GB2143232A

GB2143232A - Chemical compounds

Info

Publication number: GB2143232A
Application number: GB08416682A
Authority: GB
Inventors: Josef Roch; Josef Nickl; Erich Muller; Berthold Narr; Johannes Weisenberger; Rainer Zimmerman; Walter Haarmann
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1983-07-02
Filing date: 1984-06-29
Publication date: 1985-02-06
Also published as: DK159113C; CA1233179A; ES537785A0; DD229990A5; FI842622A; DE3323932A1; ZA844968B; IL72265A0; FI842622A0; AU565105B2; GB2143232B; ES8601205A1; EP0134922A1; JPS6025991A; DK159113B; NZ208725A; DK316284A; HUT34487A; DK316284D0; GB8416682D0

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

1 GB2143232A 1

SPECIFICATION

Chemical compounds This invention relates to new 2-piperazinopteridines and to the acid addition salts thereof, to 5 process for their preparation and to pharmaceutical compositions containing them.

US-A-2,940,972 describes tetra-substituted pteridines, which have valuable pharmacological properties including coronary dilatory, sedative, antipyretic and analgesis effects.

We have now found that new 2-piperazino-pteridines of general formula 1 10 R R 3 15 R 2 and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids, also have valuable pharmacological properties, which surprisingly include antithrombotic and metastasis-inh i biting effects.

Hence, according to one feature of the present invention there are provided compounds of general formula 1 above, wherein R, represents a phenylalkylamino, alkylamino or dialkylamino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 represents a dialkylamino, piperidino, morpholino, thiormorpholino or 1-oxidothiomorpho lino group and R3 represents a halogen atom or an alkoxy, alky[thio, phenylalkoxy or phenylaikythio group, wherein the alkyl moeity may contain from 1 to 3 carbon atoms, and the acid addition salts thereof.

R, may represent, for example, a methylamino, ethylamino, propylamino, isopropylamino, 30 benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, piperidino, morpholino, thiormorpholino or 1 oxidothio morpholino group, R2 may represent, for example, a dimethylamino, diethylaminoa, dipropylamino, diisopropy lamino, methyl-ethylamino, ethyl-propylamino, piperidino, morpholino, thiomorpholino or 1oxidothiomorpholino group and F13 may represent, for example, a chlorine or bromine atom or a methoxy, ethoxy, propoxy.

isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 2phenylpropoxy, 3 phenylpropoxy, 1-methyi-2-phenylethoxy, methyimercapto, ethyimercapto, propyimercapto, iso propyimercapto, benzyimercapto, 1-phenylethyimercapto, 2- phenylethyimercapto or 3-phenylpropyimercapto group.

Preferred compounds according to the invention are those wherein R, represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1 oxidothiomorpholino group, R2 represents a dimethylamino, piperidino, morpholino, thiormorpholino or 1-oxidothiomor45 pholino group and R3 represents a chlorine or bromine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in the alkyl moiety, or a benzyloxy or benzyimercapto group, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.

Especially preferred compounds according to the invention are those wherein R, and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R, may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in 55 the alkyl moiety or a benzyloxy or benzyimercapto group, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.

Most especially preferred compounds according to the invention are those wherein R, and R2 each represent a dimethylamino, morpholino or 1oxidothiomorpholino group and 60 R, also represents a benzylamino group and R3 represents a chlorine atom or a methyimercapto or benzyimercapto group, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.

The compounds of general formula 1 above may, for example, be prepared by the following 65 2 GB 2 143 232A 2 processes, which processes constitute further features of the present invention: a) In order to prepare compounds of general formula 1 wherein R, represents a halogen atom: a compound of general formula 11 R 1 2':-, f Z2 R 3 R 2 (II) wherein R, and R2 are as hereinbefore defined, R3' represents a halogn atom and Z2 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine 15 atom, is reacted with a piperazine of general formula 111 /r--\ H - N N - X (III) wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and subse quently, if necessary, splitting off the protecting group used.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene or dimethylgiycol ether at temperatures of between 50 and 1 WC, preferably at the 25 boiling temperature of the solvent used, or in a melt. It may be advantageous to use an acid binding agent such as sodium carbonate, triethylamine or pyridine.

