CA1233179A - 2-piperazino-pteridines, processes for the preparation thereof and pharmaceutical compositions containing these compounds - Google Patents
2-piperazino-pteridines, processes for the preparation thereof and pharmaceutical compositions containing these compoundsInfo
- Publication number
- CA1233179A CA1233179A CA000457880A CA457880A CA1233179A CA 1233179 A CA1233179 A CA 1233179A CA 000457880 A CA000457880 A CA 000457880A CA 457880 A CA457880 A CA 457880A CA 1233179 A CA1233179 A CA 1233179A
- Authority
- CA
- Canada
- Prior art keywords
- group
- pteridine
- dimethylamino
- piperazino
- morpholino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract New 2-piperazino-pteridines of general formula (I) 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.
Processes for preparing the compounds of formula (I) are also described.
Description
~3~ 7~
This invention relates to new 2-piperazino-pteridines and to the acid addition salts thereof, to processes for their preparation and to pharmaceutical compositions containing them.
United States-A-2,940,972 describes tetra-substituted pteridines, which have valuable pharmacological properties including coronary dilatory, sedative, antipyretic and analgesic effects.
We have now found that new 2-piperazino-pteridines of yeneral formula I
~ (I) and the acid addition salts thereof, particularly the physio-logically acceptable acid addition salts thereof with inorganic or organic acids, also have valuable pharmacological properties, which surprisingly include antithrombotic and metastasis-inhibiting effects.
Hence, according to one feature of the preser~t invention there are provided compounds of general formula I above, wherein Rl represents a phenyl(Cl-C3 alkyl)amino, (Cl-C3 alkyl)-amino or di(C1-C3 alkyl)amino group, a piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group, R2 represents a di(Cl--C3 alkyl)amino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group and ~ - -- .l --/, ' . '!
." ' `' ~
~33~9 R3 represents a halogen atom or 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.
Rl may represent, for example, a methylamino, ethylamino, propylamino, isopropylamino, benzylamino, l-phenylethylamino,
This invention relates to new 2-piperazino-pteridines and to the acid addition salts thereof, to processes for their preparation and to pharmaceutical compositions containing them.
United States-A-2,940,972 describes tetra-substituted pteridines, which have valuable pharmacological properties including coronary dilatory, sedative, antipyretic and analgesic effects.
We have now found that new 2-piperazino-pteridines of yeneral formula I
~ (I) and the acid addition salts thereof, particularly the physio-logically acceptable acid addition salts thereof with inorganic or organic acids, also have valuable pharmacological properties, which surprisingly include antithrombotic and metastasis-inhibiting effects.
Hence, according to one feature of the preser~t invention there are provided compounds of general formula I above, wherein Rl represents a phenyl(Cl-C3 alkyl)amino, (Cl-C3 alkyl)-amino or di(C1-C3 alkyl)amino group, a piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group, R2 represents a di(Cl--C3 alkyl)amino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group and ~ - -- .l --/, ' . '!
." ' `' ~
~33~9 R3 represents a halogen atom or 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.
Rl may represent, for example, a methylamino, ethylamino, propylamino, isopropylamino, benzylamino, l-phenylethylamino,
2-phenylethylamino, 3-phenylpropylamino, dimethylamino, diethyl-amino, dipropylamino, methylethylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group, R2 may represent, for example, a dimethylamino, diethylamino, dipropylamino, diisopropylamino, methyl-ethylamino, ethyl-propylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group and R3 may represent, for example, a chlorine or bromine atom or a methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, l-phenylpropoxy, 2-phenylpropoxy,
3-phenylpropoxy, 1-methyl-2-phenylethoxy, me-thylmercapto, e-thyl-mercapto, propylmercapto, isopropylmercapto, benzylmercapto, l-phenylethylmercapto, 2-phenylethylmercapto or 3-phenylpropyl-mercapto group.
Preferred compounds according to the invention are those wherein Rl represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group, R2 represents a dimethylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino ~3 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 benzyl-mercapto group, and the acid addition salts thereof rparticularly the physiologically acceptable acid addition salts thereof with inorganïc or organic acids.
Especially preferred compounds according to the invention are those wherein Rl and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or l-oxidothiomorpholino group and Rl may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in the alkyl moiety or a benzyloxy or benzylmercapto 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 Rl and R2 each represent a dimethylamino, ~ morpholino or l-oxidothiomorpholino group and R
: 25 also represents a benzylamino group and R3 represents a cblorine atom or a methylmercapto or benæylmercapto groupt and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.
The compounds of general formula I above may, fo~ example, be prepared by the following processes, which processes constitute further features of the present invention:
3S a) In order to prepare compounds of general formula I wherein R3 represents a halogen atom:
a compound of general formula II
~33 R1 ~ N ~ ~ ~ ~ Z2 R ' N
wherein Rl and R2 are as hereinbefore defined, R3' represents a halogen atom and ~ represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, is reacted with a piperazine of general formula III
r~
~ - N N - X (III) wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and subsequently, if necessary, splitting off the protecting group usedO
The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene or dimethylglycol 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.
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 _ 5 - ~2~3~
solvent such as methanol/water, ethanol/water or dloxan~water at temperatures up to the boiling temperature of the solvent used.
b) In order to prepare compounds of general formula I wherein R3 represents an alkoxy, alkylmercapto, phenylalkoxy or phenylalkylmercapto group:
a compound of general formula IV
..
R~ ~ N ~ ~ 3 (IV) ~,N
Z~ N
wherein : 10 Rl and R2 are as hereinbefore defined and Z3 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
3 (V) wherein R3' 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 ben2yl alcohol, and preferably in the presence of a corresponding alkali metal salt of a compound of general formula V such as sodium methoxide, sodium ethoxide or - 6 - ~ ~33~
sodium benzylmercaptide, conveniently at temperatures of between 50 and 150C, 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 inorganic or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.
The compounds of geneLal formulae II 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 I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, which particularly include antithrombotic and metastasis-inhibiting effects and an inhibiting efect on phosphodiesterase.
For example, the following compounds have been tested with regard to their inhibiting effect on phosphodiesterase (PDE) ~rom tumour cells and from human thrombocytes in vitro using the method described by P~ch et al. [see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272-279 (1971)].
A = 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine B = 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine C = 6-benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine ~33~
D = 7-benæylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino~pteridine and E = 6-chloro-2-piperazino-4~dimethylamino-7-benzylamino-pteridine a) Obtaining the enzyme:
The phosphodiesterase was obtained from B16 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-Elvehjem or by ultrasound. The supernatant containing the PDE was deep-frozen in portions at -25C. The PDE was obtained from human thrombocytes analogously by freezing/thawing and centrifuging.
b) Determining the PDE _hibition (PDE assay).
The PDE inhibition by the test substances was determined with 1 ymol/1 3H-cAMP as substrate.
The PDE inhibition was determined by measuring the degradation of the substrate 3H-cAMP to 3H-AMP by comparison with a control without any test substance. The 3H-AMP formed was separated off from the remaining 3H-cAMP by zinc sulphate/barium hydroxide precipitation.
The ED50 was calculated, by linear regression analysis, as the concentration which inhibited PDE activity by 50%.
- 8 - ~2~
PDE Inhibition (ED50) Substance Thrombocytes B16 Tumour cells A 0.051 0O088 B 35 0.95 C 10 0.88 D 0.048 0.97 E 14 0.37 _ Acute toxicity-The approximate acute toxicity of the substances being tested was determined on groups of 5 mice 1.5 after oral administration of a single dose (observation periodO 14 days).
.
Substance Approximate acute toxi~ity A ~ 250 mg/kg (0 out of 5 animals died) 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) E > 250 mg kg (0 out of 5 animals died) _ The new compounds of general formula I prepared according to the invention are suitable, owing to their above-mentioned pharmacological properties, for the prophylaxis of thromboembolic 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 ~3~L7~
g --compositions containing, as active ingredient, at least one compound of general formula I as hereinbefore defined or a physiologically 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 I or their physiologically acceptable acid addition salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination wlth other active ingredients.
