkoxy or Ph), Ph, 5-8C alkyl, 5-7C cycloalkyl, pyridyl, picolyl or furyl, all Ph parts being opt. substd. by 1 or 2 same or different 1-3C alkyl, 1-3C alkoxy, CF3, F, Cl or Br or by one methylenedioxy; or NR6R7 is 4-6C alkyleneimino, thiomorpholine or thiomorpholino-1-oxide; R2 is thiomorpholino (or its 1-oxide or 1,1-dioxide) opt. substd. by 1 or 2 Me; or one of R1 and R2 is morpholino opt. substd. by 1 or 2 Me; R3 is H, Ph, 1-5C alkyl (opt. substd. by OH or Ph), 2-4C alkanoyl (opt. substd. by OMe, COMe or COOH), CHO, acetoxybenzoyl, pyridinoyl, furoyl or thienoyl; n is 2 or 3).

Description

New 2- (perhydro-1,4-diazino) -pyrimido 5, 4-dJpyrimidines,

their preparation and the pharmaceuticals containing them ZAddition to the DBP (patent application P 29 26 804.0L7 The present invention relates to new 2- (perhydro-1,4-diazino) pyrimido [5,4-d] pyrimidines of the general formula their physiologically acceptable acid addition salts with inorganic or organic acids and processes for their preparation, as well as medicaments containing the new compounds of general formula I.

The new 2- (perhydro-1,4-diazino) -pyrimido / 5,4-d7pyrimidines and their Physiologically acceptable acid addition salts have valuable pharmacological Properties, in particular antithrombotic effects.

In general formula I, R1 denotes an amino group of the formula where R4 and R5, which can be the same or different, hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, each alkyl group being substituted by a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a phenyl group, or phenyl groups where the above-mentioned phenyl nuclei monosubstituted by a methylenedioxy group or monosubstituted or disubstituted by an alkyl or alkoxy group each having 1 to 3 'carbon atoms, a trifluoromethyl group, a fluorine, chlorine or bromine atom and the substituents of the phenyl nucleus can each be the same or different, alkyl groups having 5 to 8 carbon atoms, cycloalkyl groups with 5 to 7 carbon atoms, pyridyl, picolyl or furfuryl groups or R4 and R5 together with the intermediate nitrogen atom an alkyleneamino group with 4 to 6 carbon atoms, a thiomorpholino or thiomorpholino-1-oxide group, R2 an optionally through 1 or 2 substituted methyl groups Thiomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group or one of the radicals R1 or R2 also a morpholino group optionally substituted by 1 or 2 methyl groups, R3 a hydrogen atom, an optionally substituted by a hydroxyl group with 1 to 4 Carbon atoms, an alkanoyl group with 2 to 4 carbon atoms which is optionally substituted by a carboxy, methoxy or acetyl group, a formyl or furoyl group and n is the number 2 or 3.

For those mentioned at the beginning in the definition of the radicals R1, R2 and R3 Meanings thus comes for R1 the meaning of the amino, methylamino, ethylamino, Propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino, tert.pentylamino, hexylamino, heptylamino, octylamino, cyclopentylamino, cyclohexylamino, Cycloheptylamino, hydroxyethylamino, 3-hydroxypropylamino, 2-hydroxypropylamino, 4-hydroxybutylamino, 5-hydroxypentylamino, 8-hydroxyoctylamino, benzylamino, Fluorobenzylamino, chlorobenzylamino, bromobenzylamino, methylbenzylamino, methoxybenzylamino, Difluorobenzylamino, dichlorobenzylamino, dibromobenzylamino, dimethoxybenzylamino, Methylenedioxybenzylamino-, bromo-chloro-benzylamino-, bromo-methoxybenzylamino-, 1-phenyl-ethylamino-, 2-phenylethylamino, 2-dimethoxyphenylethylamino, 1-phenylpropylamino, 3-phenylpropylamino, 2-phenylbutylamino- r 4-phenyl-butylamino-, phenylamino-, methoxyphenylamino-, athoxyphenylamino-, Trifluorophenylamino, pyridylamino, picoylamino, furfurylamino, N-methyl-phenylamino, N-methyl-pyridylamino-, N-methyl-picolylamino-, N-methyl-benzylamino-, N-Xthylbenzylamino-, N-propyl-benzylamino-, N-isopropyl-benzylamino-, N-butyl-benzylamino-, N-pentyl-benzylamino-, N-octyl-benzylamino-, N-hydroxyethyl-benzylamino-, N-hydroxypropyl-benzylamino-, N-Hydroxybutyl-benzylamino-1 N-methyl- 2- (dimethoxyphenyl) -äthylamino-, dimethylamino-, Diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, Dihexylamino, diheptylamino -, methyl ethylamino, methyl propylamino, Ethylpropylamino, ethyl isopropylamino, diethanolamino, N-hydroxyethyl methoxyethylamino, Dihydroxypropylamino, pyrrolidino, piperidino, hexamethyleneimino, thiomorpholino, Thiomorpholino-1 -oxide, morpholino, methylmorpholino or dimethylmorpholino group, for R2 the morpholino, methylmorpholino, dimethylmorpholino, thiomorpholino, Methyl thiomorpholino, thiomorpholino-1-oxide, dimethylthiomorpholino -) - oxide or Thiomorpholino-1, 1-dioxide group and for R3 that of the hydrogen atom, the methyl, Ethyl, propyl, isopropyl, butyl, pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl, formyl, acetyl, propionyl, butyroyl, acetoacetyl, Methoxyacetyl or furanoyl group into consideration.

Preferred compounds of the general formula I are those in which R1 is a piperidino, thiormorpholino or thiomorpholino-1-oxide group, a Amino, alkylamino, N, N-dialkylamino, phenylalkylamino, N-alkyl-phenylalkylamino, Phenylamino or N-alkyl-phenylamino group, the alkyl part in each case from 1 to 4 Containing carbon atoms and substituted by a hydroxy or methoxy group can be and the above-mentioned phenyl nuclei are each replaced by a methyl, methoxy, Ethoxy, trifluoromethyl group, a fluorine or chlorine atom mono- or disubstituted can be an alkylamino group with 5 to 8 carbon atoms, a cyclohexylamino, Picolylamino, N-methyl-picolylamino or furfurylamino group, R2 the thiomorpholino, Thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group or one of the radicals R1 or R2 also the morpholino group, R3 is a hydrogen atom, a alkyl group having 1 to 3 carbon atoms which is optionally substituted by a hydroxyl group a formyl or furanoyl group and n is the number 2.

According to the invention, the new compounds of the above general formula I are obtained by the following process: a) Reaction of a pyrimidog5,4-d-pyrimidine of the general formula in which R1 and R2 are as defined at the outset and X represents a nucleophilic leaving group, with a perhydro-1,4-diazine of the general formula in which n is as defined at the beginning and R3 'represents an easily cleavable protective group or has the meanings mentioned for R3 at the beginning, and optionally cleavage of a protective radical used.

A halogen atom, for example, is used as a nucleophilic leaving group such as a chlorine or bromine atom, a substituted hydroxyl group such as the phenoxy group or a sulfonyl group such as the methylsulfonyl group and as easily split off Protective radical, for example the trimethylsilyl group, a carbonic acid ester radical such as the carbethoxy group or an alkanoyl group such as the formyl group.

The reaction is expediently carried out in an inert solvent such as acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, chlorobenzene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an inorganic base, e.g.