If it is necessary, subsequently, to split off the protecting group used, this may be effected in the presence of an acid such as hydrochloric or sulphuric acid or 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.

b) in order to prepare compounds of general formula 1 wherein R3 represents an alkoxy, alkylmercapto, phenylalkoxy or phenylalkylmercapto group:

a compound of the general formula IV R 40 3 R 2 wherein 45 R, and R2 are as hereinbefore defined and Z. represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, is reacted with a compound of general formula V R31-H (V) wherein R,' represents an alkoxy or alkylmercapto group optionally substituted by a phenyl group, and in which the alkyl moiety may contain 1 to 3 carbon atoms, or with an alkali metal salt thereof.

The reaction is preferably carried out in a suitable solvent such as dioxan, tetrahydrofuran, methanol, ethanol, propanol, isopropanol or be nzyi alcohol, and preferably in the presence of a 55 corresponding alkali metal salt of a compound of general formula V such as sodium methoxide, sodium ethoxide or sodium benzyimercaptide, conveniently at temperatures of between 50 and 1 WC, e.g. at the boiling temperature of the solvent used.

The compounds obtained from the processes according to the invention may be converted into the acid addition salts thereof, particularly the physiologically acceptable salts thereof with 60 inorganic or organic acids. Suitable acids include, for e,,ample, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.

The compounds of general formulae 11 to V used as starting materials are either known or may be obtained from the processes described in US-A-2,940,972 (see Preparations A to C).

As mentioned above the new compounds of general formula 1 and the physiologically 65 3 GB2143232A 3 acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacolo gical properties, which particularly include antithrombotic and metastasis-inhibiting effects and an inhibiting effect on phosphodiesterase.

For example, the following compounds have been tested with regard to their inhibiting effect on phosphodiesterase (PDE) from tumour cells and from human thrombocytes in vitro using the 5 method described by P6ch et aL [see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272-279 (1971)1:

A = 6-benzy[thio-4,7-dimorpholino-2-piperazinopteridine B = 6-chloro-4,7-bis-(dimethylamino)-2-piperazinopteridine C = 6-benzyithio-4,7-bis-(dimethylamino)-2-piperazinopteridine D = 7-benzy[amino-6-methyithio-4-(1-oxidothiomorpholino)-2-piperazinopteridine and E = 6-chforo-2-piperazino-4-dimethylamino-7-benzyiaminopteridine a) Obtaining the enzyme:

The phosphodiesterase was obtained from B 16 mouse melanoma tissue by centrifuging the homogenised tissue at 5000 X g (for 15 minutes at 4C). The tissue was homogenised by repeated freezing/thawing and homogenising according to Potter-Elvehjern or by ultrasound. The supernatant containing the PDE was deep-frozen in portions at - 2WC. The PDE was obtained from human thrombocytes analogously by freezing/thawing and centrifuging.

b) Determining the PDE inhibition (PDE assay):

The PDE inhibition by the test substances was determined with 1 Ymol/1 3HcAMP as substrate. The PDE inhibition was determined by measuring the degradation of the substrate 3HcAMP to 3 H-AMP by comparison with a control without any test substance. The 3 H-AMP formed was separated off from the remaining 3H-cAMP by zinc sulphate/barium hydroxide precipitation. 25 The ED,, was calculated, by linear regression analysis, as the concentration which inhibited PDE activity by 50%.

PDE Inhibition (ED 50) 30 Substance Thrombocytes B16 Tumour cells A 0.051 0.088 35 B 35 0.95 c 10 0.88 D 0.048 40 E 14 0.37 45 Acute toxicity:

The approximate acute toxicity of the substances being tested was determined on groups of 5 mice after oral administration of a single dose (observation period: 14 days).

Substance Approximate acute toxicity 50 A > 250 mg/kg (0 out of 5 animals died) 55 B > 250 mg/kg (0 out of 5 animals died) c > 250 mg/kg (0 out of 5 animals died) D > 250 mg/kg (0 out of 5 animals died) 60 E > 250 mg kg (0 out of 5 animals died) The new compounds of general formula 1 prepared according to the invention are suitable, 65 4 GB2143232A owing the their above-mentioned pharmacological properties, for the prophylaxis of thromboem bolic diseases such as coronary infarct, cerebral infarct, so-called transient ischaemic attacks and amaurosis fugax, and for the prophylaxis of arteriosclerosis and metastasis.