Preferred forms include, for example, tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/
glycerine, water/sorbitol, non-ionic surfactants such as polyoxyethylene fat~y acid esters, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose 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 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 treating a patient suEfering from, or susceptible to, thromboembolic dis~ases, arteriosclerosis or - 10 - ~3L2~ 79 metastasis which comprises administering to the said patient an effective amount of a compound of general Eormula I 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 in more detail:
2~3~
Preparation A
2,6,7~ Gb ~ rorpholino-~eridine A solution of 4.35 9 (O.OS mol~ of morpholine in 100 ml of chloroform is slowly added dropwise 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, with vigorous stirrin~ and cooling to 5 to 0C, 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 ln vacuo.
Yield: 13.5 g (84% of theory).
Melting point: 211-213C (ethyl acetate).
The following compounds are prepared in a manner analogous to Preparation A:
2,6,7-Trichloro 4-thiomorpholino-pteridine Melting point 191-193C
2,6,7-Trichloro 4~ oxidothiomorpholino)-pteridine Melting point: 212-214C (decomposition~
Pre~ation B
2~6-Dichloro-4,7-bis-(1-oxidothiomOrpholino)-pteridine 23.8 9 (0.2 ~ol) of thiomorpholine-l-oxide dissolved in 100 ml of dioxan is slowly added to a solution of 13.5 g (0005 mol) of 2,4,6,7-tetrachloro-pteridine 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. ~fter standing for some time, the reaction product which is precipitated is suction filtered and washed with water and dried at about 70C.
Yield: 19.2 g (88~ of theory).
Melting point: 237 239C (ethanol).
~3~7~
The following compounds are prepared in a manner analogous to Preparation B:
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-~ichloro-4,7-bis-(dimethylamino)-pteridine Melting point: 245-247C
2,6-Dichloro-4,7-dipiperidino-pteridine 10 Melting point: 185-187C
Preparation C
7-Benzylamino-2,6-dichloro-4-morpholino-pteridine : A solution of 7 g (0.065 mol) of benzylamine in 50 ml of dioxan is slowly added to a suspension - ; of 9.6 g (0.03 mol) of 2,6,7-trichloro-4-morpholino-pteridine in about 150 ml of dioxan at ambient temperatu~e with stirringO 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 60C.
Yield: 10.9 g (94% of theory).
Melting point: 213-214C (ethanol/dioxan = 2:1 The following compounds are prepared in a manner analogous to Preparation C:
7-Benzylamino-2,6-dichloro-4~(1-oxidothiomorpholino)-pteridine Melting point: 253-254C
30 2,6-Dichloro 7-morpholino-4-(1-oxidothiomorpholino)-pteridine Melting point: 215-217C
. , ~L~33~79 - 13 ~
2,6-Dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine Melting point: 218-220C
Example 1 6-Chloro-4,7-dimorpholino-2-~iperazino-pteridine 9.3 g (00025 moll 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 ml of dioxan. The solvent is substantially distilled off and the residue is digested with about 100 ml of waterO
After it has stood for a short time, it is suction filtered, washed with water and dried at about 15 70C (melting point 218-220C).
Yi~ld: 8.9 g (85~ of theory).
Melting point: 220-222C.
C18H25ClN~2 t420 9) Calculated: C 51.36 H 5.99Cl 8.42 ~ 26.62 Found: 51O21 5.97 8.48 26.68 Example 2 6-Benzy~thio-4,7-dimorpholino-2-piperazlno-pteridine A solution of 0.35 g of sodium and 2 ml (about 0.017 mol) of benzylmercaptan in 100 ml of dioxan is added to a solution of 6.3 g (0.015 mol) of 6-chloro-4,7-dimorpholino-2-piperazino-pteridine in 200 ml 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 ml 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 recrystal-lisation Erom ethyl acetate, the substance melts - 14 ~ 3~ ~
at 135-137C.
C25H32N~2S(508.7) Calculated:C 59.03H 6034 N 22.03 S 6.30 Found: 59.28 6.55 22.]9 6.36 Example 3 7-Benzylamino-6-methoxy-4-(1-oxidothiomorpholino)-2~piperazino-pteridine A solution of 0.23 g (0~01 mol) of sodium in 10--ml of methanol is poured into a solution of 2.9 g (0.006 mol) of 7-benzylamino-6-chloro-
Preferred compounds according to the invention are those wherein Rl represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group, R2 represents a dimethylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino ~3 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 benzyl-mercapto group, and the acid addition salts thereof rparticularly the physiologically acceptable acid addition salts thereof with inorganïc or organic acids.
Especially preferred compounds according to the invention are those wherein Rl and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or l-oxidothiomorpholino group and Rl may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylmercapto group with 1 to 3 carbon atoms in the alkyl moiety or a benzyloxy or benzylmercapto 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 Rl and R2 each represent a dimethylamino, ~ morpholino or l-oxidothiomorpholino group and R
: 25 also represents a benzylamino group and R3 represents a cblorine atom or a methylmercapto or benæylmercapto groupt and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.
The compounds of general formula I above may, fo~ example, be prepared by the following processes, which processes constitute further features of the present invention:
3S a) In order to prepare compounds of general formula I wherein R3 represents a halogen atom:
a compound of general formula II
~33 R1 ~ N ~ ~ ~ ~ Z2 R ' N
wherein Rl and R2 are as hereinbefore defined, R3' represents a halogen atom and ~ represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, is reacted with a piperazine of general formula III
r~
~ - N N - X (III) wherein X represents a hydrogen atom or a hydrolytically removable protecting group, and subsequently, if necessary, splitting off the protecting group usedO
The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxan, benzene, toluene or dimethylglycol 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.
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 _ 5 - ~2~3~
solvent such as methanol/water, ethanol/water or dloxan~water at temperatures up to the boiling temperature of the solvent used.
b) In order to prepare compounds of general formula I wherein R3 represents an alkoxy, alkylmercapto, phenylalkoxy or phenylalkylmercapto group:
a compound of general formula IV
..
R~ ~ N ~ ~ 3 (IV) ~,N
Z~ N
wherein : 10 Rl and R2 are as hereinbefore defined and Z3 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
3 (V) wherein R3' 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 ben2yl alcohol, and preferably in the presence of a corresponding alkali metal salt of a compound of general formula V such as sodium methoxide, sodium ethoxide or - 6 - ~ ~33~
sodium benzylmercaptide, conveniently at temperatures of between 50 and 150C, 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 inorganic or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.
The compounds of geneLal formulae II 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 I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, which particularly include antithrombotic and metastasis-inhibiting effects and an inhibiting efect on phosphodiesterase.
For example, the following compounds have been tested with regard to their inhibiting effect on phosphodiesterase (PDE) ~rom tumour cells and from human thrombocytes in vitro using the method described by P~ch et al. [see Naunyn-Schmiedebergs Arch. Pharmak. 268, 272-279 (1971)].
A = 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine B = 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine C = 6-benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine ~33~
D = 7-benæylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino~pteridine and E = 6-chloro-2-piperazino-4~dimethylamino-7-benzylamino-pteridine a) Obtaining the enzyme:
The phosphodiesterase was obtained from B16 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-Elvehjem or by ultrasound. The supernatant containing the PDE was deep-frozen in portions at -25C. The PDE was obtained from human thrombocytes analogously by freezing/thawing and centrifuging.
b) Determining the PDE _hibition (PDE assay).
The PDE inhibition by the test substances was determined with 1 ymol/1 3H-cAMP as substrate.
