PTERIDINES, PROCEDE DE PREPARATION ET UTILISATION COMME PRODUIT INTERMEDIAIRE OU COMPOSE PHARMACEUTIQUE

PTERIDINES, PROCESSES FOR PREPARING THEM AND THEIR USE AS INTERMEDIATE PRODUCTS OR AS PHARMACEUTICAL COMPOSITIONS

Abrégé anglais

ABSTRACT
Pteridine Derivatives
New pteridines of formula
(I)
<IMG>
(wherein
R2 represents a piperazino or N-formyl-piperazino
group,
R4 represents a dialkylamino, phenylalkylamino,
N-alkyl-phenylalkylamino, pyrrolidino, piperidino,
morpholino, thiomorpholino, 1-oxidothiomorpholino,
thiazolidino or 1-oxidothiazolidino group,
R6 represents a hydrogen atom or an alkyl
or phenyl group, and
R7 represents an alkylamino, dialkylamino,
phenylalkylamino, N-alkyl-phenylalkylamino, piperidino,
morpholino, thiomorpholino, 1-oxidothiomorpholino
or piperazino group; wherein each alkyl moiety
in groups R4, R6 and R7 contains from 1 to 3 carbon
atoms; wherein, where R4 contains one or two C2-3
alkyl moieties, one or both of said C2-3 alkyl
moieties may be substituted by a hydroxy group
in the 2 or 3 position; and wherein, where R7 contains
one or two C2-3 alkyl moieties, one or both of
said C2-3 alkyl moieties may be substituted by
a hydroxy group in the 2 or 3 position) and the
acid addition salts thereof are disclosed. When
R2 represents an N-formyl-piperazino group, these
are valuable intermediate products for preparing

the pteridines of formula I in which R2 represents
a piperazino group, which have valuable pharmacological
properties, more particularly antithrombotic and
metastasis-inhibiting effects and an inhibiting
activity on tumour growth.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of formula I
<IMG> (I)
wherein
R2 represents a piperazino or N-formyl-piperazino
group,
R4 represents a dialkylamino,- phenylalkylamino, N-
alkylphenylalkylamino, pyrrolidino, piperidino, morpholino, thio-
morpholino, 1-oxidothiomorpholino, thiazolidino or 1-oxidothia-
zolidino group,
R6 represents a hydrogen atom or an alkyl or phenyl
group, and
R7 represents an alkylamino, dialkylamino, phenylalkyl-
amino, N-alkyl-phenylalkylaminol piperidino, morpholino, thio-
morpholino, 1-oxidothiomorpholino or piperazino group; wherein
each alkyl moiety in groups R4, R6 and R7 contains from 1 to 3 car-
bon atoms; wherein, where R4 contains one or two C2-3 alkyl
moieties, one or both of said C2-3 alkyl moieties may be substitut-
ed by a hydroxy group in the 2 or 3 position; and wherein, where
R7 contains one or two C2-3 alkyl moieties, one or both of said
C2-3 alkyl moieties may be substituted by a hydroxy group in the
2 or 3 position, or an acid addition salt thereof.
2. A compound as claimed in claim 1 wherein
- 40 -

R2 represents a piperazino group.
3. A compound as claimed in claim 1, wherein
R2 represents a piperazino group,
R4 represents a dimethylamino, N-methyl-2-hydroxyethyl-
amino, bis(2-hydroxyethyl)-amino, benzylamino, N-methyl-benzyl-
amino, pyrrolidino, piperidino, morpholino, thiomorpholio, 1-
oxidothiomorpholino, thiazolidino or 1-oxidothiazolidino group,
R6 represents a hydrogen atom or a methyl or phenyl
group, and
R7 represents a dimethylamino, N-methyl-2-hydroxy-
ethylamino, benzylamino, N-methyl-benzylamino, piperidino, morpho-
lino, thiomorpholino, 1-oxidothiomorpholino or piperazino group.
4. A compound as claimed in claim 1 or 2 wherein
R4 represents a pyrrolidino, piperidino, morpholino,
thiomorpholino, 1-oxidothiomorpholino or N-methyl-2-hydroxy-ethyl-
amino group, and
R7 represents a dimethylamino, benzylamino, N-methyl-
benzylamino, morpholino, thiomorpholino or 1-oxidothiomorpholino
group.
5. A compound as claimed in claim 1 or 2 wherein
R4 represents a dimethylamino, diethylamino, di-n-
propylamino, diisopropylamino, N-methylethylamino, N-ethyl-n-
propylamino, benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino,
N-n-propylbenzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-
phenylpropylamino, N-methyl-1-phenylethylamino, N-ethyl-2-phenyl-
ethylamino, N-ethyl-3-phenylpropylamino, bis(2-hydroxyethyl)-
- 41 -

amino, bis(2-hydroxy-n-propyl)-amino, bis-(3-hydroxy-n-propyl)-
amino, N-(2-hydroxyethyl)-2-hydroxy-n-propylamino, N-methyl-2-
hydroxyethylamino, N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-
n-propylamino, N-isopropyl-2-hydroxy-ethylamino, N-(2-hydroxyethyl)-
benzylamino, pyrrolidino, piperidino, morpholino, thiomorpholino,
1-oxidothiomorpholino, thiazolidino or 1-oxidothiazolidino group,
R6 represents a hydrogen atom or a methyl, ethyl, n-
propyl, isopropyl or phenyl group, and
R7 represents a methylamino, ethylamino, n-propylamino,
isopropylamino, dimethylamino, diethylamino, di-n-propylamino,
diisopropylamino, N-methylethylamino, N-ethyl-n-propylamino,
benzylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-n-propyl-
benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropy-
lamino, N-methyl-1-phenylethylamino, N-ethyl-2-phenylethylamino,
N-ethyl-3-phenylpropylamino, 2-hydroxyethylamino, 2-hydroxy-n-
propylamino, 3-hydroxy-n-propylamino, 2-hydroxyisopropylamino,
bis(2-hydroxyethyl)-amino, bis(2-hydroxy-n-propyl)-amino, bis
(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-2-hydroxy-n-propyl-
amino, N-methyl-2-hydroxyethylamino, N-ethyl-2-hydroxyethylamino,
N-methyl-2-hydroxy-n-propylamino, N-isopropyl-2-hydroxy-ethylamino,
N-(2-hydroxyethyl)-benzylamino, piperidino, morpholino, thiomorph-
olino, 1-oxidothiomorpholino, thiazolidino, 1-oxidothiazolidino or
piperazino group.
6. A compound as claimed in claim 1 wherein
R2 represents piperazino;
R4 represents morpholino, thiomorpholino, pyrrolidino
- 42 -

or (N-methyl-2'-hydroxy-ethylamino);
R6 represents hydrogen or phenyl; and
R7 represents dimethylamino, benzylamino, morpholino
or 1-oxidothiomorpholino.
7. A compound as claimed in claim 1, 2 or 3 in the form
of a physiologically acceptable salt thereof.
8. The compound 7-benzylamino-6-phenyl-2-piperazino-4-
thiomorpholino-pteridine or a physiologically acceptable salt
thereof.
9. A process for preparing a compound of formula I as
defined in claim 1 or an acid addition salt thereof, which process
comprises
a) reacting a compound of formula II
<IMG> (II)
wherein R4 and R6 are defined in claim 1;
one of the groups Z2 or Z7 represents a nucleophili-
cally exchangeable group; and the other group Z2 or Z7 has the
meanings given for R2 or R7 above or, if a compound of formula I
is to be prepared wherein the groups R2 and R7 have the same mean-
ing, it may also represent a nucleophilically exchangeable group
with an amine of formula III
H-X (III)
wherein X has the meanings given for R2 or R7 above or represents
- 43 -

a piperazino group protected by a hydrolytically removable pro-
tecting group and subsequently, if required, splitting off any
protecting group used; or
b) to prepare a compound of formula I wherein R4 re-
presents a 1-oxidothiomorpholino or 1-oxidothiazolidino group or
R7 represents a 1-oxidothiomorpholino group oxidizing a compound
of formula IV
<IMG> (IV)
wherein R2 and R6 are as defined in claim 1 and R4' and R7' have
the meanings given for R4 and R7 above with the proviso that R4'
must represent a thiomorpholino or thiazolidino group or R7' must
represent a thiomorpholino group; or
c) to prepare a compound of formula I wherein R2 repre-
sents a piperazino group deformylating a corresponding compound of
formula I wherein R2 represents a N-formyl-piperazino group; and
if required converting a compound of formula I obtained into an
acid addition salt thereof.
10. A process as claimed in claim 9 wherein each reaction
is carried out in a solvent.
11. A process as claimed in claim 9 wherein reaction step
(a) is carried out in the presence of an acid binding agent and a
solvent.
12. A process as claimed in claim 9 wherein reaction step
- 44 -

