LU87129A1 - NOVEL PIPERAZINECARBOXYLIC ACID, ITS PREPARATION AND ITS USE AS A MEDICINE - Google Patents

Description

'% Q 7 1 / Ία GRAND-DUCHY OF LUXEMBOURG, r Brevet N ° ® ^ Mister the Minister of t \ yfi1' * of the Economy and the Middle Classes

Intellectual Property Service

Book title ............................. gC # Λ r

_LUXEMBOURG

? · '· Η Patent Application ....................................... ...........___________________________________________________________________________________________________________ (i) I. Request

The so-called company: SANDOZ SA, Lichtstrasse 35, CH-4002 Basel, Switzerland, ^ 2) represented by Mr. Louis ÉMRINGER, lawyer, residing in Luxembourg, acting in his capacity as agent ............ ...................-.............................. .................................................. .................................................. ...........; ................. ................. — ... ...... O) deposit (s) this eleven ........ f sink ...... 1.90.0 - ^^ ______________________________________________ (4) to ......... ../ [at ................ hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning: ............................................. ............. New ..... aci de pipéraziiiecarboxyliiîue ^ a .preparation and .son (5) .................. .................................... use as medicine ______________________________________________________________ 2. description in language ..... .... ................................. of the invention in triplicate: 3 ........ ............................. /. / _____________________ drawing boards, in triplicate; 4. the receipt of the taxes paid to the Luxembourg Registration Office, 28 ja n.VJL 8.X 1988.

5. the delegation of power, dated ........... Basel .______________________________________________________ on _____ 8 ....... £ é..vx, iax 1.9.88; 6. the successor document (authorization); 2d ^ m | ^ BEassHHmtiaxesp0Hsafeilk "d" ^ todéKlmtixmqad & (KS ^ iK8esaiBiK (skB3tiKKd ^ t · (6) claims (s) for the above patent application the priority of one (s) application (s) of (7). ..............................patent................... .................................................. ................................. registered in Great Britain ...... ..............................

on (9). February 18, 1987 ......................... _ ................ ... ...........

under N ° (10) ...... 8703749 .................................... .................................................. .................................................. .................................................. .................................................. .............

in the name of (11) ... the ...... applicant ................................. .................................................. .................................................. .................................................. ....................................

elect (elect) domicile for him / her and, if designated, for his / her representative, in Luxembourg 1.41 .. "JMJL6 ........ Albert ...

Linden ........ 26.5.2 ....... Luxembourg .............................. .................................................. .................................................. .................................................. .................... (12) requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, with adjournment of this delivery to ........................................ s ix___________________________________________________________________________________________________________________months. (13)

The depositor / agent: ............... ZjMjl $ / mIK & É * ___________________________________________________________________________ _____________________________________ (14) tfTPreport of deposit

The aforementioned patent application has been filed with the Ministry of the Economy and the Middle Classes. Intellectual Property Service in Luxembourg, on: | | pgy - * v. ·· KW Pr. the Minister for the Escontoie and the Middle Classes, at .......................... hours · /% ¾¾¾¾¾ ** · JLΓd.

* ï \. è The head of the intellectual intellectual service,

r \ ’ÿtyé, · # * / Z

I 1 A 68007_v v, ........ ..ί "_; _ / / _ A s HXPLICÂnONSRiL ^ TvisAÜFORMÏXA ^^ SÊÛÉfÔÏ: // IX-i 4 The wire if necessary" Request of certificate of addition athbseuetonrfcÎDal. to the DiindDal Nû patent application ....... fri. .from ........... ”- (2) enter the names. Name. profession.

500-5719 CLAIMING THE PRIORITY of the patent application In Great Britain February 18, 1987

DESCRIPTIVE MEMORY

filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New piperazinecarboxylic acid, its preparation and its use as a medicine * * "

The present invention relates to a new piperazinecarboxylic acid, its preparation and its use in therapy as a medicament.

British Patent Application No. 2,157,685 describes 4-substituted piperazine-2-carboxylic acids which have activity on the central nervous system.

The Applicant has now found that a compound of this class, which has not been described so far, exerts a particularly high activity on the central nervous system and has good tolerance as well as a long duration of action.

More particularly, the invention relates to [R (E)] - 4- (3-phosphono-2-propenyl) -piperazine-2-carboxylic acid of formula I

OH

> 0 Il ÔH

c.V

H NC00H

and its salts.

