DK159113B - 2-PIPERAZINO-PTERIDINES OR ACID ADDITIONAL SALTS THEREOF AND MEDICINALS CONTAINING THE COMPOUNDS - Google Patents

Abstract

New 2-piperazino-pteridines of general formula <IMAGE> are described wherein R1 represents a phenylalkylamino, alkylamino or dialkylamino group, a piperidino, morpholino, thiomorpholino, or 1-oxidothiomorpholino group, R2 represents a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R3 represents a halogen atom, an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, wherein the alkyl moiety may contain from 1 to 3 carbon atoms, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof which have valuable pharmacological properties, particularly antithrombotic and metastasis-inhibiting effects. Processes for preparing the compounds of formula (I) are also described.

Description

DK 159113 B

The invention relates to novel 2-piperazino-pteridines having the general formula I or acid salts thereof defined in claim 1, in particular pharmaceutically acceptable acid addition salts with inorganic or organic acids. Furthermore, the invention relates to medicaments containing the subject compounds.

US Patent 2,940,972 discloses tetrasubstituted pteridines which exhibit valuable pharmacological properties, namely coranary dilating, sedative, antipyretic and analgesic effects.

It has now been found that the present novel 2-piperazino-pteridines of general formula I:

m Ri ^ N. .N N N-H

Where R is a phenylalkylamino, alkylamino or dialkylamino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 is a dialkylamino, piperidino, morpholino, thio -25 morpholino or 1-oxidothiomorpholino group, and R 3 is a halogen atom, an alkoxy, alkylthio, phenyl-alkoxy or phenylalkylthio group, each alkyl part having 1-3 C atoms, or acid addition salts thereof, in particular their Pharmaceutical 3Q acceptable acid addition salts with inorganic or organic acids also exhibit valuable pharmacological properties, but surprisingly there are antithrombotic and metastasis inhibiting effects.

For the meanings mentioned in the definitions of the groups R ^ j ^ to R3, e.g. the following considerations:

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2 R 2: A methylamino, ethylamino, propylamino, isopropylamino, benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, dimethylamino, diethylamino, dipropylamino, methyl ethyl 5-amino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R 2: a dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, ethylpropylamino, piperidino, morpholino, thiomorpholino-10 or 1-oxidothiomorpholino group, and

Rg: a chlorine or bromine atom, a methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, 1 -methyl-2-phenylethoxy, methylmercapto, ethylmercapto, propylmercapto, isopropylmercapto, benzylmercapto, 1-phenylethylmercapto * 2-phenylethylmercapto or 3-phenylpropylmercapto group.

Preferred compounds of the general formula I or acid addition salts thereof are those wherein:

R 2 is a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R 2 is a dimethylamino, piperidino, morpholino, thio-morpholino or 1-oxidothiomorpholino group, and

Rg is a chlorine or bromine atom, an alkoxy or alkyl mercapto group having 1-3 C atoms in any alkyl moiety, one. benzyloxy or benzyl mercapto group.

However, particularly preferred compounds of the above al-2Q formula I or acid addition salts thereof are those wherein: R 1 and R 2 are the same or different and each is a dimethylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R benzylamino group, and 3

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Rg is a chlorine atom, an alkoxy or alkyl mercapto group having 1-3 C atoms in any alkyl moiety, a benzyloxy or benzyl mercapto group.

The compounds of the present invention may be prepared by the following methods: a) For the preparation of compounds of general formula X wherein R 3 is a halogen atom:

Reaction of a compound of the general formula II: 10 Z2 h3.X ^ VN (II) r2 15 where; R 2 and R 2 are as defined above, R 31 is a halogen atom, and Z 2 is a nucleophilic interchangeable group such as a halogen atom, for example «a chlorine or bromine atom, with a piperazine of the general formula III: ,, H - NN - X (IIIl

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hyor: X is a hydrogen atom or a hydrolytically cleavable protecting group and, if necessary, subsequent cleavage of the protecting group used.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene or dimethylglycol ether, at temperatures between 50 and 15 ° C, preferably at the boiling temperature of the other.

