FI80454B - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL PROPERTIES OF 2-PIPERAZINO-PTERIDINER. - 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

! 80454

Method for the preparation of pharmacologically valuable 2-piperazinopteridines - For the preparation of pharmacologically valuable 2-piperazino-pteridines

U.S. Pat. No. 2,940,972 has already described tetrasubstituted pteridines with valuable pharmacological properties, namely cardiac dilating, sedative, antipyretic and analgesic properties.

It has now been found that the novel 2-piperazino-pteridines of the general formula I R 1 N - H (I) 1 H, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, also have valuable pharmacological properties, surprisingly. however, antithrombotic metastatic inhibitory effects.

In the above general formula I

is a phenylalkylamino, dialkylamino group, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, 1 * 2 is a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and 1 * 3 is a halogen atom, alkoxy, alkoxy, , a phenylalkoxy or phenylalkylthio group, in which case the alkyl moiety may in each case have 1 to 3 carbon atoms.

2 80454

The present invention relates to a process for the preparation of these novel 2-piperazino-pteridines of the general formula I and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

In the context of the definitions of the groups R1 to R3, the following meanings are mentioned, for example: R1 is benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino , piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R 2 is dimethylamino, diethylamino, dipropylamino, diisoproylamino, methylethylamino, ethylpropylamino, piperdino, morpholino, thiomorpholino, - or a 1-oxy-dothiomorpholino group and R 3 is a chlorine or bromine atom, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenyl-ethoxy, 1-phenylpropoxy, 2-phenylpropoxy -, 3-phenyl-propoxy, 1-methyl-2-phenylethoxy, methylmercapto, ethylmercapto, propylmercapto, isopropylmercapto, benzylmercapto, 1-phenylethylmercapto, 2-phenylethylmercapto or 3-phenylmercapto

Preferred compounds of general formula I are those in which 3 80454 is a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1-oxidomorpholino group, R 2 is a dimethylamino, piperidino, morpholino, thiomorpholino or The 1-oxidothiomorpholino group and R3 are a chlorine or bromine atom, an alkoxy or alkyl mercapto group each having 1 to 3 carbon atoms in the alkyl moiety, a benzyloxy or benzyl mercapto group, and their acid addition salts, especially their physiologically acceptable acid addition salts with inorganic or organic.

However, particularly preferred compounds of the general formula I are those in which R1 and R2, which may be identical or different, in each case denote a dimethylamino, morpholino, thiomorpholino, or 1-oxidothiomorpholino group and R1 also a benzylamino group and R3 is a chlorine atom, alkoxy - or an alkyl mercapto group in which the alkyl moiety has in each case 1 to 3 carbon atoms, a benzyloxy or benzyl mercapto group, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

According to the invention, the novel compounds are obtained by the following methods: a) for the preparation of compounds of general formula I in which R3 is a halogen atom: 4 80454

Compound of general formula II R1 γΝ ^ Ζ2 I T (II) v t R2 where

R1 and R2 have the same meaning as above, R3 is a halogen atom and Z2 is a nucleophilically exchangeable group such as a halogen atom, for example a chlorine or bromine atom, is reacted with a piperazine of the general formula III / - \ H - N N - H (III)

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene or dimethyl glycol ether at temperatures between 50 and 150 ° C, at the boiling point or melt of the most preferred solvent. In this case, it may be advantageous to use an acid-binding agent such as sodium carbonate, triethylamine or pyridine.

b) For the preparation of compounds of general formula I in which R3 is an alkoxy, alkylmercapto, phenylalkoxy or phenylalkylmercapto group: 5 80454

Compound of general formula IV (IV)

Z N N

r2 where

R 1 and R 2 are as defined above and Z 3 is a nucleophilically exchangeable group such as a halogen atom, for example a chlorine or bromine atom, is reacted with a compound of general formula V R 3 'to H (V) wherein R 31 is an optionally substituted alkoxy or alkyl mercapto group, wherein the alkyl moiety may in each case contain 1 to 3 carbon atoms, or with this alkali salt.