The PDE inhibition was determined by measuring the degradation of the substrate 3H-cAMP to 3H-AMP by comparison with a control without any test substance. The 3H-AMP formed was separated off from the remaining 3H-cAMP by zinc sulphate/barium hydroxide precipitation.
The ED50 was calculated, by linear regression analysis, as the concentration which inhibited PDE activity by 50%.
- 8 - ~2~
PDE Inhibition (ED50) Substance Thrombocytes B16 Tumour cells A 0.051 0O088 B 35 0.95 C 10 0.88 D 0.048 0.97 E 14 0.37 _ Acute toxicity-The approximate acute toxicity of the substances being tested was determined on groups of 5 mice 1.5 after oral administration of a single dose (observation periodO 14 days).
.
Substance Approximate acute toxi~ity A ~ 250 mg/kg (0 out of 5 animals died) 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) E > 250 mg kg (0 out of 5 animals died) _ The new compounds of general formula I prepared according to the invention are suitable, owing to their above-mentioned pharmacological properties, for the prophylaxis of thromboembolic 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 ~3~L7~
g --compositions containing, as active ingredient, at least one compound of general formula I as hereinbefore defined or a physiologically 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 I or their physiologically acceptable acid addition salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination wlth other active ingredients.
Preferred forms include, for example, tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/
glycerine, water/sorbitol, non-ionic surfactants such as polyoxyethylene fat~y acid esters, water-polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose 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 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 treating a patient suEfering from, or susceptible to, thromboembolic dis~ases, arteriosclerosis or - 10 - ~3L2~ 79 metastasis which comprises administering to the said patient an effective amount of a compound of general Eormula I 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 in more detail:
2~3~
Preparation A
2,6,7~ Gb ~ rorpholino-~eridine A solution of 4.35 9 (O.OS mol~ of morpholine in 100 ml of chloroform is slowly added dropwise 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, with vigorous stirrin~ and cooling to 5 to 0C, 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 ln vacuo.
Yield: 13.5 g (84% of theory).
Melting point: 211-213C (ethyl acetate).
The following compounds are prepared in a manner analogous to Preparation A:
2,6,7-Trichloro 4-thiomorpholino-pteridine Melting point 191-193C
2,6,7-Trichloro 4~ oxidothiomorpholino)-pteridine Melting point: 212-214C (decomposition~
Pre~ation B
2~6-Dichloro-4,7-bis-(1-oxidothiomOrpholino)-pteridine 23.8 9 (0.2 ~ol) of thiomorpholine-l-oxide dissolved in 100 ml of dioxan is slowly added to a solution of 13.5 g (0005 mol) of 2,4,6,7-tetrachloro-pteridine 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. ~fter standing for some time, the reaction product which is precipitated is suction filtered and washed with water and dried at about 70C.
Yield: 19.2 g (88~ of theory).
Melting point: 237 239C (ethanol).
~3~7~
The following compounds are prepared in a manner analogous to Preparation B:
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-~ichloro-4,7-bis-(dimethylamino)-pteridine Melting point: 245-247C
2,6-Dichloro-4,7-dipiperidino-pteridine 10 Melting point: 185-187C
Preparation C
7-Benzylamino-2,6-dichloro-4-morpholino-pteridine : A solution of 7 g (0.065 mol) of benzylamine in 50 ml of dioxan is slowly added to a suspension - ; of 9.6 g (0.03 mol) of 2,6,7-trichloro-4-morpholino-pteridine in about 150 ml of dioxan at ambient temperatu~e with stirringO 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 60C.
Yield: 10.9 g (94% of theory).
Melting point: 213-214C (ethanol/dioxan = 2:1 The following compounds are prepared in a manner analogous to Preparation C:
7-Benzylamino-2,6-dichloro-4~(1-oxidothiomorpholino)-pteridine Melting point: 253-254C
30 2,6-Dichloro 7-morpholino-4-(1-oxidothiomorpholino)-pteridine Melting point: 215-217C
. , ~L~33~79 - 13 ~
2,6-Dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine Melting point: 218-220C
Example 1 6-Chloro-4,7-dimorpholino-2-~iperazino-pteridine 9.3 g (00025 moll 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 ml of dioxan. The solvent is substantially distilled off and the residue is digested with about 100 ml of waterO
After it has stood for a short time, it is suction filtered, washed with water and dried at about 15 70C (melting point 218-220C).
Yi~ld: 8.9 g (85~ of theory).
Melting point: 220-222C.
C18H25ClN~2 t420 9) Calculated: C 51.36 H 5.99Cl 8.42 ~ 26.62 Found: 51O21 5.97 8.48 26.68 Example 2 6-Benzy~thio-4,7-dimorpholino-2-piperazlno-pteridine A solution of 0.35 g of sodium and 2 ml (about 0.017 mol) of benzylmercaptan in 100 ml of dioxan is added to a solution of 6.3 g (0.015 mol) of 6-chloro-4,7-dimorpholino-2-piperazino-pteridine in 200 ml 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 ml 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 recrystal-lisation Erom ethyl acetate, the substance melts - 14 ~ 3~ ~
at 135-137C.
C25H32N~2S(508.7) Calculated:C 59.03H 6034 N 22.03 S 6.30 Found: 59.28 6.55 22.]9 6.36 Example 3 7-Benzylamino-6-methoxy-4-(1-oxidothiomorpholino)-2~piperazino-pteridine A solution of 0.23 g (0~01 mol) of sodium in 10--ml of methanol is poured into a solution of 2.9 g (0.006 mol) of 7-benzylamino-6-chloro-
4~ oxidothiomorpholino)-2-piperazino-pteridine in 100 ml of dioxan. The resulting mixture is heated under reflux for 30 minutes and then the solvent is substantially distilled oEf }n vacuo.
The residue is taken up in about 70 ml of water and the reaction product precipitated is suction filtered, washed with water and dried at about 60C.
Yield: 2.6 g (93% of theory).
After reprecipitation from 0.1 N hydrochloric acid using ammonia and recrystallisation from e,thyl acetate/methanol (4:1), the compound melts at 148-151C.
Calculated:C 56.39H 6.02 N 23.91 S 6.84 Found: 56.61 6.27 23.40 6.44 , Example 4 6-Chloro 4-morphollno-7-(1-oxidothiomorpholino)-2--piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine and piperazine.
Melting point: 225-227C (reprecipitation from 0.1 N HCl by means o~ ammonia).
~;~33~
Example 5 6-Chlo_o-4,7-bis-(l-oxldothiomor~olino)-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis-(l-oxidothiomorpholino)-pteridine and piperazine.
Melting point: ~ 200C (decomposition)~
Example 6 6-Chloro-4,7-di~i~eridino-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro 4,7 dipiperidino-pteridine and piperazineO
Melting point~ decomposition at about 200C.
Example 7 6-Chloro-4,7-bis-(dimethylamino)-2-~iperazino-Eterldine Prepared analogously to Example l from 2,6-dichloro-4,7-bis ~dimethylamino)-pteridine and piperaæine.
20 Melting point: 130-134C.
Example 8 6-Chloro-2-pipe_azino-4,7-bis-(thiomor~holino)-pteridine Prepared analogously to Example l from 2,6-dichloro-4,7-bis-(thiomorpholino)-pteridine and piperazine.
Melting point: 194-196C (ethyl acetate).
Example 9 6-Chloro-7-morpholino-4-(l-oxidothiomor~holino)-2-pi~erazino-pteridine Prepared analogously to Example l from 2,6-dichloro-7 morpholino-4~(1-oxidothiomorpholino)-pteridine and piperazineO ~Melting point: >240C (decomposition).
~3~
Example 10 7-Benzylamino-6-chloro-4-m~ lin 2-piperazino-,~
Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-morpholino-pteridine and piperazine.
Melting point: 195-197C (methanol/water).
Exa_E~
7-Benzylamino-6-chloro-4~ hiomorE~olino)-2-piperazino-pteridine Prepared analogously to Example 1 from 7-ben~ylamino-2,6-dichloro-4~ oxidothiomorpholino)-pteridine and piperazine.