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4 turned solvent, or in melt. Hereby, the use of an acid binding agent such as sodium carbonate, triethylamine or pyridine may be advantageous.

The optionally necessary cleavage of an employed protecting group takes place in the presence of an acid such as hydrochloric or sulfuric acid, or a base such as sodium hydroxide or potassium hydroxide, preferably in an aqueous solvent such as methanol / water, ethanol / water or dioxane / water. , at temperatures up to the boiling temperature of the solvent used.

b) For the preparation of compounds of general formula I wherein R 1 is an alkoxy, alkylmercapto, phenyl-alkoxy or phenylalkyl mercapto group:

Reaction of a compound of general formula IV: j

R, N N N - H

vvyu (IV) Z3 N [20 R2 where; and R 2 is as defined above and is a nucleophilic interchangeable group such as a halogen atom, e.g. a chlorine or bromine atom, with a compound of the general formula V: R 3 '- Η (V) wherein R 1 is an optionally substituted with a phenyl group of alkoxy or alkyl mercapto group, the alkyl moiety having 1-3 C atoms, or with an alkaline salt thereof.

The reaction is preferably carried out in a suitable solvent such as dioxane, tetrahydrofuran, methanol, ethanol, propanol, isopropanol or benzyl alcohol, and preferably in the presence of a suitable alkali salt of a compound of formula V, e.g. sodium methylate, sodium methylate or sodium benzyl mercaptide, as appropriate

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5 at temperatures between 50 and 150 ° C, e.g. at the boiling temperature of the solvent used.

For the transfer of the obtained 2-piperazino-pteridines of the general formula I into their acid addition salts, especially in their pharmaceutically acceptable acid addition salts with inorganic or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid , tartaric, succinic, maleic or fumaric acids under consideration.

The compounds of general formulas II to V used as starting materials are for the most part known. or they can be obtained by the method described in U.S. Patent No. 2,940,972 (see Examples A through C).

The medicament of the invention is characterized in that it contains a 2-piperazino-pteridine of the general formula I as defined above or a pharmaceutically acceptable acid addition salt thereof together with one or more inert carriers and / or diluents.

As mentioned above, the present compounds exhibit valuable pharmacological properties, in particular antithrombotic and metastasis inhibitory effects and an inhibitory effect on phosphodiesterase.

For example, the compounds are: A = 6 ^ Benzylthio ~ 4,7-dimorpholino-2'-piperazino-pteridine B = 6-Chloro-4,7-bis- (dimethylamino) -2-piperazino-pteridine C = 6-Benzylthio 4,7-bis- (dimethylamino) -2-piperazino-pteridine D = 7-Benzylamino-6-methylthio-4- (1-oxidothiomorpholino) - 2-Piperazino-pteridine and E = 6-Chloro-2-piperazino 4-Dimethylamino-7-benzylamino-pteridine 6

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investigated for their inhibitory effect on phosphodiesterase (PDE) from tumor cells and from human thrombocytes in vitro by that of Poch et al. method described below (see Naunyn-Schmiedebergs Arch.Pharmak.268, 5 272-279 (1971)): a) Enzyme recovery:

The phosphodiesterase was obtained from Bl6 melanoma tissue from mice by centrifugation of the tissue homogenate at 5,000 x g (15 min, 4 ° C). The homogenization of the tissue was carried out by repeated freezing / thawing and homogenization according to

Potter-Elvehjem or with Ultrasound. The PDE-containing homo-genate supernatant was deep frozen portionwise and frozen at -25 ° C. Extraction of PDE from human platelets was by analogy by freezing / thawing and centrifugation9 · b) Determination of PDE inhibition (PDE sample):

The PDE inhibition with the test compounds was determined with 1 µmol / l H-cAMP as substrate. The PDE inhibition was found by measuring the degradation of the used substrate H-cAMP to H-AMP compared to control experiments without test compound.

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The resulting H-AMP was separated from the remaining 3 H-cAMP by a zinc sulfate-barium hydroxide precipitate.