The invention also relates to a process for preparing the compound of formula I, process according to which

a compound of formula II is dealkylated

0 / “Û ,.

M

C00H- in which R represents a C 1 -C 4 alkyl group or a (C 1 -C 4) alkyl group.

The process can be carried out according to known methods 1 * t 2. The dealkylation can be carried out for example by silylation followed by the hydrolysis of the resulting silyl ester. The silylation can be carried out for example with bromotrimethylsilane in an organic solvent such as dichloromethane or chloroform, at room temperature. Subsequent hydrolysis can be carried out under mild conditions.

When R denotes a C1 ~ C4 (aryl) alkyl group, the aryl residue is advantageously a phenyl group optionally substituted, suitably by lower alkyl or alkoxy groups.

The compound of formula I and its salts can also be obtained in the form of hydrates, in particular of monohydrate. Hydrates, in particular monohydrate, also form part of the invention.

The starting materials of formula II can be prepared according to the following reaction scheme: 3? H2C6H5 ÎH2C6H5 rS T) (-) - menthol 'N / 3

^ N ^ -COOCpH, - 2) LnJ ^ H separation

CH CH? ES I 'COOiy ^

2 6 n5 diastereoisomers C ^ CgHg IJ

n CH] ch * S ^ OR ψΡ ^ / C 3 / N ° R B% ch3

r * U. T

\ / V

(C2HS) 3N C "3

? ,GOLD

BC1 N ’CH3 CH3 u CL“ y H '^ ΟΟγΝ ch3

The compound of formula I can form cationic salts and addition salts with acids. Such salts can be obtained according to known methods * 4. The cationic salts include, but are not limited to such salts, the ammonium, sodium, potassium, calcium, piperidinium, morpholinium or pyrrolidinium salts. The addition salts with acids include, without being limited to such salts, those obtained with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.

The hydrates, in particular the monohydrate of the compound of formula I, exhibit physicochemical and other properties, which are particularly advantageous, for example as regards solubility, ease of purification and stability. The hydrate can be obtained by crystallization of the compound of formula I in an aqueous medium, for example as described in example e), for example in a mixture of methanol and water.

The following example illustrates the present invention without in any way limiting its scope. In this example, the degrees are expressed in degrees Celsius and are not corrected; the values [a] D are also given uncorrected.

Example 1 [R- (E)] - 4- (3-Phosphono-2-propenyl) -piperazin-2-carboxylic acid a) (R) -1,4-bis (phenylmethyl) -piperazine-2-carboxylate of (IR, 2S, 5R) -5-methyl-2- (1-methylethyl) -cyclohexyl To a solution of 761 g of ethyl 1,4-dibenzyl-piperazine-2-carboxylate (prepared as described by E. Jucker et al in Helv. Chim, Acta 45 (1962) 2383) and 458 g of (-) - menthol, 15 g of NaH (55-60% dispersion) and one liter of toluene are added at 45 °. About 700 ml of the solvent are then slowly removed by distillation and continuously replaced with new portions of toluene (the reaction is followed by thin layer chromatography, ethyl acetate / hexane 1: 3). The reaction mixture is cooled to room temperature, treated with 1.25 liters of 2N aqueous HCl and 6 liters of diethyl ether and stirred vigorously for 1 hour. The precipitated crystals are filtered off and washed with diethyl ether and 0.1N aqueous hydrochloric acid. The crude product is recrystallized from a 0.2N aqueous ethanol / HCl mixture, which gives the hydrochloride of the title compound; la] D + 18.5 ° (c ”1.2 in CHCl 4) the product obtained is used as it is for the following reaction, without prior purification.

b) (R) -piperazine-2-carboxylate of (lRr2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl

Hydrogenated for 7 hours at room temperature and under normal pressure, 210 g of the product of step a) in 2 liters of ethanol and in the presence of 10.5 g of Pd / C (10%). The reaction mixture is then filtered and evaporated in vacuo. The residue is treated with ethanolic hydrochloric acid, the precipitate which has formed is filtered and washed with an ethanol / diethyl ether mixture (1: 1). The product is recrystallized from a water / methanol / ethyl acetate mixture, which gives the dihydrochloride of the title compound, F - 225-226 °; l "] 2 ° D" -52.0 ° (c = 1.34 in water). The dihydrochloride is treated with a diethyl ether / ammonia mixture and the organic phase is evaporated to dryness, which gives the title compound, F - 50-52 °; [a] 2 ° d - -56.7 ° (c - 1.05 in CHClj).

