CA1252783A - Pteridines, processes for preparing them and their use as intermediate products or as pharmaceutical compositions - Google Patents

Abstract

ABSTRACT
Pteridine Derivatives New pteridines of formula (I)

Description

~5~7~3 PTE~IDINE DERIVATIVES

This invention relates to pteridine derivatives, to their preparation, to their use as intermediates and to pharmaceutical compositions containing them.
US-A-2940972 has already described substituted pteridines which have valuable pharmacological properties, namely a coronary dilating effect, sedative~ anti-pyretic and analgesic effects.
It has now been found that certain new pteridines substituted at the 2~ 4 and 7 positions, and optionally also the 6 position, and their salts possess valuable properties, either as compounds possessing pharmacolo-gical properties, particularly anti-thrombotic and metastasis- and tumour growth- inhibiting effects, or as intermediates for the production of such active compounds.
According to one aspect of the invention we therefore provide compounds of formula I

R7 ~ N ~ ~ R2 (I) R6 N ~ N

(wherein R2 represents a piperazino or N-formyl piperazino group, R4 represents a~dialkylamino, phenylalkylamino, N-alkyl-phenylalkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, l-oxidothiomorpholino, thiazolidino or l-oxidothiazolidino group, R6 represents a hydrogen atom or an alk~l or phenyl group,and ~25i~ 3 R7 represents an alkylamino, dialkylamino, phenylalkylamino, N-alkyl-phenylalkylamino, piperidino, morpholino, thiomorpholino, l-oxidothiomorpholino or piperazino group wherein each alkyl moiety in groups R4, R6 and R7 contains from 1 ~o 3 carbon atoms; wherein, where R~ contains one or two C2 3 alkyl moieties, one or both of said C2 3 alkyl moieties may be substituted by a hydroxy group in the 2 or 3 position; and wherein, where R7 contains ~0 one or two C2 3 alkyl moieties, one or both of said C2_3 alkyl moieties may be subsituted by a hydroxy group in the 2 or 3 position~ and acid addition salts thereof.
When R~ represents a N-formyl-piperazino group, the compounds of formula I and salts thereof are valuable intermediate products for preparing the pteridines of formula I wherein R2 represents a piperazino group, and the acid a~dition salts thereof, particularly the physiologically acceptable acid addition salts with inorganic or organic acids, which have valuable pharmacological properties, more particularly antithrombotic effects, metastasis-inhibiting effects and an ;nhibiting effect on tumour growth.
2S The present invention thus relates to the

2-~N-formyl-piperazino)pteridines of formula I
above and the acid addition salts thereof, which are suitable as intermediate ~roducts, and the 2-piperazino-pteridines of formula I above and the acid addition salts thereof, particularly the physiologically acceptable acid addition sal~s thereof with inorganic or organic acids.
In the compounds of formula I or salts thereof:

R2 may for example represent a piperazino or N-formyl-piperazino group, ~25i~ 3 R4 maY for example represent a dimethylamino, diethyl-amino, di-n-propylamino, diisopropylamino, N-methyl-ethylamino, N-ethyl-n-propylamino, benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-n-propyl-benzylamino, l-phenylethylamino~ 2-phenylethylamino~

3-phenylpropylamino, N-methyl-l-phenylethylamino, N-ethyl-2-phenylethylamino, N-ethyl-3-phenylpropylamino, bis(2-hydroxyethyl~-amino, bis(2-hydroxy-n-propyl)-amino, bis(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-2-hydroxy-n-propylamino, N-methyl-2-hydroxyethylamino, N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-n-propylamino, N-isopropyl-2-hydroxy-ethylamino, N-(2-hydroxyethyl)-benzylamino, pyrrolidino, piperidino, morpholino r thiomorpholino, l-oxidothiomorpholin thiazolidino or l-oxidothiazolidino group, R6 may for example represent a hydrogen atom or a methyl, ethyl~ n-propyl, isopropyl or phenyl group,and R7 may ~or example represent a methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethyl-amino, di-n-propylamino, diisopropylamino, N-methyl-ethylamino, N-ethyl-n-propylamino, benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-n-propyl-benzylamino, l-phenylethylamino, 2-phenylethyl-amino, 3-phenylpropylamino, N-methyl-l-phenylethyl-amino, N-ethyl-2-phenylethylamino7 N-ethyl-3-phenyl-propylamino, 2-hydroxyethylamino, 2-hydroxy-n-propyl-amino, 3-hydroxy-n-propylamino, 2-hydroxyisopro~ylamino, bis(2-hydroxyethyl)-amino, ~is(2-hydroxy-n-propyl)-amino, bis(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-2-hvdroxy-n-propylamino, N-methyl-2-hydroxyethylamino, N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-n-propylamino, N-isopropyl-2-hydroxy-ethylamino, N-(2-hydroxyethyl)-benzylamino, piperidino, morpholino, thiomorpholino, l-oxidothiomorpholino, thiazolidino, l-oxidothiazolidino or piperazino group.

Preferred compounds according to the invention include the compounds of formula I wherein:

~ represents a piperazino group, R4 represents a dimethylamino, N-methyl-2-hydroxyethylamino, bis(2-hydroxyethyl)-amino, ben2yl-amino, N-methyl-benzylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, l-oxidothiomorpholino, thiazolidino or l-oxidothiazolidino group, R6 represents a hydrogen atom or a methyl or phenyl group, and R7 represents a dimethylamino, N-methyl-~hydroxyethylamino, benzylamino, N-methyl-benzylamino, piperidino, morpholino, thiomorpholino, l-oxidothio-morpholino or piperazino group, and the acid addition salts thereof, parti.cu-larly the physiologically acceptable acid addition salts thereof.

However, the particularly preferred compounds of the invention include the compounds of ~ormula I wherein R2 and R6 are defined as hereinbefore, R4 represents a pyrrolidino, piperidino, morpholino, thiomorpholino, l-oxidothiomorpholino or N-methyl-2-hydroxyethylamino group, and R7 represents a dimethylamino, benzylamino, N-methyl-benzylamino, morpholino, thiomorpholino or l-oxidothiomorpholino group, and the acid addition salts thereo, particularly the physiologically acceptable acid addition salt~
thereof, ~252~

Accordin~ to a further aspect of the invention we provide a process for preparing the compounds of the invention, said process comprising at least one of the followîng steps:

a) reacting a compound of ormula II

R6 X N ~

~wherein R4 and R6 are as hereinbefore defined, one of the groups Z2 or Z7 represents a nucleophili-cally exchangeable group tsuch as a halogen atom, e.g. a chlorine or bromine atom~; and :~ the other group Z2 or Z7 has the meanings given for R2 or R7 hereinbefore or, if a compound of formula I is to be prepared wherein the groups R2 and R7 have the same meaning, it may also represent lS a nucleophilically exchangeable group (such as a halogen atom, e.g. a chlorine or bromine atom)) with an amine of formula II}

H - X (III) (wherein X has the meanings given for R2 or R7 hereinbefore or represents a piperaæino group protected by a hydrolytically removable protecting group), and subsequently, if desired, splitting off any protecting group used;

b) (to prepare compounds of ~ormula I wherein R~
2S represents a l-oxidothiomorpholino or l-oxidothia-zolidino group and/or R7 represents a l-oxidothiomorph-olino group) oxidizing a compound of formula IV

~ 2~ 3 R7~ N ~ N ~ 2 (IV) R6 N/~ N
R4 l (wherein R2 and R6 are as hereinbefore defined, and R4' and R7' have the meanings given for R4 and R7 hereinbefore with the proviso that R4' must represent a thiomorpholino or thiazolidino group and/or R7' must represent a thiomorpholino group);

c) (to prepare compounds of formula I wherein represents a piperazino group) deformylating a corresponding compound of formula I wherein R2 represents a N-formyl-piperazino group; and if required, converting a compound of formula I o~tained ~nto~an acid addition salt thereof.

