NZ206222A - Acid addition salts of 2-(1-piperazinyl)pyrimidine and pharmaceutical compositions - Google Patents

Acid addition salts of 2-(1-piperazinyl)pyrimidine and pharmaceutical compositions

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Publication number
NZ206222A
NZ206222A NZ206222A NZ20622283A NZ206222A NZ 206222 A NZ206222 A NZ 206222A NZ 206222 A NZ206222 A NZ 206222A NZ 20622283 A NZ20622283 A NZ 20622283A NZ 206222 A NZ206222 A NZ 206222A
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NZ
New Zealand
Prior art keywords
piperazinyl
pyrimidine
group
dicarboxylic acid
suppositories
Prior art date
Application number
NZ206222A
Inventor
E Crisafulli
M Frigerio
J P Chambon
Original Assignee
Sanofi Sa
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Publication date
Application filed by Sanofi Sa filed Critical Sanofi Sa
Publication of NZ206222A publication Critical patent/NZ206222A/en

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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

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) An acid addition salt of 2-(1-piperazinyl)pyrimidine with a dicarboxylic acid. 1. Claims (for the contracting state : AT) A process for preparing acid salts of 2-(1-piperazinyl)pyrimidine with dicarboxylic acids, characterized in that it comprises reacting 2-(1-piperazinyl)-pyrimidine with the calculated quantity of a dicarboxylic acid in an organic or aqueous organic solvent.