The reaction is best carried out in a suitable solvent such as dioxane, tetrahydrofuran, methanol, ethanol, propanol, isopropanol or benzyl alcohol and most preferably in the presence of a corresponding alkali salt of the compound of general formula V, for example sodium methylate, sodium ethylate or sodium benzyl at the boiling point of the solvent.

The compounds obtained according to the invention can be converted into their acid addition salts, in particular into physiologically acceptable salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, malic acid or fumaric acid.

The compounds of the general formulas 11 to V used as starting materials are for the most part known or are obtained by the method described in US-A-2,940,972 (see Examples A to C).

It has already been mentioned above that the new compounds of the general formula I and their physiologically acceptable acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular, however, antithrombotic and anti-metastatic and phosphodiesterase-inhibiting effects.

As described below (see Naunyn-Schmiedebergs Arch. Pharmak. 26B, 272-279 (1971)), the inhibitory effect on phosphodiesterase (PDE) of tumor cells and coumarin platelets, for example, was investigated according to the method described by Poch et al., For example: A = 6-benzyl -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 7 80454 D = 7-benzylamino-6-methylthio-4- (1-oxidothiomorpholino) -2-piperazino-pteridine, E = 6-chloro-2-piperazino-4-dimethylamino-7-benzylamino- pteridine, F = 6-chloro-2-piperazino-4,7-bis- (thiomorpholino) -pteridine G = 7-benzylamino-6-chloro-4-morpholino-2-piperazino-pteridine H = 6-chloro-2- piperazino-4-thiomorpholino-7-benzylamino-pteridine I = 6-chloro-2-piperazino-4-thiomorpholino-7-dimethylamino-pteridine a) Enzyme recovery;

Phosphodiesterase was obtained from mouse B16 melanoma tissue by centrifugation of tissue homogenate at 5000 x g (15 minutes, 4 ° C).

The tissue was homogenized by the method of Potter-Elvehjem * by freezing / thawing several times or by ultrasound. The PDE-containing homogenate supernatant was deep-frozen and kept at -25 ° C. PDE was obtained from human platelets in an analogous manner by freezing / thawing and centrifugation.

(b) Determination of the PDE inhibitory effect (PDE assay):

The PDE enzyme inhibitory activity of the test substances was studied using 1 μmol / l H H-cAMP as a substrate. The PDE inhibitory effect was obtained by measuring the degradation of the 3h-cAMP substrate used to β-H-AMP compared to controls to which no test substance had been added. The formed β-AMP was separated from the remaining β-cAMP substrate by zinc sulfate-barium hydroxide precipitation.

Using a linear regression analysis, the ED50 was calculated as the concentration that inhibited PDE activity by 50%.

8 80454 PDE inhibitory effect (ED50)

Substance_Thrombocytes_B16 tumor cells_ A 0.051 0.088 B 35 0.95 C 10 0.88 D 0.048 0.97 E 14 0.37 F 0.73 0.18 G 0.97 0.35 H 0.16 0.033 _I ___ 2X8 ______ 0.12 _

Acute toxicity

The indicative acute toxicity of the test substances was determined approximately in groups of 5 mice by oral administration of the compound in a single dose (observation time: 14 days).

Substance__Informal acute toxicity___ A> 250 mg (5 animals died 0) B> 250 mg (5 animals died 0) C> 250 mg (5 animals died 0) D> 250 mg (5 animals died 0) E_> 250 mg (5 the animal died 0) ____

Based on the above-mentioned pharmacological properties, the novel compounds according to the invention are suitable for the prophylaxis of thromboembolic diseases such as myocardial infarction, cerebral infarction, so-called tracheal sciatica, amaurosis fugax, arteriosclerosis and metastasis.