(a) is carried out with the subsequent splitting off of a protect-
ing group being effected by hydrolysis.
13. A process as claimed in claim 9 wherein in the com-
pound of formula II used in reaction step (a) one or each of Z2
and Z7 represents a halogen atoms.
14. A process as claimed in claim 10 wherein the oxidation
of reaction step (b) is carried out with one equivalent of an
oxidising agent and in the presence of a solvent.
15. A process as claimed in claim 9 wherein reaction step
(a) or (b) is carried out at a temperature of between 0 and 150°C.
16. A process according to claim 9 wherein the compound
of formula I, wherein R2 represents a N-formyl-piperazino group,
is obtained by a process according to claim 1(a) or claim 1(b).
17. A process according to claim 9 wherein a physiological-
ly acceptable acid addition salt of a compound of formula I
according to claim 1,in which R2 represents a piperazino group, is
prepared by reacting, if required, a compound of formula I
according to claim 1 with the acid of the addition salt.
18. A process as claimed in claim 9, 10 or 11 wherein
R2 represents piperazino,
R4 represents thiomorpholino,
R6 represents phenyl and
R7 represents benzylamino.
19. A process for preparing 7-benzylamino-6-phenyl-2-piper-
- 45 -

azino-4-thiomorpholino-pteridine which process comprises deformyl-
ating 7-benzylamino-2-(N-formyl-piperazino)-6-phenyl-4-thiomorpho-
lino-pteridine.
20. A process as claimed in claim 19 wherein the 7-benzyl-
amino-2-(N-formylpiperazino)-6-phenyl-4-thiomorpholino-pteridine
is obtained by reacting 7-chloro-2-(N-formylpiperazino)-6-phenyl-
4-thiomorpholino-pteridine with benzylamine.
21. A pharmaceutical composition which comprises a com-
pound of formula I as defined in claim 1, in which R2 represents a
piperazino group, or a physiologically acceptable acid addition
salt thereof, together with a suitable diluent or carrier.
22. A process for preparing a pharmaceutical composition
for use in treatment of the human or non-human animal body to
achieve an antithrombotic or a tumour-growth or metastasis-inhibit-
ing effect therein, which process comprises incorporating a com-
pound of formula I as defined in claim 1, in which R2 represents
a piperazino group, or a physiologically acceptable acid addition
salt thereof as active ingredient in the composition.
- 46 -

Description

~5~7~3
HS 149-365
PTE~IDINE DERIVATIVES
This invention relates to pteridine derivatives,
to their preparation, to their use as intermediates
and to pharmaceutical compositions containing them.
US-A-2940972 has already described substituted
pteridines which have valuable pharmacological
properties, namely a coronary dilating effect,
sedative~ anti-pyretic and analgesic effects.
It has now been found that certain new pteridines
substituted at the 2~ 4 and 7 positions, and optionally
also the 6 position, and their salts possess valuable
properties, either as compounds possessing pharmacolo-
gical properties, particularly anti-thrombotic
and metastasis- and tumour growth- inhibiting effects,
or as intermediates for the production of such
active compounds.
According to one aspect of the invention
we therefore provide compounds of formula I
R7 ~ N ~ ~ R2 (I)
R6 N ~ N
R4
(wherein R2 represents a piperazino or N-formyl
piperazino group,
R4 represents a~dialkylamino, phenylalkylamino,
N-alkyl-phenylalkylamino, pyrrolidino, piperidino,
morpholino, thiomorpholino, l-oxidothiomorpholino,
thiazolidino or l-oxidothiazolidino group,
R6 represents a hydrogen atom or an alk~l
or phenyl group,and

~25i~ 3
-- 2 --
R7 represents an alkylamino, dialkylamino,
phenylalkylamino, N-alkyl-phenylalkylamino, piperidino,
morpholino, thiomorpholino, l-oxidothiomorpholino
or piperazino group wherein each alkyl moiety
in groups R4, R6 and R7 contains from 1 ~o 3 carbon
atoms; wherein, where R~ contains one or two C2 3
alkyl moieties, one or both of said C2 3 alkyl
moieties may be substituted by a hydroxy group
in the 2 or 3 position; and wherein, where R7 contains
~0 one or two C2 3 alkyl moieties, one or both of
said C2_3 alkyl moieties may be subsituted by a
hydroxy group in the 2 or 3 position~ and acid
addition salts thereof.
When R~ represents a N-formyl-piperazino
group, the compounds of formula I and salts thereof
are valuable intermediate products for preparing
the pteridines of formula I wherein R2 represents
a piperazino group, and the acid a~dition salts
thereof, particularly the physiologically acceptable
acid addition salts with inorganic or organic acids,
which have valuable pharmacological properties,
more particularly antithrombotic effects, metastasis-
inhibiting effects and an ;nhibiting effect on
tumour growth.
2S The present invention thus relates to the
2-~N-formyl-piperazino)pteridines of formula I
above and the acid addition salts thereof, which
are suitable as intermediate ~roducts, and the
2-piperazino-pteridines of formula I above and
the acid addition salts thereof, particularly the
physiologically acceptable acid addition sal~s
thereof with inorganic or organic acids.
In the compounds of formula I or salts thereof:
R2 may for example represent a piperazino or N-
formyl-piperazino group,

~25i~ 3
R4 maY for example represent a dimethylamino, diethyl-
amino, di-n-propylamino, diisopropylamino, N-methyl-
ethylamino, N-ethyl-n-propylamino, benzylamino,
N-methyl-benzylamino, N-ethyl-benzylamino, N-n-
propyl-benzylamino, l-phenylethylamino~ 2-phenylethylamino~
3-phenylpropylamino, N-methyl-l-phenylethylamino,
N-ethyl-2-phenylethylamino, N-ethyl-3-phenylpropylamino,
bis(2-hydroxyethyl~-amino, bis(2-hydroxy-n-propyl)-
amino, bis(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-
2-hydroxy-n-propylamino, N-methyl-2-hydroxyethylamino,
N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-
n-propylamino, N-isopropyl-2-hydroxy-ethylamino,
N-(2-hydroxyethyl)-benzylamino, pyrrolidino, piperidino,
morpholino r thiomorpholino, l-oxidothiomorpholin
thiazolidino or l-oxidothiazolidino group,
R6 may for example represent a hydrogen atom or
a methyl, ethyl~ n-propyl, isopropyl or phenyl
group,and
R7 may ~or example represent a methylamino, ethylamino,
n-propylamino, isopropylamino, dimethylamino, diethyl-
amino, di-n-propylamino, diisopropylamino, N-methyl-
ethylamino, N-ethyl-n-propylamino, benzylamino,
N-methyl-benzylamino, N-ethyl-benzylamino, N-n-
propyl-benzylamino, l-phenylethylamino, 2-phenylethyl-
amino, 3-phenylpropylamino, N-methyl-l-phenylethyl-
amino, N-ethyl-2-phenylethylamino7 N-ethyl-3-phenyl-
propylamino, 2-hydroxyethylamino, 2-hydroxy-n-propyl-
amino, 3-hydroxy-n-propylamino, 2-hydroxyisopro~ylamino,
bis(2-hydroxyethyl)-amino, ~is(2-hydroxy-n-propyl)-
amino, bis(3-hydroxy-n-propyl)-amino, N-(2-hydroxyethyl)-
2-hvdroxy-n-propylamino, N-methyl-2-hydroxyethylamino,
N-ethyl-2-hydroxyethylamino, N-methyl-2-hydroxy-
n-propylamino, N-isopropyl-2-hydroxy-ethylamino,
N-(2-hydroxyethyl)-benzylamino, piperidino, morpholino,
thiomorpholino, l-oxidothiomorpholino, thiazolidino,
l-oxidothiazolidino or piperazino group.