Description

New Zealand Paient Spedficaiion for Paient Number £06222 206222 \X -U-9X Complete Specification Filed: .!!.??. Class: Publication Cats: H?. ...
P.O. Journal, No: ...... t9\ V* % (ft Mil Ml /■ - - n Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Acid addition salts of 2-piperazinopyrimidine, process for their preparation and pharmaceutical compositions containing them" WE, SANOFI, a French Company, of 40, Avenue George V, 75008 Paris, France, hereby declare the invention, for which -3r/we pray that a patent may be granted to «e-/us, and the method by which it is to be performed, to be particularly described in and by the following statement _1~ (followed by page I A.) 206222 Acic addition salts of 2-piperazincpyrinidine, process fcr their preparation and pharmaceutical compositions containing them.
The present invention relates to novel salts of 2- piperazinopyrimidine having dopaminergic psychotropic action.
More particularly, the present invention concerns acid addition salts of 2-(1-piperazinyl)pyrimidine with 10 dicarboxylic acids, a process for their preparation and pharmaceutical compositions containing them as active ingredients.
The 2-(1-piperazinyl) pyrimidine is, in the form of free base, a compound well known in literature, utilized as 15 chemical intermediate.
It has teen tested among a number of compounds none of which has shown analgesic or antifilarial activity (H.w. piperazinyl)pyrimidine with dicarboxylic acids possess a very good psychotropic activity with dopaminergic mechanism 25 of action, particularly antipsychotic, antidepressive ar.c tranquillizing-sedative activity.
Thus, it is an object of the present invention tc provide the acid addition salts of 2-(1-piperaziny1)-pyrimidine with dicarboxylic acids. 2 Q^2,2,2, 2 Preferred acid addition salts of 2-(1-piperazinyl) -pyrimidine with dicarboxylic acids are represented by the formula wherein X represents an alkylene group of from 1 to 3 carbon atoms, a vinylene group, a hydrcxvethylene group, a 1,2-10 dihydroxyethylene group, an aminoethylene group or an amino— 1,3-prcpylene 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 mcnofunarate 15 (formula I, X = vinylene, trans) and the monoclutamate (formula I, X = 3-amino-l,3-propylene) of 2-(1-piperazinyl)-pyrimidine are particularly preferred.
The compounds of the present invention are prepared, according to a further object of the present invention, by a 20 salification process which comprises treating 2-(1-piperazinyl)pyrimidine with the calculated amount of dicarboxylic acid in an organic or organic aqueous solvent.
A compound of formula HOOC-X-QOOH in which X is as defined above, is advantageously utilized, in equimolecular amount, as dicarboxylic acid, L(+)-tartaric, succinic, maleic, fumaric and L-glutamic acids being particularly preferred.
N /"A HOOC-X-COOH I 106222 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 5 acetate or the like, is used as organic solvent.
The salt thus obtained is isolated according to conventional procedures by simple filtration and crystallisation, if necessary.
The salification may be carried out on crude 2-(1-10 piperazinyl)pyrimidine as obtained from the reaction of 2-chlorcpyrimidine with piperazine according to known procedures.
The activity of the compounds of the present invention has been evaluated in predictive tests for antipsychotic, 15 antidepressive and trancuillizing-sedative activity and for the dopaminergic mechanism of action.
The antipsychotic activity of a representative compound, 2-(1-piperazinyl)pyrimidine monomaleate, has been evaluated in the test of the antagonism of the amphetamine induced 20 group toxicity (J.H. Eurn et al., Arch. Int. Pharmacodyn. Ther. 1958, 113, 290).
The 2-(1-piperazinyl) pyrimidine monomaleate has been administered intraperitoneally in increasing doses to groups of 10 Charles River CD1 mice weighing 20-2 2 g placed 25 together in boxes which were 22 cm long, 12 cm wide and 12 cm deep. Thirty minutes after the administration, the mice were injected intraperitoneally with amphetamine at doses of 30 mg/kg. The mortality of animals was evaluated during the 24 hours following the injection of amphetamine and a22 2 ' ^ compared, in each group, to that of the controls group 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 15 the group toxicity induced by amphetamine, predictive of an antipsychotic action.
The antidepressive activity of the compounds of the invention has been evaluated in the test of antagonism of prochlorperazine-induced catalepsy (K. Eiziere et al., 20 Arzneimittel Forschung, 1982, _32 (II), 824).
A representative compound of the invention, namely 2-(1-piperazinyl)pyrimidine monomaleate, was administered intraperitoneally to groups of 10 Wistar male rats weighing 220-240 g; at the same time control animals were treated 25 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 206222 formed by three superposed corks (11 cm total height) and forced tc 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 5 prochlorperazine only.
Table II hereinbelow shows the percent of antagonism 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-piperazinyl)- pyrimidine monomaleate of the present invention is active in the test of prochlorperazine-induced catalepsy, predictive of antidepressive activity.
The tranquillizing-sedative activity of the compounds of 20 the invention was assessed in the motor activity test according tc the procedure of J.R. Eoissier et al. (Arch. Int. Pharmacodyn. 1965, 158, 212).
A representative compound of the invention, namely 2-(1-pip-erazinyl) pyrimidine monomaleate, was administered 25 intraperitoneally 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 which 206222 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 monomaleate 1 5 ** P CO.01 * p<0.05 "t" Student test From this table it results that the 2—(1— piperazinyl)pyrimidine monomaleate of the present invention 20 exhibits a good sedative activity indicated by the decrease of the spontaneous motility in the mouse.