According to a yet further feature of the present invention there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of general formula 1 as 5 hereinbefore defined or a physiological acceptable acid addition salt thereof with an inorganic or organic acid, in association with one or more inert pharmaceutical carriers and/or diluents.

For pharmaceutical administration the compounds of general formula 1 or their physiologically acceptable acid addition salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. Preferred forms include, 10 for example, tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.

The active ingredient may be incorporated in excipients customarily employed in pharmaceuti cal compositions such as, for example, corn starch, lactose, can sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, 15 water/ glycerine, water/sorbitol, non-ionic surfactants such as polyoxyethylene fatty acid esters, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, ca rboxymethylcel 1 u lose or fatty substances such as hard fat or suitable mixtures thereof.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units contain from 0.1 to 20 4.0 mg/kg of body weight, preferably from 0.2 to 3.0 mg/kg of body weight, and the dose may, for example, consist appropriately of 2 to 4 dosage units per day. The total daily dose may, however, be varied according to the compound used, the subject treated and the complaint concerned.

According to a still further feature of the present invention there is provided a method of 25 treating a patient suffering from, or susceptible to, thrombolic diseases, arteriosclerosis or metastasis which comprises administering to the said patient an effective amount of a compound of general formula 1 as hereinbefore defined or a physiologically acceptable acid addition salt thereof with an inorganic or organic acid.

The following non-limiting Examples and Preparations are intended to illustrate the invention 30 in more detail.

Preparation A 2,6,7-Trichforo-4-morpholino-pteridine A solution of 4.35 g (0.05 mol) of morpholine in 100 m] of chloroform is slowly added 35 dropwise to a suspension of 13.5 g (0.05 mol) of 2,4,6,7tetrachloropteridine in about 400 mi of chloroform and 10 g (0. 1 mol) of potassium bicarbonate, dissolved in 100 m] of water, with vigorous stirring and cooling to - 5 to O'C, and the resulting mixture is stirred for a further 30 minutes with cooling. The chloroform phase containing the reaction product is separated off, dried over anhydrous sodium sulphate and concentrated by evaporation in vacuo. Yield: 13.5 g (84% of theory). Melting point: 211-213'C (ethyl acetate).

The following compounds are prepared in a manner analogous to Preparation A: 2,6,7-Trichloro-4-thiomorpholino-pteridine Melting point: 191-19WC 2,6,7-Trichloro-4-(1 -oxidothiomorpholino)- pteridine Melting point: 212-214'C (decomposition) Preparation B Z6-Dichloro-4,7-bis-(l-oxidothiomorpholino)-pteridine 23.8 g (0.2 mol) of thiomorpholine-1 -oxide dissolved in 100 ml of dioxan is slowly added to a solution of 13.5 g (0.05 mol) of 2,4,6,7- tetrachloropteridine in 300 ml of dioxan, with stirring, at ambient temperature, whereupon a yellowish precipitate is rapidly formed. The reaction mixture is taken up in about 2 litres of water. After standing for some time, the reaction product which is precipitated is suction filtered and washed with water and dried at about 70C. 55 Yield: 19.2 g (88% of theory). Melting point: 237-239C (ethanol).

The following compounds are prepared in a manner analogous to Preparation D: 2,6-Dichloro-4,7-dimorpholino-pteridine Melting point: 206-208C 2,6-Dichloro-4,7-bis-(thiomorpholino)-pteridine Melting point: 193-195C (from dioxan) 2,6-Dichloro-4,7-bis- (dimethylamino)-pteridine Melting point: 245-247C 2,6-Dichloro-4,7-dipiperidino-pteridine GB2143232A 5 Melting point: 1135-187'C Preparation C 7-Benzylamino-2,6-dichloro-4-morpholino-pteridine A solution of 7 9 (0.065 mol) of benzylamine in 50 mi of dioxan is slowly added to a suspension of 9.6 9 (0.03 mol) of 2,6,7-trichloro-4-morpholino- pteridine in about 150 mi of dioxan at ambient temperature with stirring. After stirring for about 1 hour, the reaction mixture is taken up in about 1 litre of water. The precipitate formed after standing for some time is suction filtered, washed with water and dried at WC.