Melting point: > 200C (decomposition).
6-Benzylthio-4,7-bis-(dimethylamin_)-2-piperazino-pteridine Prepared analogously to Example 2 from 6-chloro-4,7 bis-(dimethylamino)-2-piperazino-pteridine and benzylmercaptan.
Melting point: 150-152C.
Example 13 7-Benz lamino-6-methvlthio-4-(1-oxidothiomorpholi o)-Prepared analogously to Example 2 from 7-benzylamino-6-chloro-4~ oxidothiomorpholino)-2-piperazino~pteridine and methylmercaptan.
Melting point of the hydrochloride: 159-162C.
Example 14 4-Morpholino-7-(1-oxidothiomorphol_no)-2-piperazino-_-propylthio-pteridine Prepared analogously to Example 2 from 6~
chloro~~morpholino-7-(1-oxidothiomorpholino)-2-piperazino-pteridine and propylmercaptan.
~33~
Melting point: 12S-130C.
Exam~le 15 7-Benzylam1no~6-benz~thio-4-(l=oxidothiomorpholino~-2-piperazino-pteridine Prepared analogously to Example 2 from 7-benzylamino~6-chloro~4-(1-oxidothiomorpholino)-2-piperazino-pteridine and benzylmercaptan.
Melting point: ~ 160C (decomposition).
Example 16 6-Ethox~-2-piperazlno-4,7-bis-(thiomorpholino)-pteridine Prepared analogously to Example 3 from 6-chloro-2-piperazino-4,7-bis-(thiomorpholino)-pteridine and ethanol.
Meltin~ point: 147-151C.
Example 17 6-Benz~oxy-4,7-bis _dimethylamino)-2-piperazino-pteridine : Prepared analogously to Example 3 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl alcohol.
Melting point: 166-168C.
Example_18 6-Chloro-2-piperazino-4-dimethylamino-7-benzylamino-Prepared analogously to Exampie 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine.
Melting point: 134-137C.
~ le 19 6-Chloro-2-piperazino-4-thiomorpholino-7-benzylamino-idine Prepared analogously to Example 1 from 2,6--~233~
dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.
Melting point: 160-165C.
Example 20 6-Chloro-2-piperazino-4=thiomorpholino-7-dimethylamino-teridine Prepared analogously to Example 1 from 2,6-dichloro~4-thiomorpholino-7-dimethylamino-pteridine and piperazine.
Melting point: 205-207C.
Exam~le 21 7-Benzylamino-6-benzylthio-2~piperazino-4-thiomorpholino-~teridine Prepared analogously to Example 2 from 7-benzylamino-6-chloro-2-piperazino-4-thiomorpholino-pteridine and benzylmercaptan.
Melting point. from 70C (sintering).
~23~7~
~ he following pharmaceutical Examples illustrate the preparation of compositions according to the invention:
Example A
Coated tablets containin~ 4 mg of 6-benz~lthio-4,7-dimorphol_no-2-~perazino-~terid.ine : Composition:
1 tablet core contains:
: 10 Active substance (1) 4.0 mg : Lactose (2) 27.0 mg Corn starch (3) 14.5 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 0.5 m~
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 mixture is compressed to form tablet cores~
Tablet cores: 5 mm 0, biconvex, round ; Coatin~:
Usual sugar coating to give a finished weight of 70 mg.
Tablets containin~ 8_~ of 6-benzylthio-4,7-dimorpholino-30 2-piperazino-pteridine 1 tablet contains:
Active substance 8.0 mg Lactose 23.0 mg Corn starch 14.5 mg 35 Polyvinylpyrrolidone 4.0 mg Magnesium stearate 0.5 m~
50.0 mg 3L233~9 - ~o Preparation:
Analogously to the tablet cores.
Description of tablet:
Weight: 50 mg DiameterO 5 mm, biplanar, faceted on both sides Example C
Suppositories containing 25 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-~teridine 1 supposi~ory contains:
Active substance 0.025 g Hard fat (e.g. Witepsol~H 191.675 g and Witepsol~H 45)1.700 g Preparation:
The hard fat is melted. At 38C, the ground active substance is homogeneously dispexsed 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-2-piperazino pteridine 100 ml of suspension contains:
Active substance 0.16 g Carboxymethyl cellulose 0.1 g methyl p-hydroxybenzoate 0.05 g 30 propyl p-hydroxybenzoate 0.01 g Cane sugar 10.0 9 Glycerol 5.0 g 70% sorbitol 20.0 9 Flavouring 0.3 9 35 Distilled water ad 100.0 ml Pre~ration process:
The distilled water is heated to 70C. The p~ )R~
~23~
methyl and propyl p-hydroxybenzoates and the glycerol and carboxymethylcellulose 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.
Example E
Tablets containing 100 mg of 6-benz~lthio-4r7-dimorpho-lino-2-piperazino-pteridine Composition:
1 tablet contains:
15 Active substance lOOoO mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg Preparation ~ cess:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone.
After screening the moist mass ~2.0 mm mesh size) and drying in a rack dryer at 50C, the mixture is screened again (105 mm mesh) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet. 220 mg Diameter: 10 mm, biplanar, faceted on both sides with a dividing slot on one side.
Exam~e F
Hard gelatine capsules containin~ 150 mg_of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine 1 capsule contains:
~33~79 Active substance 150.0 mg Dried corn starch approx.180.0 mg Powdered lactose approx.87.0 mg Magnesium stearate 3.0 m~
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-4,7-dimorpholino-2-piperazino-~teridine 1 suppository contains:
20 Active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyethylene sorbitan 840.0 mg monostearate 2 000.0 mg Preparation:
After the suppository mass has been melted, the active substance is homogeneously d~tributed therein and the melt is poured into chilled moulds.
Example H
Suspension containin~ 50 m~_of 6-benzylthio-4,7-dimor~ollno-2-piperazino~pteridine ~er 5 ml 100 ml of suspension contains:
35 Active substance 1.0 g Na salt of carboxymethyl cellulose 0.1 g methyl p-hydroxybenzoate 0.05 g propyL p-hydroxybenzoate O.O:L g ~33 Cane sugar 10. a g Glycerol 5.0 g 70% sorbitol solution 20-.0 g Flavouring 0.3 g
The residue is taken up in about 70 ml of water and the reaction product precipitated is suction filtered, washed with water and dried at about 60C.
Yield: 2.6 g (93% of theory).
After reprecipitation from 0.1 N hydrochloric acid using ammonia and recrystallisation from e,thyl acetate/methanol (4:1), the compound melts at 148-151C.
Calculated:C 56.39H 6.02 N 23.91 S 6.84 Found: 56.61 6.27 23.40 6.44 , Example 4 6-Chloro 4-morphollno-7-(1-oxidothiomorpholino)-2--piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4-morpholino-7-(1-oxidothiomorpholino)-pteridine and piperazine.
Melting point: 225-227C (reprecipitation from 0.1 N HCl by means o~ ammonia).
~;~33~
Example 5 6-Chlo_o-4,7-bis-(l-oxldothiomor~olino)-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro-4,7-bis-(l-oxidothiomorpholino)-pteridine and piperazine.
Melting point: ~ 200C (decomposition)~
Example 6 6-Chloro-4,7-di~i~eridino-2-piperazino-pteridine Prepared analogously to Example 1 from 2,6-dichloro 4,7 dipiperidino-pteridine and piperazineO
Melting point~ decomposition at about 200C.
Example 7 6-Chloro-4,7-bis-(dimethylamino)-2-~iperazino-Eterldine Prepared analogously to Example l from 2,6-dichloro-4,7-bis ~dimethylamino)-pteridine and piperaæine.
