CA1337813C - 2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compounds - Google Patents
2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compoundsInfo
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- CA1337813C CA1337813C CA000552565A CA552565A CA1337813C CA 1337813 C CA1337813 C CA 1337813C CA 000552565 A CA000552565 A CA 000552565A CA 552565 A CA552565 A CA 552565A CA 1337813 C CA1337813 C CA 1337813C
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- acid addition
- benzylamino
- addition salt
- pteridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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Abstract
The invention relates to new pteridines of general formula (I) wherein R4 represents a trimethyleneimino, pyrrolidino, piperidino, hexamethyleneimino or heptamethyleneimino group, R6 represents a fluorine, chlorine or bromine atom and R7 represents a phenylalkylamino, N-alkyl-phenylalkylamino, phenylamino or N-alkyl-phenylamino group, whilst the above-mentioned phenyl nuclei may in each case be mono- or di-substituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, and the acid addition salts thereof which have valuable pharmacological properties, particularly antithrombotic and metastasis-inhibiting effects and an inhibiting effect on tumour growth.
The new compounds may be prepared by methods known per se.
The new compounds may be prepared by methods known per se.
Description
1 ~378 1 3 ~ 27169-142 US-A-2,940,972 has already described tetra-substituted pteridines which have valuable pharmacological properties, namely a coronary dilating effect, sedative, anti-pyretic and analgesic effects.
It has now been found that the new 2-piperazino-pteridines of general formula A
C I ) and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts with inorganic or organic acids, also have valuable pharmacological properties, more particularly anti-thrombotic and metastasis-inhibiting effects and an inhibiting effect on tumour growth.
In general formula I above R4 represents a trimethyleneimino, pyrrolidino, piperidino, hexamethyleneimino or heptamethyleneimino group, R6 represents a chlorine atom and R7 represents a phenylalkylamino, benzylamino, N-methyl-benzylamino or a 2-phenylethylamino group.
The present invention thus relates to the new 2-piperazino-pteridines of general formula I above, the acid addition salts thereof, more particularly the physiologically acceptable acid addition salts with inorganic or organic acids, processes for preparing them and pharmaceutical compositions .~
containing these compounds.
Preferred compounds of general formula I above are those wherein R4 is as hereinbefore defined, R6 represents a chlorine atom and R7 represents a benzylamino or N-methylbenzylamino group, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof.
According to the invention, the new compounds are obtained by the following method:
Reacting a compound of general formula R 7~N~N~Z 2 R6iN~ ~ I 1 ) wherein R4, R6 and R7 are as hereinbefore defined and Z2 represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine or bromine atom, with a piperazine of general formula H--N N X C I I 1) /
wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and if necessary subsequently splitting off the protecting group used.
B
~ 27169-142 The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene or dimethyl glycol ether at temperatures of between 50 and 150C, preferably at the 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 or to use an excess of a compound of general formula III.
The splitting off of any protecting group used, if necessary, is carried out either hydrolytically 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 be split off simultaneously during the reaction if an excess of the amine of general formula III is used.
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 or fumaric acid.
The compounds of general formulae II and III
used as starting materials are, for the most part, already known or may be obtained by the process described in US-A-2,940,972 (see Examples A and B).
As already mentioned hereinbefore, the new compounds of general formula I and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids, have valuable pharmacological properties, particularly antithrombotic and metastasis-inhibiting effects and an inhibiting effect on phosphodiesterase and tumour growth.
For example, the compounds:
A = 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine B = 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine were investigated ~or their inhibitin~ effect on phosphodi-esterase (PDE) of tumour cells and human thrombocytes in vitro using the method described by Poch et al., in the following manner [see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272-291 (1971)]:
a) Obtaining the enzyme:
The 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.
15Phosphodiesterase was obtained from human thrombocytes in the same way.
b) Determining the PDE inhibition (PDE assay):
The PDE inhibition caused by the test substances was determined using 1 ~mol/l of 3H-cAMP as substrate.
The PDE inhibition was determined by measuring the degradation of the substance 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.