Yield: 10. 9 g (94% of theory). Melting point: 213-214C (ethanol/dioxan = 2:1) The melting comounds are prepared in a manner analogous to Preparation C: 7-Benzyiamino-2,6-dichloro-4-(1 -oxidothiomorpholino)-pteridine Melting point: 253-254C 2,6-Dichloro-7-morpholino-4-(1 -oxidothiomorpholino)-pteridine Melting point: 215-217'C 2,6-Dichloro-4-morpholino-7-(1 -oxidothiomorpholino)pteridine Melting point: 218-220C Example 1

6-Chloro-4,7-dimorpholino-2-piperazino-pteridine 9.3 g (0.025 mol) of 2,6-dichloro-4,7-dimorpholino-pteridine is refluxed for 1 hour with 8.6 g (0. 1 mol) of anhydrous piperazine in 200 mi of dioxan. The solvent is substantially distilled off and the residue is digested with about 100 mi of water. After is has stood for a short time, it is suction filtered, washed with water and dried at about 70C (melting point 218-220C). 25 Yield: 8.9 g (85% of theory).

Melting point: 220-222'C.

C,81-12.CIN802 (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 A solution of 0.35 g of sodium and 2 m[ (about 0.0 17 mol) of benzyimercaptan in 100 mi of dioxan is added to a solution of 6.3 9 (0.015 mol) of 6-chloro-4,7dimorpholino-2-piperazinopteridine in 200 mi of dioxan and the resulting mixture is then heated under reflux for about 2 hours. The solvent is substantially distilled off in vacuo and the residue remaining is taken up in about 200 m] of water. After it has solidified, the reaction product is suction filtered, washed with water and dried in vacuo at ambient temperature.

Yield: 6.4 g (84% of theory).

After purification over a silica gel column (eluant: methanol/conc. ammonia; 50:1) and recrystallisation from ethyl acetate, the substance melts at 135-1 37'C. C25H32NSO2S (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 A solution of 0.23 9 (0.01 mol) of sodium in 10 mi of methanol is poured into a solution of 2.9 g (0.006 mol) of 7-benzyiamino-6-chloro-4-(1-oxidothiomorpholino)-2- piperazino-pteridine in 50 m[ of dioxan. The resulting mixture is heated under reflux for 30 minutes and then the solvent is substantially distilled off in vacuo. The residue is taken up in about 70 mi of water and the reaction product precipitated is suction filtered, washed with water and dried at about WC.

Yield: 2.6 g (93% of theory).

After reprecipitation from 0.1 N hydrochloric acid using ammonia and recrystallisation from ethyl acetate/ methanol (4: 1), the compound melts at 148-15 1 'C.

C221-12,1\1802S (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-morpholino-7-(1-oxidothiomorpholino)-2-piperazino- pteridine Prepared analogously to Example 1 from 2,6-dichloro-4-morpholino-7-(1oxidothiomorpho- lino)-pteridine and piperazine.

6 GB 2 143 232A 6 Melting point: 225-227T (reprecipitation from 0.1 N HCl by means of ammonia).

Example 5

6-Chforo-4,7-bis-(1-oxidothiomorpholino)-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis-(1 oxidothiomorpholino)-pteri- 5 dine and piperazine.

Melting point: >20TC (decomposition).

Example 6

6-Chloro-4,7-dipiperidino-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4,7-dipiperidino- pteridine and pipera zine.

Melting point: decomposition at about 200T.

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.

Melting point: 130-134T.

Example 8

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

Melting point: 194-196T (ethyl acetate).

Example 9 6-Chforo-7-morpholino-4-(1-oxidothiomorpholino)-2-piperazinopteridine Prepared analogously to Example 1 from 2,6-dichloro-7-morpholino-4-(1- oxidothiomorpho- lino)-pteridine and piperazine.

Melting point: >240T (decomposition).

Example 10

7-Benzylamino-6-chloro-4-morpholino-2-piperazino-pteridine Prepared analogously to Example 1 from 7-benzyiamino-2,6-dichloro-4morpholino-pteridine 35 and piperazine.

Melting point: 195-197T (methanol /water).

Example 11

7-Benzyiamino-6-chforo-4-(1-oxidothiomorpholino)-2-piperazino-pteridine Prepared analogously to Example 1 from 7-benzylamina-2,6-doichloro-4-(1oxidothiomorpho- lino)-pteridine and piperazine.

Melting point: >200T (decomposition).