The reaction of process step (a) is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene~ dimethylsulphoxide or dlmethyl glycolether at temperatures of between 0 and 150C r preferably at temperatures between ambient temperature and the boiling temperature of the solvent used, or in a melt. It may be advan-tageous to use an acid-binding agent such as sodium carbonate, triethylamine or pyridine.
The splitting off of any protecting group used, if necessary, may be carried out either hydroly-tically in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, preferably in an aqueous solvent such as methanol/water, ethanol /water or dioxan/water at temperatures up to the boiling temperature of the solvent used.
Any protecting group used may also ~e split off simultaneously during the reaction if an excess of the amine of formula III is used.
The oxidation of process step (b) is preferably carried ou~ in a solvent or mixture of solvents, e.g. in water, water/pyridine, ace~one, glacial acetic acid, methylene chloride, dioxan, dilute sulphuric acid or ~rifluoroacetic acid, appropriately at temperatur s of between 0 and 150C depending on the oxidising agent used.
The oxidation is pre~erably carried out with an equivalent of the oxidising agent used, e.g.
with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20C
or in acetone at 0 to 60C, with a peracid such as performic acid in glacial acetic or trifluoroacetic acid at 0 to 50C or with m-chloroperbenzoic acid in methylene chloride or chloroform at 0 to 60C, with sodium metaperiodate in dioxan or ethanol at 80 to 100C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromosuccinimide in ethanol, with iodobenzodichloride in aqueous pyridine at 0 to 50C, with nitric acid in glacial acetic acid at 0 to 20C and with chromic acid in glacial acetic acid or in acetone at 0 to 20C.
The compounds obtained according to the invention can be converted into the acid addition salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic;
sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic and fumaric acid.
The compounds of formulae II to IV used as starting materials are, for the most part, already known or may be obtained by the process described in US-A-2940972 (see Examples A tv D~.
As already mentioned hereinbefore, the compounds of formula I wherein R2 represents a piperazino ~ 2S2~&~3 group and the acid addition salts thereof, particularly the physiologically acceptahle acid addition salts thereof with inorganic or organic acids, have valuable pharmacological properties, particularly antithrombotic and metastasis-inhibiting effects and an inhibiting effect on phos~hodies~erase and tumour growth.
For example, the following compounds:
A = 4,7-dimorpholino-6-phenyl-2-piperazino-pteridine, B = 4-morpholino-7-(1-oxidothiomorpholino)-2-piperazino-6-phenyl-pteridine, C = 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-pteridine, D = 7-dimethylamino-6-phenyl-2-piperazino-4-pyrrolidino-pteridine, and E = 7-benzylamino-4-(N-methyl-2'-hydroxyethylamino)-2~piperazino-pteridine were investigated for their inhibiting effect on phosphodiesterase (PDE) of tumour cells and of human thrombocytes _ vitro using the method described by Pooh et al., in the following manner (see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272 291 ~1971)):

a) Obtaining the enzyme:
~ he phosphodiesterase was obtained from B16 melanoma tissue from mice by centrifuging the homogenised tissue at 5,000 x g (15 minutes at 4C). The tissue was homogenised by repeated freezing and thawing and homogenisation according to Potter Elvehjem or by using ultrasound. The homogenised supernatant containing the PDE was divided into batches and deep frozen at -25C.

~2~ 3 g Phosphodiesterase was obtained from human thrombocytes in the same way.

b) Determinin~ the PDE inhibition (PDE assay):
The PDE inhibition caused by the test substances were determined using 1 mcmol/l of 3H-cAMP as substrate.
The PDE inhibition was determined by measuring the degradation of the subs~ance 3H-cAMP to form 3H-AMP by comparison with a control without any test substance.
The 3H-AMP formed was separated from the remaining 3H-cAMP by precipitation using zinc sulphate and barium hydroxide.
The IC50, namely the concentration which inhibits the PDE activity by 50~, was calculated by linear regression analysis.

.
PDE Inhibition (IC50 in mcmol/l) Substance Thrombocytes ~16 Tumour Cells A 0.54 4.3 B 2.2 3.1 C 0.5 0.096 D 3.6 0.78 E 3.7 8.3 25 _ _ _ _ Acute toxicity The approximate acute toxicity of the test substances was determined, as a guide, on groups of 10 mice after oral administration of a single dose (observation period: 14 days):

~5i27~3 Substance Approximate acute toxicity A > 250 mg 10 out of 5 animals died) C ~ 250 mg (0 out of 5 animals died) D > 250 mg (0 out of 5 animals died) E ~ 250 mg (0 out of 5 animals died) The new compounds of formula I according to the invention wherein R2 represents a piperazino ! group and the physiologically acceptable acid addition salts thereof may be suitable, in view of their above-mentioned pharmacological properties, for the prevention of thromboembolic diseases such as coronary infarct, cerebral infarct, so-called transient ischaemic attacks, amaurosis fugax, and to prevent arteriosclerosis, and for the prevention of metastasis and for inhibiting tumour growth.
According to a further aspect of the present invention we therefore provide a method of treatment of the human or non-human animal body to achieve an anti-thrombotic or a tumour growth- or metastasis-inhibiting effect therein, said method comprising administering to said body a compound of formula I ~wherein R2 represents a piperazino group) or a physiologically acceptable acid additîon salt thereof.
According to a still further aspect o~ the invention we provide the use of a compound of formula I (wherein R2 represents a piperazino group) or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human animal body to achieve an anti-thrombotic or a tumour growth- or metastasis-inhibiting effect therein.

~L25~7133 The dosage required in order to achieve these effects is conveniently from Ool to 4 mg/kg of body weight, preferably 0.2 to 3 mg/kg of body weight, 2 to 4 times a day. For this, the com~ounds of formula I (wherein R2 represents a piperazino group) or the physiologically acceptable acid a~dition salts thereof, optionally together with other active substances, may conveniently be combined with one or more inert conventional carriers and/or diluents.
According to another aspect of the invention we therefore provide a pharmaceutical composition comprising a compound of formula I (wherein R2 represents a piperaæino group) or a physiologically acceptable acid addition salt thereof together 1~ with at least one pharmaceutical carrier or diluent.
~ he carrier or diluent may for example be selected from corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, non-ionic surfactants such as fatty acid esters o polyoxyethylene, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat 2~ or suitable mixtures thereof, and the pharmaceutical compositions may conveniently be in this form of conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppos;tories.
According to a still further aspect of the invention we provide the use of a compound of formula I (wherein R2 represents a piperazino groupt or a physiologically acceptabIe acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human animal body to achieve an anti-thrombotic or a tumour growth- or metastasis-inhibiting effect therein.