33
Preferred compounds according to the invention
include the compounds of formula I wherein:
~ represents a piperazino group,
R4 represents a dimethylamino, N-methyl-2-
hydroxyethylamino, bis(2-hydroxyethyl)-amino, ben2yl-
amino, N-methyl-benzylamino, pyrrolidino, piperidino,
morpholino, thiomorpholino, l-oxidothiomorpholino,
thiazolidino or l-oxidothiazolidino group,
R6 represents a hydrogen atom or a methyl
or phenyl group, and
R7 represents a dimethylamino, N-methyl-
~hydroxyethylamino, benzylamino, N-methyl-benzylamino,
piperidino, morpholino, thiomorpholino, l-oxidothio-
morpholino or piperazino group,
and the acid addition salts thereof, parti.cu-
larly the physiologically acceptable acid addition
salts thereof.
However, the particularly preferred compounds
of the invention include the compounds of ~ormula
I wherein R2 and R6 are defined as hereinbefore,
R4 represents a pyrrolidino, piperidino,
morpholino, thiomorpholino, l-oxidothiomorpholino
or N-methyl-2-hydroxyethylamino group, and
R7 represents a dimethylamino, benzylamino,
N-methyl-benzylamino, morpholino, thiomorpholino
or l-oxidothiomorpholino group,
and the acid addition salts thereo, particularly
the physiologically acceptable acid addition salt~
thereof,

~252~
Accordin~ to a further aspect of the invention
we provide a process for preparing the compounds
of the invention, said process comprising at least
one of the followîng steps:
a) reacting a compound of ormula II
R6 X N ~
~wherein R4 and R6 are as hereinbefore defined,
one of the groups Z2 or Z7 represents a nucleophili-
cally exchangeable group tsuch as a halogen atom,
e.g. a chlorine or bromine atom~; and
:~ the other group Z2 or Z7 has the meanings given
for R2 or R7 hereinbefore or, if a compound of
formula I is to be prepared wherein the groups
R2 and R7 have the same meaning, it may also represent
lS a nucleophilically exchangeable group (such as
a halogen atom, e.g. a chlorine or bromine atom))
with an amine of formula II}
H - X (III)
(wherein X has the meanings given for R2 or R7
hereinbefore or represents a piperaæino group protected
by a hydrolytically removable protecting group),
and subsequently, if desired, splitting off any
protecting group used;
b) (to prepare compounds of ~ormula I wherein R~
2S represents a l-oxidothiomorpholino or l-oxidothia-
zolidino group and/or R7 represents a l-oxidothiomorph-
olino group) oxidizing a compound of formula IV

~ 2~ 3
R7~ N ~ N ~ 2 (IV)
R6 N/~ N
R4 l
(wherein R2 and R6 are as hereinbefore defined,
and R4' and R7' have the meanings given for R4
and R7 hereinbefore with the proviso that R4' must
represent a thiomorpholino or thiazolidino group
and/or R7' must represent a thiomorpholino group);
c) (to prepare compounds of formula I wherein
represents a piperazino group) deformylating
a corresponding compound of formula I wherein R2
represents a N-formyl-piperazino group; and if
required, converting a compound of formula I o~tained
~nto~an acid addition salt thereof.
The reaction of process step (a) is conveniently
carried out in a solvent such as tetrahydrofuran,
dioxan, benzene, toluene~ dimethylsulphoxide or
dlmethyl glycolether at temperatures of between
0 and 150C r preferably at temperatures between
ambient temperature and the boiling temperature
of the solvent used, or in a melt. It may be advan-
tageous to use an acid-binding agent such as sodium
carbonate, triethylamine or pyridine.
The splitting off of any protecting group
used, if necessary, may be carried out either hydroly-
tically in the presence of an acid such as hydrochloric
or sulphuric acid or in the presence of a base
such as sodium hydroxide or potassium hydroxide,
preferably in an aqueous solvent such as methanol/water,
ethanol /water or dioxan/water at temperatures
up to the boiling temperature of the solvent used.
Any protecting group used may also ~e split off

simultaneously during the reaction if an excess
of the amine of formula III is used.
The oxidation of process step (b) is preferably
carried ou~ in a solvent or mixture of solvents,
e.g. in water, water/pyridine, ace~one, glacial
acetic acid, methylene chloride, dioxan, dilute
sulphuric acid or ~rifluoroacetic acid, appropriately
at temperatur s of between 0 and 150C depending
on the oxidising agent used.
The oxidation is pre~erably carried out with
an equivalent of the oxidising agent used, e.g.
with hydrogen peroxide in glacial acetic acid,
trifluoroacetic acid or formic acid at 0 to 20C
or in acetone at 0 to 60C, with a peracid such
as performic acid in glacial acetic or trifluoroacetic
acid at 0 to 50C or with m-chloroperbenzoic acid
in methylene chloride or chloroform at 0 to 60C,
with sodium metaperiodate in dioxan or ethanol
at 80 to 100C, with bromine in glacial acetic
acid or aqueous acetic acid, with N-bromosuccinimide
in ethanol, with iodobenzodichloride in aqueous
pyridine at 0 to 50C, with nitric acid in glacial
acetic acid at 0 to 20C and with chromic acid
in glacial acetic acid or in acetone at 0 to 20C.
The compounds obtained according to the invention
can be converted into the acid addition salts thereof,
particularly the physiologically acceptable salts
thereof with inorganic or organic acids. Examples
of suitable acids include hydrochloric, hydrobromic;
sulphuric, phosphoric, lactic, citric, tartaric,
succinic, maleic and fumaric acid.
The compounds of formulae II to IV used
as starting materials are, for the most part, already
known or may be obtained by the process described
in US-A-2940972 (see Examples A tv D~.
As already mentioned hereinbefore, the compounds
of formula I wherein R2 represents a piperazino

~ 2S2~&~3
-- 8 --
group and the acid addition salts thereof, particularly
the physiologically acceptahle acid addition salts
thereof with inorganic or organic acids, have valuable
pharmacological properties, particularly antithrombotic
and metastasis-inhibiting effects and an inhibiting
effect on phos~hodies~erase and tumour growth.
For example, the following compounds:
A = 4,7-dimorpholino-6-phenyl-2-piperazino-pteridine,
B = 4-morpholino-7-(1-oxidothiomorpholino)-2-piperazino-
6-phenyl-pteridine,
C = 7-benzylamino-6-phenyl-2-piperazino-4-thiomorpholino-
pteridine,
D = 7-dimethylamino-6-phenyl-2-piperazino-4-pyrrolidino-
pteridine, and
E = 7-benzylamino-4-(N-methyl-2'-hydroxyethylamino)-
2~piperazino-pteridine
were investigated for their inhibiting effect on
phosphodiesterase (PDE) of tumour cells and of
human thrombocytes _ vitro using the method described
by Pooh et al., in the following manner (see Naunyn-
Schmiedebergs Arch. Pharmak. 268, 272 291 ~1971)):
a) Obtaining the enzyme:
~ he phosphodiesterase was obtained from B16
melanoma tissue from mice by centrifuging the homogenised
tissue at 5,000 x g (15 minutes at 4C). The tissue
was homogenised by repeated freezing and thawing
and homogenisation according to Potter Elvehjem
or by using ultrasound. The homogenised supernatant
containing the PDE was divided into batches and
deep frozen at -25C.