20 Melting point: 130-134C.
Example 8 6-Chloro-2-pipe_azino-4,7-bis-(thiomor~holino)-pteridine Prepared analogously to Example l from 2,6-dichloro-4,7-bis-(thiomorpholino)-pteridine and piperazine.
Melting point: 194-196C (ethyl acetate).
Example 9 6-Chloro-7-morpholino-4-(l-oxidothiomor~holino)-2-pi~erazino-pteridine Prepared analogously to Example l from 2,6-dichloro-7 morpholino-4~(1-oxidothiomorpholino)-pteridine and piperazineO ~Melting point: >240C (decomposition).
~3~
Example 10 7-Benzylamino-6-chloro-4-m~ lin 2-piperazino-,~
Prepared analogously to Example 1 from 7-benzylamino-2,6-dichloro-4-morpholino-pteridine and piperazine.
Melting point: 195-197C (methanol/water).
Exa_E~
7-Benzylamino-6-chloro-4~ hiomorE~olino)-2-piperazino-pteridine Prepared analogously to Example 1 from 7-ben~ylamino-2,6-dichloro-4~ oxidothiomorpholino)-pteridine and piperazine.
Melting point: > 200C (decomposition).
6-Benzylthio-4,7-bis-(dimethylamin_)-2-piperazino-pteridine Prepared analogously to Example 2 from 6-chloro-4,7 bis-(dimethylamino)-2-piperazino-pteridine and benzylmercaptan.
Melting point: 150-152C.
Example 13 7-Benz lamino-6-methvlthio-4-(1-oxidothiomorpholi o)-Prepared analogously to Example 2 from 7-benzylamino-6-chloro-4~ oxidothiomorpholino)-2-piperazino~pteridine and methylmercaptan.
Melting point of the hydrochloride: 159-162C.
Example 14 4-Morpholino-7-(1-oxidothiomorphol_no)-2-piperazino-_-propylthio-pteridine Prepared analogously to Example 2 from 6~
chloro~~morpholino-7-(1-oxidothiomorpholino)-2-piperazino-pteridine and propylmercaptan.
~33~
Melting point: 12S-130C.
Exam~le 15 7-Benzylam1no~6-benz~thio-4-(l=oxidothiomorpholino~-2-piperazino-pteridine Prepared analogously to Example 2 from 7-benzylamino~6-chloro~4-(1-oxidothiomorpholino)-2-piperazino-pteridine and benzylmercaptan.
Melting point: ~ 160C (decomposition).
Example 16 6-Ethox~-2-piperazlno-4,7-bis-(thiomorpholino)-pteridine Prepared analogously to Example 3 from 6-chloro-2-piperazino-4,7-bis-(thiomorpholino)-pteridine and ethanol.
Meltin~ point: 147-151C.
Example 17 6-Benz~oxy-4,7-bis _dimethylamino)-2-piperazino-pteridine : Prepared analogously to Example 3 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl alcohol.
Melting point: 166-168C.
Example_18 6-Chloro-2-piperazino-4-dimethylamino-7-benzylamino-Prepared analogously to Exampie 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine.
Melting point: 134-137C.
~ le 19 6-Chloro-2-piperazino-4-thiomorpholino-7-benzylamino-idine Prepared analogously to Example 1 from 2,6--~233~
dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.
Melting point: 160-165C.
Example 20 6-Chloro-2-piperazino-4=thiomorpholino-7-dimethylamino-teridine Prepared analogously to Example 1 from 2,6-dichloro~4-thiomorpholino-7-dimethylamino-pteridine and piperazine.
Melting point: 205-207C.
Exam~le 21 7-Benzylamino-6-benzylthio-2~piperazino-4-thiomorpholino-~teridine Prepared analogously to Example 2 from 7-benzylamino-6-chloro-2-piperazino-4-thiomorpholino-pteridine and benzylmercaptan.
Melting point. from 70C (sintering).
~23~7~
~ he following pharmaceutical Examples illustrate the preparation of compositions according to the invention:
Example A
Coated tablets containin~ 4 mg of 6-benz~lthio-4,7-dimorphol_no-2-~perazino-~terid.ine : Composition:
1 tablet core contains:
: 10 Active substance (1) 4.0 mg : Lactose (2) 27.0 mg Corn starch (3) 14.5 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 0.5 m~
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 mixture is compressed to form tablet cores~
Tablet cores: 5 mm 0, biconvex, round ; Coatin~:
Usual sugar coating to give a finished weight of 70 mg.
Tablets containin~ 8_~ of 6-benzylthio-4,7-dimorpholino-30 2-piperazino-pteridine 1 tablet contains:
Active substance 8.0 mg Lactose 23.0 mg Corn starch 14.5 mg 35 Polyvinylpyrrolidone 4.0 mg Magnesium stearate 0.5 m~
50.0 mg 3L233~9 - ~o Preparation:
Analogously to the tablet cores.
Description of tablet:
Weight: 50 mg DiameterO 5 mm, biplanar, faceted on both sides Example C
Suppositories containing 25 mg of 6-benzylthio-4,7-dimorpholino-2-piperazino-~teridine 1 supposi~ory contains:
Active substance 0.025 g Hard fat (e.g. Witepsol~H 191.675 g and Witepsol~H 45)1.700 g Preparation:
The hard fat is melted. At 38C, the ground active substance is homogeneously dispexsed 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-2-piperazino pteridine 100 ml of suspension contains:
Active substance 0.16 g Carboxymethyl cellulose 0.1 g methyl p-hydroxybenzoate 0.05 g 30 propyl p-hydroxybenzoate 0.01 g Cane sugar 10.0 9 Glycerol 5.0 g 70% sorbitol 20.0 9 Flavouring 0.3 9 35 Distilled water ad 100.0 ml Pre~ration process:
The distilled water is heated to 70C. The p~ )R~
~23~
methyl and propyl p-hydroxybenzoates and the glycerol and carboxymethylcellulose 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.
Example E
Tablets containing 100 mg of 6-benz~lthio-4r7-dimorpho-lino-2-piperazino-pteridine Composition:
1 tablet contains:
15 Active substance lOOoO mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg Preparation ~ cess:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone.
After screening the moist mass ~2.0 mm mesh size) and drying in a rack dryer at 50C, the mixture is screened again (105 mm mesh) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet. 220 mg Diameter: 10 mm, biplanar, faceted on both sides with a dividing slot on one side.
Exam~e F
Hard gelatine capsules containin~ 150 mg_of 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine 1 capsule contains:
~33~79 Active substance 150.0 mg Dried corn starch approx.180.0 mg Powdered lactose approx.87.0 mg Magnesium stearate 3.0 m~
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-4,7-dimorpholino-2-piperazino-~teridine 1 suppository contains:
20 Active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyethylene sorbitan 840.0 mg monostearate 2 000.0 mg Preparation:
After the suppository mass has been melted, the active substance is homogeneously d~tributed therein and the melt is poured into chilled moulds.
Example H
Suspension containin~ 50 m~_of 6-benzylthio-4,7-dimor~ollno-2-piperazino~pteridine ~er 5 ml 100 ml of suspension contains:
35 Active substance 1.0 g Na salt of carboxymethyl cellulose 0.1 g methyl p-hydroxybenzoate 0.05 g propyL p-hydroxybenzoate O.O:L g ~33 Cane sugar 10. a g Glycerol 5.0 g 70% sorbitol solution 20-.0 g Flavouring 0.3 g
5 Distilled water ad 100 ml Pre~aration:
The distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates and the glycerol and sodium salt of carboxymethylcellulose 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 ml of suspension contains 50 mg of active substance.
Example I
Tablets containing 150 m~ of 6-benzylthio-4,7-dimorpho-lino-2-piperazino-pteridine Composition:
1 tablet contains:
25 Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Colloidal silica 10.0 mg Polyvinylpyrrolidone 10~0 mg 30 Magnesium stearate 1.0 m~
300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20~
aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granulate, dried at 45C, is again passed through ~ ~ ~ 3 the screen and mixed with the given quantity of magnesium stearate. Tablets are compressed f rom the mixture.