Sodium carbonate or potassium hydroxide, or a tertiary organic Base, e.g. triethylamine or pyridine, the latter also acting as a solvent can serve, and optionally in the presence of a reaction accelerator such as a copper salt at temperatures between 20 and 1500C, but preferably at Temperatures between 30 and 1000C. However, the implementation can also without solvent or in an excess of the compound used in general Formula III can be carried out.

The subsequent cleavage of a protective residue is expedient hydrolytically in the presence of an acid or base in an aqueous solvent such as water / methanol or water / ethanol and preferably at the boiling point of the reaction mixture.

b) Implementation of a pyrimidote5,4-d7pyrimidine of the general formula in which R2, R3 and n are as defined at the outset and Y represents a lower alkyl group or an aralkyl group, with an amine of the general formula in which R4 and R5 are as defined at the outset, but the radicals R4 and R5 cannot each represent a hydrogen atom at the same time.

For Y comes, for example, the meaning of the methyl, ethyl, propyl, Benzyl, methylbenzyl, chlorobenzyl, nitrobenzyl or naphthylmethyl groups are suitable.

The reaction is expediently carried out in a solvent such as acetone, Chloroform, benzene, tetrahydrofuran, dimethylformamide or ethanol or in one Excess of the amine of the general formula V used, optionally in one Pressure vessel at temperatures between 100 and 2000C, but preferably at temperatures between 130 and 1800C.

However, the reaction can also be carried out without a solvent.

c) For the preparation of compounds of the general formula I in which at least one of the radicals R4 or R5 does not represent a hydrogen atom: conversion of a pyrimido5,4-d7pyrimidine of the general formula in which R2 and n are as defined at the outset, R3 "is an easily cleavable protective group or, with the exception of hydrogen, has the meanings mentioned for R3 at the beginning and A represents a group of the formula —NH — R4, where R4 is as defined at the outset, with a compound of the general formula Z - R5 ', (VII) in which Z is a nucleophilic leaving group such as a halogen atom or a sulfonic acid ester radical and R51 with the exception of the hydrogen atom and an optionally substituted by hydroxy, alkyl, alkoxy, trifluoromethyl, fluorine, chlorine and / or bromine atoms mono- or disubstituted phenyl group or phenyl group substituted by a methylenedioxy group has the meanings mentioned for R5 at the beginning, and optionally subsequent cleavage of a protective radical.

As a nucleophilic leaving group, for example, the chlorine, bromine or iodine atom, the methylsulfonyloxy, methoxysulfonyloxy or p-toluenesulfonyloxy group and the trimethylsilyl group, a carbonic acid ester residue, as an easily removable protective residue such as the carbethoxy group or an alkanoyl group such as the formyl group.

The reaction is expediently carried out in a solvent such as acetone, Methyl ethyl ketone, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium carbonate, Sodium hydroxide, potassium hydroxide, potassium tert-butoxide, triethylamine or pyridine, the latter can also serve as a solvent at the same time, and optionally in the presence of a reaction accelerator such as an alkali iodide, e.g.

Potassium iodide, at temperatures between 0 and 1000C, but preferably at temperatures between 20 and 800C carried out. However, the implementation can also without solvent or in an excess of the compound used in general Formula VII can be carried out.

The subsequent cleavage of a protective residue is expedient hydrolytically in the presence of an acid or base in an aqueous solvent such as water / methanol or water / ethanol and preferably at the boiling point of the reaction mixture.

According to the invention, a compound of the general formula is obtained I, in which R3 is optionally replaced by a methoxy, acetyl or carboxyl group substituted alkanoyl group with 2 to 4 carbon atoms, a formyl or furoyl group represents, this can by means of hydrolysis into a corresponding compound of general formula I, in which R3 represents a hydrogen atom, are converted or a compound of the general formula I in which R3 represents a hydrogen atom, this can be converted into a corresponding compound of the general by means of acylation Formula I in which R3 is optionally substituted by a carboxy, methoxy or acetyl group substituted alkanoyl group with 2 to 4 carbon atoms, a formyl or furoyl group represents, be transferred or a compound of general Formula I, in which R1 is a thiomorpholino group and / or R2 is optionally a Represent 1 or 2 methyl groups substituted thiomorpholino group, by means of oxidation into a corresponding thiomorpholino-1, oxide or thiomorpholino-1, 1-dioxide compound of the general formula I can be converted.

The subsequent hydrolysis is expediently carried out in an aqueous Solvents such as water, water / ethanol, water / isopropanol or water / dioxane in the presence of an acid such as hydrochloric acid or sulfuric acid or a base such as sodium or potassium hydroxide solution at elevated temperatures, but preferably at the boiling point of the reaction mixture carried out.

The subsequent acylation is expediently carried out in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, chloroform or Toluene with a corresponding carboxylic acid or its reactive derivatives such as their anhydrides, acid halides, ketenes, 1-imidazolyl derivatives or with their mixed anhydrides with carboxylic acids or carbonic acid esters, optionally in Presence of an acid-activating and / or dehydrating agent, e.g. ethyl chloroformate, Thionyl chloride, N, N'-dicyclohexylcarbodiimide or N, N'-carbonyldiimidazole, and optionally in the presence of an inorganic base such as sodium carbonate or tertiary organic Base such as triethylamine or pyridine, which also serve as solvents can, at temperatures between -25 and 1200C, but preferably at temperatures between 0 and 50tC. However, formylation is particularly advantageous performed with chloral.

The subsequent oxidation is preferably carried out in a solvent, e.g. water, water / pyridine, glacial acetic acid or methanol, depending on the oxidizing agent used expediently carried out at temperatures between -80 and 1000C.

For the preparation of the thiomorpholino-1-oxides of the general formula I the subsequent oxidation is expediently with an equivalent of the one used Oxidizing agent carried out, e.g. with hydrogen peroxide in glacial acetic acid at 0 bis 200C, with a peracid such as peracetic acid, m-chloroperbenzoic acid or peroxytrifluoroacetic acid at 0 to 50 ° C, with sodium metaperiodate in aqueous methanol or ethanol at 15 up to 250C, with tert-butyl hypochlorite in methanol at -80 to -300C, with iodobenzene dichloride in aqueous pyridine at 0 to 500C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or acetone at 0 to 20 ° C and with sulfuryl chloride in Methylene chloride at -7O0C, the thioether-chlorine complex obtained here is expedient hydrolyzed with aqueous ethanol.

For the preparation of the thiomorpholino-1,1-dioxides of the general formula I is the subsequent oxidation expediently with two equivalents of the relevant Oxidizing agent based on a thiomorpholino compound of the general formula I or

with one equivalent starting from a thiomorpholino-1-oxide compound of the general formula I carried out analogously as described above. The implementation however, it is carried out at a temperature that is 10-50 ° C higher.

Furthermore, the new compounds of the general formula I in their physiologically compatible acid addition salts with inorganic or transfer organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, or fumaric acid Salicylic acid found suitable.

The compounds of the general formulas used as starting materials II and IV are obtained by gradually replacing the chlorine atoms of the 2,4,8-trichloropyrimidote5,4-d-pyrimidine (see DE-PS 1 116 676), the compounds used as starting materials the General formulas II and IV are described in the examples and used as starting materials Compounds of the general formulas III, V and VII used are known from the literature The used as starting materials are obtained by processes known per se Compounds of the general formula VI are expediently obtained according to processes a) of the present invention.