The calculation of ED5Q as the concentration that inhibits PDE activity by 50% was by linear regression analysis.

PDE Inhibition (ED ^ q) Compound. . Thrombocyte .... Bl6.-Tumo.r c or A 0.051 0.088 B 35 0.95 C 10 0.88 35 D 0.048 0.97 ...... E ...... 14. ... ............ 0.37. . . .

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Acute Toxicity;

The acute acute orienting toxicity of the test compounds was determined in groups of 5 mice after oral administration of a single dose (observation time: 14 days):

Connection .Orienting .acute. .toxicitet. .

A> 250 mg (0 out of 5 animals dead) 10 B> 250 mg (0 out of 5 animals dead) C> 250 mg (0 out of 5 animals dead) D> 250 mg (0 out of 5 animals dead) E > 250 mg (0 out of 5 animals dead) 15

The present compounds are suitable, because of their mentioned pharmacological properties, for the prevention of thromboembolic diseases such as coronary infarction, cerebral infarction, so-called transitory ischemic attacks, Amaurosis fugax, for the prevention of arteriosclerosis and for metastatic sclerosis.

The dosage required to obtain a suitable effect is suitably 2 to 4 times daily 25 Q, 1 to 4 mg / kg body weight, preferably 0.2 to 3 mg / kg body weight. To this end, the compounds of general formula I or their pharmaceutically acceptable acid addition salts with inorganic or organic acids, optionally in combination with other active compounds, may be incorporated into conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules. , juices or suppositories, together with one or more inert usual carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol.

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8 nols, water / glycerol, water / sorbit, nonionic surfactants such as polyoxyethylene fatty acid esters, water polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat, or suitable mixtures thereof.

The invention is further described by the following examples.

Example A

2,6,7-Trichloro-4-morpholino-pteridine.

In a suspension of 13.5 g (0.05 mole) of 2,4,6,7-tetra-chloropteridine for approx. 400 ml of chloroform and 10 g (0.1 mole) of potassium carbonate, dissolved in 100 ml of water, were slowly added dropwise with a solution of 4.35 g (-5.5 ° C to 0 ° C). 0.05 mole of morpholine in 100 ml of chloroform and stirred for an additional ca. 30 minutes under cooling. The chloroform phase containing the reaction product was separated, dried over sodium sulfate and evaporated in vacuo.

Yield; 13.5 g (84¾ of that theory).

Mp: 211-213 ° C (ethyl acetate,

Analogously to Example A, the following compounds were prepared:

2,6,7-Trichloro-4-thiomorpholino-pteridine Mp: 191-193 ° C

2,6,7-Trichloro-4- (oxidothiomorpholino) -pteridine Mp: 212-214 ° C (dec.).

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Example B

2,6-dichloro-4,7-bis (1-Oxido-thiomorpholino) pteridine.

In a solution of 13.5 g (0.05 mole) of 2,4,6,7-tetrachloropteridine in 300 ml of dioxane, 23.8 g (0.2 mole) was slowly introduced under stirring at room temperature. thiomorpholine-1-oxide dissolved in 100 ml of dioxane, which precipitated a yellowish precipitate rapidly. reaction mixtures

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9 genes were recorded for approx. 2 liters of water. After standing for some time, the separated reaction product was aspirated, washed with water and dried at ca. 70 ° C.

Yield: 19.2 g (88% of theory).

Mp: 237-239 ° C (ethanol),

By Example B, the following compounds were prepared;

2.6-Dichloro-4,7-dimorpholino-pteridine mp; 2G6-2Q8 ° C

2.6-Dichloro-4,7-bis (thiomorpholino) pteridine

m.p .; 193-195 ° C (of dioxane) 2,6-Dichloro-4,7-bis- (dimethylamino-pteridine

Mp: 245-247 ° C

2.6-Dichloro-4,7-dipiperidino-pteridine Mp,; 185-187 ° C, 20

Example C

7- Benzylamino-2,6-dichloro-4-morpholino-pteridine,

To a suspension of 9.6 g (0.03 ml of 2,6,7-tri-chloro-4-morpholino-pteridine in about 150 ml of dioxane, a solution of 7 g (0.065) was slowly added at room temperature with stirring. After about 1 hour of stirring, the reaction mixture was taken up in about 1 liter of water The precipitated precipitate after some time was suctioned off, washed with water and dried at 30 ° C.