~2~ 3
g
Phosphodiesterase was obtained from human
thrombocytes in the same way.
b) Determinin~ the PDE inhibition (PDE assay):
The PDE inhibition caused by the test substances
were determined using 1 mcmol/l of 3H-cAMP as substrate.
The PDE inhibition was determined by measuring
the degradation of the subs~ance 3H-cAMP to form
3H-AMP by comparison with a control without any
test substance.
The 3H-AMP formed was separated from the
remaining 3H-cAMP by precipitation using zinc sulphate
and barium hydroxide.
The IC50, namely the concentration which
inhibits the PDE activity by 50~, was calculated
by linear regression analysis.
.
PDE Inhibition (IC50 in mcmol/l)
Substance Thrombocytes ~16 Tumour Cells
A 0.54 4.3
B 2.2 3.1
C 0.5 0.096
D 3.6 0.78
E 3.7 8.3
25 _ _ _ _
Acute toxicity
The approximate acute toxicity of the test
substances was determined, as a guide, on groups
of 10 mice after oral administration of a single
dose (observation period: 14 days):

~5i27~3
-- 10 --
Substance Approximate acute toxicity
A > 250 mg 10 out of 5 animals died)
C ~ 250 mg (0 out of 5 animals died)
D > 250 mg (0 out of 5 animals died)
E ~ 250 mg (0 out of 5 animals died)
The new compounds of formula I according
to the invention wherein R2 represents a piperazino
! group and the physiologically acceptable acid addition
salts thereof may be suitable, in view of their
above-mentioned pharmacological properties, for
the prevention of thromboembolic diseases such
as coronary infarct, cerebral infarct, so-called
transient ischaemic attacks, amaurosis fugax, and
to prevent arteriosclerosis, and for the prevention
of metastasis and for inhibiting tumour growth.
According to a further aspect of the present
invention we therefore provide a method of treatment
of the human or non-human animal body to achieve
an anti-thrombotic or a tumour growth- or metastasis-
inhibiting effect therein, said method comprising
administering to said body a compound of formula
I ~wherein R2 represents a piperazino group) or
a physiologically acceptable acid additîon salt
thereof.
According to a still further aspect o~ the
invention we provide the use of a compound of formula
I (wherein R2 represents a piperazino group) or
a physiologically acceptable acid addition salt
thereof for the manufacture of a therapeutic agent
for use in a method of treatment of the human or
non-human animal body to achieve an anti-thrombotic
or a tumour growth- or metastasis-inhibiting effect
therein.

~L25~7133
The dosage required in order to achieve these
effects is conveniently from Ool to 4 mg/kg of
body weight, preferably 0.2 to 3 mg/kg of body
weight, 2 to 4 times a day. For this, the com~ounds
of formula I (wherein R2 represents a piperazino
group) or the physiologically acceptable acid a~dition
salts thereof, optionally together with other active
substances, may conveniently be combined with one
or more inert conventional carriers and/or diluents.
According to another aspect of the invention
we therefore provide a pharmaceutical composition
comprising a compound of formula I (wherein R2
represents a piperaæino group) or a physiologically
acceptable acid addition salt thereof together
1~ with at least one pharmaceutical carrier or diluent.
~ he carrier or diluent may for example
be selected from corn starch, lactose, glucose,
microcrystalline cellulose, magnesium stearate,
polyvinyl pyrrolidone, citric acid, tartaric acid,
water, water/ethanol, water/glycerol, water/sorbitol,
non-ionic surfactants such as fatty acid esters
o polyoxyethylene, water-polyethylene glycol,
propylene glycol, cetylstearyl alcohol, carboxymethyl
cellulose or fatty substances such as hard fat
2~ or suitable mixtures thereof, and the pharmaceutical
compositions may conveniently be in this form of
conventional galenic preparations such as plain
or coated tablets, capsules, powders, suspensions,
drops, ampoules, syrups or suppos;tories.
According to a still further aspect of the
invention we provide the use of a compound of formula
I (wherein R2 represents a piperazino groupt or
a physiologically acceptabIe acid addition salt
thereof for the manufacture of a therapeutic agent
for use in a method of treatment of the human or
non-human animal body to achieve an anti-thrombotic
or a tumour growth- or metastasis-inhibiting effect
therein.

~25Z~33
- 12 -
~ he Examples which follow are provided to
illustrate the invention without serving to restrict
the scope of protection sought therefore:
S
:
:::
.
.
... . . . . ..

~2~ 27133
- 13 -
~xample A
2,7-Dichloro-4-morpholino-~teridine
7.n3 g tO.03 mol) of 2,4,7-trichloro-pteridine
are dissolved in 100 ml of chloroform and at 5C
mixed with a solution of 3.0 g (0.03 mol) of potassium
hydrogen carbonate in 50 ml of water. Then 2.62 g
(0.03 mol) of morpholine in 50 ml of chloroform
are added dropwise and the mixture is stirred for
45 minutes at ambient ~emperature. The organic
phase is then separated off, dried over sodium
sulphate and concentrated in vacuo. ~he residue
is recrystallised from ethanol.
Yield: 7.4 g S86~ of theory),
M.p.: 187-188C
The following compounds are obtained analogously
to Example A:
2,7-Dichloro-4-piperidino-pteridine
Yield: 67% of theory,
M.p.: 152-154C (ethanol)
2,7-Dichloro-4-benzylamino-pteridine
Yield: 75% of theory,
M.p.: 150-152C (methanol)
2,7-Dichloro-4-(1-oxidothiomorpholino)-pteridine
Yield: 65~ of theory,
M.p.: 230-235C
2,7-Dichloro-4-(N-methyl-2'-hydroxyethylamino)-pteridine
Yield: 74~ of theory,
M.p.: 178-180C
2,7-Dichloro-4-diethanolamino-pteridine
Yield: 71% of theory,
M.p.: 173-174C ~ethanol)

~25~
- 14 -
2,7-Dichloro-6-methyl-7-morpholino-pteridine
Yield: 73% of theory,
M.p.: 230-232C (ethanol)
Example B
2,7-Dichloro-6-phenyl-4-thiomorpholino-pteridine
35.5 g ~0.114 mol) of 2,4,7-trichloro-6-phenyl-
pteridine are dissolved in 500 ml of acetone and
mixed with 11.5 9 (0.13 mol) of sodium hydrogen
carbonate in 120 ml of water. ~hen a solution of
11.8 9 (0.114 mol) of thiomorpholine is added and
the resulting mixture is stirred for 45 minutes
at ambient temperature. This solution is poured
into 2 litres of water, the precipitate obtained
is collected and recrystallised from ethylene chloride.
Yield: 36 g (84~ of theory),
M.p.- 225-227C
~ he following compounds are obtained analogously
to Example B:
2,7-Dichloro-4-(1-oxidothiomorpholino)-6-phenyl-
pteridine
Yield: 88~ of theory,
M.p.: 222-224C
2,7-Dichloro-4-morpholino-6-phenyl-pteridine
Yleld: 78~ of theory,
M.p.: 198-201C
2,7-Dichloro-6-phenyl-4-piperidino-pteridine
Yield: 6q~ of theory,
M.p.: 168-170C ~ethyl acetate)
2,7-Dichloro-4-dimethylamino-6-phenyl-pteridine
Yield: 77% of theory,
M.p.: 236-238C (ethylene chloride)

~2527~3
- 15 -
2,7-Dichloro-4-(N-methyl-2'-hydroxyethylamino)-6-
phenyl-pteridine
Yield: 76~ of theory,
M.p.: 162-164C (ethanol)
2,7-~ichloro-4-(N-benzyl-methylamino~-6-phenyl-pteridine
Yield: 59% of theory,
M.p.: 141-143C (ethanol/dioxan~
2,7-Dichloro-6-phenyl-4-pyrrolidino-pteridine
Yield: 81~ of theory,
1.0 M.p.: 199-200C (ethyl acetate~
2,7-Dichloro-6-phenyl-4-thiazolidino-pteridine
Yield: 82~ of theory,
M.p.: 169-171C (ethyl acetate~
Example C
; 7-Chloro-2-(N-formylpip-eraz-in-o----6-phenyl-4-thiomorpholin
pterid_ne
5.S g (0.048 mol) of N-formyl-piperazine in
10 ml of dioxan is added to a solution of 7.6 g
(0.02 mol) of 2,7-dichloro-Ç-phenyl-4-thiomorpholino-
pteridine in 100 ml of dioxan and the mixture is
stirred for 1 hour at 40C. The reaction mixture
is then added to 600 ml of water, the precipitate
is suction filtered and decocted with ethyl acetate.
Yield: 88% of theory,
M.p.: 223-226C
The following compounds are obtained analogously
to Example C:
7-Chloro-4-(N-_ormylpiperazino~-4-(1-oxidothiomorpholino)-
6-phenyl-pteridine
Yield: 90% of theory,
M.p.: 230C (decomposition)

