FR2610932A1 - NOVEL PIPERAZINECARBOXYLIC ACID, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS R (E) -4- (3-PHOSPHONO-2-PROPENYL) -PIPERAZINE-2-CARBOXYLIC ACID OF FORMULA I (CF DRAWING IN BOPI) AND ITS SALTS. THIS COMPONENT WORKS ON THE CENTRAL NERVOUS SYSTEM AND CAN BE USED AS A MEDICINAL PRODUCT.

Description

1 2

  The subject of the present invention is a novel

  Piperazinecarboxylic acid, its preparation and its

  therapeutic use as a medicine.

  British Patent Application No. 2 157 685 discloses substituted piperazine-2-carboxylic acids in

  position 4 which have an activity on the ner-

want central.

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

than a long duration of action.

  More particularly, the invention relates to

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

  carboxylic acid of formula I OH! P = O <OH I N Id1 H

H 'COOH

and its salts.

  The invention also relates to a process for the preparation of the compound of formula I, in which process a compound of the formula II OR II CNHCOOH - in which R is a C1-C4 alkyl group or

(aryl) -C1-C4alkyl.

  The process can be carried out according to known methods. The dealkylation can be carried out for example by silylation followed by the hydrolysis of the resulting silyl ester. Silylation may be effected for example with bromotrimethylsilane in an organic solvent such as dichloromethane or chloroform at room temperature. The subsequent hydrolysis can be carried out under

mild conditions.

  When R is a (C 1 -C 4) arylalkyl group, the aryl radical is preferably an optionally substituted phenyl group, suitably

  lower alkyl or alkoxy groups.

  The compound of formula I and its salts may also

  can be obtained in the form of hydrates, in particular

  of monohydrate. Hydrates, especially mono-

  hydrate, are also part of the invention.

  The starting materials of formula II can be prepared according to the following reaction scheme:

2 61U 0 93

CH2C6H5 CH2C6H5

  lN1 1) (-) - enthol N CH3 CH3 CH C H 2) separation <N H of ICOOJ 'H2C6H5 diastereoisomers CH2C6H5

[H] CH

0 3Pd / C POR HPd /

I O R N CH CH3

 r To C]) - H

N 3 3

Br HN COOh

"(C2H5) 3N 3

nHO CCH3:, OR

P ",,, OR

IBI CH .. 3H 'CCH3

  The compound of formula I may form cationic salts and addition salts with acids. Such salts can be obtained according to the methods

  known. Cationic salts include, without

  so long as salts of ammonium, sodium, potassium, calcium, piperidinium, morpholinium or pyrrolidinium are limited. The addition salts with acids include, but are not limited to such salts, those obtained with hydrochloric acid,

  hydrobromic acid, sulfuric acid, methanolic acid,

  sulphonic acid, benzenesulphonic acid, p-toluene acid,

  sulfonic acid and trifluoroacetic acid.

  Hydrates, in particular the monohydrate

  compound of formula I, has physical properties

  chemicals and other properties, particularly

  for example 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 uncorrected; the values [(]] are also given non-corrected.

  Example: [R- (E)] - 4- (3-phosphono-2-propenyl) -piperazine

  (1R, 2S, 5R) -5-methyl-2- (1-methylethyl) -cyclohexyl zine-2-carboxylic acid a) (R) -1,4-bis (phenylmethyl) -piperazine-2-carboxylate

  To a solution of 761 g of 1,4-dibenzylpiperazine

  Ethyl 2-carboxylate (prepared as described by E. Jucker et al in Helv Chim Acta 45 (1962) 2383) and 458 g of (-) menthol was added to 45 g of

  NaH (55-60% dispersion) and one liter of toluene. In-

  700 ml of the solvent are then slowly distilled off 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 chlorinated

  0.1N aqueous water. The crude product is recrystallized from ethanol / 0.2N aqueous HCl to give the hydrochloride hydrate of the title compound; [a] D + 18.5 (c-1.2 in CHCl3) the product obtained is used as such for the next reaction, without prior purification.

  b) (1R, 2S, 5R) -5-methyl-2- (R) -piperazine-2-carboxylate

  (1-methylithyl) cyclohexyl 210 g of the product of step a) in 2 liters of ethanol and 10.5 g of Pd / C (10 g) are hydrogenated for 7 hours at room temperature and under normal pressure. %). The reaction mixture is then filtered and evaporated in vacuo. The residue is treated with

  ethanolic hydrochloric acid, the precipitate is filtered off

  formed and washed with ethanol / diethyl ether (1: 1). The product is recrystallized from water / methanol / ethyl acetate to give the dihydrochloride of the title compound, F-225-226; 20 - -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 to give the title compound.