Dopaminergic mechanism of a representative compound of the present invention, 2-(1-piperazinyl)pyrimidine mono-L (+)-tartrate was studied in comparison with the 25 corresponding free base and its hydrochloride by analysying the rotational behaviour in mice after unilateral lesion of the striatum (P. Protais et al., J. Pharmacol. 1976, 1, 251). 2.5 mg/kg 1.25 mg/kg 0.60 mg/kg - 51 % ** - 39 % * - 24 % ns 2.0 6 222 7 Female Charles River CD1 mice weighing 20-24 g were previously subjected to a unilateral lesion of the striatum by stereotaxic injection of 8 ti'.g/animal of 6-hydroxydcpamine. A week later, the 2-(1-piperazinyl)-5 pyrimidine mono-L(+)-tartrate, the 2-(1- piperazinyl)pyrimidine hydrochloride and the free base were 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, 1, 3 and 6 hours after 10 the administration of the three products. The turns ipsil'ateral to the lesion were plotted as positive values, the contralateral turns were plotted as negative values. The algebric sum of turns for each group of treated animals was compared tc that of control animals treated with the vehicle 15 (saline) only.
Table IV hereinbelow shews the percent variation of turns, as compared to the controls.
TAELE' IV Compound Variation % after minutes: 60 180 360 2- (1-piperazinyl)- - 94 ** - 62 ** - 60 ** pyrimidine base 2-(1-piperazinyl)- - 29 ns - 27 ns - 22 ns pyrimidine hycrochloride 2- (1-piperazinyl) - - 88 ** - 98 ** -124 ** pyrimidine mono- L (+)-tartrate ** significant p < 0.01 "t" ns: ncn significant //v c% '// s- * - \rv A 2 © 6 2 2 From this table it results that the base significantly reduces the algebric sum of turns ipsilateral . and contralateral to the lesion whilst the hydrochloride has no significant 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 time. On the contrary, the 2-(l-piperazinyl)pyrimidine mono-L (+)-tartrate of the present invention is more potent than the reference compounds and, 10 in addition, its activity increases significantly in the time. More particularly the representative compound of the invention not only reduces the above algebric sum at the sixth hour, but it shews a negative variation higher than 100%. This surprising finding proves that the number of 15 turns contralateral to the lesion is higher than that of the ipsilateral turns.
The dopaminergic psychotropic activity of the compounds of the present invention and their lev; toxicity make them useful as drugs.
Thus it is another object of the present invention to provide pharmaceutical compositions containing acid addition salts of 2-(1-piperazinyl)pyrimidine with dicarboxylic acids as active ingredients.
The preferred active ingredients are the compounds of 25 formula I above.
In the pharmaceutical compositions of the present invention for oral, parenteral, sublingual, transdermic or rectal administration, the salt of 2- (1- piperazinyl)pyrimidine with a dicarboxylic acid, utilized as ZQ6ZZZ 9 active ingredient, 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 5 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.
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 15 unit dose may be administered from 1 to 4 times daily to treat the humour or behaviour disorders.
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 400 ml of diethyl ether, the solution thus obtained 25 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 tc dryness under reduced pressure. The oil thus obtained is dissolved in 3 0 ml of isopropanol and 2.7 g 106222 of maleic acid dissolved in 30 ml of isoprcpancl is added tc the solution at about 60°C. From the solution thus obtained a product crystallizes which is filtered and dried to give 4 g of 2-(1-piperazinyl)pyrimidine monomaleate; m.p. 160-5 162°C. Ey further crystallization from 95% ethanol the melting point does not change.
EXAMPLE" 2".
To a solution of 1.64 g of 2-(1-piperazinyl)pyrimidine in 15 ml of isopropanol, is added, at a temperature of 50-10 60°C, a solution of 1.16 g of maleic acid in 15 ml of isopropanol. Thus, 2-(1-piperazinyl)pyrimidine monomaleate is obtained, identical to the product of Example 1.
In the same manner, - 2-(1-piperazinyl)pyrimidine monofumarate, m.p. 201-203°C, 15 - 2-{1-piperazinyl)pyrimidine mono-L(+)-tartrate, m.p. 165- 168°C, - 2-(1-piperazinyl)pyrimidine monosuccinate, m.p. 173-176°C are obtained.
The yield in all these preparations is about 95%. 20 EXAMPLE" 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 glutamic acid is added at a temperature of 45°C. The mixture is evaporated to dryness and the residue is taken up with 25 petrol ether to give 2-(1-piperazinyl) pyrimidine mono-L-glutamate; m.p. 188-190°C; yield 95%.
EXAMPLE" 4".
Capsules comprising one of the products described in Examples 1 to 3, having the following composition: 206222 ii active substance 15 rag lactose 120 mg magnesium stearate 5 mg are prepared by mixing intimately charges of the ingredients 5 above and introducing the mixture into hard gelatine capsule s.
EXAMPLE' 5 .
Tablets comprising one of the products described in Examples 1 to 3, having the following composition: TO active substance 20 mg lactose 100 mg microcrystalline cellulose 30 mg dried corn starch 4 0 mg magnesium stearate 5 mg are prepared by crushing the active ingredient to a particle dimension of 0.4 mm size, by passing it through a 0.4mm 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 20 substance are prepared.
EXAMPLE 6.
Ey operating as described in Example 5 hereinabove, tablets having the following composition are prepared: active substance 25 lactose cornstarch talc magnesium stearate EXAMPLF 7. 50 mg