Weight of tablet: 300 mg Punch: 10 mm, flat Example K
Coated tablets containin~ 75 mg of 6~-benzylthio-4,7=dimorpholino-2-piperazino~pteridine 1 tablet core contains:
Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg 15 Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxy-propylmethylcellulose and half the stated quantity of magnesium stearate. In a tablet-making 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 shape.
Weight of core: 230 mg Punch: 9 mm, convex The tablet cores produced are coated with a film consisting essentially of hydroxypropylmethyl-cellulose. The finished film-coated tablets are gla~ed 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.
The distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates and the glycerol and sodium salt of carboxymethylcellulose 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 ml of suspension contains 50 mg of active substance.
Example I
Tablets containing 150 m~ of 6-benzylthio-4,7-dimorpho-lino-2-piperazino-pteridine Composition:
1 tablet contains:
25 Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Colloidal silica 10.0 mg Polyvinylpyrrolidone 10~0 mg 30 Magnesium stearate 1.0 m~
300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20~
aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granulate, dried at 45C, is again passed through ~ ~ ~ 3 the screen and mixed with the given quantity of magnesium stearate. Tablets are compressed f rom the mixture.
Weight of tablet: 300 mg Punch: 10 mm, flat Example K
Coated tablets containin~ 75 mg of 6~-benzylthio-4,7=dimorpholino-2-piperazino~pteridine 1 tablet core contains:
Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg 15 Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxy-propylmethylcellulose and half the stated quantity of magnesium stearate. In a tablet-making 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 shape.
Weight of core: 230 mg Punch: 9 mm, convex The tablet cores produced are coated with a film consisting essentially of hydroxypropylmethyl-cellulose. The finished film-coated tablets are gla~ed 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 (60)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula I
(I) wherein R1 represents a phenyl(C1-C3 alkyl)amino, (C1-C3 alkyl)-amino or di(C1-C3 alkyl)amino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 represents a di(C1-C3 alkyl)amino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R3 represents a halogen atom or an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, wherein the alkyl moiety may contain from 1 to 3 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(a) to prepare a compound of general formula I wherein R3 represents a halogen atom, reacting a compound of general formula II
wherein R1 and R2 are as defined above R3' represents a halogen atom and Z2 represents a nucleophilic leaving group, with a piperazine of general formula III
(III) wherein X represents a hydrogen atom of a hydrolytically removable protecting group, and subsequently, if necessary, splitting off the protecting group used; or (b) to prepare a compound of general formula I wherein R3 represents an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, reacting a compound of general formula IV
(IV) wherein :
R1 and R2 are as defined above and Z3 represents a nucleophilic leaving group, with a compound of general formula V
R3t ? H (V) wherein R3' represents an alkoxy or alkylmercapto group unsubstituted or 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;
and, if required, converting an obtained salt into a free base of formula I or converting an obtained compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
(I) wherein R1 represents a phenyl(C1-C3 alkyl)amino, (C1-C3 alkyl)-amino or di(C1-C3 alkyl)amino group, a piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 represents a di(C1-C3 alkyl)amino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R3 represents a halogen atom or an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, wherein the alkyl moiety may contain from 1 to 3 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(a) to prepare a compound of general formula I wherein R3 represents a halogen atom, reacting a compound of general formula II
wherein R1 and R2 are as defined above R3' represents a halogen atom and Z2 represents a nucleophilic leaving group, with a piperazine of general formula III
(III) wherein X represents a hydrogen atom of a hydrolytically removable protecting group, and subsequently, if necessary, splitting off the protecting group used; or (b) to prepare a compound of general formula I wherein R3 represents an alkoxy, alkylthio, phenylalkoxy or phenylalkylthio group, reacting a compound of general formula IV
(IV) wherein :
R1 and R2 are as defined above and Z3 represents a nucleophilic leaving group, with a compound of general formula V
R3t ? H (V) wherein R3' represents an alkoxy or alkylmercapto group unsubstituted or 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;
and, if required, converting an obtained salt into a free base of formula I or converting an obtained compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
2. A process as claimed in claim l, wherein R1 represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group, R2 represents a dimethylamino, piperidino, morpholino, thio-morpholino or 1-oxidothiomorpholino group and R3 represents a chlorine or bromine atom, an alkoxy or alkyl-thio group with 1 to 3 carbon atoms in the alkyl moiety, or a benzyloxy or benzylthio group.
3. A process as claimed in claim 1, wherein R1 and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R1 may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylthio group with 1 to 3 carbon atoms in the alkyl moiety or a benzyloxy or benzyl-thio group.
4. A process as. claimed in claim l, wherein R1 and R2 each represent a dimethylamino, morpholino or 1-oxidothiomorpholino group and R1 also represents a benzylamino group and R3 represents a chlorine atom or a methylthio or benzyl-thio group.
5. A process as claimed in claim 1, 2 or 3 which includes the step of converting an obtained compound of formula I into a pharmaceutically acceptable acid addition salt.
6. A process as claimed in claim 1, 2 or 3 which includes the step of converting an obtained compound of formula I into a salt with hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid.
7. A process as claimed in claim 1(a) wherein the nucleo-philic leaving group is a halogen atom.
8. A process as claimed in claim 1(a) wherein the reaction is carried out in a solvent.
9. A process as claimed in claim 1(a) wherein the reaction is carried out in a solvent selected from tetrahydrofuran, dioxan, benzene, toluene or dimethylglycol ether.
10. A process as claimed in claim 1(a), 7 or 9 wherein the reaction is carried out at a temperature between 50 and 150°C.
11. A process as claimed in claim 1(a), 7 or 9 wherein the reaction is carried out in a melt or is carried out in a solvent at the boiling temperature of the solvent used.
12. A process as claimed in claim 1(a), 7 or 9 wherein an acid-binding agent is used.
13. A process as claimed in claim 1(a), 7 or 9 wherein an acid-binding agent selected from sodium carbonate, triethylamine and pyridine is used.
14. A process as claimed in claim 1(a), 7 or 9 wherein the protecting group used is split off in the presence of an acid or a base.
15. A process as claimed in claim 1(a), 7 or 9 wherein the protecting group used is split off in the presence of an acid selected from hydrochloric and sulphuric acid or in the presence of a base selected from sodium hydroxide and potassium hydroxide.
16. A process as claimed in claim 1(a), 7 or 9 wherein the protecting group cleavage is effected in the presence of an acid or base and in the presence of an aqueous solvent.
17. A process as claimed in claim 1(a), 7 or 9 wherein the protecting group cleavage is effected in the presence of an acid or base and in the presence of methanol/water, ethanol/water or dioxan/water as solvent.
18. A process as claimed in claim 1(a), 7 or 9 wherein the protecting group cleavage is effected in the presence of an aqueous solvent at a temperature up to the boiling temperature of the solvent used.
19. A process as claimed in claim 1(b) wherein the nucleophilic leaving group is a halogen atom.
20. A process as claimed in claim 1(b) wherein the reaction is carried out in a solvent.
21. A process as claimed in claim 1(b) wherein the reaction is carried out in a solvent selected from dioxan, tetrahydrofuran, methanol, ethanol, propanol, isopropanol and benzyl alcohol.
22. A process as claimed in claim 1(b), 19 or 20 wherein the alkali metal salt of a compound of general formula V used is selected from sodium methoxide, sodium ethoxide or sodium benzyl-mercaptide.
23. A process as claimed in claim 1(b), 19 or 20 wherein the reaction is carried out at a temperature between 50 and 150°C.
24. A process as claimed in claim 1(b), 19 or 20 wherein the reaction is carried out in a solvent at the boiling temperature of the solvent used.