Example 12 6-Benzylthio-4, 7-bis-(dimethylamino)-2-piperazino-pteridine Prepared analogously to Example 2 from 6-chloro-4,7-bis-(dimethylamino)-2piperazino-pteridine and benzyimercaptan. Melting point: 150- 1 52T.

Example 13 7-Benzylamino-6-methyithio-4-(1-oxidothiomorpholino)-2piperazino-pteridine Prepared analogously to Example 2 from 7-benzyiamino-6-chloro-4-(1- oxidothiomorpholino)-2piperazino-pteridine and methyl mercaptan.

Melting point of the hydrochloride: 159-162T.

Example 14 4-Morpholino-7-(1-oxidothiomorpholino)-2-piperazino-6propylthio-pteridine Prepared analogously to Example 2 from 6-chloro-4-morpholino-7-(1 - oxidothiomorpholino)-2- piperazino-pteridine and propyimercaptan. Melting point: 125-130T.

Example 15

7-Benzylamino-6-benzylthio-4-(1-oxidothiomorpholino)-2-piperazinopteridine Prepared analogously to Example 2 from 7-benzyiamino-6-chloro-4-(1- oxidothiomorpholino)-2-65 7 GB2143232A 7 piperazino-pteridine and benzyimercaptan. Melting point: > 1 WC (decomposition).

Example 16 6-Ethoxy-2-piperazino-4,7-bis-(thiomorpholino)-pteridine Prepared analogously to Example 3 from 6-chloro-2-piperazino-4,7-bis(thiomorpholino)-pteri-dine and ethanol. Melting point: 147-151'C.

Example 17 6-Benzyloxy.4,7-bis-(dimethylamino)-2-piperazino-pteridine Prepared analogously to Example 3 from 6-chloro-4,7-bis-(dimethylamino)-2piperazino-pteridine and benzyl alcohol. Melting point: 166-168C.

Example 18 6-Chforo-2-piperazino-4-dimethylamino-7-benzylamino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4-dimethylamino-7benzyiamino-pteridine and piperazine.

Melting point: 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-7benzyiamino-pteri- dine and piperazine. Melting point: 160-165'C.

Example 20

6-Chforo-2-piperazino-4-thiomorpholino- 7-dimethylamino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4-thiomorpholino-7dimethylamino- 30 pteridine and piperazine.

Melting point: 205-207C.

Example 21

7-Benzylamino-6-benzylthio-2-piperazino-4-thiomorpholino-pteridine Prepared analogously to Example 2 from 7-benzyiamino-6-chloro-2piperazino-4-thiomorpholino-pteridine and benzyimercaptan. Melting point: from 70C (sintering).

The following pharmaceutical Examples illustrate the preparation of compositions according to the invention.

Example A

Coated tablets containing 4 mg of 6-benzylthio-4,7-dimorpholino-2piperazino-pteridine Composition:

1 tablet core contains Active substance (1) 4.0 mg Lactose (2) 27.0 mg 50 Corn starch (3) 14.5 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 0.5 mg 55 50.0 mg Preparation:

Substances (1)-(3) are evenly moistened with an aqueous solution of (4), passed through a 1 mm mesh screen, dried and again passed through a 1 mm screen. After the addition of (5), the 60 mixture is compressed to form tablet cores.

Tablet cores: 5 mm 0, biconvex, round Coating:

Usual sugar coating to give a finished weight of 70 mg.

8 GB2143232A 8 Example B Tablets containing 8 mg of 6-benzylthio-4,7-dimorpholino-2- piperazino-pteridine 1 tablet contains:

Active substance 8.0 mg Lactose 23.0 mg Corn starch 14.5 mg 10 Polyvinylpyrrolidone 4.0 mg Magnesium stearate -0.5 mg 50.0 mg 15 Preparation:

Analogously to the tablet cores.

Description of tablets: Weight: 50 mg Diameter: 5 mm, biplanar, faceted on both sides

Example C Suppositories containing 25 mg of 6-benzylthio-4,7-dimorpholino2-piperazino-pteridine 1 suppository contains:

Active substance 0.025 g 30 Hard fat (e.g. Witepsol H 19 1.675 q and Witepsol H 45) 1.700 g Preparation:

The hard fat is melted. At 38'C, the ground active substance is homogeneously dispersed in the melt. It is cooled to 35C and poured into slightly chilled suppository moulds. Weight of suppository: 1.7 g Example D Suspension containing 8 mg of 6-benzylthio-4,7-dimorpholino-2piperazino-pteridine 100 mi of suspension contains:

Active substance 0.16 9 45 Carboxymethyl dellulose 0.1 9 methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g 50 Cane sugar 10.0 g Glycerol 5.0 g 70% sorbitol 20.0 g 55 Flavouring 0.3 9 Distilled water ad 100.0 M1 Preparation process:

The distilled water is heated to 70'C. The methyl and propyl phydroxybenzoates and the glycerol and carboxymethylcel lu lose 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 to remove any air, with stirring.