~25~ 3
- 16 -
7-Chloro-2-(N-formylpiperazino)-~-morpholino-6-phenyl-
pteri~ine
Yield: 90% of theory,
M.p.: 247C (decomposition)
7-Chloro-2-(N-formylpiperazino)-6-phenyl-4-piperidino-
pteridine
Yield: 66% of theory,
M.p.: 210-213C (ethyl acetate)
7-Chloro-4-dimethylamino-2-(N-formylpiperazino)-
6-phenyl-pteridine
Yield: 89% of theory,
M.p.: 232-234C (ethyl acetate)
7-Chloro-2-(N-formylpiperazino)-4-(N-methyl-2'-
hydroxyethylamino)-6-phenyl-pteridine
Yield: 86% of theory,
M.p.: sinters from 170C
7-Chloro-2-~N-formylpiperazino!-4-(N-methyl-benzylamino)-
6-phenyl-pteridine
Yield: 63% of theory,
M.p.: 143-145C (ethyl acetate)
7-Chloro-2-(N-formylpiperazino)-6-phenyl~4-pyrrolidino-
pteridine
Yield: 60% of theory,
M.p.~ 210C (decomposition)
7-Chloro-2-(N-formylpiperazino)-6-phenyl-4-thiazOlidinO-
pteridine
Yield: 82~ of theory,
M.p.: 180-190C (ethyl acetate)

~252'71~3
- ]7
Example D
2-Chloro-4,7-dimorpholino-pteridine
7.4 g (0.025 mol) of 2,7-dichloro-4-morpholino-
pteridine are dissolved in 150 ml of methylene
chloride and stirred wi~h 4.4 g ro.o5 mol) of morpholine
for 15 minutes at 40C. The mixture is then left
to cool, mixed with 200 ml of water, the organic
phase is separated off, dried over sodium sulphate
and concentrated by evaporation in vacuo. The
residue is recrystallised from ethanol.
Yield: 57% of theory,
M.p.: 253-255C
The following compounds are obtained analogously
to ~xample D:
7-Benzylamino-2-chloro-4-piperidino-pteridine
Yield: 94~ of theory/
M.p.: 220-222C ~dioxan)
4-Benzylamino-2-chloro-7-(1-oxidothiomorpholino~-
pteridine
~0 Yield: 45% of theory,
M.p.: 264-265C (ethanol)
7-Benzylamino-2-chloro-4-(1-oxidothiomorpholino)-
pteridine
Yield: 65% of theory,
M.p.: 239-240C (dioxan/ethanol)
2-chloro-4-(N-methyl-2'-hydroxyethylamino)-7-morpholino-
pteridine
Yield: 74% of theory,
M.p.: 190-192C
7-Benzylamino-2-chloro-4-(N-methyl-2'-hydroxyethylamino)-
pteridine

~25~7~3
- 18 -
Yield: 66~ of theory,
M.p.: 169-170C
2-Chloro-4-(N-methyl-2'-hyaroxyethylamino3-7-thiomorpholino-
pteridine
Yield: 80% of theory,
M.p.: 214-215C
7-BPnzylamino-2-chloro-4-diethanolamino-pteridine
Yield: 79~ of theory,
M.p. 188-189C (dioxan)
2-Chloro-4-diethanolamino-7-morpholino-p~eridine
Yield: 74~ of theory,
M.p.: 197-199C (ethanol)
2~Chloro-6~me~hyl-4,7-dimorpholino-pteridine
Yield: 29% of theory,
M.p.: 195-200C
2-Chloro-6-methyl-4-morpholino-7-thiomorpholino-
pteridine
Yield: 27% of theory,
M.p.: ~50-155C

~.252~33
-- 19 --
Example 1
4,7-Dimorpholino-2-piperazino-pteridine
4.2 g (0.0125 mol~ of 2-chloro-4,7-dimorpholino-
pteridine are dissolved in 200 ml of dimethylsulphoxide
and stirred with a solution of 10.8 g (0.125 mol)
of anhydrous piperazine for 1 hour at ambient temperature.
Then 1 litre of water is added and the mixture
is extracted twice with 100 ml of methylene chloride.
The organic phases are dried over sodium sulphate
and concentrated by centrifuging. The residue
is washed with ether.
Yield: 85~ of theory,
M.p.: 257-259C (decomposition)
Calculated: C 55.94 H 6.78 N 24.00
Found: 56.~6 6~90 23.60
~max (ethanol): 380, 279, 248 nm
Example 2
7-Benzylamino-2-piperazino-4-pi~eridino pteridine
5.3 g (0.015 mol) o~ 7-benzylamino-2-chloro-
4-piperidino-pteridine are dissolved in 250 ml
of chloroform and refluxed with a solution of 10.3 g
(0.12 mol~ o~ ~iperazine. After 2 hours the mixture
is extracted with 200 ml of water and the organic
phase is dried over sodium sulphate and concentrated
by evaporation in vacuo. The residue is recrystallised
from dioxan.
Yield: 79% of theory,
M.p.: 18S-188C
Calculated: C 65.32 H 6.98 N 27.70
Found: 6S.21 7.35 27.46
~max (ethanol): 370, 280, 242 nm
Example 3
4-Benzylamino-7-(l-oxidothiomorpholino~-2-piperazino-
pteridine
Prepared analoqously to Example 2 from 4-

~25Z7~3
- 20 -
benzylamino-2-chloro-7-(1-oxidothiomorpholino)-
pteridine and piperazine.
Yield: 85% of theory,
M.p.: 190-192C (methanol)
Calculated: C 57.51 H 5.98 N 25.55 S 7.31
Found: 57.35 6.12 25.29 7.24
~Max (ethanol): 375, 275, 247 nm
Example 4
7-Benzylamino-4-(1-ox _ thiomorpholino)-2-piperazino-
pteridine
Prepared analogously to Example 2 from 7-
benzylamino-2-chloro-4-(1-oxidothiomorpholino~-
pteridine and piperazine.
Yield: 90% of theory,
M.p.: 259-261C (methanol)
Calculated: C 57052 H 5 48 N 25.-55 S 7.31
Found: 57.46 5.84 25.60 7.66
~max (ethanol): 375, 286, 247 nm
Example 5
4-(N-Methyl-2'-hydroxyethylamino~-7-mor~holino-
2-piperazino-~teridine
Prepared analogously to Example 2 from 2-
chloro-4-(N-methyl-2'-hydroxyethylamino~-7-morpholino-
pteridine and piperazine.
Y;eld: 78~ o~ theory,
M.p. 172-174C
Calculated: C 54.53 H 7.00 N 29.93
Found: 54.~R 7.40 29.64
~max (ethanol): 384, 278, 247 nm
Example 6
7-Benzylamino-_-(N-methyl-2'-hydroxyet~ylamino)-
2-piperazino-pteridine
Prepared analogously to Example 2 from 7-
benzylamino-2-chloro-4-(N-methyl-2'-hydroxyethylamino)-
pteridine and piperazine.

~2~ 33
2~ -
Yield: 70~ of theory,
M.p.: 220-222C
Calculated: C 60.84 H 6.64 N 28.41
Found: 61.03 6.45 28.12
S ~max (ethanol): 372, 277, 243 nm
Example 7
4-(N-Methyl-2'-hydroxyethylamino)-2-piperazino-
7-thiomor~holino-pteridine
Prepared analogously to Example 2 from 2-
chloro-4-(N-methyl-2'-hydroxye~hylamino)-7-thiomorpholino-
; pteridine and piperazine.
Yield: 65% of theory,
M.p.: 175-177C
Calculated: C 52.28 ~ 6.71 N 28.70 S 8.21
Found: 52006 6.44 28.42 8.35
~max tethanol): 384, 278, 247 nm
Example 8
7-Benzylamino-4-diethanolamino-2-piperazino-pteridine
Prepared analogously to Exam~le 2 from 7-
benzylamino-2-chloro-4-die~hanolamino-pteridine
and piperazine.
Yield: 76% of theory,
M.p.: 203-208~C
Calculated: C 59.42 H 6.65 N 26.40
Found: 59.24 6.76 26.24
~max (ethanol): 372, 278, 243 nm
Example 9
4-Diethanolamino-7-morpholino-2-piperaæino pteridine
Prepared analogously to Example 2 from 2-
chloro-4-diethanolamino-7-morpholino-pteridine
and piperazine.
~5 Yield: 62% of theory,
M.p.: 187-195C
Calculated: C 53.46 H 6.98 N 27.70