25. A compound of formula I as defined in claim 1 or a pharm-aceutically acceptable salt thereof.
26. A compound according to claim 25 wherein R1 represents a dimethylamino, benzylamino, piperidino, morpholino, thio-morpholino or 1-oxidothiomorpholino group; R2 represents a dimethyl-amino, piperidino, morpholino, thiomorpholino or 1-oxidothio-morpholino group and R3 represents a chlorine or bromine atom, an alkoxy or alkylthio group with 1 to 3 carbon atoms in the alkyl moiety, or a benzyloxy or benzylthio group.
27. A compound according to claim 25 wherein R1 and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R1 may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylthio group with 1 to 3 carbon atoms in the alkyl moiety or a benzyloxy or benzylthio group.
28. A compound according to claim 25 wherein R1 and R2 each represent a dimethylamino, morpholino or 1-oxidothiomorpholino group and R1 also represents a benzylamino group and R3 represents a chlorine atom or a methylthio or benzylthio group.
29. A process as claimed in claim 1 wherein R1 and R2 are both morpholino groups and R3 is a benzylthio group.
30. A process for preparing 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine which comprises reacting 6- chloro -4,7-dimorpholino-2-piperazino-pteridine with benzylmercaptan.
31. A process as claimed in claim 30 wherein the reaction is carried out at reflux temperature in dioxan and in the presence of sodium benzylmercaptide formed in situ.
32. A process as claimed in claim 30 wherein the 6-chloro-4,7-dimorpholino-2-piperazino-pteridine is obtained by refluxing 2,6-dichloro-4,7-dimorpholino-pteridine with anhydrous piperazine in dioxan.
33. The compound 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.
34. A process as claimed in claim 1 wherein R1 and R2 are both dimethylamino groups and R3 is a chlorine atom.
35. A process for preparing 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine which comprises reacting 2,6-dichloro-4,7-bis-(dimethylamino)-pteridine with piperazine.
36. A process as claimed in claim 35 wherein the reaction is carried out at reflux temperature in dioxan.
37. The compound 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine.
38. A process as claimed in claim 1 wherein R1 and R2 are both dimethylamino groups and R3 is a benzylthio group.
39. A process for preparing 6-benzylthio-4,7-bis-(dimethyl-amino)-2-piperazino-pteridine which comprises reacting 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine with benzylmercap-tan.
40. A process as claimed in claim 39 wherein the reaction is carried out at reflux temperature in dioxan and in the presence of sodium benzylmercaptide prepared in situ.
41. A process as claimed in claim 39 wherein the 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine is obtained by reacting 2,6-dichloro-4,7-bis-(dimethylamino)-pteridine with piperazine at reflux temperature in dioxan.
42. The compound 6-benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine.
43. A process as claimed in claim 1 wherein R1 is a benzyl-amino group, R2 is a 1-oxidothiomorpholino group and R3 is a methylthio group.
44. A process for preparing 7-benzylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino-pteridine which comprises reacting 7-benzylamino-6-chloro-4-(1-oxidothiomorpholino)-2-piperazino-pteridine with methyl mercaptan.
45. A process as claimed in claim 44 wherein the reaction is carried out at reflux temperature in dioxan and in the presence of sodium methylmercaptide formed in situ.
46. A process as claimed in claim 44 wherein the 7-benzyl-amino-6-chloro-4-(1-oxidothiomorpholino)-2-piperazino-pteridine is obtained by reacting 7-benzylamino-2,6-dichloro-4-(1-oxidothio-morpholino)-pteridino with piperazine.
47. The compound 7-benzylamino-6-methylthio-4-(1-oxidothio-morpholino)-2-piperazino-pteridine.
48. A process as claimed in claim 1 wherein R1 is a benzyl-amino group, R2 is a dimethylamino group and R3 is a chlorine atom.
49. A process for preparing 6-chloro-2-piperazino-4-dimethyl-amino-7-benzylamino-pteridine which comprises reacting 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine with piperazine.
50. A process as claimed in claim 49 wherein the reaction is carried out at reflux temperature in dioxan.
51. The compound 6-chloro-2-piperazino-4-dimethylamino-7-benzylamino-pteridine.
52. A pharmaceutical composition for antithrombotic or anti-metastatic use which comprises a compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent.
53. A composition according to claim 52 wherein in the compound of formula I R1 represents a dimethylamino, benzylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group; R2 represents a dimethylamino, piperidino, morpholino, thiomorpholino or l-oxidothiomorpholino group and R3 represents a chlorine or bromine atom, an alkoxy or alkylthio group with 1 to 3 carbon atoms in the alkyl moiety, or a benzyloxy or benzylthio group.
54. A composition according to claim 52 wherein in the compound of formula I R1 and R2, which may be the same or different, each represent a dimethylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino group and R1 may also represent a benzylamino group and R3 represents a chlorine atom, an alkoxy or alkylthio group with 1 to 3 carbon atoms in the alkyl moiety or a benzyloxy or benzylthio group.
55. A composition according to claim 52 wherein in the compound of formula I R1 and R2 each represent a dimethylamino, morpholino or 1-oxidothiomorpholino group and R1 also represents a benzylamino group and R3 represents a chlorine atom or a methyl-thio or benzylthio group.
56. A composition according to claim 52 which comprises 6-benzylthio-4,7-dimorpholino-2-piperazino-pteridine.
57. A composition according to claim 52 which comprises 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine.
58. A composition according to claim 52 which comprises 6-benzylthio-4,7-bis-(dimethylamino)-2-piperazino-pteridine.
59. A composition according to claim 52 which comprises 7-benzylamino-6-methylthio-4-(1-oxidothiomorpholino)-2-piperazino-pteridine.