~25Z~33 ~ he Examples which follow are provided to illustrate the invention without serving to restrict the scope of protection sought therefore:

S

:

:::

.
.

... . . . . ..

~2~ 27133 ~xample A
2,7-Dichloro-4-morpholino-~teridine 7.n3 g tO.03 mol) of 2,4,7-trichloro-pteridine are dissolved in 100 ml of chloroform and at 5C
mixed with a solution of 3.0 g (0.03 mol) of potassium hydrogen carbonate in 50 ml of water. Then 2.62 g (0.03 mol) of morpholine in 50 ml of chloroform are added dropwise and the mixture is stirred for 45 minutes at ambient ~emperature. The organic phase is then separated off, dried over sodium sulphate and concentrated in vacuo. ~he residue is recrystallised from ethanol.
Yield: 7.4 g S86~ of theory), M.p.: 187-188C
The following compounds are obtained analogously to Example A:

2,7-Dichloro-4-piperidino-pteridine Yield: 67% of theory, M.p.: 152-154C (ethanol) 2,7-Dichloro-4-benzylamino-pteridine Yield: 75% of theory, M.p.: 150-152C (methanol) 2,7-Dichloro-4-(1-oxidothiomorpholino)-pteridine Yield: 65~ of theory, M.p.: 230-235C

2,7-Dichloro-4-(N-methyl-2'-hydroxyethylamino)-pteridine Yield: 74~ of theory, M.p.: 178-180C

2,7-Dichloro-4-diethanolamino-pteridine Yield: 71% of theory, M.p.: 173-174C ~ethanol) ~25~

2,7-Dichloro-6-methyl-7-morpholino-pteridine Yield: 73% of theory, M.p.: 230-232C (ethanol) Example B
2,7-Dichloro-6-phenyl-4-thiomorpholino-pteridine 35.5 g ~0.114 mol) of 2,4,7-trichloro-6-phenyl-pteridine are dissolved in 500 ml of acetone and mixed with 11.5 9 (0.13 mol) of sodium hydrogen carbonate in 120 ml of water. ~hen a solution of 11.8 9 (0.114 mol) of thiomorpholine is added and the resulting mixture is stirred for 45 minutes at ambient temperature. This solution is poured into 2 litres of water, the precipitate obtained is collected and recrystallised from ethylene chloride.
Yield: 36 g (84~ of theory), M.p.- 225-227C

~ he following compounds are obtained analogously to Example B:

2,7-Dichloro-4-(1-oxidothiomorpholino)-6-phenyl-pteridine Yield: 88~ of theory, M.p.: 222-224C

2,7-Dichloro-4-morpholino-6-phenyl-pteridine Yleld: 78~ of theory, M.p.: 198-201C

2,7-Dichloro-6-phenyl-4-piperidino-pteridine Yield: 6q~ of theory, M.p.: 168-170C ~ethyl acetate) 2,7-Dichloro-4-dimethylamino-6-phenyl-pteridine Yield: 77% of theory, M.p.: 236-238C (ethylene chloride) ~2527~3 2,7-Dichloro-4-(N-methyl-2'-hydroxyethylamino)-6-phenyl-pteridine Yield: 76~ of theory, M.p.: 162-164C (ethanol) 2,7-~ichloro-4-(N-benzyl-methylamino~-6-phenyl-pteridine Yield: 59% of theory, M.p.: 141-143C (ethanol/dioxan~

2,7-Dichloro-6-phenyl-4-pyrrolidino-pteridine Yield: 81~ of theory, 1.0 M.p.: 199-200C (ethyl acetate~

2,7-Dichloro-6-phenyl-4-thiazolidino-pteridine Yield: 82~ of theory, M.p.: 169-171C (ethyl acetate~

Example C
; 7-Chloro-2-(N-formylpip-eraz-in-o----6-phenyl-4-thiomorpholin pterid_ne 5.S g (0.048 mol) of N-formyl-piperazine in 10 ml of dioxan is added to a solution of 7.6 g (0.02 mol) of 2,7-dichloro-Ç-phenyl-4-thiomorpholino-pteridine in 100 ml of dioxan and the mixture is stirred for 1 hour at 40C. The reaction mixture is then added to 600 ml of water, the precipitate is suction filtered and decocted with ethyl acetate.
Yield: 88% of theory, M.p.: 223-226C

The following compounds are obtained analogously to Example C:

7-Chloro-4-(N-_ormylpiperazino~-4-(1-oxidothiomorpholino)-6-phenyl-pteridine Yield: 90% of theory, M.p.: 230C (decomposition) ~25~ 3 7-Chloro-2-(N-formylpiperazino)-~-morpholino-6-phenyl-pteri~ine Yield: 90% of theory, M.p.: 247C (decomposition) 7-Chloro-2-(N-formylpiperazino)-6-phenyl-4-piperidino-pteridine Yield: 66% of theory, M.p.: 210-213C (ethyl acetate) 7-Chloro-4-dimethylamino-2-(N-formylpiperazino)-6-phenyl-pteridine Yield: 89% of theory, M.p.: 232-234C (ethyl acetate) 7-Chloro-2-(N-formylpiperazino)-4-(N-methyl-2'-hydroxyethylamino)-6-phenyl-pteridine Yield: 86% of theory, M.p.: sinters from 170C

7-Chloro-2-~N-formylpiperazino!-4-(N-methyl-benzylamino)-6-phenyl-pteridine Yield: 63% of theory, M.p.: 143-145C (ethyl acetate) 7-Chloro-2-(N-formylpiperazino)-6-phenyl~4-pyrrolidino-pteridine Yield: 60% of theory, M.p.~ 210C (decomposition) 7-Chloro-2-(N-formylpiperazino)-6-phenyl-4-thiazOlidinO-pteridine Yield: 82~ of theory, M.p.: 180-190C (ethyl acetate) ~252'71~3 - ]7 Example D
2-Chloro-4,7-dimorpholino-pteridine 7.4 g (0.025 mol) of 2,7-dichloro-4-morpholino-pteridine are dissolved in 150 ml of methylene chloride and stirred wi~h 4.4 g ro.o5 mol) of morpholine for 15 minutes at 40C. The mixture is then left to cool, mixed with 200 ml of water, the organic phase is separated off, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is recrystallised from ethanol.
Yield: 57% of theory, M.p.: 253-255C

The following compounds are obtained analogously to ~xample D:

7-Benzylamino-2-chloro-4-piperidino-pteridine Yield: 94~ of theory/
M.p.: 220-222C ~dioxan)

4-Benzylamino-2-chloro-7-(1-oxidothiomorpholino~-pteridine ~0 Yield: 45% of theory, M.p.: 264-265C (ethanol) 7-Benzylamino-2-chloro-4-(1-oxidothiomorpholino)-pteridine Yield: 65% of theory, M.p.: 239-240C (dioxan/ethanol) 2-chloro-4-(N-methyl-2'-hydroxyethylamino)-7-morpholino-pteridine Yield: 74% of theory, M.p.: 190-192C

7-Benzylamino-2-chloro-4-(N-methyl-2'-hydroxyethylamino)-pteridine ~25~7~3 Yield: 66~ of theory, M.p.: 169-170C