~L~S~3
- 22 -
Found: 53.11 6.94 27.53
~max (ethanol): 382, 278, 247 nm
Example 10
6-Methyl-4,7-dimorpholino-2-piperazino-pteridine
Prepared analogously to Example 2 from 2-
chloro-6-methyl-4,7-dimorpholino-pteridine and
piperazine.
Yield 66% o theory,
M.p.: 180-185C
Calculated: C 56.98 H 7.05 N 27.98
Found: 56.78 6.78 27.70
lmax (ethanol): 3R2, 279, 248 nm
Example 11
6-Methyl-4-morpholino-2-piperazino-7-thiomorpholino-
pteridine
Prepared analogously to Example 2 from 2-
; chloro-6-methyl-4-morpholino-7-thiomorpholino-pteridine
and piperazine.
Yield: 58% of theory,
M.p.: 185-188C
Calculated: C 54.77 H 6.78 N 26.90 S 7.70
Found: 54.99 7.05 26.69 7.93
~max (ethanol): 382, 280, 247 nm
Example 12
4-(N-Methyl-2'-hydroxyethylamino)-7-(1-oxidothio-
morpholino)-2-piperazino-pteridine
2.92 g of 4-(N-methyl-2'-hydroxyethylamino)-
7-thiomorpholino-2-piperazino-pteridine are dissolved
in 50 ml of methylene chloride and stirred with
a solution of 1.72 g of m~chloroperbenzoic acid
for 2 hours at ambient temperature. The mixture
is then concentrated by centrifuging and the residue
is washed with ether. The residue is dissolved
in a little water, made alkaline with 2N sodium

g~ 3
- 23 -
hydroxide solution and then extracted with methylene
chloride. The organic phases are dried and concentrated
by centrifuging.
Yield: l.l g (36% of theory),
M.p.: 223-226C
Calculated: C 50.23 H 6.45 S 7.88
Found: 49.93 6.42 ~.03
~max (ethanol): 386, 278, 245 nm
10 Example 13
7-Benzylamino-2-(N-formylpiperazino~-6-phenyl-4-
thiomorpholino-pteridine
3.2 g (7 mmol) of 7-chloro-2-(N-formylpiperazino)-
6-phenyl-4-thiomorpholino~pteridine are refluxed
with 2.2 g 121 mmol) of benzylamine in 15 ml of
dioxan. After 3 hours the solvent is drawn off
in vacuo and the oily residue is poured into 100 ml
of water. The product precipitated is collected,
dried and chromatographed over a short silica gel
column with ethyl acetate/me~hanol (15~1). The
substance is then recrystallised from ethyl acetate.
Yield: 80~ of theory,
M.p.: 21~-221C
The following compounds are obtained analogously
to Example 13:
2-(N-Formylpiperazino)-7-(N-methyl-2'-hydroxyethylamino)-
6-phenyl-4-thiomorphQlino-pteridine
Yield: 55~ of theory,
M.p.: sintexs from 130C (ethyl acetate)
2-(N-Formylpiperazino)-4-morpholino-7-(1-oxidothio-
morpholino)-6-phenyl-pteridine
Yield: 50% of theory,
M.p.: 250-252C (water)

~252~3
- 24 -
2-(N-Formylpiperazino)-4-(N-methyl-2'-hydroxyethylamino)-
7-morpholino-6-phenyl-pteriaine
Yield: 80~ of theory,
M.p.: 165-175C
2-(N-Formylpiperazino~-7-(N-methyl-benzylamino)-
4-(N-methyl-2'-hydroxy-ethylamino)-6-phenyl-pteridine
Yield: 80~ of theory,
M.p.: 135-155C
2-(N-Formylpiperazino~-4-(N-methyl-2'-hydroxyethylamino~-
7-thiomorpholino-6-phenyl-pteridine
Yield: 80~ of theory,
M.p.: sinters from 155C
4,7-Di-(N-methyl-benzylamino)-2-(N-formylpiperazino)-
6-phenyl-pteridine
Yield: 50% of theor~,
M.p.: 50-70C
7-Dimethylamino-2-(N-formylpiperazino)-4-(N-methyl-
benzylamino~-6-phenyl-pteridine
Yield: 90% of theory,
M.p.: sinters from 90C
2-(N-Formylpiperazino)-4-(N-methyl-benzylamino)-
7-morpholino-6-phenyl-pteridine
Yield: 80% of theory,
M.p.: sinters from 40C
Example 14
7-E~enzylamino-6-phenYl-2 piperazino-4-thiomorPholino-
pteridine
1.58 g (3 mmol) of 7-benzylamino-2-(N-formyl-
piperazlno)-6-phenyl-4-thiomorpholino-pteridine
are refluxed with 15 ml of 10% hydro~hloric acid
for 30 minutes~ After ~ooling, the solution is

~2~ 7~33
- ~5
mixed with aqueous potassium carbonate solution
and the product is extracted with chloroform.
The or~anic phase is concentrated by e~aporation
in vacuo and the produc~ is chromatographed over
a silica gel column with methanol/conc. ammonia
80:l.
Yield: 0O8 g (54% of theory),
M.p.: 115-130C
Calculated~ C 65.03 H 6.06 N 22.47
Found: 65.20 6.22 22.07
~max (ethanol): 386, 292, 248 nm
Example 15
7-(N-Methyl-2'-hydroxyethylamino)-6-phenyl-2-piperazino-
4-thiomorpholino-Pteridine
Prepared from 2-(N-formylpiperazino)-7-~N-
methyl-2'-hydroxyethylamino)-6-phenyl-4-thiomorpholino-
pteridine analogously to Example 14.
Yield: 52% of theory,
20 M.p.: sinters from 70C
Calculated: C 59.20 ~ 6.48 N 24.02
Found: 59.44 6.22 23.35
~max (ethanol): 400, 297, 258 nm
25 Example 16
4-Morpbolino-7-(1-oxidothiomorpholino)-6-phenyl-
2-piperazino-pteridine
Prepared from 2~(N-formylpiperazino)-4-morpholino-
7-(t-oxidothiomorpholino)-6-phenyl-pteridine analogously
30 to Example l4.
Yield: 43% of theory
M.p.: 196-199C
Calculated: C 58.28 H 6~11 N 22.66 S 6.48
Found: 57.93 6.31 22.72 6.44
~max (ethanol): 400, 295, 258 nm

~5æ~
- 26 -
Example 17
4-(N-Methyl-2'-hydroxyethylamino)-7-morpholino-
6-phenyl-2-piperazino-pteridine
Prepared from 2-(N-formylpiperazino-4-(N-
methyl-2'-hydroxyethylamino~-7-morpholino-6-phenyl-
pteridine analogously to Example 14.
Yield: 31~ of theory
M.p.: sinters from 90C
Calculated: C 61.30 H 6.71 N 24.87
10 Found 61.52 6.73 24.75
~max (ethanol): 398, 296, 258 nm
Example 18
7-(N-Methyl-benz,ylami o~-4-(N-methyl-2 7 -hydroxyethylamino)-
6-phenyl-2-piperazino-pteridine
Prepared from 2-(N-formylpiperazino)-7-(N-
methyl-benzylamino)-4-(N-methyl-2'-hydroxyethylamino)-
6-phenyl-pteridine analo~ously to Example 14.
I Yield: 19% of theory,
20 M.p.: 80-110C
Calculated: C 66.91 H 6.66 N 23.13
Found: 66.80 6.58 22.70
~max ~ethanol): 395, 294, 258 nm
25 Example 19
4-(N-Methyl-2~-hydroxyethYlamino)-6-phenyl-2-piperazin
7-thiomorpholino-pteridine
Prepared from 2-fN-formylpiperazino~-4-(N-
methyl-2'-hydroxyethylamino~-6-phenyl-7-thiomorphoIino-
pteridine analogously to ~xample 14.
Yield: 13~ of theory,
M.p.: 100-140C
Calculated: C 59.20 H 6.48 M 24.02
Found: 59.66 6.45 23.74
~max (ethanol): 398, 296, 258 nm