As already mentioned at the outset, those produced according to the invention have new compounds of general formula I and their physiologically acceptable Acid addition salts have valuable pharmacological properties, especially antithrombotic Properties. In addition, they have a PDE inhibitory effect and an inhibitory effect the aggregation of cancer cells washed into the bloodstream.

The compounds are suitable on the basis of their pharmacological properties of the general formula I and their physiologically acceptable acid addition salts with inorganic or organic acids for the prophylaxis of thrombo-embolic diseases like coronary infarction, cerebral infarction, sogn. transient ischaemic attacks, amaurosis fugax and for the prophylaxis of arteriosclerosis and the formation of metastases. To do this, let these, possibly in combination with other active substances, in the usual pharmaceutical preparation forms such as dragees, tablets, capsules, suppositories, Incorporate solutions or suspensions.

The single dose for adults is 0.1-20 mg, preferably 0.5 - 5 mg, 2 - 4 times a day and thus the daily dose 0.2 - 80 mg.

The following examples are intended to explain the invention in more detail: Preliminary remark: The melting point data are uncorrected melting points.

Examples for the preparation of the starting compounds: Example A 2, 8-chloro-4-morpholino-pyrimidoL5,4-djpyrimidine 118 g (0.5 mol) 2,4,8-trichloro-pyrimidoL5,4-dupyrimidine are suspended in 1.2 l of acetone and then with stirring at room temperature a solution of 44 ml (0.5 mol) of morpholine and 70 ml (0.5 mol) of triethylamine in 100 ml of acetone slowly run in. After stirring for about half an hour 1.3 l of water are added to the reaction mixture, the triethylamine hydrochloride being formed dissolves and separates further reaction product. After standing for a while, suction is performed, the precipitate was washed well with water and then with a little methanol and heated at 60.degree dried.

Yield: 132 g (92% of theory) with a melting point of 179-181 ° C., melting point: 183 - 1850C (from ethanol) The implementation can also take place in a completely analogous manner Use of an aqueous potassium carbonate solution carried out instead of triethylamine will.

The following compounds were prepared analogously to Example A: 2,8-dichloro-4-thiomorpholino-pyrimidoZ5,4-dS pyrimidine Melting point: 154-157 0C 2,8-dichloro-4- (1-oxido-thiomorpholino) -pyrimidoZ5,4-4 / pyrimidine Melting point: 195-1980C (dioxane) 2,8-dichloro-4- (1,1-dioxido-thiomorpholino) -pyrimido / 5,4-dupyrimidine Melting point: 270-2730C (dec., Dioxane).

Example B 8- (n-Benzyl-methylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimidote 5 , 4-d / pyrimidine To a suspension of 15.9 g (0.05 mol) of 2,8-dichloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine a solution of 12.2 g (0.1 mol) of N-benzylmethylamine is added to about 250 ml of dioxane with stirring slowly poured into 50 ml of dioxane and then the whole thing for about 30 minutes warmed to 30-400C for a long time. When taking up the reaction mixture in about 1 liter of water the reaction product separates out as a pale yellowish precipitate. To Standing for some time is suctioned off, washed with water and dried at about 600C.

Yield: 18.6 g (92% of theory).

After recrystallization from ethanol, the 8- (N-benzylmethylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine melts at 158-160 ° C.

The following compounds were prepared analogously: 2-chloro-8-diethanolamino-4-morpholino-pyrimidoL5,4-d / pyrimidine Melting point: 129-131 ° C. 8-Amino-2-chloro-4-morpholino-pyrimidoL5,4-d / pyrimidine Melting point: 206-208 0C 8-Amino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 270-2720C (dec.) 2-Chloro-8-methylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine Melting point: 278-2800C 2-chloro-4- (1 -oxido-thiomorpholino) -8-propylamino-pyrimido- [5,4-d] pyrimidine Melting point: 174-176 ° C 2-chloro-8-isopropylamino-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 210-212 ° C 8-Butylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine Melting point: 179-181 ° C 2-chloro-8-isopropylamino-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 176-178 ° C 2-chloro-8-octylamino-4- (1-oxido-thiomorpholino) -pyrimido [5, pyrimidine Melting point: 145-1470C 2-Chloro-8-cyclohexylamino-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 207-209 ° C 2-Chloro-8-diethylamino-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 184-1860C 2-chloro-8-dibutylamino-4- (1-oxido-thiomorpholino) -pyrimide 4-d] pyrimidine. Melting point: 187-1890C 2-Chloro-4- (1-oxido-thiomorpholino) -pyrimido-8-piperidino-pyrimido [5,4-d] -pyrimidine Melting point: 203-2050C 2-Chloro-4- (1-oxido-thiomorpholino) -8-thiomorpholino-pyrimido- [5,4-d] pyrimidine Melting point: 229-231 ° C 2-Chloro-8-morpholino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine Melting point: 232-233 ° C. 8-Benzylamino-2-chloro-4-morpholino-pyrimido-pyrimido [5,4-d] pyrimidine Melting point: 139-141 ° C. 8-Benzylamino-2-chloro-4-thiomorpholino-pyrimidoL5,4-dU pyrimidine Melting point: 94-96 0C 8-Benzylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine Melting point: 232-233 ° C 8-Benzylamino-2-chloro-4- (1,1-dioxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 213-2150C 2-chloro-4-morpholino-8-phenethylamino-pyrimido [5,4-d] pyrimidine Melting point: 132-134 0C 2-chloro-4- (1 -oxido-thiomorpholino) -8-phenethylamino-pyrimido-5,4-d7-pyrimidine Melting point: 198-200 ° C 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-phenylpropylamino) -pyrimidor5,4-d / pyrimidine Melting point: 152-1540C 2-Chloro-4- (1-oxido-thiomorpholino) -8- (D-1-phenylethylamino) -pyrimido [5,4-d] pyrimidine Melting point: 167-169 0C 2-chloro-4- (1-oxido-thiomorpholino) -8- (L-1-phenylethylamino) -pyrimidoC5 ,, 4-d7-pyrimidine Melting point: 167-169 ° C (N-Benzyl-methylamino) -2-chloro-4-morpholino-pyrimido [5,4-d] -pyrimidine Melting point: 121-1230C 8- (N-Ethyl-benzylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimidoC5,4-d / pyrimidine Melting point: 163-165 ° C 8- (N-Benzyl-propylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 183-184 ° C 8- (N-Benzyl-butylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 153-155 ° C. 8-anilino-2-chloro-4-morpholino-pyrimido [5,4-d] pyrimidine Melting point: 193-195 ° C 8-Anilino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] -pyrimidine Melting point: 230-232 ° C 2-chloro-8- (N-methylanilino) -4-morpholino-pyrimido [5,4-d] pyrimidine Melting point: 150-152 ° C 2-Chloro-8- (N-methylanilino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 237-239 ° C 2-chloro-8- (2-hydroxyethylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 227-229 ° C 2-Chloro-8- (4-hydroxybutylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 179-181 ° C 2-chloro-8-diethanolamino-4-thiomorpholino-pyrimido [5,4-d] pyrimidine Melting point: 121-1230C 2-chloro-8-diethanolamino-4- (1-oxido-thiomorpholine Q) -pyrimido- [5,4-d] pyrimidine Melting point: 187-189 ° C 2-chloro-8-diisopropanolamino-4- (1-oxido-thiomorpholino) -pyrimido-5,4- S pyrimidine Melting point: 205-2080C 2-chloro-8-tN- (2-hydroxyethyl) -2-methoxyethylaminoJ-4- (i-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine Melting point: 143-145 ° C 8- [N-benzyl- (2-hydroxyethylamino)] - 2-chloro-4- (1-oxido-thiomorpholino) - pyrimido [5,4-d] pyrimidine Melting point: 153-155 ° C 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-picolylamino) -pyrimido- [5,4-d] pyrimidine Melting point: 227-229 ° C 2-Chloro-8- [N-methyl- (3-picolylamino)] -4- (1-oxido-thiomorpholino-pyrimido [5,4-d] pyrimidine Melting point: 154-1560C 2-Chloro-8-furfurylamino-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 203-2050C 2-Chloro-8- (4-fluorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 210-212 ° C 2-chloro-8- (4-chlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimidoL5,4-d7pyrimidine Melting point: 216-2180C 2-Chloro-8- (3-chlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 239-241 ° C 2-Chloro-8- (2-chlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 238-2400C 2-Chloro-8- (4-methylbenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 185-187 ° C 2-chloro-8- (3,4-dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Melting point: 259-261 ° C 2-chloro-8- (2,4-dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimidoL5,4-d / pyrimidine Melting point: 196-1980C 2-Chloro-8- (3,4-dimethoxylbenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 218-2200C 2-chloro-8- (3,4-methylenedioxy-benzylamino) -4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 239-2410C 2-chloro-8- (3,4-dimethoxyphenethylamino) -4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 214-216 ° C 2-chloro-8- [N- (3,4-dimethoxyphenethyl) -methylamino] -4- (1-oxidothiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 178-1790C 8- (4-Ethoxyanilino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido- [5,4-d] pyrimidine Melting point: 237-240 ° C 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-trifluoromethyl-anilino) -pyrimido- [5,4-d] pyrimidine Melting point: 215-2180C Example 1 8- (N-Benzyl-methylamino) -4- (1-oxido-thiomorpholino) -2-piperazynopyrimidot5, 4-d2pyrimidine -8.1 g (0.02 mol) of 8- (N-benzyl-methylamino) -2-chloro-4- (1-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine (Melting point: 158-160 ° C.) are mixed with 6.9 g (0.08 mol) of anhydrous piperazine in Heated 150 ml of dioxane under reflux for about 30 minutes. Then the Solvent distilled off in vacuo and the remaining residue in about 600 ml of water added.