Claims (2)

12 Suppositories, . comprising one of the products described in Examples 1 to 3, are prepared having the following composition: active substance 50 mg 5 lactose 25 0 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 suppositories. The suspension is poured into cooled moulds 10 to form suppositories weighing 1.7 g. 13 WHAT^/WE CLAIM IS:-OLAing
1. An acid addition salt of • 2-(1-piperazinyl)pyrimidine with a dicarboxylic acid.
2. A salt as claimed in claim 1, of formula ^ jj N JJH . HOOC-X-COOH wherein X represents an alkylene group of from 1 tc 3 carbon atoms, a vinylene group, a hydroxyethylene group, a 1,2-dihydroxyethylene group, an aminoethylene group or an amino-1,3-propylene' group. •3. 2-(1-piperazinyl)pyrimidine monomaleate. 4. 2-(l-piperazinyl)pyrimidine monofumarate. 15. 2-(1-piperazinyl) pyrimidine monosuccinate. >6. 2-(1-piperazinyl)pyrimidine mono-L(+)tartrate. ,7. 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 in an organic or organic aqueous solvent.
8. A process as claimed in claim 7, in which salification is carried out on a crude 2-(1-piperazinyl)pyrimidine, as obtained from the reaction of 2-chloropyrimidine with piperazine.
9. A process as claimed in claim 7, in which the dicarboxylic acid utilized is a compound of formula HOOC-X-COOH wherein X is as defined in claim 2. MQ622 2 14
10. A process as claimed in claim 9, in which the 2-(l-piperazinyl)pyrimidine and the dicarboxylic acid are utilized in equimolecular amount.
11. A pharmaceutical composition having dopaminergic psychotropic action containing, as active ingredient, a compound as claimed in claims 1 to 6.
12. A pharmaceutical composition as claimed in claim 11 which is in dosage unit form.
13. A pharmaceutical composition as claimed in claim 12 containing from 1 to 300 mg of active ingredient in admixture with a pharmaceutical carrier per dosage unit.
14. A pharmaceutical composition substantially as particularly described herein with reference to any one of the Examples. BALDVW^ SON & CAREY "—• ATTORNEYS FOR THE APPL(CAN^rS~
NZ206222A 1982-11-12 1983-11-10 Acid addition salts of 2-(1-piperazinyl)pyrimidine and pharmaceutical compositions NZ206222A (en)

Applications Claiming Priority (1)

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

Publications (1)

Publication Number Publication Date
NZ206222A true NZ206222A (en) 1985-09-13

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NZ206222A NZ206222A (en) 1982-11-12 1983-11-10 Acid addition salts of 2-(1-piperazinyl)pyrimidine and pharmaceutical compositions

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EP (1) EP0109340B1 (en)
JP (1) JPS59144766A (en)
AT (1) ATE19243T1 (en)
AU (1) AU567311B2 (en)
CA (1) CA1249275A (en)
DE (1) DE3363093D1 (en)
FR (1) FR2536071B1 (en)
IE (1) IE56184B1 (en)
NZ (1) NZ206222A (en)
ZA (1) ZA838423B (en)

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* Cited by examiner, † Cited by third party
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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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IE832631L (en) 1984-05-12
EP0109340A3 (en) 1984-06-27
ATE19243T1 (en) 1986-05-15
CA1249275A (en) 1989-01-24
FR2536071A1 (en) 1984-05-18
DE3363093D1 (en) 1986-05-22
AU567311B2 (en) 1987-11-19
ZA838423B (en) 1984-06-27
EP0109340A2 (en) 1984-05-23
FR2536071B1 (en) 1986-07-11
IE56184B1 (en) 1991-05-08
JPS59144766A (en) 1984-08-18
EP0109340B1 (en) 1986-04-16
AU2116483A (en) 1984-05-17

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