2-Chloro-4-(N-methyl-2'-hyaroxyethylamino3-7-thiomorpholino-pteridine Yield: 80% of theory, M.p.: 214-215C

7-BPnzylamino-2-chloro-4-diethanolamino-pteridine Yield: 79~ of theory, M.p. 188-189C (dioxan) 2-Chloro-4-diethanolamino-7-morpholino-p~eridine Yield: 74~ of theory, M.p.: 197-199C (ethanol) 2~Chloro-6~me~hyl-4,7-dimorpholino-pteridine Yield: 29% of theory, M.p.: 195-200C

2-Chloro-6-methyl-4-morpholino-7-thiomorpholino-pteridine Yield: 27% of theory, M.p.: ~50-155C

~.252~33 Example 1 4,7-Dimorpholino-2-piperazino-pteridine 4.2 g (0.0125 mol~ of 2-chloro-4,7-dimorpholino-pteridine are dissolved in 200 ml of dimethylsulphoxide and stirred with a solution of 10.8 g (0.125 mol) of anhydrous piperazine for 1 hour at ambient temperature.
Then 1 litre of water is added and the mixture is extracted twice with 100 ml of methylene chloride.
The organic phases are dried over sodium sulphate and concentrated by centrifuging. The residue is washed with ether.
Yield: 85~ of theory, M.p.: 257-259C (decomposition) Calculated: C 55.94 H 6.78 N 24.00 Found: 56.~6 6~90 23.60 ~max (ethanol): 380, 279, 248 nm Example 2 7-Benzylamino-2-piperazino-4-pi~eridino pteridine

5.3 g (0.015 mol) o~ 7-benzylamino-2-chloro-4-piperidino-pteridine are dissolved in 250 ml of chloroform and refluxed with a solution of 10.3 g (0.12 mol~ o~ ~iperazine. After 2 hours the mixture is extracted with 200 ml of water and the organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is recrystallised from dioxan.
Yield: 79% of theory, M.p.: 18S-188C
Calculated: C 65.32 H 6.98 N 27.70 Found: 6S.21 7.35 27.46 ~max (ethanol): 370, 280, 242 nm Example 3 4-Benzylamino-7-(l-oxidothiomorpholino~-2-piperazino-pteridine Prepared analoqously to Example 2 from 4-~25Z7~3 benzylamino-2-chloro-7-(1-oxidothiomorpholino)-pteridine and piperazine.
Yield: 85% of theory, M.p.: 190-192C (methanol) Calculated: C 57.51 H 5.98 N 25.55 S 7.31 Found: 57.35 6.12 25.29 7.24 ~Max (ethanol): 375, 275, 247 nm Example 4 7-Benzylamino-4-(1-ox _ thiomorpholino)-2-piperazino-pteridine Prepared analogously to Example 2 from 7-benzylamino-2-chloro-4-(1-oxidothiomorpholino~-pteridine and piperazine.
Yield: 90% of theory, M.p.: 259-261C (methanol) Calculated: C 57052 H 5 48 N 25.-55 S 7.31 Found: 57.46 5.84 25.60 7.66 ~max (ethanol): 375, 286, 247 nm Example 5 4-(N-Methyl-2'-hydroxyethylamino~-7-mor~holino-2-piperazino-~teridine Prepared analogously to Example 2 from 2-chloro-4-(N-methyl-2'-hydroxyethylamino~-7-morpholino-pteridine and piperazine.
Y;eld: 78~ o~ theory, M.p. 172-174C
Calculated: C 54.53 H 7.00 N 29.93 Found: 54.~R 7.40 29.64 ~max (ethanol): 384, 278, 247 nm Example 6 7-Benzylamino-_-(N-methyl-2'-hydroxyet~ylamino)-2-piperazino-pteridine Prepared analogously to Example 2 from 7-benzylamino-2-chloro-4-(N-methyl-2'-hydroxyethylamino)-pteridine and piperazine.

~2~ 33 2~ -Yield: 70~ of theory, M.p.: 220-222C
Calculated: C 60.84 H 6.64 N 28.41 Found: 61.03 6.45 28.12 S ~max (ethanol): 372, 277, 243 nm Example 7 4-(N-Methyl-2'-hydroxyethylamino)-2-piperazino-7-thiomor~holino-pteridine Prepared analogously to Example 2 from 2-chloro-4-(N-methyl-2'-hydroxye~hylamino)-7-thiomorpholino-; pteridine and piperazine.
Yield: 65% of theory, M.p.: 175-177C
Calculated: C 52.28 ~ 6.71 N 28.70 S 8.21 Found: 52006 6.44 28.42 8.35 ~max tethanol): 384, 278, 247 nm Example 8 7-Benzylamino-4-diethanolamino-2-piperazino-pteridine Prepared analogously to Exam~le 2 from 7-benzylamino-2-chloro-4-die~hanolamino-pteridine and piperazine.
Yield: 76% of theory, M.p.: 203-208~C
Calculated: C 59.42 H 6.65 N 26.40 Found: 59.24 6.76 26.24 ~max (ethanol): 372, 278, 243 nm Example 9 4-Diethanolamino-7-morpholino-2-piperaæino pteridine Prepared analogously to Example 2 from 2-chloro-4-diethanolamino-7-morpholino-pteridine and piperazine.
~5 Yield: 62% of theory, M.p.: 187-195C
Calculated: C 53.46 H 6.98 N 27.70 ~L~S~3 Found: 53.11 6.94 27.53 ~max (ethanol): 382, 278, 247 nm Example 10

6-Methyl-4,7-dimorpholino-2-piperazino-pteridine Prepared analogously to Example 2 from 2-chloro-6-methyl-4,7-dimorpholino-pteridine and piperazine.
Yield 66% o theory, M.p.: 180-185C
Calculated: C 56.98 H 7.05 N 27.98 Found: 56.78 6.78 27.70 lmax (ethanol): 3R2, 279, 248 nm Example 11 6-Methyl-4-morpholino-2-piperazino-7-thiomorpholino-pteridine Prepared analogously to Example 2 from 2-; chloro-6-methyl-4-morpholino-7-thiomorpholino-pteridine and piperazine.
Yield: 58% of theory, M.p.: 185-188C
Calculated: C 54.77 H 6.78 N 26.90 S 7.70 Found: 54.99 7.05 26.69 7.93 ~max (ethanol): 382, 280, 247 nm Example 12 4-(N-Methyl-2'-hydroxyethylamino)-7-(1-oxidothio-morpholino)-2-piperazino-pteridine 2.92 g of 4-(N-methyl-2'-hydroxyethylamino)-