After standing for a short time, the reaction product is filtered off with suction, with water washed and dried at about 600C.

Yield: 9.1 g (95% of theory).

For purification, the crude product is once extracted from 0.2 N hydrochloric acid by means of Ammonia reprecipitated and recrystallized from methanol.

The 8- (N-benzyl-methylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine thus obtained melts at 114-115 ° C.

C22H28N8OS (452.6) Calc .: C 58.38 H 6.24 N 24.76 S 7.08 Found: 58.22 6.45 24.68 7.22 The same compound is obtained in an analogous manner by two hours Heat 8- (N-benzyl-methylamino) -4- (1 -oxido-thiomorpholino) -2-phenoxypyrimido [5,4-d] pyrimidine (Melting point: 187-1890C; prepared from 8- (N-benzyl-methylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimidot5,4-d7pyrimidine and sodium phenolate in phenol) with piperazine at about 110 ° C or by oxidation of 8- (N-Benzyl-methylamino) -2-piperazino-4-thiomorpholino-pyrimido [5,4-d] pyrimidine (Melting point: 108-110 ° C) with hydrogen peroxide in glacial acetic acid or with potassium permanganate in dilute hydrochloric acid with cooling.

By reacting the 8- (n-benzyl-methylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine with an excess of the appropriate acids in isopropanol, the following were made Salts made: Melting point of succinate: 195-1980C, melting point of maleate: 135-138 ° C, melting point of the tartrate: 195-2000C (dec.), Melting point of the tosylate: 270-2730C (dec.).

Example 2 8-ethanolamino-4-morpholino-2-piperazino-pyrimidoL5,4-d7-pyrimidine 8.9 g (0.025 mol) of 2-chloro-8-diethanolamino-4-morpholino-pyrimido- [5,4-d] pyrimidine (Melting point: 129-131 ° C.) with 21.5 g of 0 (0.25 mol) piperazine for one hour heated to about 120 C for a long time.

The melt obtained is taken up in about 200 ml of water.

After standing for some time, the reaction product separates out as a yellowish color Precipitation from. It is filtered off with suction, washed with water and dried at 70.degree.

Yield: 8.8 g (87% of theory).

After one reprecipitation from 0.1N hydrochloric acid using ammonia, it melts the 8-diethanolamino-4-morpholino-2-piperazino-pyrimidote5,4-d7pyrimidine at 188-1900C.

C18H28N803 (404.5) Calc .: C 53.45 H 6.98 N 27.70 Found: 53.20 7.03 27.40 Example 3 8-Benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidoss, 4-pyrimidine ~ 1.9 g (0.005 mol) of 8-methylthio-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine (Melting point: 253-255 ° C) with 25 ml of benzylamine for about an hour Heated to 150 ° C. The excess amine is then largely distilled off in vacuo, the remaining residue taken up in about 150 ml of water and diluted using Hydrochloric acid adjusted to pH 7. The separated reaction product is suctioned off, washed with water and dried.

Yield: 1.6 g (73% of theory).

After recrystallization from ethanol / water, the 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] -pyrimidine melts at 229-232 ° C.

C21H26N80S (438.6) Calcd .: C 57.51 H 5.96 N 25.55 S 7.32 Found: 57.60 6.07 25.65 7.33 Example 4 8-Amino-4-morpholino-2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-amino-2-chloro-4-morpholinopyrimidoL5,4-d / pyrimidine (Melting point: 206-208 ° C) and piperazine.

Melting point: 260-263 ° C.

Example 5 8-Amino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] -pyrimidine Prepared analogously to Example 1 from 8-amino-2-chloro-4- (1-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine (Melting point: 270-2720C, dec.) And piperazine.

Melting point: 248-2500C (methanol).

Example 6 8-Methylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido- [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8-methylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (Melting point: 278-280 ° C) and piperazine in dioxane at 80 C.

Melting point: 257-2590C.

Example 7 4- (1-Oxido-thiomorpholino) -2-piperazino-8-propylamino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 6 from 2-chloro-4- (1-oxido-thiomorpholino) 8-propylamino-pyrimido / 5,4-d7-pyrimidine (melting point: 174-1760C) and piperazine.

Melting point: 198-2000C.

Example 8 8-Isopropylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 6 from 2-chloro-8-isopropylamino-4- (l-oxido-thiomorpholino) pyrimido / 5,4-d7pyrimidine (melting point: 210-2120C) and piperazine.

Melting point: 179-181 ° C (ethyl acetate).

Example 9 8-Butylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido-4-d] pyrimidine Prepared analogously to Example 6 from 8-butylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (Melting point: 179-181 ° C) and piperazine.

Melting point: 138-1400C (dioxane).

Example 10 8-Isoamylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido-£ 5 , 4-d2pyrimidine Prepared analogously to Example 6 from 2-chloro-8-isoamylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 176-178 ° C) and piperazine: melting point: 206-208 ° C (Methanol / water).

Example 11 8-Octylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido-4-d] pyrimidine Prepared analogously to Example 6 from 2-chloro-8-octylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 145-1470C) and piperazine.

Melting point: 142-1440C (ethyl acetate).