The dosage required to achieve a similar effect is suitably 2-4 times a day 0.1-4 mg / kg body weight, preferably 0.2-3 mg / kg body weight. For this purpose, the compounds of the general formula I prepared according to the invention and their physiologically acceptable acid addition salts with inorganic or organic acids, optionally in combination with other active ingredients, and together with one or more inert conventional carriers and / or diluents, e.g. corn starch, milk sugar, cane sugar, cane cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, nonionic surfactants such as, for example, polyoxyethylene fatty acid esters, water polyethylene glycol; with fatty substances such as hard fat or suitable mixtures thereof to be processed into conventional galenic preparations, such as tablets, granules, capsules, powders, suspensions, drops, ampoules, juices or pellets formulations.

The following examples further illustrate the invention:

Example A

2t6,7-trichloro-4-morpholino-pteridine

To a suspension of 13.5 g (0.05 mol) of 2,4,6,7-tetrachloropteridine in about 400 ml of chloroform and 10 g (0.1 mol) of potassium bicarbonate dissolved in 100 ml of water is slowly added dropwise and with vigorous stirring and cooling at -5 to 0 ° C, a solution containing 4.35 g (0.05 mol) of morpholine in 100 ml of chloroform is stirred for a further 30 minutes with cooling. The chloroform phase containing the reaction product is separated, dried over sodium sulfate and evaporated in vacuo.

Yield: 13.5 g (84 S of theory),

Melting point: 211-213 ° C (ethyl acetate)

The following compounds are prepared according to Example A: ίο 80454

2.6.7-Trichloro-4-thiomorpholino-pteridine Melting point: 191-193 ° C

2.6.7-Trichloro-4- (1-oxidothiomorpholino) -pteridine Melting point: 212-214 ° C (decomposes)

Example B

2,6-dichloro-4,7-bis- (1-oxidothiomorpholino) -pteridine

To a solution of 13.5 g (0.05 mol) of 2,4,6,7-tetrachloropteridine in 300 ml of dioxane is slowly added, with stirring at room temperature, 23.8 g (0.2 mol) of thianorpholine. l-oxide dissolved in 100 ml of dioxane, whereupon a yellowish precipitate rapidly precipitates. The reaction mixture is taken up in about 2 liters of water, allowed to stand for some time, after which the separated reaction product is filtered off with suction and washed with water and dried at about 70 ° C.

Yield: 19.2 g (88% of theory),

Melting point, 237-239 ° C (ethanol).

According to Example B, the following compounds are prepared:

2,6-dichloro-4,7-dimorpholino-pteridine Melting point: 206-208 ° C

2,6-dichloro-4,7-bis- (thiomorpholino) -pteridine Melting point: 193-195 ° C (from dioxane)

2,6-dichloro-4,7-bis- (dimethylamino) -pteridine Melting point: 245-247 ° C

2,6-dichloro-4,7-dipiperidino-pteridine Melting point: 185-187 ° C

Example C

u 80454 7-Benzylamino-2,6-dichloro-4-morpholino-pteridine

To a suspension of 9.6 g (0.03 moles) of 2,6,7-trichloro-4-morpholinopteridine in about 150 ml of dioxane is slowly added, with stirring at room temperature, a solution of 7 g (0.065 moles). benzylamine in 50 ml of dioxane. Stir for about 1 hour, then take up the reaction mixture in about 1 liter of water. After standing for some time, the separated precipitate is filtered off with suction, washed with water and dried at 60 ° C.

Yield: 10.9 g (94% of theory),

Melting point: 213-214 ° C (ethanol / dioxane s 2: 1)

The following compounds are prepared according to Example C: 7-Benzylamino-2,6-dichloro-4- (1-oxidothiomorpholino) -pteridine

Melting point: 253-254 ° C

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: 218-220 ° C.