c) [R- (E)] - 4- (3-diethoxyphosphinyl-2-propenyl) pipé raz ine-2- carboxylate from (1R, 2S, 5R) -5-methyl-2- (1-methylethyl) -cyclohexyl To a solution kept under stirring and consisting of 11.3 g of the free base of step b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran and added at -30 ° and in the space of 30 minutes 10.7 g of diethyl 3-bromo-propene-2-yl-phosphonate (prepared 6 as described by K. Hemmi et al. in Chem. Pharm.

Bull 22 ”1982, 111) in 45 ml of tetrahydrofuran. Stirring continues for 20 hours at -25 °. After filtering the precipitate, the solution is concentrated under reduced pressure and the resulting syrup is chromatographed on silica gel using as eluent dichloromethane added with increasing amounts of a 1:19 mixture of concentrated ammonia / ethanol reaching 10% after 2 hours . The fraction eluted with a dichloromethane / concentrated ammonia / ethanol 200: 1: 19 mixture (Rf "0.35) is isolated and concentrated under vacuum, which gives the title compound in the form of an oil; [a] ^ ° D "-56.0e (c" 1.3 in 2N aqueous HCl). By treating the product obtained with an ethanolic HCl / ether mixture, the dihydrochloride is obtained, mp 157-163 °; {a] 2 ° D - -48.2e (c = 1.4 in 2N HCl).

d) [R- (E)] - 4- (3-Diethoxyphosphinyl-2-propenyl) -pipe-razine-2-carboxylic acid A solution maintained under stirring consists of 5.79 g of the product from step c ) in 58 ml of anhydrous dichloromethane, 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane (approximately 2.2 M) are added at -30 ° and over 30 minutes. The reaction mixture is stirred for 1 hour at -25 ° and for 3.5 hours at 0 °. At 0 °, 50 ml of water are added and the mixture is neutralized by adding 2N aqueous NaOH and it is distributed between water and dichloromethane. After evaporation of the aqueous phase in vacuo until dry, the residue is taken up in chloroform, the chloroform solution is filtered, dried over Na2SO4 and evaporated to dryness in vacuo, which gives the title compound. The product is used as it is for the following reaction, without prior purification.

A sample for analysis purified by HPLC chromatography (Nucleosil RP-8, HjO / CH ^ OH 3: 2), 7 gives the product in the form of a foam; [<x] 20d - -18.0 ° (c - 1.1 in 0.5 N HCl).

1H-NMR spectra (360 MHz, DMSO, 150eC): I, 24 (6H, t, J = 7.0 Hz), 2.26 (1H, dxdxd, J = 11.3 x 9.0 x 3.3 Hz), 2.35 (1H, dxd, J = 11.3 x 8.6 Hz), 2.52 - 2.58 (1H, m), 2.77 (1H, dxdxd, J = 12.1 x 9.0 x 3.3 Hz), 2.83 (1H, dxdxd, J * II, 3 x 3.3 x 1.7 Hz), 2.99 (1H, dxt, J = 12.1 x 3, 9 Hz), 3.10 - 3.15 (2H, m), 3.33 (1H, dxd, J = 8.6 x 3.3 Hz), 3.97 (4H, dxq, J = 8.6 x 7.0 Hz), 5.50 (2H, wide) ', 5.88 (1H, dxdxt, J = 21.5 x 17.1 x 2.1 Hz), 6.52 (1H, dxdxt, J = 22.0 x 17.1 x 5.6 Hz).

e) [R- (E)] - 4- (3-phosphono-2-propenyl) -piperazine-2-carboxylic acid

3.9 g of the crude product from step d) are dissolved in 300 ml of anhydrous CHjClj, treated at room temperature with 9.6 ml of bromotrimethylsilane and stirred for 16 hours. The reaction mixture is evaporated, the residue is taken up in water, stirred for one hour and filtered. The pH of the solution is adjusted to 6 by addition of Dowex 1x4 (OH form) and the mixture is chromatographed on a column of Dowex 1x4 (acetate form). Elution with an aqueous acetic acid gradient (0.05 to 0.25N) gives the product in the form of a foam after evaporation to dryness under vacuum.

The foam is crystallized from an H2O / CH3OH mixture and the product is recrystallized from a H2 ° / C2H5OH 'mixture, this title compound in the form of a monohydrate, P 206 ° (decomposition); [a] D ”-21.6e (c” 1.1 in 2N HCl). The absolute configuration is deduced by chemical correlation with D-asparagine and confirmed by X-ray structure analysis.

8 4

The compound of formula I has interesting pharmacological properties and can be used therapeutically as a medicament.

The compound of formula I exerts in particular an inhibitory activity on the secretion of luteinizing hormone (LH) and testosterone, as appears from the following tests:

The test compound is administered intraperitoneally to adult male rats of the Wistar strain (SIV, Kissleg, Federal Republic of Germany, 200-300g). After 2 hours, the rats are decapitated and blood samples are taken. The concentration of LH in the blood is determined according to a biological test method based on the production of testosterone in rats by Leydig interstitial cells dispersed and treated with collagenase which have been exposed to serum containing LH or to a standardized sample of rat LH. Serum testosterone levels are determined by the radioimmunological assay method (125-J-T, Cis, Medipro Teufen, Switzerland) [E. del Pozo, A. Podesta, A. Solano, J. Calaf, M. Marko, Biorhythms and Stress in the Physiopathology of Reproduction, P. Pancheri and L. Zibella (Eds), Hemisphere Publishing Co. Washington, 389-398 (1988 )].

The compound of formula I significantly inhibits the secretion of LH and testosterone at a dose of 3.2 mg / kg after administration intraperitoneally. The corresponding racemic of the compound of formula I, namely (^) - 4- (3-phosphono-2-propenyl) -piperazine-2-carboxylic acid (hereinafter referred to as CPP-ene), has no effect on the secretion of LH and weakly inhibits the secretion of testosterone after administration at the dose of 3.2 mg / kg intraperitoneally.

In rats, the compound of formula I

9 inhibits spontaneous LH-dependent ovulation, as shown in the following trial [M. Marko and E.

Flückiger, Neuroendocrinology 30, 228-231 (1980)]:

During the period of 1 to 3 o'clock preestrus, the test substance is administered intraperitoneally to rats of Wistar strain (Siv, Kissleg, Federal Republic of Germany, 200-300 g) having regular cycles of 4 days. The next day at 9 am, during estrus, the animals are sacrificed, the fallopian tubes are examined under a microscope and the number of eggs is counted. Ovulation is considered to be inhibited if no egg is observed. The compound of formula I (as monohydrate) significantly inhibits spontaneous ovulation when administered intraperitoneally at a dose of 2 times 3.2 mg / kg (3.2 mg / kg at 1 p.m. and 3.2 mg / kg at 3 p.m.). Under identical experimental conditions, CPP-ene very slightly inhibits spontaneous ovulation, after intraperitoneal administration of 2 times 3.2 mg / kg.

Thanks to these properties, the compound of formula I can therefore be used therapeutically for the treatment of disorders having an etiology associated with or modulated by the secretion of LH or having an etiology in which physiological regulation of the secretion of LH LH is involved, for example for the treatment of an enlarged prostate, menopausal syndrome, as well as breast and prostate cancer. For this use, the daily dose indicated is between approximately 1 and approximately 800 mg of active substance, administered in divided doses 2 to 4 times per day in the form of unit doses each containing for example between approximately 0.25 and approximately 400 mg of active substance, or in a sustained release form.

10 '

The compound of formula I exerts a muscle relaxant activity demonstrated in awake rabbits after administration by intravenous route at doses between 0.01 and 0.05 mg / kg [H.J. Teschendorf et al., Arch. Exp. Pharmacol., 266, p. 467-468 (1970)]. In this test, the monohydrate of the compound of formula I causes a 50% inhibition of the muscle tonic reflex after intravenous administration at the dose of 0.02 mg / kg, while the CPP-ene inhibits by 47% muscle tonic reflex after intravenous administration at a dose of 0.5 mg / kg, the compound of formula I being approximately 25 times more active than the corresponding racemic.

Thanks to these properties, the compound of formula I can therefore be used in therapy for the treatment of increased muscle tone, for example for the treatment of painful muscle spasms attributable to static and functional disorders of the lumbar or cervical part of the body. the spine or following an operation, or for the treatment of spasticity caused, for example, by multiple sclerosis, diseases of the spinal cord, cerebrovascular accidents, cerebral trauma or cerebral palsy.

For this indication, the daily dose is between approximately 1 and approximately 800 mg of active substance, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, from approximately 0.25 to approximately 400 mg of active substance or in a sustained release form.

In addition, the compound of formula I reduces the alterations in neurons caused by ischemia and the symptoms resulting from occlusion of the middle cerebral artery (ACM) in the rat, after π administration subcutaneously with a dose of 1 to 30 mg / kg, and in particular after intraperitoneal administration of 3 X 10 mg / kg [A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, p. 53-60 (1981), A.

Sauter and M. Rudin, Stroke 17, p. 1228-1234 (1986)]. The area of tissue affected by the infarction is measured using an MCID image analysis device (from the company Imaging Research Inc.) in 5 horizontal layers of 20 μτ & thickness sectioned at various levels and colored. by cresyl violet. The total volume of brain having undergone ischemic deterioration is evaluated by adding the 5 zones obtained from the 5 layers. The extent of the infarction determined 5 days after occlusion of the MCA is reduced by more than 20% after administration of the monohydrate of the compound of formula I intraperitoneally at a dose of 3 times 10 mg / kg ( first injection immediately after occlusion of the ACM, second and third injection respectively after 8 and 16 hours).

Thanks to these properties, the compound of formula I can be used in therapy for the prophylaxis and treatment of conditions associated with cerebral ischemia, for example for cerebral attacks. For this indication, the appropriate daily dose is between approximately 25 and approximately 800 mg of active substance, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, from approximately 6 to approximately 400 mg of active substance, or in a sustained release form.

In addition, the compound of formula I exerts a powerful, selective and competitive antagonist activity on the receptors of NMDA (N-methyl-D-aspartic acid). Thus, the monohydrate of the compound of formula I inhibits depolarizations of the isolated spinal cord of frog induced by NMDA [P.L. Herrling, Neuroscience. 14, p.417-426 (1985)] with a pA2 value of 6.8 and CPP-ene with a pA2 value of 6.2, the compound of formula I being approximately 4 times more active than the corresponding racemic. The (+) - 3- (2-carboxypiperazine-4-yl) -propyl-1-phosphonic acid (CPP) from British Patent Application No. 2,157,685 has a pA2 value of 5.8.

In rat brain sections, sodium efflux can be induced by NMDA, quisqualate or kainate [A. Luini et al., Proc. Natl. Acad.

Sei. USA 78, p. 3250-3254 (1981)]. The monohydrate of the compound of formula I exerts an antagonistic effect on the sodium efflux induced by NMDA (pA2 value = 6.5). In this trial, the CPP-ene has a pA2 value of 6.2 and the CPP a pA2 value of 6.0. The compound of formula I is approximately 2 times more active than the corresponding racemic.

The compound of formula I is selective in that, like CPP-ene and CPP, it has no antagonistic effect on the sodium efflux induced by quisqualate and kainate up to a concentration of ImM .

Thanks to their antagonistic effect on NMDA receptors, the compound of formula I can be used therapeutically for the treatment of anxiety, schizophrenia and depression or degenerative diseases of the CNS, such as Huntington's disease, Alzheimer's disease or Parkinson's disease. For these uses, the compound of formula I will be administered at a daily dose of between approximately 25 and approximately 800 mg, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, from approximately 6 to approximately 400 mg of active substance 13, or in a sustained-release form.

Thanks to their antagonistic activity on NMDA receptors, the compound of formula I is also suitable for use in therapy in the treatment of tinnitus. For this indication, it will be administered at a daily dose of between approximately 25 and approximately 800 mg, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, from approximately 6 to approximately 400 mg of substance. active, or in sustained release form.

The compound of formula I also exerts an anticonvulsant activity; in mice, it inhibits convulsions caused by electroshock [E.A. Swinyard, J. Am. Pharm. Assoc. Scientist. Ed 38, p. 201 (1949) and J. Pharmacol. Expt. Therap. 106, 319 (1952)]. In this test, groups of 6 male mice (18-26 g, OF-1, Sandoz Basel) receive the substance to be tested intraperitoneally. After 1, 2 and 4 hours, a 50 mA shock is applied for 200 ms with corneal electrodes coated with an electrolyte jelly. This supra-maximal shock produces tonic convulsions of the extensor muscles. Inhibition of extension of the hind limb is considered to be a protective effect. After testing various doses, the threshold dose is determined. The threshold dose after one hour, or the dose required to inhibit the extension of the hind limb, is <1 mg / kg (intraperitoneally) for the compound of formula I (monohydrate) and between 3 and 10 mg / kg (intraperitoneally) for the CPP-ene. The threshold dose indicated in the literature for the CPP is 10 mg / kg (intraperitoneally).

In the following table, the inhibition of the extension of the hind limbs expressed in% is given for the compound of formula I as well as for the corresponding racemic:% of inhibition of Dose T extension of the mg / kg hind limb induced by ip electroshock

Compound of formula I 1 67 * 67 * 33 * (monohydrate) 2.5 83 * 83 * 67 * 3 100 * 100 * 83 * CPP-ene 1 20 50 25 3 33 67 * 17 10 67 * 80 * 80 *

Fischer test, control group / group receiving the test substance * p <* 0.05.

As shown in the table, the compound of formula I exerts a higher anticonvulsant activity than the corresponding racemic, in the test of convulsions induced by electroshock in mice.

In addition, the compound of formula I inhibits convulsions caused by N-methyl-D-aspartic acid (NMDA) in mice. In this test, groups of 6 female mice (18-26 g, OF-1, Sandoz Basel) are pretreated intraperitoneally with the test substance. After 30 minutes, they are given 400 mg / kg of NMDA subcutaneously in the neck area and observed for 30 minutes. We note the waiting times for the appearance of the first signs of convulsions, for the first tonic convulsions and for death. The significance of any possible difference is determined using the Mann-Whitney U test [S. Siegel, Non-parametric Statistics, McGraw-Hill, New York 1956], 15

The threshold dose is the lowest dose at which significant inhibition of symptoms of seizures occurs. The threshold dose of the compound of formula I (monohydrate) is approximately 5 mg / kg intraperitoneally, and that of the CPP is 10 mg / kg intraperitoneally.

Thanks to its anticonvulsant activity, the compound of formula I can be used therapeutically for the treatment of epilepsy. For this indication, the daily dose is between approximately 25 and approximately 800 mg administered advantageously in divided doses 2 to 4 times per day in the form of unit doses each containing for example from approximately 6 to approximately 400 mg of active substance, or under sustained release form.

The compound of formula I exerts in vitro also an analgesic activity on the lumbar spinal cord isolated from the rat by using capsaicin (0.8-1 μη) as a toxic chemical stimulus which causes depolarization of the ventral endings [M. Yanagisawa et al., European J. Pharmacol. 106, p. 231-239 (1984)]. The monohydrate of the compound of formula I reduces the chemical stimulus by 75-80% at a concentration of 10 μη.

The compound of formula I is therefore suitable for use in therapy as an analgesic. For this indication, the daily dose is between approximately 25 and approximately 800 mg, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, from approximately 6 to approximately 400 mg of active substance. , or in an extended release form.

In addition, the compound of formula I and the corresponding racemic have no effect on blood pressure and heart rate in the anesthetized cat 16, at doses up to 10 mg / kg administered intravenously. venous. In 4 week pilot toxicity tests in dogs, a daily dose of 3 mg / kg of compound of formula I, administered intravenously, was well tolerated.

As evidenced by the results of the above tests, the strong inhibitory activity on the secretion of LH, the marked increase (25 times) in muscle relaxant activity as well as the antagonistic effect of the compound of formula I on NMDA receptors 2 to 4 times higher than that of the corresponding racemic, are not accompanied by a similar increase in side effects, in particular cardiovascular effects.

The compound of formula I can be administered as such or in the form of a pharmaceutically acceptable salt. The salts have the same order of activity as the compound of formula I.

The invention therefore relates to the compound of formula I or a pharmaceutically acceptable salt of this compound, for use in therapy as a medicament, for example for the treatment of disorders associated with the secretion of LH, of increase in muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression or degenerative diseases of the CNS, tinnitus, epilepsy, or to suppress pain.

