Note: Descriptions are shown in the official language in which they were submitted.
1203S37
Process for the preparation of 2-piperazinopyrimidine derivatives.
The present invention concerns a process for
the preparation of 2-piperazinopyrimidine derivatives with a dopa-
minergic psychotropic activity.
More particularly, the present invention concerns
a pharmaceutical composition containing, as active ingredient,
a 2-piperazinopyrimidine of formula
~ ~ N N_R2
Rl N
wherein R represents hydrogen or a hydroxy group and R represents
hydrogen or an alkyl group of from 1 to 6 carbon atoms, or a
pharmaceutically acceptable addition salt thereof.
Compounds of formula I wherein R is hydrogen or a
hydroxy group and R is hydrogen are known, in literature, as
chemical intermediates.
The 2-(1-piperazinyl)pyrimidine has been tested
among a number of compounds none of which has shown analgesic
or antifilarial activity (H.~. Stewart et al., J. Org. Chem. 1953,
8, 1478).
Its addition salt with hydrochloric acid is
described in Indian patent specification 147 985 as intermediate
in the preparation of tetracycline derivatives.
It has now been found that compounds of formula I
above, as well as their pharmaceutically acceptable acid addition
salts, pOSS6S a very good psychotropic activity with dopaminergic
mechanism of action, particularly antipsychotic, antidepressive
and tranquillizing-sedative activity which make them useful as
drugs in pharmaceutical compositions for the treatment of psychic,
neurological and neuromuscular disorders of mammals, human beings
included.
The activity of the compounds of the present
invention has been evaluated in predictive tests for antipsychotic,
antidepressive and tranquillizing-sedative activity and for the
dopaminergic mechanism of action.
., .
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The antipsychotic activity of a representative
compound, 2~ piperazinyl)pyrimidine monomaleate, has been evaluated
in the test of the antagonism of the amphetamine-induced group
toxicity (J.H. Purn et al., Arch. Int. Pharmacodyn. Ther. 1958,
113, 290).
The 2~ piperazinyl)pyrimidine monomaleate has
beenadministered intraperitoneally in increasing doses to groups
of 10 Charles River CDl mice weighing 20-22 g placed together in
boxes which were 22 cm long, 12cm wide and 12 cm deep. Thirty
minutes after the administration, the mice were injected intra-
peritoneally withamphetamine at a dose of 30 mg/kg. The mortalityof animals was evaluated during the 24 hours following the injec-
tion of amphetamine and compared, in each group, to that of the
controls groups treated with the vehicle (saline) only.
Table I hereinbelow shows the median effective
dose (ED50) of antagonism to amphetamine-induced mortality.
TABLE I
Compound ED50
(confidence limits)
-
2-(1-piperazinyl)pyrimidine 16.5 mg/kg
monomaleate (10.1 - 26.7)
From this table it results that the compound of
the present invention exhibits a good activity in the test of
the amphetamine-induced group toxicity, predictive of an anti-
psychotic action.
The antidepressive activity of the compounds of
the invention has been evaluated in the test of antagonism of
prochlorperazine-induced catalepsy (K. Biziere et al., Arzneimittel
Forschung, 1982, 32 (II), 824).
-1
1:~03537
A representative compound of the invention, namely
2-(1-piperazinyl)pyrimidine monomaleate, was administered intra-
peritoneally to groups of 10 Wistar male rats weighing 220-240 g; at
the same time control animals were treated with saline. One hour
later, prochlorperazine was administered subcutaneously at a dose
of 10 mg/kg. Five hours after this administration, the number of
cataleptic animals was assessed by the cork test. According to this
test the animals were placed with their forepaws on a stand
formed by three superposed corks (11 cm total height) and forced
to maintain this position for 20 seconds at least.The performances
of each group of animals were compared with those of the controls
having received the vehicle and prochlorperazine only.
Table II hereinbelow shows the percent of anta-
gonism of prochlorperazine-induced catalepsy.
TABLE II
Compound Dose Antagonism
2-(1-piperazinyl~pyrimidine 0.1 mg/kg 20%
monomaleate 1 mg/kg 80%
From this table it results that the 2-(1-piper-
azinyl)pyrimidine monomaleate of the present invention is active in
the test of prochlorperazine-induced catalepsy, predictive of anti-
depressive activity.