Yield; 10.9 g (94% of theory).

mp ,; 213-214 ° C (ethanol / dioxane = 2: 1),

Analogously to Example C, the following compounds were prepared: 7-Benzylamino-2,6-dichloro-4- (1-oxidothiomorpholino) pteridine,

MP '; 253-254 ° C

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2,6-Dichloro-7-morpholino-4- (1-oxidothiomorpholino) -pteridine

Mp: 215-217 ° C.

2,6-Dichloro-4-morpholino-7- (1-oxidothiomorpholino) -pteridine Mp: 218-220 ° C.

Example 1 6-Chloro-4,7-dimorpholino-2-piperazino-pteridine.

9.3 g (0.025 mole) of 2,6-Dichloro-4,7-dimorpholino-pteridine, together with 8.6 g (0.1 mole) of anhydrous piperazine in 200 ml of dioxane, were heated at reflux for one hour. The solvent was distilled off and the residue evaporated by ca. 100 ml of water.

After a short time, suction was washed, washed with water and dried at ca. 7 ° C (mp 218-220 ° C).

Yield: 8.9 g (85% of theory)

Mp: 220-222 ° C.

C18H25ClNgO2 (420.9)

Calculated: C: 51.36 H: 5.99 Cl: 8.42 N: 26.62

Found: 51.21 5.97 8.48 26.68

Example 2 6-Benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

To a solution of 6.3 g (0.015 mol) of 6-chloro-4,7-dimorpholino-2-piperazino-pteridine in 200 ml of dioxane was added a solution of 0.35 g of sodium and 2 ml (ca.

0.017 mol) of benzyl mercaptan in 100 ml of dioxane, and then heated to ca. 2 hours at reflux. The solvent was distilled off in vacuo and the residue was taken up for approx. 200 ml of water. After solidification, the reaction product was aspirated, washed with water and dried at room temperature in vacuo.

Yield: 6.4 g (84% of theory).

After purification over a silica gel column (eluent; methanol / conc. Ammonia 50: 1) and recrystallization from ethyl acetate, the compound had m.p. 135-137 ° C.

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C25H32N8 ° 2S (508'7)

Calculated: C: 59.03 H: 6.34 N: 22.03 S: 6.30

Found: 59.28 6.55 22.19 6.36 Example 3 7-Benzylamino-6-methoxy-4- (1-oxidothiomorpholino) -2-piperazino-pteridine.

To a solution of 2.9 g (0.006 mol) of 7-benzylamino-6-chloro-4- (1-oxidothiomorpholino) -2-piperazino-pteridine 10 in 100 ml of dioxane was poured a solution of 0.23 g (0 , 01 moles) of sodium in 10 ml of methanol. The obtained mixture was heated at reflux for 30 minutes and then the solvent was distilled off in vacuo. The evaporation residue was taken up for approx. 70 ml of water, 15 and the separated reaction product were extracted, washed with water and dried at ca. 60 ° C,

Yield; 2.6 g (93% of theory).

After reaction of 0.1N hydrochloric acid by ammonia and recrystallization from ethyl acetate / methanol (4: 1), the compound had mp, 148-151 ° C.

C22H28N8 ° 2S (468.6)

calculated; C; 56.39 H; 6.02 N: 23.91 S; 6.84

Found: 56.61 6.27 23.40 6.44 Example 4 6-Chloro-4-morpholine O'-7 '(1' oxidothiomorpholino) -2-pipe-razino-pteridine,

Prepared analogously to Example 1 from 2,6-dichloro-4'-morpholino'-7- (1-oxidothiomorpholino) -pteridine and piperazine.

m.p .; 225 DEG-227 DEG C. (precipitation of Q, 1N HCl by ammonia).