30PDE Inhibition (IC50 in ~mol/l) Substance Thrombocytes B16 Tumour Cells A 3.8 0.079 B 5.4 0.0067 Acute toxicity The approximate acute toxicity of the test substance was determined, as a guide, on groups of 5 mice after oral administration of a single dose (observation period: 14 days):
Substance Approximate acute toxicity A 250 mg (0 out of 5 animals died) The new compounds of general formula I prepared according to the invention and the physiologically acceptable acid addition salts thereof are 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.
The dosage required in order to achieve these effects is conveniently from 0.1 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 compounds of general formula I prepared according to the invention and the physiologically acceptable acid addition salts thereof with inorganic or organic acids, optionally together with other active substances, may be combined with one or more inert conventional carriers and/or diluents, e.g. 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 of polyoxyethylene, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, to form conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The Examples which follow are intended to illustrate the invention:
Example A
It has now been found that the new 2-piperazino-pteridines of general formula A
C I ) and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts with inorganic or organic acids, also have valuable pharmacological properties, more particularly anti-thrombotic and metastasis-inhibiting effects and an inhibiting effect on tumour growth.
In general formula I above R4 represents a trimethyleneimino, pyrrolidino, piperidino, hexamethyleneimino or heptamethyleneimino group, R6 represents a chlorine atom and R7 represents a phenylalkylamino, benzylamino, N-methyl-benzylamino or a 2-phenylethylamino group.
The present invention thus relates to the new 2-piperazino-pteridines of general formula I above, the acid addition salts thereof, more particularly the physiologically acceptable acid addition salts with inorganic or organic acids, processes for preparing them and pharmaceutical compositions .~
containing these compounds.
Preferred compounds of general formula I above are those wherein R4 is as hereinbefore defined, R6 represents a chlorine atom and R7 represents a benzylamino or N-methylbenzylamino group, and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof.
According to the invention, the new compounds are obtained by the following method:
Reacting a compound of general formula R 7~N~N~Z 2 R6iN~ ~ I 1 ) wherein R4, R6 and R7 are as hereinbefore defined and Z2 represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine or bromine atom, with a piperazine of general formula H--N N X C I I 1) /
wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and if necessary subsequently splitting off the protecting group used.
B
~ 27169-142 The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene or dimethyl glycol ether at temperatures of between 50 and 150C, preferably at the 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 or to use an excess of a compound of general formula III.
The splitting off of any protecting group used, if necessary, is carried out either hydrolytically 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 be split off simultaneously during the reaction if an excess of the amine of general formula III is used.
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 or fumaric acid.
The compounds of general formulae II and III
used as starting materials are, for the most part, already known or may be obtained by the process described in US-A-2,940,972 (see Examples A and B).
As already mentioned hereinbefore, the new compounds of general formula I and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids, have valuable pharmacological properties, particularly antithrombotic and metastasis-inhibiting effects and an inhibiting effect on phosphodiesterase and tumour growth.
For example, the compounds:
A = 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine B = 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine were investigated ~or their inhibitin~ effect on phosphodi-esterase (PDE) of tumour cells and human thrombocytes in vitro using the method described by Poch et al., in the following manner [see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272-291 (1971)]:
a) Obtaining the enzyme:
The 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.
15Phosphodiesterase was obtained from human thrombocytes in the same way.
b) Determining the PDE inhibition (PDE assay):
The PDE inhibition caused by the test substances was determined using 1 ~mol/l of 3H-cAMP as substrate.
The PDE inhibition was determined by measuring the degradation of the substance 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.
30PDE Inhibition (IC50 in ~mol/l) Substance Thrombocytes B16 Tumour Cells A 3.8 0.079 B 5.4 0.0067 Acute toxicity The approximate acute toxicity of the test substance was determined, as a guide, on groups of 5 mice after oral administration of a single dose (observation period: 14 days):
Substance Approximate acute toxicity A 250 mg (0 out of 5 animals died) The new compounds of general formula I prepared according to the invention and the physiologically acceptable acid addition salts thereof are 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.