9 GB2143232A 9 Example E Tablets containing 100 mg of 6-benzylthio-4,7-dimorpholino-2- piperazino-pteridine Composition:

5 1 tablet contains:

Active substance 100.0 mg Lactose 80.0 mg 10 Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 15 220.0 mg Preparation process:

The active substances, lactose and starch-are mixed together and uniformly moistened with an aqueous solution of the polyvinyl pyrrol idone. After screening the moist mass (2.0 mm mesh 20 size) and drying in a rack dryer at 5WC, the mixture is screened again (1. 5 mm mesh) and the lubricant is added. The finished mixture is compressed to form tablets.

Weight of tablet: 220 mg Diarnter: 10 mm, biplanar, faceted on both sides with a dividing slot on one side.

Example F Hard gelatine capsules containing 150 mg of 6-benzylthio-4,7dimorpholino-2-piperazino-pte dine 1 capsule contains:

30 Active substance 150.0 mg Dried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg 35 Magnesium stearate 3.0 mg approx. 420.0 mg Preparation:

The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed in a suitable apparatus.

The finished mixture is packed into hard gelatine capsules, size 1.

Capsule filling: about 420 mg Capsule shell: hard gelatine capsule, size 1.

Example G Suppositories containing 150 mg of 6-benzylthio-4,7dimorpholino-2-piperazino-pteridine 1 suppository contains:

50 Active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg 55 Polyoxyethylene sorbitan 840.0 mg monostearate 2 000.0 mg Preparation: 60 After the suppository mass has been melted, the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example H

Suspension containing 50 mg of 6-benzy[thio-4,7-dimorpholino-2-piperazinopteridine per 5 mi 65 GB 2 143 232A 10 m[ of suspension contains:

Active substance 1.0 g Na salt of carboxymethyl cellulose 0.1 g 5 methyl p-hydroxybenzoate 0.05 9 propyl p-hydroxybenzoate 0.01 9 Cane sugar 10.0 g 10 Glycerol 5.0 g 70% sorbitol solution 20.0 g Flavouring 0.3 g 15 Distilled water ad 100 M1 Preparation:

The distilled water is heated to 7WC. The methyl and propyl phydroxybenzoates and the glycerol and sodium salt of ca rboxymethylcel 1 u lose are dissolved therein with stirring. The solution is cooled to ambient temperature and, with stirring, the active substance is added and homogeneously dispersed therein. After the sugar, sorbitol solution and flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate any air.

5 mi of suspension contains 50 mg of active substance.

Example 1 Tablets containing 150 mg of 6-benzyithio-4,7-dimorpholino-2piperazino-pteridine Composition:

1 tablet contains: 30 Active substance 150.0 mg Powdered lactose 89.0 mg 35 Corn starch 40.0 mg - Colloidal silica 10.0 mg Polyvinylpyrrolidone 10.0 mg 40 Magnesium stearate 1.0 mg 300.0 mg Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% 45 aqueous polyvinyl pyrrol idone solution and passed through a screen with a mesh size of 1.5 mm.

The granulate, dried at 4WC, is again passed through the screen and mixed with the given quantity of magnesium stearate. Tablets are compressed from the mixture.

Weight of tablet: 300 mg Punch: 10 mm, flat Example K Coated tablets containing 75 mg of 6-benzylthio4,7-dimorpholino- 2-piperazino-pteridine: 1 tablet core contains:

11 GB2143232A 11 Active substance Calcium phosphate Corn starch Polyvinylpyrrolidone Hydroxypropylmethylcellulose magnesium stearate 75. 0 mg 93.0 mg 35.5 mg 10.0 mg 15. 0 mg 1. 5 mg 230.0 mg Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hyd roxypropyimethylcel 1 u lose and half the stated quantity of magnesium stearate. In a tabletmaking machine, blanks are produced measuring about 13 mm in diameter, which are passed through a screen with a mesh size of 1.5 mm and mixed with the remaining magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired 20 shape. Weight of core: 230 mg Punch: 9 mm, convex The tablet cores produced are

coated with a film consisting essentially of hydroxypropylme25 thylcellulose. The finished film-coated tablets are glazed with beeswax.