Example 12 8-Cyclohexylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidote 5 , 4-pyrimidine Prepared analogously to Example 6 from 2-chloro-8-cyclohexylamino-4- (1-oxido-thiomorpholino) -pyrimido g, 4-d7pyrimidine (melting point: 207-209 ° C) and piperazine.

Melting point: 207-209 ° C.

Example 13 8-Diethylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido- [5,4-d] pyrimidine Prepared analogously to Example 6 from 2-chloro-8-diethylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 184-1860C) and piperazine.

Melting point: 185-1 870C (ethyl acetate).

Example 14 8-Dibutylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidots , 4-pyrimidine Prepared analogously to Example 6 from 2-chloro-8-dibutylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 187-1890C) and piperazine.

Melting point: 171-173 ° C (ethyl acetate).

Example 15 4- (1-Oxido-thiomorpholino) -2-piperazino-8-piperidino-pyrimido-4-d] pyrimidine Prepared analogously to Example 6 from 2-chloro-4- (1-oxido-thiomorpholino) -8-piperidine-pyrimido [5.4-d] (melting point: 203-205 ° C) and piperazine.

Melting point: 115-1170C (ethyl acetate).

Example 16 4- (1-Oxido-thiomorpholino) -2-piperazino-8-thiomorpholino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8-thiomorpholino-pyrimido [5,4-d] pyrimidine (melting point: 229-231 ° C.) and piperazine.

Melting point: 207-209 ° C. (dioxane).

Example 17 8-Morpholino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido- £, 4-7dpyrimidine Prepared analogously to Example 1 from 2-chloro-8-morpholino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-2330C) and piperazine.

Melting point: 168-171 ° C.

Example 18 8-Benzylamino-4-morpholino-2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4-morpholino-pyrimido / 5,4-b7pyrimidine (Melting point: 139-141 ° C) and piperazine.

Melting point: 154-1570C.

Example 19 8-Benzylamino-2-piperazino-4-thiomorpholinopyrimidine [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4-thiomorpholino-pyrimido 85,4-d] pyrimidine (melting point: 94-96 0C) and piperazine.

Melting point: 109-111 ° C.

Example 20 8-Benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido-5,4- pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-233 ° C.) and piperazine in dioxane at 70 ° C.

Melting point: 229-232 ° C (ethanol / water).

The substance is also made from 8-benzylamino-2-piperazino-4-thiomorpholino-pyrimido [5,4-d] pyrimidine by refluxing with sodium metaperiodate in methanol obtain.

Example 21 8-Benzylamino-4- (1,1-dioxido-thiomorpholino) -2-piperazino-pyrimido85,4-β7-pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4- (1,1-dioxido-thiomorpholino) -pyrimidoL5,4-dg pyrimidine (melting point: 213-2150C) and piperazine.

Melting point: 203-2050C.

The substance is also made from 8-benzylamino-4- (l-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine by oxidation with potassium permanganate in dilute hydrochloric acid obtain.

Example 22 4-Morpholino-8-phenethylamino-2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4-morpholino-8-phenethylamino-pyrimido [5,4-d] pyrimidine (melting point: 132-134 ° C) and piperazine.

Melting point: 125-1270C (cyclohexane).

Example 23 4- (1-Oxido-thiomorpholino) -8-phenethylamino-2-piperazino-pyrimidoJ, 4-'d / pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8-phenethylamino-pyrimido [5,4-d] pyrimidine (melting point: 198-200 ° C) and piperazine.

Melting point: 213-215 ° C (methanol).

Example 24 4- (1-Oxido-thiomorpholino) -8- (3-phenylpropylamino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-phenylpropylamino) -pyrimido [5,4-d] pyrimidine (melting point: 152-1540C) and piperazine.

Melting point: 210-2120C (methanol).

Example 25 4- (1-Oxido-thiomorpholino) -8- (D-1-phenylethylamino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8- (D-1-phenylethylamino) -pyrimido 85,4-d] pyrimidine (melting point: 167-1690C) and piperazine.

Melting point: 115-1200C.

Example 26 4- (1-Oxido-thiomorpholino) -8- (L-1-phenylethylamino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8- (L-1-phenylethylamino) -pyrimido 85,4-d9 pyrimidine (melting point: 167-1690C) and piperazine.

Melting point: 115-1200C.

Example 27 8- (N-Benzyl-methylamino) -4-morpholino-2-piperazino-pyrimidojs, 4-d7pyrimidine Prepared analogously to Example 1 from 8- (N-benzyl-methylamino) -2-chloro-4-morpholino-pyrimido [5,4-d9 pyrimidine (melting point: 121-1230C) and piperazine.

Melting point: 147-1490C.

Example 28 8- (N-Benzyl-methylamino) -2-piperazino-4-thiomorpholino-pyrimidots, 4-4ipyrimidine Prepared analogously to Example 1 from 8- (N-benzyl-methylamino) -2-chloro-4-thiomorpholino-pyrimido / 5,4-d7-pyrimidine and piperazine.

Melting point: 108-1100C (methanol).

Example 29 8- (N-Ethyl-benzylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8- (N-ethylbenzylamino) -2-chloro-4- (1-oxido-thiomorpholino) pyrimido 5,4-4Jpyrimidín (melting point: 163-165 ° C) and piperazine.

Melting point: 174-176 ° C (methanol / water).

Example 30 8- (N-Benzyl-propylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8- (N-benzyl-propylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido / 5,4-d / pyrimidine (Melting point: 183-184 ° C) and piperazine.

Melting point: 158-160 ° C (methanol / water).

Example 31 8- (N-Benzyl-butylamino) -4- (1-oxido-thimorpholino) -2-piperazinopyrimidot5, 4-Idpyrimidine Prepared analogously to Example 1 from 8- (N-benzyl-butylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimidog5,4-d7pyrimidine (Melting point: 153-1550C) and piperazine.

Melting point: 154-156 ° C.

Example 32 8-Anilino-4-morpholino-2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-anilino-2-chloro-4-morpholinopyrimidoC5 4-d7pyrimidine (Melting point: 193-195 ° C) and piperazine.

Melting point: 184-1860C (methanol).

Example 33 8-Anilino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido- [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-anilino-2-chloro-4- (1-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine (melting point: 230-232 ° C) and piperazine.

Melting point: 208-210 ° C (ethanol).

Example 34 8- (N-Methylanilino) -4-morpholino-2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (N-methylanilino) - 4-morpholino-pyrimido [5,4-d] pyrimidine (melting point: 150-152 ° C) and piperazine.

Melting point: 212-215 ° C.

Example 35 8- (N-Methylanilino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (N-methylanilino) -4- (1-oxido-thiomorpholino) -pyrimido g, 4-d7pyrimidine (melting point: 237-239 ° C) and piperazine.

Melting point: 257-259 0C (dioxane).

Example 36 8- (2-Hydroxyethylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimidoJ , 4- / pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (2-hydroxyethylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 227-229 ° C) and piperazine.

Melting point: 228-230 ° C (ethanol).

Example 37 8- (4-Hydroxyäthylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido £ 5, 4-pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (4-hydroxybutylamino) -4- (1-oxido-thiomorpholino) -2-piperazino- (melting point: 179-181 ° C) and piperazine.

Melting point: 187-189 ° C (ethanol / ethyl acetate).