  F - 50-520; [α] 20 - 56.7 (c - 1.05 in CHCl 3).

  c) [R- (E) 1] -4- (3-Diethoxyphosphinyl-2-propenyl) piperazine-2-

  (1R, 2S, 5R) -5-methyl-2- (1-methylethyl) carboxylate

  To a stirred solution consisting of 11.3 g of the free base of step b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran was added at -300 and over a period of 30 minutes. 10.7 g of diethyl 3-bromo-propen-2-yl-phosphonate (prepared as described by K. Hemmi et al in Chem Pharm Bull, 1982, 111) in 45 ml of tetrahydrofuran. Stirring is continued for 20 hours at -250. After filtering off the precipitate, concentrate the solution under

  reduced pressure and the resulting syrup is chromatographed

  both on silica gel using as eluent dichloromethane added with increasing amounts

  of a 1:19 concentrated ammonia / ethanol mixture

  staining 10% after 2 hours. The fraction eluted with a

  dichloromethane / concentrated ammonia / ethanol

  200: 1: 19 (Rf - 0.35) is isolated and concentrated in vacuo to give the title compound as an oil; [] 20 -56.0 (c-1.3 in aqueous HCl D 2 N). By treating the product obtained with an ethanolic HCl / ether mixture, the dihydrochloride is obtained,

  F 157-163o; [c] 20 - -48.2 (c-1.4 in 2N HCl).

D

  d) [R- (E)] - 4- (3-diethoxyphosphinyl-2-propenyl) -piperidine

  razine-2-carboxylic acid A stirred solution is constituted

  5.79 g of the product of step c) in 58 ml of di-

  Under anhydrous methylene chloride, 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane (about 2.2 M) are added at -300 and in the course of 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 addition of NaOH.

  2N and is distributed between water and di-

  chloromethane. After evaporation of the aqueous phase to dryness in vacuo, the residue is taken up in chloroform, the chloroform solution is filtered, dried over Na 2 SO 4 and evaporated to dryness in vacuo.

  which gives the title compound. The product is used

  as is for the next reaction without purification

prior notification.

  A sample for analysis purified by

  HPLC matography (Nucleosil RP-8, H20 / CH 3 OH 3: 2), gives the product as a foam;

  lu] 20D = -18.0 (c-1.1 in 0.5 N HCl).

  1H-NMR spectra (360 MHz, DMSO, 150 ° C): 1.24 (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, G.dxd, J =

  11.3 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 3.3Hz), 3.97 (4H, dxq, J = 8.6 x 7.0Hz), , 50 (2H, broad), 5.88 (1H, dxdxt, J - 21.5x

  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 of step d) are dissolved in 300 ml of anhydrous CH 2 Cl 2, 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 and shaken for

  an hour and filter it. The pH of the solu-

  to 6 by addition of Dowex 1 x 4 (OH form) and the mixture is chromatographed on Dowex lx4 column (acetate form). Elution with a gradient of aqueous acetic acid (0.05 to 0.25N) gives the product under

  form of a foam after dry evaporation under vacuum.

  The foam was crystallized from H 2 O / CH 3 OH and recrystallized from H 2 O / C 2 H 5 OH to give the title compound as monohydrate, F-2060 (dec);

  a] 20D -21.60 (c-1.1 in 2N HCl). The configuration

  The absolute concentration is deduced by chemical correlation with D-asparagine and confirmed by X-ray structure analysis.

  The compound of formula I has

  resenting pharmacological properties and can be

  used therapeutically as a medicine.

  The compound of formula I exerts in particular

  inhibit the secretion of luteinizing hormone (LH) and testosterone, as shown by the following tests: The compound to be tested intraperitoneally is administered to male adult rats of Wistar strain (SIV, Kissleg, Republic of Federal Republic of Germany, -300g). After 2 hours, the rats were decapitated and blood samples taken. The concentration of LH in the blood is determined according to a method

  biological test based on the production of testosterone

  rat sterility by dispersed and collagenase-treated Leydig interstitial cells that were exposed to LH-containing serum or to a standardized sample of rat LH. Serum levels

  testosterone are determined by the radio-

  immunological assay (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 inhibits

  significant secretion of LH and testosterone

  terone at a dose of 3.2 mg / kg after intraperitoneal administration. The corresponding racemic

  of the compound of formula I, namely (+) - 4- (3-

  phosphono-2-propenyl) -piperazine-2-carboxylic acid

  hereinafter 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 female rats, the compound of formula I