The tranquillizing-sedative activity of the
compounds of the invention was assessed in the motor activity test
according to the procedure of J.R. Boissier et al. (Arch. Int.
Pharmacodyn. 1965, 158, 212).
A representative compound of the invention, namely
2-(1-piperazinyl)pyrimidine monomaleate, was administered intra-
peritoneally to groups of 12 mice per dose; at the same time, a group
of control animals received saline only. Each animal was individually
placed 45 minutes after the administration in Apelab motility cages
(26 cm long, 21.5 cm wide, 10 cm deep) crossed by two luminous rays
lZ03537
which sensitize a photoelectric cell. Each crossing of a luminous
beam was recorded by an individual counter. The scores corresponding
to the displacements of the animals were recorded during ten minutes.
Table III hereinbelow shows the percent variation
of the spontaneous motility of the animals treated at the different
doses as compared to the control animals.
TABLE III
Compound Dose Variation %
2-(1-piperazinyl)pyrimidine 2.5 mg/kg - 51 % ++
monomaleate 1.25 mg~kg - 39 % +
0.60 mg/kg - 24 % ns
-
++ p < 0.01 + p <0.05 "t" Student test
ns : non significant
From this table it results that the 2-~1-piperazi-
nyl)pyrimidine monomaleate of the present invention exhibits a good
sedative activity indicated by the decrease of the spontaneous
motility in the mouse.
Dopaminergic mechanism of an active ingredient,
representative of the present invention, 2-(1-piperazinyl)pyrimidine
hydrochloride was studied by analysing the rotational behaviour
in mice after unilateral lesion of the striatum (P. Protais et al.,
. Pharmacol. 1976, 7, 251).
Female Charles River CDl mice weighing 20-24 g
were previously subjected to a unilateral lesion of the striatum
by stereotaxic injection of 8 mcg/animal of 6-hydroxydopamine. A
week later, the compound studied was administered by oral route
to groups of six mice at a dose corresponding to 0.15 mg/kg of
free base. The number of turns was recorded, during 2 minutes,
15 and 30 minutes after the administration of the product. The
turns ipsilateral to the lesion were plotted as positive values,
the contralateral turns were plotted as negative values. The
~03~37
algebric sum of turns for each group of treated animals was compared
to that of control animals treated with the vehicle (saline) only.
Table IV hereinbelow shows the percent variation
of turns, as compared to the controls.
TABLE IV
Compound ¦ Variation ~ after minutes :
I
1 15 30
_
2-(l-piperazinyl)-pyri- - 117 ++ - 58 ++
midine hydrochloride
++ significant p < 0.01 "t" Student test
Prom this table it results that the active ingre-
dient of the pharmaceutical compositions of the present invention
significantly reduces the algebric sum of turns ipsilateral and
contralateral to the lesion.
The dopaminergic psychotropic activity of the
compounds of the present invention and their low toxicity make them
useful as drugs.
Thus, the object of the present invention is to
provide pharmaceutical compositions containing the compounds of
formula I above as active ingredient.
In the pharmaceutical compositions of the present
invention for oral, parenteral, sublingual, transdermic or rectal
administration, the active ingredients may be administered in
dosage unit forms, in admixture with conventional pharmaceutical
carriers to animals and human beings for the treatment of humour
and behaviour disorders, more particularly in the management
of psychosis, depression, as well as anxiety and insomnia.
Appropriate dosage unit forms include forms for oral administration,
such as tablets, capsules, powders, granules and oral solutions
or suspensions and suppositories for rectal administration.
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6 ~.
In order to obtain the desired psychotropic effect,
the daily dose of active ingredient may vary between 0.1 and 100 mg
per kg of body-weight.
Each unit dose may contain from 1 to 300 mg of
active ingredient in admixture with a pharmaceutical carrier. This
unit dose may be administered from 1 to 4 times daily to treat
the humour of behaviour disorders.
Those compounds of formula I which are not known
may be easily prepared by reacting a 2-substituted pyrimidine of
formula
X
wherein X represents a chlorine atom or a methylene group and R
is as defined hereinabove, with a piperazine of formula
H/N~_R2
~J'
wherein R is as defined hereinabove or, when R is other than
hydrogen, by reacting a 2-piperazinopyrimidine of formula :
~ ~ ~
Rr
wherein R is as defined hereinabove, with an alkyl halide
according to known procedures.
The following examples illustrate the invention
without, however, limiting it.
EXAMPLE 1
A mixture of 3.2 g of 2-chloropyrimidine and 12.1 g
of anhydrous piperazine in 100 ml of absolute ethanol is heated
at reflux for 18 hours, then it is thoroughly evaporated under
reduced pressure and in the warm. The residue is taken up with
lZ03537
400 ml of diethyl ether, the solution thus obtained is washed with
10 ml of an aqueous solution of sodium hydroxide 1:1, then with
20 ml of water. The organic solution is dried over anhydrous sodium
sulfate, filtered and evaporated to dryness under reduced pressure.
The oil thus obtained is dissolved in 30 ml of isopropanol and 2.7g
of maleic acid dissolved in 30 ml of isopropanol is added to
the solution at about 60C. From the solution thus obtained a product
crystallizes which is filtered and dried to give 4 g of 2-(1-pipera-
zinyl)pyrimidine monomaleate; m.p. 160-162C. By further crystalli-
zation from 95~ ethanol the melting point does not change.
EXAMPLE 2
To a solution of 5.6 g of 2-(1-piperazinyl)pyri-
midine monomaleate and 10.6 g of sodium carbonate in 100 ml of
dimethylsulfoxide, 2.1 ml of 2-bromopropane are added and the
reaction mixture is heated at 100C for 5 hours. The solvent is
concentrated under reduced pressure, the residue is taken up with
water, extracted three times with ethyl acetate, dried on anhydrous
sodium sulfate, filtered and concentrated under vacuum. The
residue is chromatographed on silica gel, then eluted with ethyl
acetate : methanol 9:1 and the fractions containing the wished
product alone are concentrated. The residue is dissolved in diethyl
ether and the solution is treated with hydrogen chloride
in diethyl ether. After evaporation, the residue is recrystallized
from absolute ethanol. Thus, 2 g of 2-(4-isopropyl-1-piperazinyl)
pyrimidine hydrochloride are obtained ; m.p. ~ 200C with subli-
mation.
EXAMPLE 3
A mixture of 7 g of 4-hydroxy-2-methylthiopyridine
(Berichte, 1973, 106, 3058b) and 6.2 ml of l-methylpiperazine in
125 ml of butanol is heated at reflux for 15 hours. Then, the
reaction mixture is left to return to room temperature, the
crystals are filtered and crystallized from absolute ethanol. Thus,
6.2 g of 4-hydroxy-2-(4-methyl-1-piperazinyl)pyrimidine are
obtained; m.p. 180-182C.
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EXAMPLE 4
By operating as described in Example 3, by
reacting the 4-hydroxy-2-methylthiopyrimidine with piperazine,
4-hydroxy-2-(1-piperazinyl)pyrimidine is obtained; m.p.~ 260.
EXAMPLE 5
Capsules having the following composition :
2-(1-piperazinyl)pyrimidne 15 mg
-lactose 120 mg
magnesium stearate 5 mg
are prepared by intimately mixing charges of the above ingredients
and introducing the mixture into hard gelatine capsules.
EXAMPLE 6
Tablets comprising having the following compo-
sition :
2-(1-piperazinyl)pyrimidine hydrochloride 20 mg
lactose 100 mg
microcrystalline cellulose 30 mg
dried corn starch 40 mg
magnesium stearate 5 mg
20 are prepared by crushing the active ingredient to a particle
dimension of 0.4 mm size, by passing it through a 0.4 mm sieve,
by mixing the crushed mixture with the other constituents and
compressing to form the tablets.
In the same manner, tablets comprising 40 mg
of active substance are prepared.
EXAMPLE 7
-
By operating as described in Example 6 herein-
above, tablets having the following composition are prepared :
2-(1-piperazinyl)pyrimidine monomaleate 50 mg
lactose 95 mg
cornstarch 100 mg
talc 4,5mg
magnesium stearate 0,5mg
lZI)353~7
EXAMPLE 8
Suppositories are prepared having the following
composition :
2-tl-piperazinyl)pyrimidine 50 mg
S lactose 250 mg
mass for suppositories to 1,7 g
The active substance is mixed with the lactose
and the mixture is placed uniformly in the molten mass for suppo-
sitories. The suspension is poured into cooled moulds to form
suppositories weighing 1.7 g.