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Example 5 6-Chloro-4,7-bis- (1-oxidothiomorpholino) -2-piperazino-pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis (1-oxidothiomorpholino) pteridine and pipe razine.

Mp:> 200¾ (dec,).

Example 6 6-Chloro-4,7-dipiperidino-2-piperazino-pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4,7-dipiperidino-pteridine and piperazine.

Mp: at about 20 ° C (dec).

Example 7..

6-Chloro-4,7-bis- (dimethylamino) -2-piperazino-pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis (dimethylamino) pteridine and piperazine.

m.p .; 13q-134 ° C.

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Example 8 6-Chloro-2-piperazino-4,7-bis (thiomorpholino) pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis (thiomorpholino) pteridine and piperazine.

Mp; 194-196 ° (ethyl acetate).

Example 9 6-Chloro-7-morpholino-4- (1-oxidothiomorpholino) -2-piperazino-pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-7-morpholino-4- (1-oxidothiomorpholino) pteridine and piperazine.

m.p .; > 240 ° C (dec).

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Example 10 7-Benzylamino-6-chloro-4-morpholino-2-piperazino-pteridine.

Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-morpholino-pteridine and piperazine.

Mp: 195-197 ° C (methanol / water).

Example 11 7-Benzylamino-6-chloro-4- (1-oxidothiomorpholino) -2-pipe-razino-pteridine.

Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4- (1-oxidothiomorpholino) pteridine and piperazine.

Mp:} 200 ° C (dec).

Example 12 6- Benzylthio-4,7-bis (dimethylamino) -2-piperazino-pteridine.

Prepared analogously to Example 2 from 6-chloro-4,7-bis- (dimethylamino) -2-piperazino-pteridine and benzyl-2Q mercaptan.

Mp: 150-152 ° C.

Example 13 7- Benzylamino-6-methylthio-4- (1-oxidothiomorpholino) -2-25 piperazino-pteridine.

Prepared analogously to Example 2 from 7-benzylamino-6-chloro-4- (1-oxidothiomorpholino) -2-piperazino-pteridine and methyl mercaptan.

Mp. of hydrochloride; 159-162 ° C, 30.

Example 14 4-Morpholino-7- (1-oxidothiomorpholino) -2-piperazino-6-propylthio-pteridine.

Prepared analogously to Example 2 from 6-chloro-4-morpholino-7- (1-oxidothiomorpholino) -2-piperazino-pteridine and propyl mercaptan.

Snip .; 125-130 ° C.

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Example 15 7-Benzylamino-6-benzylthio-4- (1-oxidothiomorpholino) -2-piperazino-pteridine.

Prepared analogously to Example 2 from 7-benzyl-5. amino-6-chloro-4- (1-oxidothiomorpholino) -2-piperazino-pteridine and benzylmercaptan.

Mp:> 160 ° C (dec).

Example 16 10 6-Ethoxy-2-piperazino-4,7-bis (thiomorpholino) pteridine Prepared analogously to Example 3 from 6-chloro-2-piperazino-4,7-bis (thiomorpholino) pteridine and ethanol .

Mp: 147-151 ° C.

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Example 17 6-Benzyloxy-4,7-bis-(dimethylamino) -2-piperazino-pteridine.

Prepared analogously to Example 3 from 6-chloro-4,7-bis (dimethylamino) -2-piperazino-pteridine and benzyl alcohol.

Mp: 166-168 ° C.

Example 18 6-Chloro-2-piperazino-4-dimethylamino-7-benzylamino-pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine.

3Q mp .; 134-137 ° C.

Example 19 6-Chloro-2-piperazino-4-thiomorpholino-7-benzylamino pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.

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M.p .: 160-165 ° C.

Example 20 6- Chloro-2-piperazino-4-thiomorpholino-7-dimethylamino · pteridine.

Prepared analogously to Example 1 from 2,6-dichloro-4-thiomorpholino-7-dimethylamino] pteridine and piperazine.