60. A composition according to claim 52 which comprises 6-chloro-2-piperazino-4-dimethylamino-7-benzylamino-pteridine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3323932.0 | 1983-07-02 | ||
| DE19833323932 DE3323932A1 (en) | 1983-07-02 | 1983-07-02 | NEW 2-PIPERAZINO-PTERIDINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1233179A true CA1233179A (en) | 1988-02-23 |
Family
ID=6203017
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000457880A Expired CA1233179A (en) | 1983-07-02 | 1984-06-29 | 2-piperazino-pteridines, processes for the preparation thereof and pharmaceutical compositions containing these compounds |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0134922B1 (en) |
| JP (1) | JPS6025991A (en) |
| AT (1) | ATE39253T1 (en) |
| AU (1) | AU565105B2 (en) |
| CA (1) | CA1233179A (en) |
| DD (1) | DD229990A5 (en) |
| DE (2) | DE3323932A1 (en) |
| DK (1) | DK159113C (en) |
| ES (2) | ES533298A0 (en) |
| FI (1) | FI80454C (en) |
| GB (1) | GB2143232B (en) |
| HU (1) | HU190932B (en) |
| IL (1) | IL72265A (en) |
| NO (1) | NO160920C (en) |
| NZ (1) | NZ208725A (en) |
| PH (1) | PH22493A (en) |
| ZA (1) | ZA844968B (en) |
Cited By (5)
| 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 |
| US8877756B2 (en) | 2006-05-24 | 2014-11-04 | Boehringer Ingelheim International Gmbh | Substituted pteridines |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3445298A1 (en) * | 1984-12-12 | 1986-06-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW PTERIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF AS INTERMEDIATE PRODUCTS OR AS A MEDICINAL PRODUCT |
| DE3540952C2 (en) * | 1985-11-19 | 1997-08-14 | Thomae Gmbh Dr K | 2-Piperazino-pteridines, process for their preparation and medicaments containing these compounds |
| US7276506B2 (en) | 1998-12-28 | 2007-10-02 | 4 Aza Bioscience Nv | Immunosuppressive effects of pteridine derivatives |
| DE10202468A1 (en) * | 2002-01-23 | 2004-09-30 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Pteridine derivatives, process for their preparation and their use |
| AU2004267885A1 (en) * | 2003-08-29 | 2005-03-10 | 4 Aza Bioscience Nv | Immunosuppressive effects of pteridine derivatives |
| GB2407089A (en) * | 2003-10-17 | 2005-04-20 | 4 Aza Bioscience Nv | Pteridine derivatives |
| US20100234347A1 (en) * | 2006-05-24 | 2010-09-16 | Boehringer Ingelheim Internationl Gmbh | Substituted Pteridines substituted with a Four-Membered Heterocycle |
| WO2008003149A2 (en) * | 2006-07-06 | 2008-01-10 | Gilead Sciences , Inc. | Substituted pteridines for the treatment and prevention of viral infections |
| WO2008009079A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | Substituted pteridines useful for the treatment and prevention of viral infections |
| MD3097102T2 (en) | 2015-03-04 | 2018-02-28 | Gilead Sciences Inc | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-D]pyrimidine compounds |
| WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
| PT3507276T (en) | 2016-09-02 | 2022-01-11 | Gilead Sciences Inc | Toll like receptor modulator compounds |
| TWI751517B (en) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
| TW202210480A (en) | 2019-04-17 | 2022-03-16 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
| TW202115056A (en) | 2019-06-28 | 2021-04-16 | 美商基利科學股份有限公司 | Processes for preparing toll-like receptor modulator compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2940972A (en) * | 1957-06-27 | 1960-06-14 | Thomae Gmbh Dr K | Tri-and tetra-substituted pteridine derivatives |
| FR1352111A (en) * | 1962-01-25 | 1964-02-14 | Lumiere Lab | Triamino pteridines and their preparation |
-
1983
- 1983-07-02 DE DE19833323932 patent/DE3323932A1/en not_active Withdrawn
-
1984
- 1984-06-11 ES ES533298A patent/ES533298A0/en active Granted
- 1984-06-19 DE DE8484106993T patent/DE3475620D1/en not_active Expired
- 1984-06-19 AT AT84106993T patent/ATE39253T1/en not_active IP Right Cessation
- 1984-06-19 EP EP84106993A patent/EP0134922B1/en not_active Expired
- 1984-06-28 DK DK316284A patent/DK159113C/en not_active IP Right Cessation
- 1984-06-28 JP JP59132187A patent/JPS6025991A/en active Pending
- 1984-06-29 PH PH30906A patent/PH22493A/en unknown
- 1984-06-29 NO NO842631A patent/NO160920C/en unknown
- 1984-06-29 ZA ZA844968A patent/ZA844968B/en unknown
- 1984-06-29 IL IL72265A patent/IL72265A/en unknown
- 1984-06-29 DD DD84264739A patent/DD229990A5/en not_active IP Right Cessation
- 1984-06-29 FI FI842622A patent/FI80454C/en not_active IP Right Cessation
- 1984-06-29 CA CA000457880A patent/CA1233179A/en not_active Expired
- 1984-06-29 GB GB08416682A patent/GB2143232B/en not_active Expired
- 1984-06-29 NZ NZ208725A patent/NZ208725A/en unknown
- 1984-07-02 AU AU30092/84A patent/AU565105B2/en not_active Ceased
- 1984-07-02 HU HU842559A patent/HU190932B/en not_active IP Right Cessation
- 1984-11-20 ES ES537785A patent/ES537785A0/en active Granted
Cited By (5)
| 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 |
| US8877756B2 (en) | 2006-05-24 | 2014-11-04 | Boehringer Ingelheim International Gmbh | Substituted pteridines |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3009284A (en) | 1985-01-03 |
| ES8601205A1 (en) | 1985-10-16 |
| ES8503352A1 (en) | 1985-02-16 |
| DE3323932A1 (en) | 1985-01-10 |
| NO160920C (en) | 1989-06-14 |
| FI80454B (en) | 1990-02-28 |
| HUT34487A (en) | 1985-03-28 |
| GB2143232A (en) | 1985-02-06 |
| AU565105B2 (en) | 1987-09-03 |
| ATE39253T1 (en) | 1988-12-15 |
| DD229990A5 (en) | 1985-11-20 |
| PH22493A (en) | 1988-09-12 |
| DE3475620D1 (en) | 1989-01-19 |
| DK316284A (en) | 1985-01-03 |
| NO842631L (en) | 1985-01-03 |
| ES533298A0 (en) | 1985-02-16 |
| FI842622A0 (en) | 1984-06-29 |
| HU190932B (en) | 1986-12-28 |
| JPS6025991A (en) | 1985-02-08 |
| IL72265A (en) | 1987-08-31 |
| ZA844968B (en) | 1986-03-26 |
| DK316284D0 (en) | 1984-06-28 |
| FI842622A (en) | 1985-01-03 |
| EP0134922A1 (en) | 1985-03-27 |
| ES537785A0 (en) | 1985-10-16 |
| IL72265A0 (en) | 1984-10-31 |
| DK159113B (en) | 1990-09-03 |
| DK159113C (en) | 1991-02-18 |
| EP0134922B1 (en) | 1988-12-14 |
| GB2143232B (en) | 1986-11-05 |
| GB8416682D0 (en) | 1984-08-01 |
| NO160920B (en) | 1989-03-06 |
| FI80454C (en) | 1990-06-11 |
| NZ208725A (en) | 1988-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1233179A (en) | 2-piperazino-pteridines, processes for the preparation thereof and pharmaceutical compositions containing these compounds | |
| CA1252783A (en) | Pteridines, processes for preparing them and their use as intermediate products or as pharmaceutical compositions | |
| EP0637300B1 (en) | Antiproliferative quinazolines | |
| US5939422A (en) | Chemical compounds having PDE-IV inhibition activity | |
| Novinson et al. | 2-(Alkylthio)-1, 2, 4-triazolo [1, 5-a] pyrimidines as adenosine 3', 5'-monophosphate phosphodiesterase inhibitors with potential as new cardiovascular agents | |
| EP0674627A1 (en) | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors | |
| CA2471265C (en) | Pyrimidotriazines as phosphatase inhibitors | |
| US4560685A (en) | 2-Piperazino-pteridines useful as antithrombotics and antimetastatics | |
| US5447956A (en) | Treatment of leukemia with a imidazo carbamate | |
| US6166016A (en) | Amide derivatives | |
| US4714698A (en) | 8-alkylthio-2-piperazino-pyrimido[5,4-d]-pyrimidines | |
| US4528288A (en) | Substituted triazolo[1,5-c]pyrimidines | |
| CA1337813C (en) | 2-piperazino-pteridines, process for preparing them and pharmaceutical compositions containing these compounds | |
| GB2078214A (en) | Benzoguanamine derivatives | |
| US4100286A (en) | 2-(Substituted heterocyclic amine)benzoic acids | |
| US4728646A (en) | 2-(perhydro-1,4-diazino)-pyrimido[5,4-d]-pyrimidines and salts thereof | |
| Marsham et al. | Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series | |
| EP0121341B1 (en) | Triazolo(4,3-c)pyrimidines and triazolo(1,5-c)pyrimidines substituted by nitrogen-containing heterocyclic rings | |
| US4260612A (en) | Antiallergic nitrogen bridge-head compounds | |
| EP0040872A1 (en) | Pyrazolo-quinazoline derivatives and methods of producing such derivatives | |
| KR900006857B1 (en) | Highly soluble antibacterially active pyridobenzothiazines and its preparation | |
| CA1225645A (en) | Substituted 9h-8-oxo-pyrimido[2,1-f]purine-2,4- diones, process for their production and pharmaceutical compositions containing them | |
| GB2035316A (en) | 5,6,7,8-Tetrahydro-4(3H)- quinazolinone derivatives useful as spasmolytics | |
| FR2470130A2 (en) | Amino-pyrimido-isoquinolinone derivs. - useful as hypotensives, bronchodilators and antiallergic agents | |
| JPH058198B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |