CA1249275A - Process for the preparation of acid addition salts of 2-piperazinopyrimidine - Google Patents

Process for the preparation of acid addition salts of 2-piperazinopyrimidine

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Publication number
CA1249275A
CA1249275A CA000440928A CA440928A CA1249275A CA 1249275 A CA1249275 A CA 1249275A CA 000440928 A CA000440928 A CA 000440928A CA 440928 A CA440928 A CA 440928A CA 1249275 A CA1249275 A CA 1249275A
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Prior art keywords
piperazinyl
pyrimidine
group
compound
active ingredient
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CA000440928A
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French (fr)
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Jean-Pierre Chambon
Emilio Crisafulli
Marco Frigerio
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Sanofi SA
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurosurgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

IN THE CANADIAN PATENT AND TRADEMARK OFFICE

PATENT APPLICATION

entitled: Process for the preparation of acid addition salts of 2-piperazinopyrimidine.

Inventors : Emilio CRISAFULLI
Marco FRIGERIO
Jean-Pierre CHAMBON

Applicant : SANOFI

ABSTRACT OF THE DISCLOSURE

A process for the preparation of acid addition salts of 2-(1-piperazinyl)pyrimidine with dicarboxylic acids which comprises reacting 2-(1 piperazinyl)pyrimidlne with a calculated amount of a dicarboxylic acid in an organic or organic aqueous solvent.

Description

The present invention concerns certain novel acid addition salts of 2-piperazinopyrimidine, their production and pharmaceutical compositions con~aining the same.
The 2 (1-piperazinyl) pyrimidine is, in the form of free base, a compound well known in literature, utilized as chemical intermediate.
It has been tested among a number of compounds none of which has shown analgesic or antifilarial activity (H.W.Stewart et al., J. Org. Chem.
1953 18, 1478).
Its addition salt with hydroch]oric acid is described in Indian patent specification 147 985 as intermediate in the preparation of tetracycline derivatives.
It has now been found that acid addition salts of 2~ piperazinyl) pyrimidine with dicarboxylic acid possess a very good psychotropic activity with dopaminergic mechanism of action, particularly anti-p~ychotic, antidepressive and tranquillizing-sedative activity.
In accordance with one embodiment of the invention, there we provided acid addition salts of 2-(1-piperazinyl)-pyrimidine with dicarboxylic acids represented by the formula:

~ OOC-X-COOH

wherein X represents an alkylene group of from 1 to 3 carbon atoms, a vinylene group, a hydroxyethylene group, a 1,2-dihydroxyethylene group, an aminoethylene group or an amino-1,3-propylene group.

,, ., ~

The mono~L(+) tartrate (formula I, X =
1,2~dihydroxyethylene, the monosuccinate (formula I, X =
ethylene), the monomaleate (formula I, X = vinylene, cis), the monofumarate (formula I, X = vinylene, trans) and the monoglutamate (formula I, X = 3-amino-1,3-propylene) of 2-(1-piperazinyl)-pyrimidine are particularly preferred.
The compounds of the present invention are prepared, according to a further embodiment of the present invention, by a sali~ication process which comprises treating 2-(1-piperazinyl) pyrimidine with the calculated amount o* a dicarboxylic acid of the ~ormula HOOC-X-COOH
in which X is as defined above, generally in equimolecular amount, in an organic aqueous solvent.
The dicarboxylic acids, L(~)-tartaric, succinic, maleic, fumaric and L-glutamic acids are particularly preferrPd.
The dicarboxylic acid may be utilized as such or dissolved in the same solvent utilized for 2-(1-piperazinyl) pyrimidine or also dissolved in water.
An alcohol, preferably isopropanol, acetone, ethyl acetate or the like, is used as organic solvent.
The salt thus obtained is isolated according to conventional procedures by simple filtration and crystallization if ne~essary.
The salification may be carried out on crude 2-~1-piperazinyl) pyrimidine as obtained from the reaction of 2-chloropyrimidine with piperazine according to known procedures.
The activity of the compounds of the present invention has been evaluated in predictive tests for antipsychotic, antidepressive and tranquillizing-sedative activih~and for the dopaminer~i.c mechanism of action.
The ant,ipsychotic activity of a repre-sentative compound, 2~ piperazinyl)pyrimidille mono-maleate r has b~en evaluated in the test of the antagonism of the amphetamine induced yroup toxicity (J.ll. Burn et al., Arch. Int. Pharmacodyn. Ther. 1958, 113, 290).
The 2-~l-piperazinyl~pvrimidine'mono-maleate has been administered intraperi-toneally in increasing doses -to groups of lO Charles River CDl mice weighiny 20-22 g placed together in boxes which were 22 cm long, 12 cm wide and 12 cm deep. Thirty minutes after the administration, the mice were injected intrap~ritoneal.ly with amphetamine at doses of 30 mg/kg.
The mortality of animals was evaluated during the 24 hours ollowing the injection of amvhetamlne and comPared, in each group~ to that of the control grou?s treated with the vehicle (saline) only.
Table I hereinbelow shows the median effective dose (ED50) of antagonism to amphetaminP-i.nduced mor~ali.ty.
TABLE I
_ _ _ _ _ ~ _ _, _ _ . .~ _ . . . _ _. _ .. _ _ _ _ _ _ _ _ _ _ . _ _ _ . _ ~ _ _ _ _ . _ . _ _ _ _. _ _ _ _ _ _ Compound ED5Q
(confidence limits) _ _ _ _ ._ _ ~. _ _ _. _ . _ _ _ _ _ _ . _ _ _ _ . . .. _ _ _ _ .-- . _ _ ~ _ _ _ _ _. _ . . _ ~ . _ _ _ ._ _
2~ pi,perazinyl)pyrimidine 16.$ m~3/ky monomaleate (lO.l - 26.7) _ _ _ _ _ _ _ .. _ _ _ _ ._ _ ,~ _ _ . _ _ _ _ ... _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ J.`rom this table it results that the compound O the presen-t invention exhibits a c~ood activity i.n the test of the yroup toxicity induced by amphetamine, predictive of an antips~lchotic action.
The antidepressive activit~ of the comP~

327~

ounds 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).
A representative compound of the invention, namely 2-(l-piperazinyl)pyrlmldine mono-maleate, was administered tntraperitoneally to groups of lO Wister male rats weiyhin~ 220-240 g; at the same time control animals were -treated with salineO
One hour later, prochlorperazlne was administered subcutaneously at ~ dose of lO mg/kg. Five hours after thls 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 (ll cm total he~ight) and forced to maintain this position for 20 seconds at least. The performances of each group of animals were compared with thos~ of the controls ha~ing received the vehicle and prochlorp~razine only.
Table II hereinbelow shows the ~rcent o~ antagonism of prochlorperazine-inducPd catalepsy.
TABLE II
_ _ _ . _ _ _ _ _ . _ _ .. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ . . _ _ _ , . _ . _ _ _ _ _ _ _ Compound Dose antagonism ~
_ _ _. _ _ _ _ _ .. _ _ _ _ _ _ ~ _ ~ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ ._ _ _ ~ _ . ~ _ _ _ _ . . _ . . _ _ . _ _ _ _ 2-(l-piperazinyl)pyrimidine O.l mg/kg20%
25monomaleate l m~k~ ~O?o _ _ _ _ _ ._ _ _ _ _ _ _ . ._ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~_ ... _ _ _ _. _ _ ~ _ _ ._ _ _ _ _ _ _ ._ _ _ _ _ _ _ From this table i~ re5ult5 that the 2-(l-pipeLazinyl)-pyrimidine monomaleate of the present invention is active in the test of prochlorpe~azine inducecl catalepsy, ~redictive of antide~resslve activity.
The tranquillizincJ-sedatlve ac~ivity o~ the compounds of the lnvention was assessed in the motor acti~tty test according to the procedure of J.R.
Boissier et al. (Arch. Int. Pharmacodyn. l965, 158, 2l2).

~%~
s A representative compound of tlle invention, namely 2~ piperazinyl)pyrimidine mono-maleate, was administered intraperitoneall.y to groups of 12 mice per dose; at the same time, a group of control animals received saline only. Each animal was lndividually placed 45 minutes after the adminlstra-tion in Apelab motility cages (26 cm long, 21.5 cm wlde, 10 cm deep) crossed by two luminous rays which sensitlze a photoelectric cell~ Each crossing of a lumi.nous beam was recorded by an individual counter. The scores corresponding to the displacements of the animals were recorded during ten minutes.
Table IIIhereinbelow shows the percent variation of the spontaneous motility of the animals treated at the different doses as com ared to the control animals~
TABLE III

Compound Dose Variatlon %

2-(1-piperaz.inyl)pyrimidine 2.5 mg/kg - 51 monomaleate 1.25 mg/kg - 3~ % ~
0.60 mg/kcJ - 24 ~ ns ____ ____________,_________ ___________._.__________ ____ ~ p ~0.01 ~ p~ 0~05 "t" 5tudent test _ _ _ _ _ ~ _ _ _ _ _ _ _ ~ _ _ _ _ _ _ _ _ ~ . _ .. _ _ ~ . _ _ _ _ . _ _ _ _ _ _ . _ _ _ . _ _ ~ . _ _ _ _ From this table it results tha~. the 2-tl-piperazinvl)pyrlmidine monomaleate o~ the present invention exhibits a good sedative activity i.ndicated by the decrease of the spontaneous motil.it~ ln the mouse~
Dopaminergic mechanism of a representative compound of the pxesent invention, 2-(1-piperazinyl) pyrimidine mono-Lt~)tartrate was studied in comparison with the corresponding free base and its hydrochl.oride by analysing the rotational behaviour in mice after 2~5 unilateral lesion of the striatum (P. Protals et al., JO
Phar~!acol. 1976, 7, 251).
~ emale Charles River CDl mice wei~hing Z0-24 g were previously subjected to a unilateral les.ion of the s-triatum by stereot~xic injection of 8 mcg/animal of 6-hydroxydopamine. ~ week ].ater, the 2~(1-iperazinyl~-vyrimidine mono-L(-~-)-tartrate, the 2-(1-piperazinyl) pyrimi.dine hydrochloride and the free base were ad-mlnistered by oral route to yroups of six mice at a dose corresponding to 0.15 rng/kg of free base. The nur~er of turns was recorded, during 2 minute~, 1, 3 and 6 hours after the admi.nistration of ths~hree products. The turns ipsilateral to the lesion were plotted as positive values, ~he contralateral turns were plo~ted a9 negative values. The algebric sum of turns for each grouv of treated an:imals was compared to that of control animals t~eated with the vehicle (saline) only.
Table IV hereinbelow shows the percent variatlon o~ turns, as compared to the controls.
TABLE I~
~ _____ __ _______________ ___________ Compound Variation ~ after minutes __ ____~____ ____ ____ ..._ .__~____ l~0 360 _ ____~_ _____ _ . _ _ _ ____ _ __~_ _~ _ _ _. __ _.___ ~_ . ___,.~ . _ ___ ____ 2-~l-piE~erazinylj- - 94 ~s~ -- 62 ~s60 *ss~S
pyrirnidine base 2~(1-piperazinyl)- - 2g ns - 27 ns - 22 llS
pyrimidiTIe hydrochloride 2--(l-piperazinyl)- - 8$ ~s _ 9~ ~ -L2~ ~s~s pyrimidine mono-L(~)-tartra-te ... _____~.____~________ _ ._________ ________ _ ______~_____ significant p ~0.01 "t" Student test ns non significant _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ._ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ._ _ _ _ _ _ _ _ _ _ _ ,_ - _ _ From this table it results that the base significantly reduces the algebric sum of turns ipsilater-al and contralateral to the lesion whilst the hydro-chloride nas no slgniflcant effect.
This table also shows that the hydrochloride is inactive in the time too and that the activity of the free base tends to decrease in the t~me. On the contrary, the ~ piperazinyl)pyrimidine mono-L(+) -tartrate of the present inventlon is more potent than the reference compouncLs and, in addition, its activity increases slgnificantly in the time. More part.icularly the representative compound of the in~ention not only reduces the above algebrlc sum at the sixth hour, but it shows a negative variation higher than 100%. This surprising finding pxoves that the num~er of turns contralateral to the lesi~n is higher than that of the ipsilateral turns.
The dopaminergic psychotropic activity o F
the compounds of the present invent.ion and their low toxici-ty make them useful as drugs.
Thus it is another object o~ the present invention to provi.de pharmaceutical compositions con-taining ac.id addition salts of 2~ piperazinyl) pyrimidine with dicarboxylic acids as active ingredients.
The pxeferred active ingxedients are the compounds of formula I above.
In the pharmaceutical compositions of the present invention for oral r parenteral, sublingual, transdermic or rectal administration, the s.llt of 2 piperazinyl)py.rimidine with a dicarboxylic acid, utilized as active lnyredl.ent, may be administered i~ dosa~e unit forms, in admixture with conventional pharmaceutical carriers to animals and human beings for the treatment of humoux and behaviour disorders, ~ore particularly in the management of psychosis, 7~

depression, as well as anxiety and insomnia. Anpropriat2 dosage unit forms include forms for oral administration, such as tablets, capsules, powders, granules and oral solutions or suspensions and suppositories for rectaL
administration.
In order to obtain the desired psvchotropic effect, ~he daily dose of ac~ive ingredien-t may vary between 0.1 and 100 mg per kg or body-weight.
Each unit dose may contain from 1 t~ 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 or behaviour disorders.
The followlng examples illustrate the invention without, however, limiting i~.
EXA~PLE 1._ A mixture of 3.2 ~ of 2-chloropyrimidine and 12.1 g of anhydrous pipe~azine in 100 ml of absolute ethanol i5 heated at re1ux for 18 hours, then it is thoroughly evaporated under reduced pressure and in the warm. The residue is taken up with 400 ml of diethyl ether, the solution thus obtained is washed with 10 ml of an aqueous solution of sodium hydroxide ~ then with 20 ml of water~ The organic solutlon is dried over anhydrous sodium sulfate, filterecl and evaporated to dryness uncler reduced pressure. The oil thus obtained is dissolved ln 30 ml of isopropanol and 2.7 g o:E male:ic acid dissolved in 30 ml of isopropanol is added to the solution at about 60C. From the solution thus obtained a product crystalliæes which is filtered and dried to g:ive 4 g of 2~ piperazinyl)pyrimidine monomaleate; m.p. 160-162~C. By further crystallization from 95~ ethanol the melting point does not change.
EXAMPLE 2.
To a solution of 1.64 g of 2-(1-piperazin~1) pyrimidine :in 15 ml of isopropanol, is added, at a temperature of 50 60C, a solution of 1..16 g of maleic acid in 15 ml of isopropanol. Thus, 2~ piperazinyl) pyrimidine monomaleate is obtained, identical to the product of Example 1.
In the same manner, - 2-(1-piperazinyl)pyrimidine monoEumarate, m p. 201-203C, - 2-(1-piperazinyl)pyrimidine mono-L(+)-tartrate, m.p.
165 -16 8 C , 2-(l-piperaæinyl)~yrimidine monosuccinate, m. 173-176 are obtained.
The yield in all these preparations is absut 95%.
EXAMPI,E 3.
To a solution of 1.64 g of 2-(1-piperazinyl) pyrimidine in 100 ml of acetone, an aqueous solution of 1.47 g of ~lutamic acid is added at a temperature of 45C. The mixture is evaporated to dryness and the residue is taken up with petrol ether to give 2-(1-piperazinyl~pyrimidine mono-L-glutamate; m.p. 188-190C; yield 95%.
EXAMPLE 4.
CapsuLes comprising one of the products described in Examples l to 3, having the following ~5 composition :
actiVe substance 15 mg lactose 120 mg magnesium stearate 5 mg are prepared by mixing intimately charges of the ingredients above and introducing the mixture into hard gelatine capsules.
EXAMPLE 5.
Tablets comprising one of the products described in Examples l to 3, having the following composltion:

active substance 20 mg lactose 100 mg microcrystalline cellulose 30 mg dried corn starch 40 mg ma~nesium stearate 5 mg are prepared by crushing the active ingredient to a particle dimension of 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 6.
-By operating as described in Example 5hereinabove, tablets having the following composition are prepared :
active suhstance . 50 mg lactose 95 mg corn starch 100 mg talc 4 5 ~g magnesium stearate 0.5 mg EXAMPLE 7.
Suppositories, comprising one of the produc-ts described in Examples 1 to 3, are prepared having the following composition :
25 active substance 50 mg lactose 250 my mass for suppositories to 1.7 g The active substance is mixed with the lactose and the mixture is placed uni.formly in the molten mass ~or suppositories. The suspension is poured into cooled moulds to form suppositories weighing 1.7 g.

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. An acid addition salt of the formula:

HOOC-X-COOH

wherein X represents an alkylene group of from 1 to 3 carbon atoms, a vinylene group, a hydroxyethylene group, a 1,2-dihydroxyethylene group, an aminoethylene group or an amino-1,3-propylene group.
2. 2-(1-piperazinyl) pyrimidine monomaleate.
3. 2-(1-piperazinyl) pyrimidine monofumarate.
4. 2-(1-piperazinyl) pyrimidine monosuccinate.
5. 2-(1-piperazinyl) pyrimidine mono-L(+) tartrate.
6. A process for the preparation of acid addition salts of 2-(1-piperazinyl) pyrimidine with dicarboxylic acids,which comprises reacting 2-(1-piperazinyl) pyrimidine with a calculated amount of a dicarboxylic acid of the formula HOOC-X-COOH
wherein X is an alkylene group of from 1 to 3 carbon atoms, a vinylene group, a hydroxyethylene group, a 1,2-dihydroxyethylene group, an aminoethylene group or an amino-1,3-propylene group,in an organic or organic aqueous solvent.
7. A process as claimed in claim 6, in which salification is carried out on a crude 2-(1-piperazinyl) pyrimidine, as obtained from the reaction of 2-chloropyrimidine with piperazine.
8. A process as claimed in claim 6, in which the 2-(1-piperazinyl) pyrimidine and the dicarboxylic acid are utilized in equimolecular amount.
9. A pharmaceutical composition having dopaminergic psychotropic action, comprising, as the active ingredient, a compound as claimed in any one of claims 1 to 3 and a pharmaceutical carrier.
10. A pharmaceutical composition having dopaminergic psychotic action containing, as the active ingredient, a compound as claimed in any one of claims 1 to 3 and a pharmaceutical carrier, which composition is in dosage unit form.
11. A pharmaceutical composition comprising, from 1 to 300 mg of an active ingredient, which is a compound as claimed in any of claims 1 to 3, in admixture with a pharmaceutical carrier per dosage unit.
12. A pharmaceutical composition having dopaminergic psychotropic action, comprising, as the active ingredient, a compound as claimed in either claim or 5 and a pharmaceutical carrier.
13. A pharmaceutical composition having dopaminergic psychotic action containing, as the active ingredient, a compound as claimed in either claim 4 or 5 and a pharmaceutical carrier, which composition is in dosage unit form.
14. A pharmaceutical composition comprising from 1 to 300 mg of an active ingredient, which is a compound as claimed in either claim 4 or 5, in admixture with a pharmaceutical carrier per dosage unit.
CA000440928A 1982-11-12 1983-11-10 Process for the preparation of acid addition salts of 2-piperazinopyrimidine Expired CA1249275A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8218975A FR2536071B1 (en) 1982-11-12 1982-11-12 2-PIPERAZINOPYRIMIDINE ACID SALTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FR8218975 1982-11-12

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CA1249275A true CA1249275A (en) 1989-01-24

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DE (1) DE3363093D1 (en)
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WO1987004928A1 (en) * 1986-02-24 1987-08-27 Mitsui Petrochemical Industries, Ltd. Agents for treating neurophathy
JP2561689B2 (en) * 1986-02-24 1996-12-11 三井石油化学工業株式会社 Neurological drug
YU39503A (en) * 2000-11-22 2006-05-25 F. Hoffmann-La Roche Ag. Pyrimidine derivatives
TW200302728A (en) 2002-02-01 2003-08-16 Novartis Ag Substituted amines as IgE inhibitors
JP4726622B2 (en) * 2005-12-14 2011-07-20 三洋電機株式会社 Leaded battery

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US985657A (en) * 1910-12-10 1911-02-28 Baldwin Locomotive Works Car-truck.
US2985657A (en) * 1959-10-12 1961-05-23 Paul A J Janssen 1-(aroylalkyl)-4-heterocyclylpiperazines
US4547505A (en) * 1983-03-25 1985-10-15 Degussa Aktiengesellschaft N-Phenyl-N-'-cycloalkylalkanoylpiperazine useful as analgetics and process for its production
DE3321969A1 (en) * 1983-06-18 1984-12-20 Troponwerke GmbH & Co KG, 5000 Köln 2-PYRIMIDINYL-1-PIPERAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME

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IE56184B1 (en) 1991-05-08
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EP0109340B1 (en) 1986-04-16
ATE19243T1 (en) 1986-05-15
FR2536071B1 (en) 1986-07-11
EP0109340A3 (en) 1984-06-27
NZ206222A (en) 1985-09-13
AU2116483A (en) 1984-05-17
AU567311B2 (en) 1987-11-19
FR2536071A1 (en) 1984-05-18
DE3363093D1 (en) 1986-05-22
ZA838423B (en) 1984-06-27
JPS59144766A (en) 1984-08-18

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