7-thiomorpholino-2-piperazino-pteridine are dissolved in 50 ml of methylene chloride and stirred with a solution of 1.72 g of m~chloroperbenzoic acid for 2 hours at ambient temperature. The mixture is then concentrated by centrifuging and the residue is washed with ether. The residue is dissolved in a little water, made alkaline with 2N sodium g~ 3 hydroxide solution and then extracted with methylene chloride. The organic phases are dried and concentrated by centrifuging.
Yield: l.l g (36% of theory), M.p.: 223-226C
Calculated: C 50.23 H 6.45 S 7.88 Found: 49.93 6.42 ~.03 ~max (ethanol): 386, 278, 245 nm 10 Example 13 7-Benzylamino-2-(N-formylpiperazino~-6-phenyl-4-thiomorpholino-pteridine 3.2 g (7 mmol) of 7-chloro-2-(N-formylpiperazino)-6-phenyl-4-thiomorpholino~pteridine are refluxed with 2.2 g 121 mmol) of benzylamine in 15 ml of dioxan. After 3 hours the solvent is drawn off in vacuo and the oily residue is poured into 100 ml of water. The product precipitated is collected, dried and chromatographed over a short silica gel column with ethyl acetate/me~hanol (15~1). The substance is then recrystallised from ethyl acetate.
Yield: 80~ of theory, M.p.: 21~-221C

The following compounds are obtained analogously to Example 13:

2-(N-Formylpiperazino)-7-(N-methyl-2'-hydroxyethylamino)-6-phenyl-4-thiomorphQlino-pteridine Yield: 55~ of theory, M.p.: sintexs from 130C (ethyl acetate) 2-(N-Formylpiperazino)-4-morpholino-7-(1-oxidothio-morpholino)-6-phenyl-pteridine Yield: 50% of theory, M.p.: 250-252C (water) ~252~3 2-(N-Formylpiperazino)-4-(N-methyl-2'-hydroxyethylamino)-7-morpholino-6-phenyl-pteriaine Yield: 80~ of theory, M.p.: 165-175C

2-(N-Formylpiperazino~-7-(N-methyl-benzylamino)-4-(N-methyl-2'-hydroxy-ethylamino)-6-phenyl-pteridine Yield: 80~ of theory, M.p.: 135-155C

2-(N-Formylpiperazino~-4-(N-methyl-2'-hydroxyethylamino~-7-thiomorpholino-6-phenyl-pteridine Yield: 80~ of theory, M.p.: sinters from 155C

4,7-Di-(N-methyl-benzylamino)-2-(N-formylpiperazino)-6-phenyl-pteridine Yield: 50% of theor~, M.p.: 50-70C

7-Dimethylamino-2-(N-formylpiperazino)-4-(N-methyl-benzylamino~-6-phenyl-pteridine Yield: 90% of theory, M.p.: sinters from 90C

2-(N-Formylpiperazino)-4-(N-methyl-benzylamino)-7-morpholino-6-phenyl-pteridine Yield: 80% of theory, M.p.: sinters from 40C
Example 14 7-E~enzylamino-6-phenYl-2 piperazino-4-thiomorPholino-pteridine 1.58 g (3 mmol) of 7-benzylamino-2-(N-formyl-piperazlno)-6-phenyl-4-thiomorpholino-pteridine are refluxed with 15 ml of 10% hydro~hloric acid for 30 minutes~ After ~ooling, the solution is ~2~ 7~33 - ~5 mixed with aqueous potassium carbonate solution and the product is extracted with chloroform.
The or~anic phase is concentrated by e~aporation in vacuo and the produc~ is chromatographed over a silica gel column with methanol/conc. ammonia 80:l.
Yield: 0O8 g (54% of theory), M.p.: 115-130C
Calculated~ C 65.03 H 6.06 N 22.47 Found: 65.20 6.22 22.07 ~max (ethanol): 386, 292, 248 nm Example 15 7-(N-Methyl-2'-hydroxyethylamino)-6-phenyl-2-piperazino-4-thiomorpholino-Pteridine Prepared from 2-(N-formylpiperazino)-7-~N-methyl-2'-hydroxyethylamino)-6-phenyl-4-thiomorpholino-pteridine analogously to Example 14.
Yield: 52% of theory, 20 M.p.: sinters from 70C
Calculated: C 59.20 ~ 6.48 N 24.02 Found: 59.44 6.22 23.35 ~max (ethanol): 400, 297, 258 nm 25 Example 16 4-Morpbolino-7-(1-oxidothiomorpholino)-6-phenyl-2-piperazino-pteridine Prepared from 2~(N-formylpiperazino)-4-morpholino-7-(t-oxidothiomorpholino)-6-phenyl-pteridine analogously 30 to Example l4.
Yield: 43% of theory M.p.: 196-199C
Calculated: C 58.28 H 6~11 N 22.66 S 6.48 Found: 57.93 6.31 22.72 6.44 ~max (ethanol): 400, 295, 258 nm ~5æ~

Example 17 4-(N-Methyl-2'-hydroxyethylamino)-7-morpholino-6-phenyl-2-piperazino-pteridine Prepared from 2-(N-formylpiperazino-4-(N-methyl-2'-hydroxyethylamino~-7-morpholino-6-phenyl-pteridine analogously to Example 14.
Yield: 31~ of theory M.p.: sinters from 90C
Calculated: C 61.30 H 6.71 N 24.87 10 Found 61.52 6.73 24.75 ~max (ethanol): 398, 296, 258 nm Example 18 7-(N-Methyl-benz,ylami o~-4-(N-methyl-2 7 -hydroxyethylamino)-6-phenyl-2-piperazino-pteridine Prepared from 2-(N-formylpiperazino)-7-(N-methyl-benzylamino)-4-(N-methyl-2'-hydroxyethylamino)-6-phenyl-pteridine analo~ously to Example 14.
I Yield: 19% of theory, 20 M.p.: 80-110C
Calculated: C 66.91 H 6.66 N 23.13 Found: 66.80 6.58 22.70 ~max ~ethanol): 395, 294, 258 nm 25 Example 19 4-(N-Methyl-2~-hydroxyethYlamino)-6-phenyl-2-piperazin 7-thiomorpholino-pteridine Prepared from 2-fN-formylpiperazino~-4-(N-methyl-2'-hydroxyethylamino~-6-phenyl-7-thiomorphoIino-pteridine analogously to ~xample 14.
Yield: 13~ of theory, M.p.: 100-140C
Calculated: C 59.20 H 6.48 M 24.02 Found: 59.66 6.45 23.74 ~max (ethanol): 398, 296, 258 nm ~:252~7~3 Example 20 4,7-Bis-(N-methyl-benzylamino)-6-phenyl-2-piperazino-pteridine Prepared from 2-(N-formylpiperazino~-4,7-bis-(N-methyl-benzylamino)-6-phenyl-pteridine analogously to Example 14.
Yield: 56% of theory, M.p.: resin-like product Calculated: C 72.47 H 6.46 N 21.12 Found: 72.60 6.62 20.90 ~max (ethanol): 398, 294, 258 nm Example 21 7-Dimethylamino-4-(N-methyl-benzylamino)-6-phenyl-2-piperazino-pteridine Prepared from 2-(N-formylpiperazino3-7-dimethyl-amino-4-(N-methyl~benzylamino)-6-phenyl-pteridine analogously to Example 14.
Yield- 69~ of theory, M.p.: 129-132C (ethyl acetate~
Calculated: C 68.69 H 6.65 N 24.65 Found: 68.84 6.81 24.37 ~max ~ethanol~: 396, 294, 258 nm Example 22 4-~N-Methyl-benzylamino~-7-morpholino-6-phenyl-2-piperazino-pteridine Prepared from 2-rN-formylpiperazino!-4-(N-methyl-benzylamino)-7-morpholino-6-phenyl-pteridine 30 analogously to Example 14.
Yield: 60~ of theory, M.p.: 70-100C
Calculated: C 67.71 H 6.50 N 22~57 Found: 67.96 6.49 22.55 3S ~max (ethanol): 396, 294, 258 nm ~2~i;27~