2 6 1 0 93

  inhibits LH-dependent spontaneous ovulation, as shown by the following test [M. Marko and E. Fleckiger, Neuroendocrinology 30, 228-231 (1980)]: During the period of preoestrus at 13 and 15 hours, the test substance is administered intraperitoneally to female rats of strain Wistar (SIV, Kissleg, Republic Federal Republic of Germany, 200-300 g) with regular cycles of 4 days. The following day, at 9 o'clock, during oestrus, the animals are sacrificed, the fallopian tubes are examined under the microscope, and the number of ovules is counted. Ovulation is considered to be inhibited if no ovum is observed. The compound of formula I (as monohydrate) significantly inhibits spontaneous ovulation when administered intraperitoneally at a dose of twice 3.2 mg / kg (3.2 mg / kg at 13 hours). and 3.2 mg / kg at 15 hours). Under identical experimental conditions,

  CPP-ene very weakly inhibits spontaneous ovulation

  after administration intraperitoneally

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 the secretion of LH or modulated by it or

  having an etiology in which the physical regulation

  logic of LH secretion is involved, for example for the treatment of prostatic hypertrophy, menopausal syndrome, as well as

  breast and prostate cancer. For this use

  the indicated daily dose is between

  about 1 and about 800 mg of active substance, administered

  administered in divided doses 2 to 4 times daily in unit dose form, each containing, for example, between about 0.25 and about 400 mg of the substance

  active, or in sustained release form.

  The compound of formula I exerts a myorelaxant activity demonstrated in the awake rabbit after intravenous administration to

  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 muscular tonic reflex after intravenous administration at the dose of 0.02 mg / kg, whereas the CPP-ene inhibits by 47% the muscular tonic reflex after intravenous administration at a dose of 0.5 mg / kg, the compound of formula I being approximately 25

  more active than the corresponding racemic.

  Thanks to these properties, the compound of formula I can therefore be used therapeutically 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 portion of the body. the spine or following an operation, or for the treatment of spasticity caused, for example, by multiple sclerosis, diseases of the marrow

  spinal cord, stroke, trauma

  cerebral palsy or cerebral palsy.

  For this indication, the daily dose is between about 1 and about 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 about 0.25 to about 400 mg of active substance or in a form

extended release.

  In addition, the compound of formula I reduces the alterations of neurons caused by ischemia and

  symptoms resulting from occlusion of the cerebral artery.

  in the rat, following subcutaneous administration of a dose of 1 to 30 mg / kg, and

  particular after intravenous administration

  peritoneal dose 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. 12281234 (1986)]. Infarcted tissue area is measured using an MCID image analyzer (from Imaging Research Inc.) in 5 horizontal layers of 20 μm thickness cut at various levels and colored by cresyl violet. The total volume of brain that has undergone ischemic deterioration is evaluated by adding the 5 zones obtained from the 5 layers. The extent of the infarction determined 5 days after the occlusion of the ACM is reduced by more than 20% after administration of the monohydrate of the compound of formula I by intraperitoneal route at the dose of 3 times 10 mg / kg ( first injection immediately after ACM occlusion, second and third injection

  respectively after 8 and 16 hours).

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

extended release form.

  In addition, the compound of formula I has a

  potent, selective and competent antagonistic

  titrate on NMDA receptors (N-methyl-D-

  aspartic). Thus, the monohydrate of the compound of formula I inhibits the depolarizations of the marrow

2 6109 32

  isolated spindle of frog induced by NMDA [P.L. Herrling, Neuroscience 14, p.417-426 (1985)] with a pA2 value of 6.8 and CPPene with a pA2 value of 6.2, the compound of formula I being about 4-fold

  more active than the corresponding racemic. Acid (+) -

  3- (2-Carboxypiperazine-4-yl) -propyl-1-phosphonic acid (CPP) of British Patent Application No. 2,157,685

has a pA2 value of 5.8.

  In rat brain sections, sodium efflux may be induced by NMDA, quisqualate or kainate [A. Luini et al., Proc. Natl. Acad. Sci. USA 78, p. 3250-3254 (1981)]. The monohydrate of the compound of formula I has an antagonistic effect on NMDA-induced sodium efflux (pA2 value - 6.5). In this test, 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 does not exert an antagonistic effect on sodium efflux induced by quisqualate and kainate to a concentration

from lmM.

  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. Parkinson. For these uses, the compound of formula I will be administered at a daily dose of between about 25 and about 800 mg, advantageously administered in divided doses 2 to 4 times per day in unit dose form each containing, for example, from about 6 to about 400 mg of substance

  active, or in sustained release form.

  Thanks to their antagonistic activity on

  NMDA receptors, the compound of formula I is also

  It is also suitable for therapeutic use in the treatment of tinnitus. For this indication, it will be administered at a daily dose of between about 25 and about 800 mg, advantageously administered in doses.treated 2 to 4 times per day in unit dose form each containing for example from about 6 to about 400 mg of substance

  active, or in sustained release form.

  The compound of formula I also has anticonvulsant activity; in the mouse, it inhibits

  convulsions caused by electroshock [E.A.

  Swinyard, J. Am. Pharm. Assoc. Scient. 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 test substance intraperitoneally. After 1, 2 and 4 hours, a shock of 50 mA is applied for 200 ms with

  corneal electrodes coated with an electrolyte jelly

  trolyte. This supra-maximal shock produces tonic convulsions of the extensor muscles. Inhibition of hindlimb extension is considered a protective effect. After experimenting with various doses, the threshold dose is determined. The threshold dose after one hour, or the dose required to inhibit hindlimb extension, is <1 mg / kg (intraperitoneally) for the compound of the formula

  I (monohydrate) and between 3 and 10 mg / kg (intra-

  peritoneal) for CPP-ene. The threshold dose indicated in the literature for CPP is 10 mg / kg (per

intraperitoneal route).

  In the following table, the inhibition of posterior limb extension expressed in% is given for the compound of formula I as well as for the corresponding racemic:% inhibition of Dose the extension of the mg / kg member induced by ip electroshock Compound of formula I 67 * 67 * 33 * (monohydrate) 2.5 83 * 83 * 67 *

3 100 * 100 * 83 *

  __________________________________________________

CPP-ene 1 20 50 25

3 33 67 * 17

67 * 80 * 80 *

  __________________________________________________

  Fischer trial, control group / group receiving the

substance to be tested * 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

  Electroconvulsive convulsions in mice.

  In addition, the compound of formula I inhibits in mice convulsions caused by N-methyl-D-aspartic acid (NMDA). 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, 400 mg / kg of NMDA was administered subcutaneously

  the neck area and observed for 30 minutes.

  There are 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].

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

intraperitoneal route.

  Thanks to its anticonvulsant activity, the compound of formula I can be used therapeutically

  for the treatment of epilepsy. For this indi-

  cation, the daily dose is between about and about 800 mg advantageously administered in divided doses 2 to 4 times per day in unit dosage form each containing for example from about 6 to about 400 mg of active substance, or in form to

sustained release.

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

-80% at a concentration of 10 UM.

  The compound of formula I is therefore appropriate

  for use in therapy as an analgesic.

  For this indication, the daily dose is included

  between about 25 and about 800 mg, preferably administered

  in divided doses 2 to 4 times a day in unit dose form each containing, for example, from about 6 to about 400 mg of the substance

  active, or in sustained release form.

  In addition, the compound of formula I and the corresponding racemic have no effect on blood pressure and heart rate in cats.

2 261093

  anesthetized at doses up to 10 mg / kg admi-

  administered intravenously. In 4-week dog toxicity tests, a daily dose of 3 mg / kg of the intravenously administered formula I compound was

well tolerated.

  As evidenced by the results of the above assays, the strong inhibitory activity on LH secretion, the marked (25-fold) increase in myorelaxant activity as well as the antagonistic effect of the compound of formula I on NMDA receptors 2-4 fold higher than racemic

  corresponding, are not accompanied by an increase

  similar effects of side effects, in particular

cardiovascular effects.

  The compound of formula I may be

  mined as such or in the form of a pharmaceutical salt

  ceutically acceptable. 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 thereof, for use in therapy as a medicament, for example for the treatment of disorders associated with LH secretion, increased muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression or degenerative CNS, tinnitus, epilepsy , or to suppress the pain.

  The invention further relates to a composition

  pharmaceutical composition comprising the compound of formula

  I or a pharmaceutically acceptable salt thereof

  se, in combination with a thinner or vehicle

pharmaceutically acceptable.