The dosage required in order to achieve these effects is conveniently from 0.1 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 compounds of general formula I prepared according to the invention and the physiologically acceptable acid addition salts thereof with inorganic or organic acids, optionally together with other active substances, may be combined with one or more inert conventional carriers and/or diluents, e.g. 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 of polyoxyethylene, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, to form conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The Examples which follow are intended to illustrate the invention:
Example A
2,6,7-trichloro-4-piperidino-pteridine 5.4g (0.02 mol) of 2,4,6,7-tetrachloro-pteridine are dissolved in 100 ml of chloroform and at 0C
a solution of 4g (0.04 mol) of potassium hydrogen carbonate in 20 ml of water is added. Then 1.7g (0.02 mol) of piperidine in 10 ml of chloroform is added dropwise, the mixture is stirred for one hour with cooling and finally 50 ml of water are added.
Then the organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. The residue is washed with 50 ml of ether and then re-crystallised from ethyl acetate.
Yield: 2.7g (42% of theory), Melting point: 184-186C.
The following compounds were obtained analogously:
2,6,7-trichloro-4-pyrrolidino-pteridine Melting point: 245-248C
2,6,7-trichloro-4-hexamethyleneimino-pteridine Melting point: 164-172C
2,6,7-trichloro-4-heptamethyleneimino-pteridine Melting point: 185-187C
Example B
7-benzylamino-2,6-dichloro-4-piperidino-pteridine 1.6g (5 mmol) of 2,6,7-trichloro-4-piperidino-pteridine are stirred in 25 ml of dioxan with 1.2g (11 mmol) of benzylamine for one hour at ambient temperature.
Then the mixture is concentrated in vacuo, the residue is washed with water and recrystallised from ethanol.
Yield: 1.4g (72% of theory), Melting point: 170 - 172C
The following compounds were obtained analogously:
2,6-dichloro-7-(N-methyl-benzylamino)-4-piperidino-pteridine Melting point: 127-129C
7-benzylamino-2,6-dichloro-4-pyrrolidino-pteridine Melting point: 150-154C
2,6-dichloro-7-phenylamino-4-pyrrolidino-pteridine Melting point: 265-270C
7-benzylamino-2,6-dichloro-4-heptamethyleneimino-pteridine Melting point: 157-159C
2,6-dichloro-4-hexamethyleneimino-7-phenylethylamino-pteridine Melting point: 90-95C (ethyl acetate) 7-benzylamino-2,6-dichloro-4-hexamethyleneimino-pteridine Melting point: 83-85C (ethyl acetate) - ~3378i3 Example 1 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 5.8 g (15 mmol) of 7-benzylamino-2,6-dichloro-4-piperidino-pteridine are refluxed with 5.2 g t60 mmol) of piperazine in 120 ml of dioxan for one hour.
The mixture is then concentrated by centrifuging, the residue is washed with water and then dried.
Finally, it is chromatographed over a silica gel column with ethanol/conc. ammonia 50:1.
Yield: 5.1 g (78% of theory), Melting point: sinters from 70C
Calculated: C 60.19 H 6.20 Cl 8.08 N 25.53 Found: 60.53 6.18 7.91 25.39 Example 2 6-Chloro-7-(N-methyl-benzylamino)-4-piperidino-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-7-(N-methyl-benzylamino)-4-piperidino-pteridine and piperazine.
Yield: 53% of theory, Melting point: 73-76C
Calculated: C 60.98 H 6.45 N 24.74 Cl 7.83 Found: 60.80 6.72 25.07 7.72 Example 3 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-di-chloro-4-pyrrolidino-pteridine and piperazine.
Yield: 40% of theory, Melting point: 190-198C
Calculated: C 59.35 H 5.93 N 26.38 Cl 8.34 Found: 59.39 5.63 26.70 8.14 ~;
Example 4 6-Chloro-7-phenylamino-2-piperazino-6-pyrrolidino-pteridine Prepared analogously to Example 1 from 2,6-S dichloro-7-phenylamino-4-pyrrolidino-pteridine.