Example 23 7-Dimethylamino-6-phenyl-2-pi~erazino-4-pyrrolidino-pteridine Prepared from 2-(N-formylpi~erazino)-7-dimethyl-amino-6-phenyl-4-pyrrolidino-pteridine analogously to Example l4.
Yield: 30% of the theory, ~1.p.: 125-130C
Calculated: C 59.20 H 6.48 N 24.02 Found: 59.44 6.71 23.65 ~max (ethanol): 394, 29~, 2-57 nm Example 24 7-Morpholino-6-phenyl-2-piperazino-4-thiazolidino-Pteridine Prepared from 2-(N-formylpiperazino)-7-morpholino-6-phenyl-4-thiazolidino-pteridine analogously to Example 14.
Yield: 56% of theory, M.p.: 120-150C
Calculated: C 59.46 H 6.07 N 24.12 S 6O90 Found: S9.13 6.13 24.36 6.68 ~max (ethanol): 396, 294, 258 nm Example 25 7-Mor~holino-4-(1-oxidothiazolidino)-6-phenyl-2-piperazino-~teridine 0.93 g (2 mmol) of 7-morpholino-6-phenyl-2-piperazino-4-thiazolidino~-pteridine are dissolved in 15 ml of dioxan and refluxed for 1.5 hours with 0.86 g of sodium metaperiodate in 5 ml of water.
The mixture is then concentrated by centrifuging, the residue is taken up in chloroform and chromatographed over a silica gel column with ethanol/ammonia 25:1.
Yield: 31% of theory, M.p.: 190-250C
Calculated: C 57.49 H 5.~7 S 6.67 ~2$;~7~3 Found 57.24 6.10 7.15 ~max (ethanol): 394, 290, 258 nm Example 26 4-(N-Methyl-2'-hydroxyethylamino)-7-(1-oxidothio-morpholino)-6-phenyl-2-piperazino-pteridine Prepared analogously to Example 25 from 4-(N-methyl-2'-hydrvxy-ethylamino)-7-thiomorpholino-6-phenyl-2-pipera~ino-pteridine.
tO Calculated: C 57.25 H 6.27 S 6.64 Found: 57.45 6.59 6.96 ~max (ethanol~: 396, 296, 255 nm Yield: 58~i of theory.
M.p.: sinters from 110C
Example 27 4~7-Bis-dimethylamino-6-phenyl-2-piperazino-pteridine Prepared from 4,7-bis-di~ethylamino-2-(N-formylpiperazino~-6-phenyl-pteridine analogously 20 to Example 14.
Yield: 85% of yield.
M.p.: sinters from 50C
Calculated: C 63.46 H 6.93 N 2g.61 Found: 63.22 7.07 29.82 ~max (ethanol): 394, 293, 257 nm Example 28 6-Phenyl-2-piperazino-4,7-dipiper _ino-pteridine Prepared from 2-(N-formylpiperazino)-6-phenyl-4,7-dipiperidino-pteridine analogously to ~xample 14.
Yield: 43~i of theory.
M.p.: sinters from 90C
Calculated: C 68.10 H 7.47 N 24.43 Found: 68.00 7.47 24.29 ~max (ethanol): 400, 299, 260 nm , ,,,, ,, - ,, ~æ783 Example 29 2,7-Dipiperazino-4-morpholino-6-phen~l-pteridine 25~2 g (0.07 mol) of 2,7-dichloro-4-morpholino-6-phenyl-pteridine are stirred in 70 ml of ethanol with 36 g of piperazine for 1 hour at ambient temperature.
The mixture is then stirred into 700 ml of water, the precipitate formed is suction filtered, dissolved in 4 N acetic acid and reprecipitated with 8 N
sodium hydroxide solution.
Yield: 24 g (74~ of theory~, M.p.: sinters from 130C
Calculated: C 62.44 H 6.77 N 27.31 Found: 62.78 6.70 27.31 ~max (ethanol): 400, 298, 260 nm Example 30 2,7-Dipiperazino-4-thiomorpholino-6-phenyl-pteridine Prepared from 2,7-dichloro-4-thiomorpholino-6-phenyl-pteridine analogously to Example 29.
Yield: 79% of theory, M.p.: sinters from 80C
Calculated: C 60.35 H 6.54 N 6.71 Found: 60.20 6.67 6.32 ~max ~ethanol): 400, 299, 259 nm Example 31 7-Morpholino-4-(1-oxidothiomorpholino)-6-~henyl-2-piperazino-pteridine 4.6 g (0~01 mol) of 7-chloro-2-(N-formylpiperazino)-4-(1-oxidothiomorpholino~-6-phenyl-pteridine are heated to 100C in 8.7 g (n . 1 mol) of morpholine for 1 hour. The solution is concentrated by evaporation in vacuo and the residue is chromatographed over a silica gel column with methanol/ammonia 50:1.
Yield: 1.5 g ~30% of theory), M.p.: 151-154C (methanol) Calculated: C 58.28 H 6.11 N 22.66 S 6.48 ` ~2~;27~3 Found: 57.99 6.13 22.22 6.65 ~max (ethanol~: 398, 294, 258 nm Example 32 7-~enzylamino-4-(1-oxidothiomorpholino)-6-phenyl-2-piperazino-pteridine Prepared from 7-chloro-2-(N-formyl-piperazino~-4-(1-oxidothiomorpholino)-6-phenyl-pteridine and benzylamine analogously to Example 31.
10 Yield: 50% of theory, M.p.: 200C (decomposition) Calculated: C 63.01 H 5.88 N 21.77 S 6.23 Found: 62.89 6.07 2-.45 6.20 Example 33 7-Benzylamino-4-morpholino-6-phenyl-2-piperazino-pterid_ne Prepared from 7-chloro-2-(N-formyl-piperazino)-4-morpholino-6-phenyl-pteridine and benzylamine 20 analogously to Example 31.
Yield: 35% of theory, M.p.: 135-138C (ethyl acetate) Calculated: C 67.20 H 6.27 N 23.22 Found: 67.25 6.34 23.42 ~max (ethanol): 385, 290, 248 nm Example 34 4,7-Dimorpholino-6-phenyl-2-piperazino-pteridine Prepared from 7-chloro-2-(N-formy~-piperazino)-4-morpholino-6-phenyl-pteridine and morpholine analogously to Example 31.
Yield: 13% of theory, M.p.: 220-223C
Calculated: C 62.32 H 6.54 N 24.23 35 Found: 62.21 6.64 24.05 ~max (ethanol): 400, 296, 259 nm ~5~7~3 - 32 ~
Example 35 4,7-Bis-(l-oxidothiomorpholino)-6-phenyl-2-piperazino-~teridine Prepared from 7-chloro-2-(N-formyl-piperazino)-4-(1-oxidothiomorpholino)-6-phenyl-pteridine and l-oxidothiomorpholine analogously ~o Example 31.
Yield: 25% of theory.
M.p.: 250C (decomposition) Calculated: C 54.73 H 5~74 N 24.28 Found: 54.60 5.71 24.04 ~max (ethanol): 400, 296, 259 nm ~5Z~33 Example I
Coated tablets containing 4 mq of 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-pteridine Composition:
5 l tablet core contains:
Active substance (1)4.0 mg Lactose (2)27.0 mg Corn starch (3)14.5 mg Polyvinylpyrrolidone (4~4.0 mg lO Magnesium stearate (5)0.5 m~
50.0 mg Preparation:
Substances 1-3 are uniformly moistened with an aqueous solution of 4, screened through a 1 mm mesh screen, dried and again screened through a 1 mm mesh screen. After 5 has been added the mixture is compressed to form tablet coresO
Cores: 5 mm in diameter, biconvex, round.
Coating:
Conventional sugar coating to give a finished tablet weight of 70 mg.