Weight of coated tablet: 245 mg.

All the compounds of general formula I may be used as active substances in the pharmaceutical compositions described above.

Claims

CLAIMS 1. Compounds of general formula 1 r 1 R 3 N N R2 wherein R,

represents a phenylalkylamino, alkylamino or dialkylamino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 represents a dialkylamino, piperidino, morpholino, thiomorpholino or 1oxidothiomorpho lino group and R3 represents a halogen atom or an alkoxy, alkylthio, phenylaikoxy or phenylalkylthio group, 45 wherein the alkyl moiety may contain from 1 to 3 carbon atoms, and the acid addition salts thereof.
2. Compounds of general formula 1 as claimed in claim 1, wherein R, represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1- oxidothiomorpholino group, R2 represents a dimethylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R3 represents a chlorine or bromine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in the alkyl moiety, or a benzyloxy or benzyimercapto group, and the acid addition salts thereof.
3. Compounds of general formula 1 as claimed in claim 1, wherein R, and F12, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or 1 -oxidothiomorpholino group and R, may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in 60 the alkyl moiety or a benzyloxy or benzyimercapto group, and the acid addition salts thereof.
4. Compounds of general formula 1 as claimed in claim 1, wherein R, and R, each represent a dimethylamino, morpholino or 1- oxidothiomorpholino group and R, also represents a benzylamino group and R3 represents a chlorine atom or a methyimercapto or benzyimercapto group, and the acid 65 12 GB 2 143 232A 12 addition salts thereof.
5. 6-Benzyithio-4,7-dimorpholino-2-piperazino-pteridine and the acid addition salts thereof.
6. 6-Chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and the acid addition salts thereof.
7. 6-Benzyithio-4,7-bis-(dimethylamino)-2-piperazino-pteridine and the acid addition salts 5 thereof.
8. 7-Benzylamino-6-methyithio-4-(1-oxidothiomorpholino)-2-piperazinopteridine and the acid addition salts thereof.
9. 6-Chloro-2-piperazino-4-dirnethylamino-7-benzyiamino-pteridine and the acid addition salts thereof.
10. Physiologically acceptable acid addition salts of the compounds as claimed in any one of the preceding claims with inorganic or organic acids.
11. Salts as claimed in claim 10 formed with hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.
12. Compounds of general formula 1 as claimed in claim 1 substantially as herein described 15 in any one of Examples 1 to 20.
13. A compound of general formula 1 as claimed in claim 1 substantially as herein described in Example 21.
14. Compounds of general formula 1 as claimed in claim 1 and physiologically acceptable acid addition salts thereof in a form suitable for use in the treatment of thromboembolic 20 diseases, arteriosclerosis and metastasis.
15. A process for the preparation of compounds of general formula 1 as claimed in claim 1 wherein R3 represents a halogen atom, which comprises reacting a compound of general formula H R 3 R,:CNf 1 1 N R 2 Z2 (II) wherein R, and R2 are as defined in claim 1, R3' represents a halogen atom and 35 Z2 represents a nucleophilic leaving group, with a piperazine of general formula Ill H - N N - X wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and subsequently, if necessary, splitting off the protecting group used.
16. A process as claimed in claim 15 wherein the nucleophilic leaving group is a halogen atom.
17. A process as claimed in claim 15 or claim 16 wherein the reaction is carried out in a solvent.
18. A process as claimed in claim 17 wherein the solvent used is selected from tetrahydrofu ran, dioxan, benzene, toluene or dimethylglycol ether..
19. A process as claimed in any one of claims 15 to 18 wherein the reaction is carried out 50 at temperatures of between 50 and 1 50T.
20. A process as claimed in claim 19 wherein the reaction is carried out at the boiling temperature of the solvent used, or in a melt.
21. A process as claimed in any one of claims 15 to 20 wherein an acidbinding agent is used.
22. A process as claimed in claim 21 wherein the acid-binding agent used is selected from sodium carbonate, triethylamine or pyridine.
23. A process as claimed in any one of claims 15 to 22 wherein the protecting group used is split off in the presence of an acid or a base.
24. A process as claimed in claim 23 wherein th-3 acid used is selected from hydrochloric or 60 sulphuric acid and the base used is selected from sodium hydroxide or potassium hydroxide.
25. A process as claimed in claim 23 or claim 24 wherein the protecting group cleavage is effected in the presence of an aqueous solvent.
26. A process as claimed in claim 25 wherein the solvent used is selected from metha- no]/water, ethanol/water or dioxan/water.