~:252~7~3
- 27 -
Example 20
4,7-Bis-(N-methyl-benzylamino)-6-phenyl-2-piperazino-
pteridine
Prepared from 2-(N-formylpiperazino~-4,7-
bis-(N-methyl-benzylamino)-6-phenyl-pteridine analogously
to Example 14.
Yield: 56% of theory,
M.p.: resin-like product
Calculated: C 72.47 H 6.46 N 21.12
Found: 72.60 6.62 20.90
~max (ethanol): 398, 294, 258 nm
Example 21
7-Dimethylamino-4-(N-methyl-benzylamino)-6-phenyl-
2-piperazino-pteridine
Prepared from 2-(N-formylpiperazino3-7-dimethyl-
amino-4-(N-methyl~benzylamino)-6-phenyl-pteridine
analogously to Example 14.
Yield- 69~ of theory,
M.p.: 129-132C (ethyl acetate~
Calculated: C 68.69 H 6.65 N 24.65
Found: 68.84 6.81 24.37
~max ~ethanol~: 396, 294, 258 nm
Example 22
4-~N-Methyl-benzylamino~-7-morpholino-6-phenyl-
2-piperazino-pteridine
Prepared from 2-rN-formylpiperazino!-4-(N-
methyl-benzylamino)-7-morpholino-6-phenyl-pteridine
30 analogously to Example 14.
Yield: 60~ of theory,
M.p.: 70-100C
Calculated: C 67.71 H 6.50 N 22~57
Found: 67.96 6.49 22.55
3S ~max (ethanol): 396, 294, 258 nm

~2~i;27~
Example 23
7-Dimethylamino-6-phenyl-2-pi~erazino-4-pyrrolidino-
pteridine
Prepared from 2-(N-formylpi~erazino)-7-dimethyl-
amino-6-phenyl-4-pyrrolidino-pteridine analogously
to Example l4.
Yield: 30% of the theory,
~1.p.: 125-130C
Calculated: C 59.20 H 6.48 N 24.02
Found: 59.44 6.71 23.65
~max (ethanol): 394, 29~, 2-57 nm
Example 24
7-Morpholino-6-phenyl-2-piperazino-4-thiazolidino-
Pteridine
Prepared from 2-(N-formylpiperazino)-7-morpholino-
6-phenyl-4-thiazolidino-pteridine analogously to
Example 14.
Yield: 56% of theory,
M.p.: 120-150C
Calculated: C 59.46 H 6.07 N 24.12 S 6O90
Found: S9.13 6.13 24.36 6.68
~max (ethanol): 396, 294, 258 nm
Example 25
7-Mor~holino-4-(1-oxidothiazolidino)-6-phenyl-2-
piperazino-~teridine
0.93 g (2 mmol) of 7-morpholino-6-phenyl-
2-piperazino-4-thiazolidino~-pteridine are dissolved
in 15 ml of dioxan and refluxed for 1.5 hours with
0.86 g of sodium metaperiodate in 5 ml of water.
The mixture is then concentrated by centrifuging,
the residue is taken up in chloroform and chromatographed
over a silica gel column with ethanol/ammonia 25:1.
Yield: 31% of theory,
M.p.: 190-250C
Calculated: C 57.49 H 5.~7 S 6.67

~2$;~7~3
- 29 -
Found 57.24 6.10 7.15
~max (ethanol): 394, 290, 258 nm
Example 26
4-(N-Methyl-2'-hydroxyethylamino)-7-(1-oxidothio-
morpholino)-6-phenyl-2-piperazino-pteridine
Prepared analogously to Example 25 from 4-
(N-methyl-2'-hydrvxy-ethylamino)-7-thiomorpholino-
6-phenyl-2-pipera~ino-pteridine.
tO Calculated: C 57.25 H 6.27 S 6.64
Found: 57.45 6.59 6.96
~max (ethanol~: 396, 296, 255 nm
Yield: 58~i of theory.
M.p.: sinters from 110C
Example 27
4~7-Bis-dimethylamino-6-phenyl-2-piperazino-pteridine
Prepared from 4,7-bis-di~ethylamino-2-(N-
formylpiperazino~-6-phenyl-pteridine analogously
20 to Example 14.
Yield: 85% of yield.
M.p.: sinters from 50C
Calculated: C 63.46 H 6.93 N 2g.61
Found: 63.22 7.07 29.82
~max (ethanol): 394, 293, 257 nm
Example 28
6-Phenyl-2-piperazino-4,7-dipiper _ino-pteridine
Prepared from 2-(N-formylpiperazino)-6-phenyl-
4,7-dipiperidino-pteridine analogously to ~xample
14.
Yield: 43~i of theory.
M.p.: sinters from 90C
Calculated: C 68.10 H 7.47 N 24.43
Found: 68.00 7.47 24.29
~max (ethanol): 400, 299, 260 nm
, ,,,, ,, - ,,

~æ783
- 30 -
Example 29
2,7-Dipiperazino-4-morpholino-6-phen~l-pteridine
25~2 g (0.07 mol) of 2,7-dichloro-4-morpholino-
6-phenyl-pteridine are stirred in 70 ml of ethanol
with 36 g of piperazine for 1 hour at ambient temperature.
The mixture is then stirred into 700 ml of water,
the precipitate formed is suction filtered, dissolved
in 4 N acetic acid and reprecipitated with 8 N
sodium hydroxide solution.
Yield: 24 g (74~ of theory~,
M.p.: sinters from 130C
Calculated: C 62.44 H 6.77 N 27.31
Found: 62.78 6.70 27.31
~max (ethanol): 400, 298, 260 nm
Example 30
2,7-Dipiperazino-4-thiomorpholino-6-phenyl-pteridine
Prepared from 2,7-dichloro-4-thiomorpholino-
6-phenyl-pteridine analogously to Example 29.
Yield: 79% of theory,
M.p.: sinters from 80C
Calculated: C 60.35 H 6.54 N 6.71
Found: 60.20 6.67 6.32
~max ~ethanol): 400, 299, 259 nm
Example 31
7-Morpholino-4-(1-oxidothiomorpholino)-6-~henyl-
2-piperazino-pteridine
4.6 g (0~01 mol) of 7-chloro-2-(N-formylpiperazino)-
4-(1-oxidothiomorpholino~-6-phenyl-pteridine are
heated to 100C in 8.7 g (n . 1 mol) of morpholine
for 1 hour. The solution is concentrated by evaporation
in vacuo and the residue is chromatographed over
a silica gel column with methanol/ammonia 50:1.
Yield: 1.5 g ~30% of theory),
M.p.: 151-154C (methanol)
Calculated: C 58.28 H 6.11 N 22.66 S 6.48

` ~2~;27~3
- 31
Found: 57.99 6.13 22.22 6.65
~max (ethanol~: 398, 294, 258 nm
Example 32
7-~enzylamino-4-(1-oxidothiomorpholino)-6-phenyl-
2-piperazino-pteridine
Prepared from 7-chloro-2-(N-formyl-piperazino~-
4-(1-oxidothiomorpholino)-6-phenyl-pteridine and
benzylamine analogously to Example 31.
10 Yield: 50% of theory,
M.p.: 200C (decomposition)
Calculated: C 63.01 H 5.88 N 21.77 S 6.23
Found: 62.89 6.07 2-.45 6.20
Example 33
7-Benzylamino-4-morpholino-6-phenyl-2-piperazino-
pterid_ne
Prepared from 7-chloro-2-(N-formyl-piperazino)-
4-morpholino-6-phenyl-pteridine and benzylamine
20 analogously to Example 31.
Yield: 35% of theory,
M.p.: 135-138C (ethyl acetate)
Calculated: C 67.20 H 6.27 N 23.22
Found: 67.25 6.34 23.42
~max (ethanol): 385, 290, 248 nm
Example 34
4,7-Dimorpholino-6-phenyl-2-piperazino-pteridine
Prepared from 7-chloro-2-(N-formy~-piperazino)-
4-morpholino-6-phenyl-pteridine and morpholine
analogously to Example 31.
Yield: 13% of theory,
M.p.: 220-223C
Calculated: C 62.32 H 6.54 N 24.23
35 Found: 62.21 6.64 24.05
~max (ethanol): 400, 296, 259 nm

~5~7~3
- 32 ~
Example 35
4,7-Bis-(l-oxidothiomorpholino)-6-phenyl-2-piperazino-
~teridine
Prepared from 7-chloro-2-(N-formyl-piperazino)-
4-(1-oxidothiomorpholino)-6-phenyl-pteridine and
l-oxidothiomorpholine analogously ~o Example 31.
Yield: 25% of theory.
M.p.: 250C (decomposition)
Calculated: C 54.73 H 5~74 N 24.28
Found: 54.60 5.71 24.04
~max (ethanol): 400, 296, 259 nm