Example 38 8-Diethanolamino-2-piperazino-4-thiomorpholino-pyrimido [5,4-d] -pyrimidine Prepared analogously to Example 2 from 2-chloro-8-diethanolamino-4-thiomorpholino-pyrimido [5,4-d] pyrimidine (melting point: 121-123 ° C) and piperazine.

Melting point: 192-1950C.

Example 39 8-Diethanolamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido- [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8-diethanolamino-4- (1-oxido-thiomorpholino) -pyrimido g5,4-d / pyrimidine (melting point: 187-189 ° C) and piperazine.

Melting point: 226-228 ° C (ethanol).

Example 40 8-Diisopropanolamino-4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8-diisopropanolamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 205-208 ° C) and piperazine.

Melting point: 222-225 ° C (ethanol).

Example 41 8-EN- (2-hydroxyethyl) -2-methoxyethylamineJ / -4- (1 -oxido-thiomorpholino) -2-piperazino-pyrimido 85,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- £ N- (2-hydroxyethyl) -2-methoxyethylamino] -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 143-1450C) and piperazine.

Melting point: 143-1460C (ethyl acetate).

Example 42 8- [N-Benzyl- (2-hydroxyethylamino)] - 4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidoC5,4-g7-pyrimidine Prepared analogously to Example 1 from 8- / N-benzyl- (2-hydroxyethylamino] -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 153-1550C) and piperazine.

Melting point: 138-141 ° C.

Example 43 4- (1-Oxido-thiomorpholino) -8- (3-picolylamino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-picolylamino) -pyrimido [5,4-d] pyrimidine (melting point: 227-229 ° C) and piperazine.

Melting point: 267-2690C.

Example 44 8 Methyl- (3-picolylamino) / - 4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- [N-methyl- (3-picolylamino)] - 4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 154-156 ° C) and piperazine.

Melting point: 191-194 ° C (methanol).

Example 45 8-Furfurylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8-furfurylamino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 203-205 ° C) and piperazine in dioxane at 80 ° C.

Melting point: 219-221 ° C.

Example 46 8-Benzylamino-2- (N-methylpiperazino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-233 ° C) and N-methylpiperazine.

Melting point: 203-205 ° C (ethanol).

Example 47 8-Benzylamino-2- (N-hydroxyethylpiperazino) -4-morpholino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8-benzylamino-2-chloro-4-morpholino-pyrimido [5,4-d] pyrimidine (melting point: 139-141 ° C.) and N-hydroxyethylpiperazine in dioxane at 70 C.

Melting point: 161-1 630C (cyclohexane / ethyl acetate).

Example 48 8-Benzylamino-2- (N-hydroxyethylpiperazino) -4- (1-oxido-thimorpholino) -pyrimidoL5,4-D-pyrimidine prepared analogously to Example 1 from 8-benzylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-233 ° C.) and N-hydroxyethylpiperazine.

Melting point: 184-186 ° C (ethanol).

Example 49 8- (N-Benzyl-methylamino) -2- (N-hydroxyethylpiperazino) -4- (1-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8- (N-benzyl-methylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimidoL5,4- S pyrimidine (melting point: 158-160 ° C) and N-hydroxyethylpiperazine.

Melting point: 126-130 ° C. (ethyl acetate).

Example 50 2- (N-hydroxyethylpiperazino) -4- (1-oxido-thiomorpholino) -8-phenethylamino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8-phenethylamino-pyrimido [5,4-d] pyrimidine (melting point: 198-2000C) and N-hydroxyethylpiperazine.

Melting point: 166-1680C (ethyl acetate).

Example 51 8- (4-Fluorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (4-fluorobenzylamino) -4 (1 -oxido-thiomorpholino) -pyrimidoJ5,4-dJpyrimidine (melting point: 210-2120C) and piperazine in dioxane at 800C.

Melting point: 148-t5000.

Example 52 8- (4-Chlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (4-chlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido / 5,4-d / pyrimidine (Melting point: 216-2180C) and piperazine.

Melting point: 227-229 ° C (dioxane).

Example 53 8- (3-Chlorobenzylamino) -4- (1-oxido-thimorpholino) -2-piperazinopyrimido £ 5 , 4-p7pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (3-chlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimidoE5, 4-dpyrimidine (melting point: 239-241 0C) and piperazine.

Melting point: 208-2180C (dioxane).

Example 54 8- (2-Chlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido, 4-pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (2-Chlo5robenzylamino) -4- (1-oxido-thiomorpholino) pyrimidot5, 4-djpyrimidine (melting point: 238-2400C) and piperazine.

Melting point: 193-1950C (dioxane).

Example 55 8- (4-Methylbenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazinopyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (4-methylbenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 185-1870C) and piperazine.

Melting point: 172-1740C (methanol).

Example 56 8- (3,4-Dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (3,4-dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 259-261 ° C.) and piperazine.

Melting point: 201-2030C.

Example 57 8- (2,4-Dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (2,4-dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 196-198 ° C) and piperazine.

-Melting point: 235-237 0C (dioxane).

Example 58 8- (3,4-Dimethoxybenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (3,4-dimethoxybenzylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 218-2200C) and piperazine.

Melting point: 198-2000C (dioxane).

Example 59 8- (3,4-Dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 51 from 2-chloro-8- (3,4-methylenedioxybenzylamino) -4- (1-oxido-thiomorpholino) -pyrimidoZ5,4-d / pyrimidine (Melting point: 239-2410C) and piperazine.

Melting point: 233-2350C (ethyl acetate / dioxane).

Example 60 8- (3,4-Dichlorobenzylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8- (3,4-dimethoxyphenethylamino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 214-216 ° C) and piperazine.

Melting point: 166-167 ° C (methanol).

Example 61 8- [N- (3,4-Dimethoxyphenethyl) methylamino] -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-8-LN- (3,4-dimethoxyphenethyl) methylamino] -4- (1-oxido-thiomorpholino) -pyrimido-5 , 4-d / pyrimidine (melting point: 178-179 ° C) and piperazine.

Melting point: 145-147 ° C (ethyl acetate).

Example 62 8- (4-Ethoxyanilino) -4- (1-oxido-thiomorpholino) -2-piperazino pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 8- (4-ethoxyanilino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 237-2400C) and piperazine.

Melting point: 215-217 ° C (ethanol).

Example 63 4- (1-Oxido-thiomorpholino) -2-piperazino-8- (3-trifluoromethylanilino) -pyrimido [5,4-d] pyrimidine Prepared analogously to Example 1 from 2-chloro-4- (1-oxido-thiomorpholino) -8- (3-trifluoromethyl-anilino) -pyrimido / 5,4-d-pyrimidine (Melting point: 215-2180C) and piperazine.

Melting point: 263-2660C (dioxane).

Example 64 2- (N-Formylpiperazino) -8-morpholino-4- (1-oxido-thiomorpholino) -pyflmidoE5, 4-d2pyrimidine Prepared analogously to Example 2 from 2-chloro-8-morpholino-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-2330C) and'N-formylpiperazine at 1000C.

Melting point: 189-191 ° C (methanol / water).

Example 65 8-Amino-2- (N-formylpiperazino) -4- (1-oxido-thiomorpholino) -pyrimidot5, 4-Wpyrimidine Prepared analogously to Example 64 from 8-amino-2-chloro-4- (1-oxidothiomorpholino) pyrimido [5,4-d] pyrimidine (melting point: 270-2720C, dec.) And N-formylpiperazine at 1300C.

Melting point: 278-2800C.