The invention further relates to a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

The compound of formula I can be administered by any of the usual routes, in particular enterally, preferably orally or parenterally. It can be administered as is or combined with conventional pharmaceutical vehicles. For oral administration, for example in the form of tablets or capsules, the compound of formula I can be mixed with usual pharmaceutical excipients, for example inert diluents such as lactose, mannitol, calcium sulfate, microcrystalline cellulose, disintegrating agents such as starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, alginic acid, crospovidone, binders such as cellulose derivatives (methyl-, hydroxymethyl-, hydroxypropylmethyl-cellulose ), povidone, gelatin, lubricants such as silica, stearic acid, magnesium or calcium stearate, hydrogenated oils such as castor oil, glycerol esters, for example palmitostearate and / or flavorings, colors and sweeteners. The tablets may be uncoated or coated according to known techniques to delay the decomposition and absorption of the active substance in the gastrointestinal tract and thereby produce a prolonged action. The compositions to be administered parenterally are preferably in the form of sterile injectable aqueous solutions. If necessary, such aqueous solutions should be buffered and made isotonic with a sufficient amount of physiological solution. Optionally, a preservative such as benzyl alcohol can be added.

A unit dose may contain from about 0.25 to about 400 mg of the compound of formula I or a pharmaceutically acceptable salt of this compound.

18

The pharmaceutical compositions can be prepared according to the usual methods.

For the preparation of tablets, the compound of formula I can be mixed with lactose and granulated with water, 0.5% sodium alginate solution or 5% hydroxypropylmethyl cellulose. The dry granulate is put in the form of tablets in the presence of approximately 20% of corn starch and 1% of magnesium stearate. It is thus possible to obtain tablets having the following composition:

Composition Tablets _Weight (mg)

Compound of formula I

(monohydrate) 50

Lactose 97

Corn starch 40

Hydroxypropylmethylcellulose 10

Magnesium stearate 2

Silica 1,200

These tablets, which have a slit, can be administered orally at a dose of half a tablet to 1 to 4 times a day.

The capsules may contain the active substance alone or in combination with an inert solid excipient, as indicated above.

The capsules containing the ingredients indicated below can be prepared according to the usual methods and are administered at the rate of 1 capsule 1 to 4 times per day: _Composition_Capsule / weight (mg)

Compound of formula I

(monohydrate) 50

Inert solid excipient (corn starch, lactose, aerosil, magnesium stearate) 250

It is also possible to prepare tablets and capsules containing 25 mg and 100 mg of compound of formula I.

The following solution for injection is formulated with the indicated amount of active substance, according to the usual techniques. The solution for injection is suitable for a single daily administration: Composition Sterile solution _injectable / Weight (mq / ml)

Compound of formula I monohydrate 25

Sodium chloride 7.0

Potassium dihydrogen phosphate 3.63

Disodium hydrogen phosphate 5.68

Benzyl alcohol 9.0

Water for injection q.s.p. 1 ml

The solutions can be filtered through a sterile 0.2 µm filter and poured into ampoules under aseptic conditions. The ampoules are placed under carbon dioxide.

The invention also relates to the use of the compound of formula I or of a pharmaceutically acceptable salt of this compound, for the preparation of a medicament intended for the treatment of disorders associated with the secretion of LH, of the increase in tone 20 muscle, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression, degenerative diseases of the CNS, tinnitus, epilepsy or to suppress pain.

Claims (7)

1. [R (E)] - 4— (3-phosphono-2-propenyl) -piperazine-2-carboxylic acid of formula I OH il OH Cil ·. H COOH and its salts. 2. The compound according to claim 1, in the form of monohydrate, and the salts of the moaohydrate. 3. A process for the preparation of [R- (E)] - 4- (3-phosphono-2-propenyl) -piperazine-2-carboxylic acid specified in claim 1, and its salts, characterized in that a compound of formula II 0 sk * \\ "R rna" H nC00H in which R represents a C 1 -C 4 alkyl or (aryl) C 1 -C 4 alkyl group, and optionally forms a salt of this compound. 4. a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a medicament. 5. A compound according to claim 4 for use in the treatment of disorders associated with the secretion of LH, increase in muscle tone, conditions associated with cerebral ischemia r 1, 22, anxiety, schizophrenia, depression, degenerative CNS disease, tinnitus, epilepsy or to suppress pain. 6. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 or 2, or a pharmaceutically acceptable salt of this compound, in combination with a pharmaceutically acceptable diluent or vehicle. 7. The use of the compound of formula I or of the monohydrate of this compound, or of a pharmaceutically acceptable salt of this compound or of the monohydrate, for the preparation of a medicament intended for the treatment of disorders associated with the secretion of LH , increased muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression, degenerative CNS disease, tinnitus, epilepsy or to suppress pain.