  The compound of formula I can be administered

  in any of the usual routes, particularly enterally, preferably orally or parenterally. It can be administered as

  or associated with pharmaceutical vehicles used

  tual. For oral administration, for example in the form of tablets or capsules, the compound of formula I may be mixed with usual pharmaceutical excipients, for example inert diluents such as lactose, mannitol, calcium sulphate , microcrystalline cellulose,

  disintegration such as starch, carboxymethyl

  sodium cellulose, sodium carboxymethyl starch, alginic acid, crospovidone, binders such as cellulose derivatives (methyl-, hydroxymethyl-,

  hydroxypropylmethylcellulose), povidone,

  lubricants such as silica, stearic acid, magnesium or calcium stearate, hydrogenated oils such as castor oil, esters of glycerol, for example palmitostearate;

  and / or flavorings, dyes and sweeteners

  corants. The tablets may be uncoated or coated by known techniques to retard the decomposition and absorption of the active substance in the gastrointestinal tract and to produce

  thus a prolonged action. The compositions to be administered parenterally are preferably in the form of solutions.

  Sterile injectable water. If necessary, such aqueous solutions must be buffered and made isotonic with a quantity

  sufficient physiological solution. We can

  add a preservative such as

benzyl alcohol.

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

  pharmaceutically acceptable compound thereof.

  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, a solution of alginate

  0.5% sodium or 5% hydroxypropylmethylcellulose.

  The dry granulate is tableted in the presence of about 20% corn starch and 1% magnesium stearate. Tablets having the following composition can thus be obtained: Composition Tablets Weight (mg) Compound of formula I (monohydrate) 50 Lactose 97 Corn starch 40

hydroxypropyl

* Cellulose 10 Magnesium Stearate 2 Silica 1 These tablets which have a slit, can be administered orally at a dose of one-half to

one tablet 1 to 4 times a day.

  The capsules may contain the active substance alone or in combination with a solid carrier

inert, as indicated above.

  Capsules containing the ingredients listed below may be prepared by the usual methods and are administered at a rate of 1 capsule i to 4 times daily: Composition Capsule / weight (mg) Compound of formula I (monohydrate) 50 Inert solid carrier ( corn starch, lactose, aerosil, magnesium stearate) 250 Tablets and capsules containing 25 mg and 100 mg of the compound of formula I can also be prepared. 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 single daily administration: Composition Sterile injectable solution / Weight (mg / ml) Compound of formula I monohydrate Sodium chloride 7.0 Dihydrogen phosphate potassium 3.63 Disodium hydrogen phosphate 5.68 Alcohol Benzyl 9.0 Water for injection qs 1 ml The solutions can be filtered through a sterile 0.2 micron filter and poured into ampoules under aseptic conditions. The lightbulbs

  are put under carbon dioxide.

  The invention also relates to the use of the compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of disorders associated with the secretion of LH, the increase of tone of cerebral ischemia, anxiety, schizophrenia, depression, degenerative CNS disease,

  tinnitus, epilepsy or to suppress pain.

2610 932

Claims (7)

1. [R (E) 1-4- (3-phosphono-2-) acid   propenyl) -piperazine-2-carboxylic acid of formula I ## STR1 ## and its salts.   2. The compound of claim 1, in which   monohydrate form, and monohydrate salts.   3. A process for the preparation of [R- (E)] - 4- (3-   phosphono-2-propenyl) -piperazine-2-carboxylic acid specified in   1, and its salts, characterized in that a compound of formula II (II   Wherein R is (C1-C4) alkyl or (aryl) (C1-C4) alkyl and optionally salt of this compound.   4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,   for use as a medicine.   5. A compound according to claim 4 for use in the treatment of disorders associated with the secretion of LH, increased muscle tone, conditions associated with ischemia 26109 2   cerebral palsy, anxiety, schizophrenia, depression, degenerative diseases of the CNS,   tinnitus, epilepsy or to suppress pain.   6. A pharmaceutical composition, characterized   in that it includes a compound according to   claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a   diluent or pharmaceutically acceptable carrier.   7. The use of the compound of formula I or   monohydrate of this compound, or a pharmaceutical salt   acceptable for this compound or the monohydrate,   for the preparation of a medicinal product for the   disorders associated with LH secretion, increased muscle tone, conditions associated with cerebral ischemia, anxiety,   schizophrenia, depression, degenerative diseases,   CNS, tinnitus, epilepsy or remove the pain.