Example 66 8-Benzylamino-2- (N-formylpiperazino) -4-thiomorpholino-pyrimido- [5,4-d] pyrimidine prepared analogously to Example 64 from 8-benzylamino-2-chloro-4-thiomorpholino-pyrimido [5,4-d] pyrimidine (melting point: 94-96 ° C.) and N-formylpiperaz in.

Melting point: 187-189 ° C.

Example 67 8-Benzylamino-2- (N-formylpiperazino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine Prepared analogously to Example 64 from 8-benzylamino-2-chloro-4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 232-233 ° C) and N-formylpiperazine.

Melting point: 152-1550C (ethanol / water).

The substance is also made from 8-amino-2- (N-formylpiperazino) -4- (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine by reaction with benzyl chloride and potassium tert. butylate in Obtained dimethyl sulfoxide.

Example 68 8- (N-Benzyl-methylamino) -2- (N-formylpiperazino) -4- (1-oxido-thiomorpholino-pyrimido [5,4-d] pyrimidine Prepared analogously to Example 64 from 8- (N-benzyl-methylamino) -2-chloro-4- (1-oxido-thiomorpholino) -pyrimido5,4-pyrimidine (Melting point: 158-1600C) and N-formylpiperazine.

Melting point: 135-1370C (methanol).

The substance is also made from 8- (N-benzyl-methylamino) -4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidog, 4-d7pyrimidine (Melting point: 114-1150C) by refluxing with chloral hydrate in chloroform obtain.

Example 69 2- (N-Formylpiperazino) -4- (1-oxido-thiomorpholino) -8-phenethylamino-pyrimidot5 , 4-d2pyrimidine Prepared analogously to Example 64 from 2-chloro-4- (1-oxido-thiomorpholino) -8-phenethylamino-pyrimido [5,4-d] pyrimidine (melting point: 198-2000C) and N-formylpiperazine.

Melting point: 204-207 ° C.

Example 70 2-Piperazino-4,8-bis (1-oxido-thiomorpholino) -pyrimido / 5,4-d / -pyrimidine.

Prepared analogously to Example 1 from 2-chloro-4,8-bis (1-oxido-thiomorpholino) -pyrimido [5,4-d] pyrimidine (melting point: 295-297 ° C) and piperazine.

Melting point: 251-2530C.

Example A Dragees with 1 mg of 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine Composition: 1 tablet core contains: Active ingredient (1) 1.0 mg Milk sugar (2) 30.0 mg corn starch (3) 14.5 mg polyvinylpyrrolidone (4) 4.0 mg magnesium stearate (5) 0.5 mg 50.0 mg Preparation: Substances 1-3 are mixed with an aqueous solution evenly moistened by 4, sieved through 1 mm mesh size, dried and again sieved through 1 mm mesh size. After adding 5 5, the mixture becomes tablet cores pressed.

Dragee cores: 5 mm, biconvex, round. Dragee: Usual sugar coating to 70 mg final weight.

Example B Tablets containing 2 mg of 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine 1 tablet contains: Active ingredient 2.0 mg lactose 29.0 mg corn starch 14.5 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 0.5 mg 50.0 mg Manufacturing: Analogous to the dragee cores, tablet description: Weight: 50 mg Diameter: 5 mm, biplan, double-sided facet Example C suppositories of 5 mg 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine 1 suppository contains: active substance 0.005 g hard fat (e.g. Witepsol H 19 1.695 g and Witepsol W 45 ~~~~~~~~ 1.700 g Preparation: The hard fat is melted. At 380C the milled active substance becomes in the melt homogeneously dispersed. It is cooled to 350C and placed in slightly pre-chilled suppository molds poured out.

Suppository weight: 1.7 g Example D suspension with 2 mg of 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido / 3,4-d7-pyrimidine 100 ml suspension contain: active substance 0.04 g carboxymethyl cellulose 0.1 g p-hydroxybenzoic acid methyl ester 0.05 g propyl p-hydroxybenzoate 0.01 g cane sugar 10.0 g glycerin 5.0 g sorbitol solution 70% 20.0 g aroma 0.3 g distilled water. ad 100.0 ml Manufacturing process: distilled water is heated to 700C. P-hydroxybenzoic acid methyl ester is added with stirring and propyl esters as well as glycerine and carboxymethyl cellulose dissolved. It gets to room temperature cooled and the active ingredient added with stirring and homogeneously dispersed. To Adding and dissolving the sugar, the sorbitol solution and the flavor becomes the suspension evacuated with stirring for venting.

Example E Ampoules containing 1 mg of 8-benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimidote 5 , 4-pvrimidin 1 ampoule contains: active substance 1.0 mg acetic acid 0.01 N 0.3 ml NaCl 18.0 mg water for injections to 2.0 ml Production: in one In a calibrated preparation vessel, the active ingredient base is suspended in water for injection purposes and completely dissolved by heating and dropping acetic acid. After filtration The solution is filled into ampoules through a membrane filter and autoclaved.

Claims (1)