Example 1 6-Chloro-4,7-dimorpholino-2-piperazino-pteridine 9.3 g (0.025 moles) of 2,6-dichloro-4,7-dimorpholino-pteridine and 8.6 g (0.1 moles) of anhydrous piperazilin in 200 ml of dioxane is heated at reflux for 1 hour. Most of the solvent is distilled off and the remaining residue is extracted with about 100 ml of water. After standing for a short time, it is separated by suction, washed with water and dried at about 80 DEG C. (melting point: 218 DEG-220 DEG C.).

Yield: 8.9 g (85% of theory),

Melting point: 220-222 ° C.

C18H25ClN8 ° 2 <420’9)

Calculated: C 51.36 H 5.99 Cl 8.42 N 26.62 Found: 51.21 5.97 8.48 36.68

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 is added a solution of 0.35 g of sodium and 2 ml (about 0.017 mol) of ) benzyl mercaptan in 100 ml of dioxane and then heated at reflux for about 2 hours.

Most of the solvent is distilled off in vacuo and the remaining residue is taken up in about 200 ml of water. After solidification, the reaction product is filtered off with suction, washed with water and dried at room temperature under vacuum.

Yield: 6.4 g (84 Å of theory).

Purify on a silica gel column (propellant: methanol / concentrated ammonia; 50: 1) and recrystallize from ethyl acetate to give a melting point of 135-137 ° C.

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 moles) of 7-benzylamino-6-chloro-4- (1-oxidothiomorpholino) -2-piperazino-80454 pteridine in 100 ml of dioxane is poured into a solution of 0, 23 g (0.01 mol of sodium in 10 ml of methanol. The mixture obtained is heated at reflux for 30 minutes and then most of the solvent is removed by distillation in vacuo. The residue is taken up in about 70 ml of water and the separated reaction product is filtered off with suction, washed with water and dried at 60 ° C. At C. Yield: 2.6 g (93% of theory).

Recrystallize from 0.1 N hydrochloric acid with ammonia and recrystallize from acetic acid ethyl ester / methanol (4: 1) to give a melting point of 148-151 ° C.

C22H28N8 ° 25 (468 »6)

Calculated: C 56.39 H 6.02 N 23.91 S 6.84 Found: 59.61 6.27 23.40 6.44

Example 4 6-Chloro-4-morpholino-7- (1-oxidothiomorpholino) -2-piperazinopteridine

Prepared according to Example 1 from 2,6-dichloro-4-morpholino-7- (1-oxidothiomorpholino) -pteridine and piperazine. Melting point: 225-227 ° C (Mixture of 0.1 N hydrochloric acid with ammonia).

Example 5 6-Chloro-4,7-bis- (1-oxidothiomorpholino) -2-piperazinopteridine

Prepared according to Example 1 from 2,6-dichloro-4,7-bis- (1-oxidothiomorpholino) -pteridine and piperazine. Melting point:> 200 ° C (decomposes).

Example 6 14 80454 6-Chloro-4,7-dipiperidino-2-piperazino-pteridylamine

Prepared according to Example 1 from 2,6-dichloro-4,7-di-piperidino-pteridine and piperazine.

Melting point: decomposes at about 200 ° C.

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

Prepared according to Example 1 from 2,6-dichloro-4,7-bis- (dimethylamino) -pteridine and piperazine. Melting point: 13D-134 ° C.

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

Prepared according to Example 1 from 2,6-dichloro-4,7-bis- (thiomorpholino) -pteridine and piperazine. Melting point: 194-196 ° C (ethyl acetate).

Example 9 6-Chloro-7-morpholino-4- (1-oxidothiomorpholino) -2-piperazino-p-eridine

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

Melting point:> 240 ° C decomposes.

Example 10 80454 7-Benzylamino-6-chloro-4-morpholino-2-piperazino-pteridine

Prepared according to Example 1 from 7-benzylamino-2,6-dichloro-4-morpholino-phthricin and piperazine. Melting point: 195-197 ° C (methane 1 l / water).