Mp: 205-2Q7 ° C.

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Example 21 7- Benzylamino-6-benzylthio-2-piperazino-4-thiomorpholino-pteridine.

Prepared analogously to Example 2 from 7-benzyl-15-amino-6-chloro-2-piperazino-4β-thiomorpholino-pteridine.

Mp: from 70 ° C (sintering).

Example A

Dragée with 4 mg of 6 '= - benzylthio-4,7 - dimorph] iolino 2-piperazinopteridine.

composition; 1 The dragons contained:

Active compound (1) 4.0 mg Milk sugar (2) 27.0 mg 25 Corn starch (3) 14.5 mg

Polyvinylpyrrolidone (4), 4.0 mg

Magnesium stearate (5) 0.5 mm mg 50.0 mg

preparation; 30. The fabrics 1 ^ 3 were wetted with an aqueous solution of 4, sieved through a mesh of 1 mm, dried and again sieved through a mesh of 1 mm. After admixture of 5, the mixture was pressed into dragee cores. Dragée core: diameter 5 mm, biconvex, round.

Dragging; Usual sugar coating for final weight of 7 Q mg.

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Example B

Tablets with 8 mg of 6-Benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

1 Tablet Contained: 5 Active Compound 8.0 mg Milk Sugar 23.0 mg

Corn starch 14.5 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 0.5 mg 50.0 mg

preparation;

Analogous to the dragon cores.

Tablet description; Weight; 5Q mg

Diameter; 5 mm, biplane, facets on both sides.

Example C

Suppositories for 25 mg of 6-benzylthio-4,7-dimorpholino-2-20 piperazino-pteridine, 1 Suppository contained;

Active Compound 0.025 g Hard Fat (e.g. Witepsol H 19 '1.675' g and Witepsol H 45] 1,700 g 25 Preparation; Hard fat was melted. At 38 ° C, the ground active ingredient was homogeneously dispersed in the melt. ° C and poured into slightly pre-cooled suppository molds.

30 Suppository weight; 1.7 g.

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Example D

Suspension with 8 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

100 ml Suspension Contained: Active Compound 0.16 g

Carboxymethyl cellulose 0.1 g p-Hydroxybenzoic acid methyl ester 0.05 g p-Hydroxybenzoic acid propyl ester 0.01 g Cane sugar · 10.0 g 10 Glycerol 5.0 g

Sorbit solution 7Q% 20.0 g

Flavor 0.3 g

Water, dest., To 100.0 ml Preparation Method;

Distilled water was heated to 70 ° C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose were dissolved with stirring.

It was cooled to room temperature and with stirring 20 the active substance was added and dispersed homogeneously. After adding and dissolving the sugar, sorbit solution and aroma, the suspension was evacuated with stirring for deaeration.

Example E

Tablets containing 1QQ mg of 6-benzylthio-4,7-dimorpholino-2-piperazinopteridine.

S ammen phrase; 1 Tablet contained; Active Compound 100.0 mg Milk Sugar 80.0 mg

Maize starch 34.0 mg

Polyvinylpyrrolidone 4, · Ό mg

Magnesium stearate '2.0' mg 35 2 2 0, Q mg 18

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Method:

Active substance, milk sugar and starch were mixed and wetted uniformly with an aqueous solution of polyvinylpyrrolidone. After sifting the moist mass (2.0 5 mm mesh width) and drying in Horden dryer cabinet at 50 ° C, again sieve (1.5 mm mesh width) and the lubricant was mixed. The ready-made mixture was processed into tablets.

Tablet weight: 220 mg 10 Diameter: 10 mm, biplane with facets on both sides and split notches on one side.

Example F

Hard gelatin capsules with 150 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

1 capsule contained;

Active compound 150.0 mg

Corn starch, dried approx. 180.0 mg Milk sugar approx. 87.0 Magnesium stearate 3.0 mg 320.0 mg

preparation;

The active substance was mixed with the excipients, passed through a sieve with a mesh width of 0.75 mm and mixed homogeneously in a suitable apparatus. The final mixture was filled into size 1 hard gelatin capsules.