P atent claims 1. New 2- (perhydro-1,4-diazino) -pyrimido g, 4-d7pyrimidines of the general formula in which R1 is an amino group of the formula where R4 and R5, which can be the same or different, hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, each alkyl group being substituted by a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a phenyl group, or phenyl groups, the above-mentioned Phenyl nuclei monosubstituted by a methylenedioxy group or by an alkyl or alkoxy group each having 1 to 3 carbon atoms, a trifluoromethyl group, a fluorine, chlorine or bromine atom, mono- or disubstituted and the substituents of the phenyl nucleus can each be the same or different, alkyl groups having 5 up to 8 carbon atoms, cycloalkyl groups with 5 to 7 carbon atoms, pyridyl, picolyl or furfuryl groups or R4 and R5 together with the intermediate nitrogen atom an alkyleneimino group with 4 to 6 carbon atoms, a thiomorpholino or thiomorpholino-1-oxide group, R2 an optionally substituted by 1 or 2 methyl groups substituted te thiomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group or one of the radicals R1 or R2 also a morpholino group optionally substituted by 1 or 2 methyl groups, R3 a hydrogen atom, a phenyl group, an alkyl group optionally substituted by a hydroxyl group with 1 to 4 carbon atoms, an alkanoyl group with 2 to 4 carbon atoms optionally substituted by a methoxy, acetyl or carboxy group, a formyl or furoyl group and n denotes the number 2 or 3, and their physiologically acceptable acid addition salts with inorganic or organic acids. 2. New compounds of general formula I according to claim 1, in the R1 is a piperidino, thiomorpholino or thiomorpholino-1-oxide group, a Amino, alkylamino, N, N-dialkylamino, phenylalkylamino, N-alkyl-phenylalkylamino, Phenylamino or N-alkyl-phenylamino group, the alkyl part in each case from 1 to 4 Contain carbon atoms and be substituted by a hydroxyl or Me group can and the above n mentioned phenyl nuclei are each replaced by a methyl, methoxy, Ethoxy, trifluoromethyl group, a fluorine or chlorine atom mono- or disubstituted or may be monosubstituted by a methylenedioxy group, an alkylamino group with 5 to 8 carbon atoms, a cyclohexylamino, picolylamino, N-methylpicolylamino or furfurylamino group, R2 is a thiomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group or one of the radicals R1 or R2 also the morpholino group, R3 is a hydrogen atom, one which is optionally substituted by a hydroxyl group An alkyl group with 1 to 2 carbon atoms, a formyl or furoyl group and n mean the number 2, and their physiologically acceptable acid addition salts with inorganic or organic acids. 3. New compounds of general formula I according to claim 1, in R1 is a phenylamino, phenylalkylamino or N-alkyl-phenylalkylamino group, the alkyl part each containing 1 to 3 carbon atoms and a hydroxyl group can be substituted and the phenyl nucleus in each case by a hydroxy, methoxy, Ethyl, trifluoromethyl group, a fluorine and / or chlorine atom mono- or disubstituted or can be substituted by a methylenedioxy group, R2 is a morpholino, Thiomorpholino or 1-oxidothiomorpholino group, R3 is a hydrogen atom, a methyl, 2-hydroxyethyl, formyl or furoyl (2) group and n is the number 2. and their physiologically compatible acid addition salts with inorganic or organic Acids 4. 8-Benzylamino-4- (1-oxido-thiomorpholino) -2-piperazino-pyrimido [5,4-d] pyrimidine and canned acid addition salts. 5. 8- (N-Benzyl-methylamino) -4 * o -thiomorpholino) -2-piper azino-pyrimido [5,4-d] pyrimidine and its acid addition salts. 6. 8-Benzylamino-2-piperazino-4-thiomorpholino-pyrimido [5,4-d] -pyrimidine and its acid addition salts 7. 8- (N-Benzyl-methylamino) -2- (N-formylpiperazino) -4- (1-oxidothiomorpholino-pyrimido 5,4-d-pyrimidine and its acid addition salts. 8. Medicaments containing a compound of the general formula I according to claims 1-7 in addition to one or more inert carriers or Thinners. 9. Use of a compound of general formula I according to Claims 1-7 for the production of a therapeutic agent for prophylaxis of thromboembolic Diseases, for the prophylaxis of arteriosclerosis and the formation of metastases. 10. Process for the preparation of new 2- (perhydro-1,4-diazino) pyrimido / 5,4-d7pyrimidines of the general formula in which R1 is an amino group of the formula where R4 and R5, which can be the same or different, hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, each alkyl group being substituted by a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a phenyl group, or phenyl groups, where the above-mentioned phenyl nuclei monosubstituted by a methylenedioxy group or monosubstituted or disubstituted by an alkyl or alkoxy group each having 1 to 3 carbon atoms, a trifluoromethyl group, a fluorine, chlorine or bromine atom and the substituents of the phenyl nucleus can each be the same or different, alkyl groups having 5 to 8 Carbon atoms, cycloalkyl groups with 5 to 7 carbon atoms, pyridyl, picolyl or furfuryl groups or R4 and R5 together with the intermediate nitrogen atom an alkyleneimino group with 4 to 6 carbon atoms, a thiomorpholino or thiomorpholino-1-oxide group, R2 an optionally through 1 or 2 Methyl groups substituted Th iomorpholino, thiomorpholino-1-oxide or thiomorpholino-1,1-dioxide group or one of the radicals R1 or R2 also a morpholino group optionally substituted by 1 or 2 methyl groups, R3 a hydrogen atom, an optionally substituted by a hydroxyl group with 1 to 4 Carbon atoms, an alkanoyl group with 2 to 4 carbon atoms optionally substituted by a carboxy, methoxy or acetyl group, a formyl or furoyl group and n denotes the number 2 or 3, as well as their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that that a) a pyrimido 5,4-d7pyrimldine of the general formula in which R 2 are as defined at the outset and X represents a nucleophilic leaving group, with a perhydro-1,4-diazine of the general formula in which n is as defined at the outset and R3 'represents an easily cleavable protective group or has the meanings mentioned for R3 is implemented and, if necessary, subsequent cleavage of a protective radical R3' or b) a pyrimido / 5,4-d7pyrimidine of the general formula in which R2, R3 and n are as defined at the outset and Y represents a lower alkyl group or an aralkyl group, with an amine of the general formula in which R4 and R5 are as defined at the outset, but the radicals R4 and R5 cannot simultaneously each denote a hydrogen, or c) for the preparation of compounds of the general formula I in which R1 is a group of the formula represents, where R5 is not a hydrogen atom and the remainder does not represent a cyclic amino group, a pyrimido-L5,4-d7pyrimidine of the general formula in which R2 and n are as defined at the outset, R3 "is an easily cleavable protective group or, with the exception of hydrogen, has the meanings mentioned for R3 at the beginning and A represents a group of the formula —NH — R4, where R4 is as defined at the outset, with a compound of the general formula Z - R5 ', (VII) in which Z is a nucleophilic leaving group such as a halogen atom or a sulfonic acid ester radical, and R5' with the exception of the hydrogen atom and optionally by hydroxy, alkyl, alkoxy, trifluoromethyl, fluorine, chlorine - and / or bromine atoms mono- or disubstituted phenyl group or phenyl group substituted by a methylenedioxy group has the meanings mentioned for R5 at the beginning, is reacted and, if necessary, subsequent cleavage of a protective radical R3 used and, if desired, then a compound of the general formula I obtained according to the invention, in which R3 is a optionally substituted by a carboxy, methoxy or acetyl group ituted alkanoyl group with 2 to 4 carbon atoms, a formyl or furoyl group, is converted by hydrolysis into a compound of the general formula I in which R3 is a hydrogen atom and / or a compound of the general formula I obtained in which R3 is a hydrogen atom represents, by means of acylation into a compound of the general formula I in which R3 represents an alkanoyl group with 2 to 4 carbon atoms optionally substituted by a carboxyl, methoxy or acetyl group, a formyl or furoyl group, and / or a compound obtained from the general formula I in which R1 and / or R2 represents a thiomorpholino group optionally substituted by 1 or 2 methyl groups, by means of oxidation in a compound of general formula I in which R1 and / or R2 is a 1-oxidothiomorpholino group optionally substituted by 1 or 2 methyl groups represents, is transferred and / or a compound obtained of the general formula I in which R2 represents a thiomorpholino or thiomorpholino-1-oxide group optionally substituted by 1 or 2 methyl groups, by means of oxidation in a compound of the general formula I in which R2 is a thiomorpholino-1 optionally substituted by 1 or 2 methyl groups , 1-dioxide group is converted and / or a compound of the general formula I obtained is converted into its physiologically acceptable acid addition salt with an inorganic or organic acid. 11. The method according to claim 10a, characterized in that the Reaction at temperatures between 20 and 150 ° C., but preferably at temperatures between 30 and 1000C. 12. The method according to claims 10a and 11, characterized in that that the reaction is carried out in a solvent. 13. The method according to claims 10a, 11 and 12, characterized in that that the reaction in the presence of an inorganic or tertiary organic base is carried out. 14. The method according to claims 10a and 11-13, characterized in that that the reaction is carried out in the presence of a reaction accelerator. 15. The method according to claim 10b, characterized in that the Reaction at temperatures between 100 and 200 ° C, but preferably at temperatures between 130 and 1800C. 16. The method according to claims 1Ob and 15, characterized in that that the reaction in a solvent or in an excess of that used Amine of the general formula V is carried out. 17. The method according to claims 1 Ob, 15 and 16, characterized in that that the reaction is carried out in a pressure vessel. 18. The method according to claim 10c, characterized in that the Reaction at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 800C. 19. The method according to claims loc and 18, characterized in that that the reaction is carried out in a solvent. 20. The method according to claims 10c, 18 and 19, characterized in that that the reaction is carried out in the presence of a base. 21. The method according to claims 10c and 18-20, characterized in that that the reaction is carried out in the presence of a reaction accelerator.