Example II
Tablets containing 8 mg of 7-benzylam no-6-phenyl-2-piperazino-4-thiomor~holino-pteridine I tablet contains:
Active substance 8.0 mg 30 Lactose 23.0 mg Corn starch 14.5 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 0.5 mq 50.0 mg Preparation:
Analogously to the cores of the coated tablets of Example I.

~L~52~E~3 Description of tablet:
Weight: 50 mg Diameter: 5 mm, biplanar, faceted on both sides.

Example III
Suppositories containin~ 25 mq of 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-pteridine 1 suppository contains:
Active substance 0.025 g Hard fat (e.g. Witepsol ~ 19 1.695 g and Witepsol H 45) 1.700 g Preparation:
The hard fat is melted. At 38C the ground active subs~ance is homogeneously dispersed in the melt. It is cooled to 35C and poured into slightly chilled suppository moulds.
Weight of sùppository: 1.7 g Example IV
Suspension_containing 8 mg of 7-benzylamino-6-~henyl-2-piperazino-4-thiomorpholino-pteridine per 5 ml lO0 ml of suspension contain:
Active substance 0.16 g Carboxymethylcellulose 0.1 g 25 Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate 0.01 g Glucose 10.0 g Glycerol 5.0 g 70% Sorbitol 20.0 g 30 Flavouring 0.3 g Distilled water ad 100~0 ml Method of preparation:
The distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates and the glycerol and carboxylmethylcellulose are dissolved therein n~

~252~7~33 with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed with stirring. After the sugar, sorbitol solution and flavouring have been added and dissolved the suspension is evacuated with stirring to eliminate air.

Example V
Tablets containin~ 100 m~ of 7-benzylamino-6-phenyl-10 2-piperazino-4-thiomorpholino~ eridine Composition:
1 tablet contains:
Active substance 100.0 mg Lactose 80.0 mg 15 Corn starch 34~0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 m~
220.0 mg 20 Method of p-eparation The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone.
After the moist mass has been screened (2.0 mm mesh) and dried in a rack dryer at 50C it is screened again (1.5 mm mesh) and the lubricant is added.
The mixture ready ~or compressing is processed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar faceted on both sides and notched on one side.

Example VI
Hard qelatine ca~sules containin~ 150 m~ o~ 7-benzyl-35 amino-6-phenyl-2-~
1 capsule contains:
Active substance 150~0 mg 9~2527~33 Dried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg Magnesium stearate 3.0 m~
approx. 320.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a 0O75 mm mesh and homogeneously mixed in a suitable apparatus.
The finished mixture is packed into hard gelatine capsules, siæe 1.
Capsule filling: approx. 320 mg Capsule shell: hard gelatine capsule, size 1.

Example VII
Suppositories containing 150 m~ of 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-pteridine 1 suppository contains:
Active substance 150.0 mg Polyethyleneglycol 1500 550.0 mg Polyethyleneglycol 6000 460.0 mg Polyoxyethylene sorbitan monostearate 840.0 mg 2 000.0 mg Preparation After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example VIII
Suspension containing 50 mg of 7-benzylamino-6-~hen~1-2~piperazino-4-thiomorpholino-pteridine per 5 mI
100 ml of suspension contain:
35 Active substance 1.0 g Sodium salt of carboxymethylcellulose 0.1 g Methyl p~hydroxybenzoate 0.05 g 2'7~3~

Propyl p-hydroxybenzoate 0.Ol ~
Glucose 10.0 g Glycerol S.0 g 70% Sorbitol solution 20.0 g 5 Flavouring 0.3 g Distilled water ad 100 ml Preparation The distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates and the glycerol and carboxymethylcellulose sodium salt are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed with stirring.
After the sugar, sorbitol solution and flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example IX
Tablets contain n~ 150 mg of 7-benzylamino-6-Pheny 2-piperazino-4-thiomor~holino-pteridine Composition:
25 1 tablet contains:
Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Colloidal silica 10.0 mg 30 Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 mq 300.0 mg Preparation The active substance mixed with lactose, corn starch and silica is moistened with a ~0~
a~ueous polyvinylpyrrolidone solution and passed ~5~

through a screen with a 1.5 mm mesh. The granulate dried at 45C is again passed through the same screen and mixed with the stated quantity of magnesium stearate. Tablets are compressed from the mixture.
Weight of tablet: 300 mg Punch: 10 mm, flat.

Example X
Coated tablets containing 75 m~_~f 7-benzylamino-10 6-phen,y~ ~piperazino-4-thiomorpholino-pteridine 1 tablet core contains:
Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg 15 Polyvinylpyrrolidone 10.0 mg Hydroxypropylmethylcellulose 15O0 mg Magnesium stearate ~
230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxy-propylmethylcelullose and half the stated quantity of magnesium stearate. In a tablet-making machine, blanks are produced with a diameter of about 13 mm which are then rubbed through a screen with a 1.5 mm mesh in a suitable machine and mixed with the remaining magnesium stearate. This granulate is compressed to form tablets of the required shape in a tablet making machine.
Weight of core: 230 mg Punch: 9 mm, convex.

The tablet cores thus produced are coated with a film consisting essentially of hydrox~propyl-methylcellulose. The finished film-coated tablets are polished with beeswax.

~ , i ~;~5æ78;~

Weight of coated tablet: 245 mg.
Obviously, all the other compounds of formula I (wherein R2 represents a piperazino group) and the physiologically acceptable acid addition salts thereof may be used as active substances in the galenic preparations described hereinbefore.

Claims (22)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of formula I

(I) wherein R2 represents a piperazino or N-formyl-piperazino group, R4 represents a dialkylamino,- phenylalkylamino, N-alkylphenylalkylamino, pyrrolidino, piperidino, morpholino, thio-morpholino, 1-oxidothiomorpholino, thiazolidino or 1-oxidothia-zolidino group, R6 represents a hydrogen atom or an alkyl or phenyl group, and R7 represents an alkylamino, dialkylamino, phenylalkyl-amino, N-alkyl-phenylalkylaminol piperidino, morpholino, thio-morpholino, 1-oxidothiomorpholino or piperazino group; wherein each alkyl moiety in groups R4, R6 and R7 contains from 1 to 3 car-bon atoms; wherein, where R4 contains one or two C2-3 alkyl moieties, one or both of said C2-3 alkyl moieties may be substitut-ed by a hydroxy group in the 2 or 3 position; and wherein, where R7 contains one or two C2-3 alkyl moieties, one or both of said C2-3 alkyl moieties may be substituted by a hydroxy group in the 2 or 3 position, or an acid addition salt thereof.