Capsule filling: about, 320 mg

Capsule Holster; Hard gelatin capsule size 1.

Example G

Suppositories with 150 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

1 Suppository contained;

Active substance 150.0 mg Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

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Preparation:

After melting the suppository mass, the active substance was distributed homogeneously therein and the melt was poured into pre-cooled molds.

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Example H

Suspension with 50 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine pr. 5 ml.

100 ml Suspension contained; Active substance 1.0 g

Carboxymethyl cellulose Na salt 0.1 g p-Hydroxybenzoic acid methyl ester 0.05 g p-Hydroxybenzoic acid propyl ester 0.01 g Tube sugar 10.0 g Glycerol 5.0 g

Sorbit solution 70% 20.0 g

Flavor 0.3 g

Water, dest., To 100 ml 20 Preparation;

Distilled water was heated to 70 ° C, dissolving with stirring hydroxybenzoic acid methyl ester and propyl ester, as well as glycerol and carboxymethyl cellulose sodium salt. It was cooled to room temperature and, while stirring, the active substance was added and dispersed homogeneously. After adding and dissolving the sugar, sorbit solution and aroma, the suspension was evacuated with stirring for deaeration.

5 ml of suspension contained 50 mg of active substance.

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Example I

Tablets containing 150 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.

Composition: 5 1 Tablet Contained:

Active substance 150.0 mg Milk sugar, powder. 89.0 mg

Corn starch 40.0 mg

Colloidal silica gel 10.0 mg 10 Polyvinylpyrrolidone 10.0 mg

Magnesium stearate 1.0 mg 300.0 mg

preparation;

The active ingredient mixed with milk sugar, corn starch and silicic acid was wetted with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve having a mesh width of 1.5 mm.

The granulate dried at 45 ° C was again grated through the same sieve and mixed with the specified amount of magnesium stearate. Tablets were pressed from the mixture. Tablet weight; 3QQ mg

Piston; 10 mm, flat.

Example K

25 Dragée with 75 mg of 6-benzylthio-4,7-dimorpholino-2-piperazin-pteridine * 1 containing the dragees;

Active substance 75.0 mg

Calcium phosphate 93.0 mg 30 Corn starch 35.5 mg

Polyvinylpyrrolidone 10.0 mg

Hydroxypropylmethyl cellulose 15.0 mg

Magnesium stearate 1.5 'mg 230.0 mg 35

Claims (2)

R 2 is a dimethylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, and R 3 is a chloro or bromine atom, an alkoxy or alkyl mercapto group having 1-3 C atoms in any alkyl moiety, a benzyloxy group. or benzyl mercapto group. 3. 2-Piperazino pteridines of the general formula I according to claim 1 or acid addition salts thereof, characterized in that R 1 and R 2 are the same or different and each is a dimethylamino, morpholino, thiomorpholino or 1-oxide. 25 is also a benzylamino group and R 3 is a chlorine atom, an alkoxy or alkyl mercapto group having 1-3 C atoms in any alkyl moiety, a benzyloxy or benzyl mercapto group. 4. 2-Piperazino peptides of general formula I according to claim 1 or acid addition salts thereof, characterized in that R 1 and R 2 are each a dimethylamino, morpholino or 1-oxidothiomorpholino group and R 1 also a benzylamino group R 3 is a chlorine atom, a methyl mercapto or benzyl mercapto group. 5. 159-Benzylthio-4,7-dimorpholino-2-piperazino-pteridine or acid addition salts thereof. 6,6-Chloro-4,7-bis- (dimethylamino) -2-piperazino-pteridine or acid addition salts thereof. 7. 6 "-Benzylthio-4,7-bis- (dimethylamino) -2-piperazino-pteridine or acid addition salts thereof. Medicament, characterized in that it contains a 2-piperazino-pteridine according to any one of claims 1-7 or a pharmaceutically acceptable acid addition salt thereof together with one or more inert carriers and / or diluents.