13 GB 2 143 232A 13
27. A process as claimed in claim 25 or claim 26 wherein the protecting group cleavage is effected at temperatures up to the boiling temperature of the solvent used.
28. A process for the preparation of compounds of general formula I as claimed in claim 1 wherein R3 represents an alkoxy, alkylmercapto, phenylalkoxy or phenylalkylmercapto group, 5 which comprises reacting a compound of general formula IV Z3 R 2 wherein 15 R, and R, are as defined in claim 1 and Z3 represents a nucleophilic leaving group, with a compound of general formula V R3'-1-1 (V) wherein R31 represents an alkoxy or alkylmercapto group optionally substituted by a phenyl group, and in which the alkyl moiety may contain 1 to 3 carbon atoms, or with an alkali metal salt thereof.
29. A process as claimed in claim 28 wherein the nucleophilic leaving group is a halogen atom.
30. A process as claimed in claim 28 or claim 29 wherein the reaction is carried out in a 25 solvent.
31. A process as claimed in claim 30 wherein the solvent used is selected from dioxan, tetrahydrofuran, methanol, ethanol, propanol, isopropanol or benzy] alcohol.
32. A process as claimed in any one of claims 28 to 31 wherein the alkali metal salt of a compound of general formula V used is selected from sodium methoxide, sodium ethoxide or 30 sodium benzyimercaptide.
33. A process as claimed in any one of claims 28 to 32 wherein the reaction is carried out at temperatures of between 50 and 1 50T.
34. A process as claimed in claim 33 wherein the reaction is carried out at the boiling temperature of the solvent used.
35. A process as claimed in any one of claims 15 to 34 wherein a compound of general formula 1 initially obtained is subsequently converted into an acid addition salt thereof.
36. A process as claimed in claim 35 wherein a physiologically acceptable salt of a compound of general formula 1 with an inorganic acid is obtained.
37. A process as claimed in claim 15 or claim 28 for the preparation of compounds of general formula 1 as defined in claim 1 substantially as herein described.
38. A process as claimed in claim 15 or claim 28 for the preparation of compounds of general formula 1 as defined in claim 1 substantially as herein described in any one of Examples 1 to 21.
39. A process as claimed in claim 15 or claim 28 for the preparation of compounds of 45 general formula 1 as defined in claim 1 substantially as herein described in any one of Examples 1 to 20.
40. Compounds of general formula 1 as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 15-39.
41. Compounds of general formula 1 as claimed in claim 1 whenever prepared by a process 50 as claimed in claim 39.
42. Pharmceutical compositions containing, as active ingredient, at least one compound of general formula 1 as claimed in claim 1 or a physiologically acceptable acid addition salt thereof with an inorganic or organic acid, in association with one or more inert carriers and/or diluents.
43. Compositions as claimed in claim 42 in the form of tablets, coated tablets, capsules, 55 powders, suspensions, drops, ampoules, syrups or suppositories.
44. Compositions as claimed in claim 42 or claim 43 in the form of dosage units.
45. Compositions as claimed in claim 44 wherein each dosage unit contains from 0.1 to 4.0 mg/kg of body weight of active ingredient.
46. Pharmaceutical compositions as claimed in claim 42 substantially as herein described. 60
47. Pharmaceutical compositions as claimed in claim 42 substantially as herein described in any one of Examples A to K.
48. A method of treating a patient suffering from, or susceptible to, thromboembolic diseases, arteriosclerosis or metastasis which comprises administering to the said patient an effective amount of a compound of general formula 1 as defined in claim 1 or a physiologically 65 14 GB 2 143 232A 14 acceptable acid addition salt thereof with an inorganic or organic acid.
49. Each and every novel method, process, compound or composition herein disclosed.

Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935, 1985, 4235. Published at The Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies may be obtained.