Example 11 7-Benzylamino-6-chloro-4- (1-oxidothiomorpholino) -2-piperazino-pteridine

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

Melting point:> 200 ° C, decomposes.

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

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

Melting point: 150-152 ° C.

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

Prepared according to Example 2 from 7-benzylamino-6-chloro-4- (1-okeidothiomorpholino) -2-piperazino-pteridine and methylmercaptan.

16 80454

Melting point of the hydrochloride: 159-162 ° C.

Example 14 4-Morpho Lino-7- (1-oxides isomorpho) -2-piperazino-6-pyropylo-thiopteridine

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

Melting point: 125-130 ° C.

Example 15 7-Benzylarino-6-benzylthio-4- (1-oxothiomorpholino) -2-piperazino-pteridine

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

Melting point: ^ 160 ° C (decomposes).

Example 16 6-Ethoxy-2-piperazino-4,7-bis- (thiomorpholino) -pteridine

Prepared according to Example 3 from 6-chloro-2-piperazino-4,7-bis- (thiomorpholino) -pteridine and ethanol. Melting point: 147-151 ° C.

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

Prepared according to Example 3 from 6-chloro-4,7-bis- (di-1780454 methylamino) -2-piperazino-pteridine and benzyl alcohol.

Melting point: 155-168 ° C.

Example 18 6-Chloro-2-piperazino-4-dimethylamino-7-benzylaminopteridine

Prepared according to Example 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine. Melting point: 134-137 ° C.

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

Prepared according to Example 1 from 2,6-dichloro-4-thiomorpholino-7-benzylaminopteridine and piperazine. Melting point: 160-165 ° C.

Example 20 6-Chloro-2-piperazino-4-thiomorpholino-7-dimethylaminopteridine

Prepared according to Example 1 from 2,6-dichloro-4-thiomorpholino-7-dimethylaminopteridine and piperazine. Melting point: 205-207 ° C.

1β 80454

Example 21 7-Benzylamino-6-benzylthio-2-piperazino-4-thiomorpho-Lino-pteridine

Prepared according to Example 2 from 7-benzylamino-6-chloro-2-piperazino-4-thiomorpholino-pteridine. Melting point: from 70 ° C (sintered).

Claims (4)

A process for the preparation of pharmacologically valuable 2-piperazinopteridines of formula I R1 NNN N- H (I) R2 wherein R1 is phenylacrylamino dialkylamino group, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 is dialkylamino , piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R inorganic or organic acids, characterized in that a) for the preparation of compounds of general formula I, wherein R 3 is a halogen atom, a compound of general formula II R is the halogen atom and Z 2 is a nucleophilically exchangeable group, such as a halogen atom, to react with a piperazine with the general to formula II H - NN - H (III) or b) to prepare compounds of general formula I wherein R 3 is alkoxy, alkyl mercapto, phenyl alkoxy or phenyl alkyl mercapto group, a compound of general formula IV R . N 2 / N N - H Ύ Y z 3 2 n * 2 where R 2 and R 2 are the same as above and Z 3 is a nucleophilically exchangeable group, such as a halogen atom, to react with a compound of general formula V R 31 - H ( V) where R 31 is optionally a phenyl group substituted alkoxy or alkyl mercapto group, wherein the alkyl moiety contains 1-3 carbon atoms, respectively, or is reacted with its alkali salt and then, if necessary, a slurry of compound of formula I is converted to its acid addition salt, especially to its physiologically suitable acid addition salt with an inorganic or organic acid. 2. A process according to claim 1, characterized in that the compound of formula I is prepared Mr 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine or its acid addition salt. Process according to claim 1, characterized in that the compound of the formula of Mr 6-chloro-4,7-bis- (dimethylamino) -2-piperazino-pteridine or its acid addition salt is prepared. 4. A process according to claim 1, characterized in that the compound of formula I is prepared from Mr. 6-benzylthio-4,7-bis- (dimethylamino) -2-piperazino-pteridine or its acid addition salt. in!