Note: Descriptions are shown in the official language in which they were submitted.
~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)
R2
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
2 -
~3
-- 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
-- 4 --
R1 ~ N ~ ~ ~ ~ Z2
R ' N
3 R2
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
R2
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~
-- 7 --
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~
- 12 -
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.
C22H28N8 2
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~
- 16
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~
- 18 -
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~
- 21 -
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
-- 22 --
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
- 23
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
- 24 -
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.