Yield: 45% of theory, Melting point:>300C
Calculated: C 58.47 H 5.64 N 27.26 Cl 8.63 Found: 58.21 5.78 27.35 8.90 Example 5 7-Benzylamino-6-chloro-4-hexamethyleneimino-2-piperazino-pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-hexamethyleneimino-pteridine.
Yield: 59% of theory, Melting point: sinters from 75C
Calculated: C 60.98 H 6.45 N 24.74 Cl 7.83 Found: 60.69 6.77 24.48 7.99 Example 6 6-Chloro-4-hexamethyleneimino-7-(2'-phenylethylamino)-2-piperazino-pteridine !
Prepared analogously to Example 1 from 2,6-dichloro-4-hexamethyleneimino-7-(2'-phenylethylamino)-pteridine.
Yield: 62% of theory, Melting point: sinters from 75C
Calculated: C 61.72 H 6.69 N 23.99 Cl 7.59 30 Found: 61.55 7.05 23.41 7.75 ExamPle 7 7-Benzylamino-6-chloro-4-heptamethyleneimino-2-piPerazin pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-heptamethyleneimino-pteridine.
Yield: 48% of theory, Melting point: 200-205C
Yield: C 61.72 H 6.69 N 23.99 Cl 7.59 Found: 61.40 6.78 23.17 7.47 The following compound may be prepared analogously to the preceding Examples:
7-Benzylamino-6-chloro-2-piperazino-4-trimethyleneimino-pteridine.
Example I
Coated tablets containing 4 mg of 7-~enzylamino-6-chloro-2-piperazino-4-piperidino-pteridine Composition:
5 1 tablet core contains:
Active substance (1)4.0 mg Lactose (2)27.0 mg Corn starch (3)14.5 mg Polyvinyl pyrrolidone (4)4.0 mg 10 Magnesium stearate (5)0.5 mg 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 cores.
Cores: 5 mm in diameter, biconvex, round Coating:
Usual sugar coating to give a finished weight of 70 mg.
Example II
Tablets containing 8 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 1 tablet contains:
Active substance 8.0 mg 30 Lactose 23.0 mg Corn starch 14.5 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 0.5 mg 50.0 mg Preparation:
Analogously to the tablet cores.
~ 33781 3 Description of tablet:
Weight: 50 mg Diameter: 5 mm, biplanar, faceted on both sides Example III
Suppositories containing 25 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 1 suppository contains:
Active substance 0.025 g , 10 Hard fat (e.g. Witepsol H 19 1.695 g and Witepsol H 45) 1.700 g Preparation:
The hard fat is melted. At 38C 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 IV
Suspension containing 8 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine per 5 ml 100 ml of suspension contain:
Active substance 0.16 g Carboxymethylcellulose 0.1 9 25 Methyl p-hydroxybenzoate 0.05 9 Propyl p-hydroxybenzoate 0.01 g Glucose 10.0 g Glycerol 5.0 9 70% sorbitol solution 20.0 9 30 Flavouring 0-3 9 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 ~ Tr~d ~ r~ ~ K
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 containing 100 mg of 7-benzylamino-6-chloro-10 2-piperazino-4-piperidino-pteridine Composition:
1 tablet contains:
Active substance 100.0 mg Lactose 80.0 mg 15 Corn starch 34.0 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg 20 Method of preparation The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinyl pyrrolidone.
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 for 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 gelatine capsules containing 150 mg of 7-benzyl-amino-6-chloro-2-piperazino-4-piperidino-pteridine 1 capsule contains Active substance 150.0 mg ~ried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg Magnesium stearate 3.0 mg approx. 320.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a 0.75 mm mesh and homogeneously mixed in a suitable apparatus.
The finished mixture is packed into hard gelatine capsules, size 1.
Capsule filling: approx. 320 mg Capsule shell: hard gelatine capsule, size 1.
a solution of 4g (0.04 mol) of potassium hydrogen carbonate in 20 ml of water is added. Then 1.7g (0.02 mol) of piperidine in 10 ml of chloroform is added dropwise, the mixture is stirred for one hour with cooling and finally 50 ml of water are added.
Then the organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. The residue is washed with 50 ml of ether and then re-crystallised from ethyl acetate.
Yield: 2.7g (42% of theory), Melting point: 184-186C.
The following compounds were obtained analogously:
2,6,7-trichloro-4-pyrrolidino-pteridine Melting point: 245-248C
2,6,7-trichloro-4-hexamethyleneimino-pteridine Melting point: 164-172C
2,6,7-trichloro-4-heptamethyleneimino-pteridine Melting point: 185-187C
Example B
7-benzylamino-2,6-dichloro-4-piperidino-pteridine 1.6g (5 mmol) of 2,6,7-trichloro-4-piperidino-pteridine are stirred in 25 ml of dioxan with 1.2g (11 mmol) of benzylamine for one hour at ambient temperature.
Then the mixture is concentrated in vacuo, the residue is washed with water and recrystallised from ethanol.
Yield: 1.4g (72% of theory), Melting point: 170 - 172C
The following compounds were obtained analogously:
2,6-dichloro-7-(N-methyl-benzylamino)-4-piperidino-pteridine Melting point: 127-129C
7-benzylamino-2,6-dichloro-4-pyrrolidino-pteridine Melting point: 150-154C
2,6-dichloro-7-phenylamino-4-pyrrolidino-pteridine Melting point: 265-270C
7-benzylamino-2,6-dichloro-4-heptamethyleneimino-pteridine Melting point: 157-159C
2,6-dichloro-4-hexamethyleneimino-7-phenylethylamino-pteridine Melting point: 90-95C (ethyl acetate) 7-benzylamino-2,6-dichloro-4-hexamethyleneimino-pteridine Melting point: 83-85C (ethyl acetate) - ~3378i3 Example 1 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 5.8 g (15 mmol) of 7-benzylamino-2,6-dichloro-4-piperidino-pteridine are refluxed with 5.2 g t60 mmol) of piperazine in 120 ml of dioxan for one hour.
The mixture is then concentrated by centrifuging, the residue is washed with water and then dried.
Finally, it is chromatographed over a silica gel column with ethanol/conc. ammonia 50:1.
Yield: 5.1 g (78% of theory), Melting point: sinters from 70C
Calculated: C 60.19 H 6.20 Cl 8.08 N 25.53 Found: 60.53 6.18 7.91 25.39 Example 2 6-Chloro-7-(N-methyl-benzylamino)-4-piperidino-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-7-(N-methyl-benzylamino)-4-piperidino-pteridine and piperazine.
Yield: 53% of theory, Melting point: 73-76C
Calculated: C 60.98 H 6.45 N 24.74 Cl 7.83 Found: 60.80 6.72 25.07 7.72 Example 3 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-di-chloro-4-pyrrolidino-pteridine and piperazine.
Yield: 40% of theory, Melting point: 190-198C
Calculated: C 59.35 H 5.93 N 26.38 Cl 8.34 Found: 59.39 5.63 26.70 8.14 ~;
Example 4 6-Chloro-7-phenylamino-2-piperazino-6-pyrrolidino-pteridine Prepared analogously to Example 1 from 2,6-S dichloro-7-phenylamino-4-pyrrolidino-pteridine.
Yield: 45% of theory, Melting point:>300C
Calculated: C 58.47 H 5.64 N 27.26 Cl 8.63 Found: 58.21 5.78 27.35 8.90 Example 5 7-Benzylamino-6-chloro-4-hexamethyleneimino-2-piperazino-pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-hexamethyleneimino-pteridine.
Yield: 59% of theory, Melting point: sinters from 75C
Calculated: C 60.98 H 6.45 N 24.74 Cl 7.83 Found: 60.69 6.77 24.48 7.99 Example 6 6-Chloro-4-hexamethyleneimino-7-(2'-phenylethylamino)-2-piperazino-pteridine !
Prepared analogously to Example 1 from 2,6-dichloro-4-hexamethyleneimino-7-(2'-phenylethylamino)-pteridine.
Yield: 62% of theory, Melting point: sinters from 75C
Calculated: C 61.72 H 6.69 N 23.99 Cl 7.59 30 Found: 61.55 7.05 23.41 7.75 ExamPle 7 7-Benzylamino-6-chloro-4-heptamethyleneimino-2-piPerazin pteridine Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-heptamethyleneimino-pteridine.
Yield: 48% of theory, Melting point: 200-205C
Yield: C 61.72 H 6.69 N 23.99 Cl 7.59 Found: 61.40 6.78 23.17 7.47 The following compound may be prepared analogously to the preceding Examples:
7-Benzylamino-6-chloro-2-piperazino-4-trimethyleneimino-pteridine.
Example I
Coated tablets containing 4 mg of 7-~enzylamino-6-chloro-2-piperazino-4-piperidino-pteridine Composition:
5 1 tablet core contains:
Active substance (1)4.0 mg Lactose (2)27.0 mg Corn starch (3)14.5 mg Polyvinyl pyrrolidone (4)4.0 mg 10 Magnesium stearate (5)0.5 mg 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 cores.
Cores: 5 mm in diameter, biconvex, round Coating:
Usual sugar coating to give a finished weight of 70 mg.
Example II
Tablets containing 8 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 1 tablet contains:
Active substance 8.0 mg 30 Lactose 23.0 mg Corn starch 14.5 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 0.5 mg 50.0 mg Preparation:
Analogously to the tablet cores.
~ 33781 3 Description of tablet:
Weight: 50 mg Diameter: 5 mm, biplanar, faceted on both sides Example III
Suppositories containing 25 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine 1 suppository contains:
Active substance 0.025 g , 10 Hard fat (e.g. Witepsol H 19 1.695 g and Witepsol H 45) 1.700 g Preparation:
The hard fat is melted. At 38C 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 IV
Suspension containing 8 mg of 7-benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine per 5 ml 100 ml of suspension contain:
Active substance 0.16 g Carboxymethylcellulose 0.1 9 25 Methyl p-hydroxybenzoate 0.05 9 Propyl p-hydroxybenzoate 0.01 g Glucose 10.0 g Glycerol 5.0 9 70% sorbitol solution 20.0 9 30 Flavouring 0-3 9 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 ~ Tr~d ~ r~ ~ K
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 containing 100 mg of 7-benzylamino-6-chloro-10 2-piperazino-4-piperidino-pteridine Composition:
1 tablet contains:
Active substance 100.0 mg Lactose 80.0 mg 15 Corn starch 34.0 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg 20 Method of preparation The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinyl pyrrolidone.
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 for 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 gelatine capsules containing 150 mg of 7-benzyl-amino-6-chloro-2-piperazino-4-piperidino-pteridine 1 capsule contains Active substance 150.0 mg ~ried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg Magnesium stearate 3.0 mg approx. 320.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a 0.75 mm mesh and homogeneously mixed in a suitable apparatus.
The finished mixture is packed into hard gelatine capsules, size 1.
Capsule filling: approx. 320 mg Capsule shell: hard gelatine capsule, size 1.
Claims (17)
1. A pteridine of general formula (I) wherein R4 represents a trimethyleneimino, pyrrolidino, piperidino, hexamethyleneimino or heptamethyleneimino group, R6 represents a chlorine atom and R7 represents a phenylalkylamino, benzylamino, N-methyl-benzylamino or a 2-phenylethylamino group, or an acid addition salt thereof.
2. A compound as claimed in claim 1, wherein R4 is defined as in claim 1 and R7 represents a benzylamino or N-methyl-benzylamino group.
3. 7-Benzylamino-6-chloro-2-piperazino-4-piperidino-pteridine or an acid addition salt thereof.
4. 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine or an acid addition salt thereof.
5. A compound as claimed in any one of claims 1 to 4 in the form of a physiologically acceptable acid addition salt with an inorganic or organic acid.
6. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof together with one or more inert carriers and/or diluents.
7. Use of a compound as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof for inhibiting tumour growth.
8. Process for preparing a pharmaceutical composition, characterized in that a compound as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
9. A commercial package containing as active pharmaceu-tical ingredient a compound as claimed in any one of claims 1 to 4, or a physiologically acceptable acid addition salt thereof, together with instructions for use for inhibiting tumour growth.
10. A process for preparing a pteridine of formula (I) as defined in claim 1, or an acid addition salt thereof, character-ized in that a compound of general formula (II) wherein R4, R6 and R7 are as defined in claim 1 and Z2 represents a nucleophilically exchangeable group, is reacted with a piperazine of formula (III) wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and subsequently, if necessary any protecting group used is split off and subsequently, if required, a compound of general formula (I) thus obtained is converted into an acid addition salt thereof.
11. A process as claimed in claim 10 wherein R4 is as defined in claim 10, R6 represents a chlorine atom and R7 represents a benzylamino or N-methyl-benzylamino group.
12. A process as claimed in claim 10 or 11 which includes the step of converting an obtained pteridine of formula (I) into a physiologically acceptable acid addition salt thereof.
13. A process as claimed in claim 10, wherein the reaction is carried out in a solvent.
14. A process as claimed in claim 10 wherein the reaction is carried out in the presence of an acid binding agent.
15. A process as claimed in claim 10 wherein the reaction is carried out at a temperature of between 0 and 150°C.
16. A process as claimed in claim 10 wherein the reaction is carried out in a solvent at a temperature between ambient temperature and the boiling temperature of the solvent used.
17. A process as claimed in claim 10 wherein the subsequent splitting off of a protecting group is carried out by hydrolysis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3540952A DE3540952C2 (en) | 1985-11-19 | 1985-11-19 | 2-Piperazino-pteridines, process for their preparation and medicaments containing these compounds |
| CA000552565A CA1337813C (en) | 1985-11-19 | 1987-11-24 | 2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3540952A DE3540952C2 (en) | 1985-11-19 | 1985-11-19 | 2-Piperazino-pteridines, process for their preparation and medicaments containing these compounds |
| CA000552565A CA1337813C (en) | 1985-11-19 | 1987-11-24 | 2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1337813C true CA1337813C (en) | 1995-12-26 |
Family
ID=25671603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000552565A Expired - Fee Related CA1337813C (en) | 1985-11-19 | 1987-11-24 | 2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compounds |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1337813C (en) |
| DE (1) | DE3540952C2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7550472B2 (en) | 2004-11-29 | 2009-06-23 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| JP2009537590A (en) * | 2006-05-24 | 2009-10-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted pteridines substituted with four-membered heterocycles |
| US7648988B2 (en) | 2004-11-29 | 2010-01-19 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| US7718654B2 (en) | 2004-11-29 | 2010-05-18 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| US7750009B2 (en) * | 2004-11-29 | 2010-07-06 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| JP2010526764A (en) * | 2006-05-24 | 2010-08-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted pteridine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10202468A1 (en) * | 2002-01-23 | 2004-09-30 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Pteridine derivatives, process for their preparation and their use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3323932A1 (en) * | 1983-07-02 | 1985-01-10 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW 2-PIPERAZINO-PTERIDINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
-
1985
- 1985-11-19 DE DE3540952A patent/DE3540952C2/en not_active Expired - Fee Related
-
1987
- 1987-11-24 CA CA000552565A patent/CA1337813C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7550472B2 (en) | 2004-11-29 | 2009-06-23 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| US7648988B2 (en) | 2004-11-29 | 2010-01-19 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| US7718654B2 (en) | 2004-11-29 | 2010-05-18 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| US7750009B2 (en) * | 2004-11-29 | 2010-07-06 | Boehringer Ingelheim International Gmbh | Substituted pteridines for the treatment of inflammatory diseases |
| JP2009537590A (en) * | 2006-05-24 | 2009-10-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted pteridines substituted with four-membered heterocycles |
| JP2010526764A (en) * | 2006-05-24 | 2010-08-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted pteridine |
| US8877756B2 (en) | 2006-05-24 | 2014-11-04 | Boehringer Ingelheim International Gmbh | Substituted pteridines |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3540952A1 (en) | 1987-05-21 |
| DE3540952C2 (en) | 1997-08-14 |
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