~5Z~33
- 33 -
Example I
Coated tablets containing 4 mq of 7-benzylamino-
6-phenyl-2-piperazino-4-thiomorpholino-pteridine
Composition:
5 l tablet core contains:
Active substance (1)4.0 mg
Lactose (2)27.0 mg
Corn starch (3)14.5 mg
Polyvinylpyrrolidone (4~4.0 mg
lO Magnesium stearate (5)0.5 m~
50.0 mg
Preparation:
Substances 1-3 are uniformly moistened with
an aqueous solution of 4, screened through a 1 mm
mesh screen, dried and again screened through a
1 mm mesh screen. After 5 has been added the mixture
is compressed to form tablet coresO
Cores: 5 mm in diameter, biconvex, round.
Coating:
Conventional sugar coating to give a finished
tablet weight of 70 mg.
Example II
Tablets containing 8 mg of 7-benzylam no-6-phenyl-
2-piperazino-4-thiomor~holino-pteridine
I tablet contains:
Active substance 8.0 mg
30 Lactose 23.0 mg
Corn starch 14.5 mg
Polyvinylpyrrolidone 4.0 mg
Magnesium stearate 0.5 mq
50.0 mg
Preparation:
Analogously to the cores of the coated tablets
of Example I.

~L~52~E~3
- 34 -
Description of tablet:
Weight: 50 mg
Diameter: 5 mm, biplanar, faceted on both sides.
Example III
Suppositories containin~ 25 mq of 7-benzylamino-
6-phenyl-2-piperazino-4-thiomorpholino-pteridine
1 suppository contains:
Active substance 0.025 g
Hard fat (e.g. Witepsol ~ 19 1.695 g
and Witepsol H 45) 1.700 g
Preparation:
The hard fat is melted. At 38C the ground
active subs~ance is homogeneously dispersed in
the melt. It is cooled to 35C and poured into
slightly chilled suppository moulds.
Weight of sùppository: 1.7 g
Example IV
Suspension_containing 8 mg of 7-benzylamino-6-~henyl-
2-piperazino-4-thiomorpholino-pteridine per 5 ml
lO0 ml of suspension contain:
Active substance 0.16 g
Carboxymethylcellulose 0.1 g
25 Methyl p-hydroxybenzoate 0.05 g
Propyl p-hydroxybenzoate 0.01 g
Glucose 10.0 g
Glycerol 5.0 g
70% Sorbitol 20.0 g
30 Flavouring 0.3 g
Distilled water ad 100~0 ml
Method of preparation:
The distilled water is heated to 70C. The
methyl and propyl p-hydroxybenzoates and the glycerol
and carboxylmethylcellulose are dissolved therein
n~

~252~7~33
- 35 -
with stirring. The solution is cooled to ambient
temperature and the active substance is added and
homogeneously dispersed with stirring. After the
sugar, sorbitol solution and flavouring have been
added and dissolved the suspension is evacuated
with stirring to eliminate air.
Example V
Tablets containin~ 100 m~ of 7-benzylamino-6-phenyl-
10 2-piperazino-4-thiomorpholino~ eridine
Composition:
1 tablet contains:
Active substance 100.0 mg
Lactose 80.0 mg
15 Corn starch 34~0 mg
Polyvinylpyrrolidone 4.0 mg
Magnesium stearate 2.0 m~
220.0 mg
20 Method of p-eparation
The active substance, lactose and starch
are mixed together and uniformly moistened with
an aqueous solution of the polyvinylpyrrolidone.
After the moist mass has been screened (2.0 mm
mesh) and dried in a rack dryer at 50C it is screened
again (1.5 mm mesh) and the lubricant is added.
The mixture ready ~or compressing is processed
to form tablets.
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar faceted on both sides
and notched on one side.
Example VI
Hard qelatine ca~sules containin~ 150 m~ o~ 7-benzyl-
35 amino-6-phenyl-2-~
1 capsule contains:
Active substance 150~0 mg

9~2527~33
- 36 -
Dried corn starch approx. 180.0 mg
Powdered lactose approx. 87.0 mg
Magnesium stearate 3.0 m~
approx. 320.0 mg
Preparation:
The active substance is mixed with the excipients,
passed through a screen with a 0O75 mm mesh and
homogeneously mixed in a suitable apparatus.
The finished mixture is packed into hard
gelatine capsules, siæe 1.
Capsule filling: approx. 320 mg
Capsule shell: hard gelatine capsule, size 1.
Example VII
Suppositories containing 150 m~ of 7-benzylamino-
6-phenyl-2-piperazino-4-thiomorpholino-pteridine
1 suppository contains:
Active substance 150.0 mg
Polyethyleneglycol 1500 550.0 mg
Polyethyleneglycol 6000 460.0 mg
Polyoxyethylene sorbitan monostearate 840.0 mg
2 000.0 mg
Preparation
After the suppository mass has been melted
the active substance is homogeneously distributed
therein and the melt is poured into chilled moulds.
Example VIII
Suspension containing 50 mg of 7-benzylamino-6-
~hen~1-2~piperazino-4-thiomorpholino-pteridine
per 5 mI
100 ml of suspension contain:
35 Active substance 1.0 g
Sodium salt of carboxymethylcellulose 0.1 g
Methyl p~hydroxybenzoate 0.05 g

2'7~3~
- 37 -
Propyl p-hydroxybenzoate 0.Ol ~
Glucose 10.0 g
Glycerol S.0 g
70% Sorbitol solution 20.0 g
5 Flavouring 0.3 g
Distilled water ad 100 ml
Preparation
The distilled water is heated to 70C. The
methyl and propyl p-hydroxybenzoates and the glycerol
and carboxymethylcellulose sodium salt 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 with stirring to eliminate air.
5 ml of suspension contain 50 mg of active
substance.
Example IX
Tablets contain n~ 150 mg of 7-benzylamino-6-Pheny
2-piperazino-4-thiomor~holino-pteridine
Composition:
25 1 tablet contains:
Active substance 150.0 mg
Powdered lactose 89.0 mg
Corn starch 40.0 mg
Colloidal silica 10.0 mg
30 Polyvinylpyrrolidone 10.0 mg
Magnesium stearate 1.0 mq
300.0 mg
Preparation
The active substance mixed with lactose,
corn starch and silica is moistened with a ~0~
a~ueous polyvinylpyrrolidone solution and passed

~5~
- 38 -
through a screen with a 1.5 mm mesh. The granulate
dried at 45C is again passed through the same
screen and mixed with the stated quantity of magnesium
stearate. Tablets are compressed from the mixture.
Weight of tablet: 300 mg
Punch: 10 mm, flat.
Example X
Coated tablets containing 75 m~_~f 7-benzylamino-
10 6-phen,y~ ~piperazino-4-thiomorpholino-pteridine
1 tablet core contains:
Active substance 75.0 mg
Calcium phosphate 93.0 mg
Corn starch 35.5 mg
15 Polyvinylpyrrolidone 10.0 mg
Hydroxypropylmethylcellulose 15O0 mg
Magnesium stearate ~
230.0 mg
Preparation:
The active substance is mixed with calcium
phosphate, corn starch, polyvinylpyrrolidone, hydroxy-
propylmethylcelullose and half the stated quantity
of magnesium stearate. In a tablet-making machine,
blanks are produced with a diameter of about 13 mm
which are then rubbed through a screen with a 1.5 mm
mesh in a suitable machine and mixed with the remaining
magnesium stearate. This granulate is compressed
to form tablets of the required shape in a tablet
making machine.
Weight of core: 230 mg
Punch: 9 mm, convex.
The tablet cores thus produced are coated
with a film consisting essentially of hydrox~propyl-
methylcellulose. The finished film-coated tablets
are polished with beeswax.
~ , i

~;~5æ78;~
- 39 -
Weight of coated tablet: 245 mg.
Obviously, all the other compounds of formula
I (wherein R2 represents a piperazino group) and
the physiologically acceptable acid addition salts
thereof may be used as active substances in the
galenic preparations described hereinbefore.