2. A compound as claimed in claim 1 wherein R2 represents a piperazino group.

3. A compound as claimed in claim 1, wherein R2 represents a piperazino group, R4 represents a dimethylamino, N-methyl-2-hydroxyethyl-amino, bis(2-hydroxyethyl)-amino, benzylamino, N-methyl-benzyl-amino, pyrrolidino, piperidino, morpholino, thiomorpholio, 1-oxidothiomorpholino, thiazolidino or 1-oxidothiazolidino group, R6 represents a hydrogen atom or a methyl or phenyl group, and R7 represents a dimethylamino, N-methyl-2-hydroxy-ethylamino, benzylamino, N-methyl-benzylamino, piperidino, morpho-lino, thiomorpholino, 1-oxidothiomorpholino or piperazino group.

4. A compound as claimed in claim 1 or 2 wherein R4 represents a pyrrolidino, piperidino, morpholino, thiomorpholino, 1-oxidothiomorpholino or N-methyl-2-hydroxy-ethyl-amino group, and R7 represents a dimethylamino, benzylamino, N-methyl-benzylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group.

5. A compound as claimed in claim 1 or 2 wherein R4 represents a dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, N-methylethylamino, N-ethyl-n-propylamino, benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-n-propylbenzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, N-methyl-1-phenylethylamino, N-ethyl-2-phenyl-ethylamino, N-ethyl-3-phenylpropylamino, bis(2-hydroxyethyl)-amino, bis(2-hydroxy-n-propyl)-amino, bis-(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-2-hydroxy-n-propylamino, N-methyl-2-hydroxyethylamino, N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-n-propylamino, N-isopropyl-2-hydroxy-ethylamino, N-(2-hydroxyethyl)-benzylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, 1-oxidothiomorpholino, thiazolidino or 1-oxidothiazolidino group, R6 represents a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl or phenyl group, and R7 represents a methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, N-methylethylamino, N-ethyl-n-propylamino, benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-n-propyl-benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropy-lamino, N-methyl-1-phenylethylamino, N-ethyl-2-phenylethylamino, N-ethyl-3-phenylpropylamino, 2-hydroxyethylamino, 2-hydroxy-n-propylamino, 3-hydroxy-n-propylamino, 2-hydroxyisopropylamino, bis(2-hydroxyethyl)-amino, bis(2-hydroxy-n-propyl)-amino, bis (3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-2-hydroxy-n-propyl-amino, N-methyl-2-hydroxyethylamino, N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-n-propylamino, N-isopropyl-2-hydroxy-ethylamino, N-(2-hydroxyethyl)-benzylamino, piperidino, morpholino, thiomorph-olino, 1-oxidothiomorpholino, thiazolidino, 1-oxidothiazolidino or piperazino group.

6. A compound as claimed in claim 1 wherein R2 represents piperazino;
R4 represents morpholino, thiomorpholino, pyrrolidino or (N-methyl-2'-hydroxy-ethylamino);
R6 represents hydrogen or phenyl; and R7 represents dimethylamino, benzylamino, morpholino or 1-oxidothiomorpholino.

7. A compound as claimed in claim 1, 2 or 3 in the form of a physiologically acceptable salt thereof.

8. The compound 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-pteridine or a physiologically acceptable salt thereof.

9. A process for preparing a compound of formula I as defined in claim 1 or an acid addition salt thereof, which process comprises a) reacting a compound of formula II

(II) wherein R4 and R6 are defined in claim 1;
one of the groups Z2 or Z7 represents a nucleophili-cally exchangeable group; and the other group Z2 or Z7 has the meanings given for R2 or R7 above or, if a compound of formula I
is to be prepared wherein the groups R2 and R7 have the same mean-ing, it may also represent a nucleophilically exchangeable group with an amine of formula III
H-X (III) wherein X has the meanings given for R2 or R7 above or represents a piperazino group protected by a hydrolytically removable pro-tecting group and subsequently, if required, splitting off any protecting group used; or b) to prepare a compound of formula I wherein R4 re-presents a 1-oxidothiomorpholino or 1-oxidothiazolidino group or R7 represents a 1-oxidothiomorpholino group oxidizing a compound of formula IV

(IV) wherein R2 and R6 are as defined in claim 1 and R4' and R7' have the meanings given for R4 and R7 above with the proviso that R4' must represent a thiomorpholino or thiazolidino group or R7' must represent a thiomorpholino group; or c) to prepare a compound of formula I wherein R2 repre-sents a piperazino group deformylating a corresponding compound of formula I wherein R2 represents a N-formyl-piperazino group; and if required converting a compound of formula I obtained into an acid addition salt thereof.

10. A process as claimed in claim 9 wherein each reaction is carried out in a solvent.

11. A process as claimed in claim 9 wherein reaction step (a) is carried out in the presence of an acid binding agent and a solvent.

12. A process as claimed in claim 9 wherein reaction step (a) is carried out with the subsequent splitting off of a protect-ing group being effected by hydrolysis.

13. A process as claimed in claim 9 wherein in the com-pound of formula II used in reaction step (a) one or each of Z2 and Z7 represents a halogen atoms.

14. A process as claimed in claim 10 wherein the oxidation of reaction step (b) is carried out with one equivalent of an oxidising agent and in the presence of a solvent.

15. A process as claimed in claim 9 wherein reaction step (a) or (b) is carried out at a temperature of between 0 and 150°C.

16. A process according to claim 9 wherein the compound of formula I, wherein R2 represents a N-formyl-piperazino group, is obtained by a process according to claim 1(a) or claim 1(b).

17. A process according to claim 9 wherein a physiological-ly acceptable acid addition salt of a compound of formula I
according to claim 1,in which R2 represents a piperazino group, is prepared by reacting, if required, a compound of formula I
according to claim 1 with the acid of the addition salt.

18. A process as claimed in claim 9, 10 or 11 wherein R2 represents piperazino, R4 represents thiomorpholino, R6 represents phenyl and R7 represents benzylamino.

19. A process for preparing 7-benzylamino-6-phenyl-2-piper-azino-4-thiomorpholino-pteridine which process comprises deformyl-ating 7-benzylamino-2-(N-formyl-piperazino)-6-phenyl-4-thiomorpho-lino-pteridine.

20. A process as claimed in claim 19 wherein the 7-benzyl-amino-2-(N-formylpiperazino)-6-phenyl-4-thiomorpholino-pteridine is obtained by reacting 7-chloro-2-(N-formylpiperazino)-6-phenyl-4-thiomorpholino-pteridine with benzylamine.

21. A pharmaceutical composition which comprises a com-pound of formula I as defined in claim 1, in which R2 represents a piperazino group, or a physiologically acceptable acid addition salt thereof, together with a suitable diluent or carrier.

22. A process for preparing a pharmaceutical composition for use in treatment of the human or non-human animal body to achieve an antithrombotic or a tumour-growth or metastasis-inhibit-ing effect therein, which process comprises incorporating a com-pound of formula I as defined in claim 1, in which R2 represents a piperazino group, or a physiologically acceptable acid addition salt thereof as active ingredient in the composition.