PT86776B - PROCESS FOR THE PREPARATION OF PIPERAZINOCARBOXYLIC ACID AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING IT - Google Patents

Abstract

Piperazinecarboxylic acid useful in the treatment of disorders associated with LH secretion, increased muscle tone, conditions associated with cerebral ischaemia, anxiety, depression, CNS degenerative disorders, tinnitus, epilepsy or in relieving pain.

Description

United Kingdom patent application ns. 2,157,585 describes 2-piperazinocarboxylic acids substituted at position 4, which have an activity on the central nervous system.

It has been found out that a compound of the aforementioned class, which has not been described to date, exerts a particularly strong activity on the central nervous system, is well tolerated and has a long-lasting activity.

The present invention relates to / ?-('··)-4-(3~phosphono-2aspr?penil)-2-piperazinoca.-?boxylic acid of formula I ΐ

r.

ν ... *

I

.u (I) with its pharmaceutically acceptable salts, co: .. ui :. process for Bua preparation, with pharmaceutical compositions containing such product and with its use as a drug ·

The compound of formula I can be prepared by dialkylation of a compound of formula II,

(II) in which R means an alkyl or aryl-alkyl group

The process can be carried out in a known manner. Thus, for example, dialkylation can be carried out by Bilylation with subsequent hydrochlorides of the resulting silyl ester. Silylation can be carried out, for example, with bromotrimethylBilane in an organic solvent, also as dichloromethane

or chloroform, at room temperature. k subsequent hydrolysis can be carried out under mild conditions.

When the symbol? represents an aryl-alkyl group where aryl is advantageously an optionally substituted phenyl group in which suitable substituents include lower alkyl or lower alkoxy groups.

The compound of formula X as well as its salts, can also be obtained without the form of its hydrates, in particular the monohydrate. Hydrates, in particular monohydrate, are also part of the present invention.

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

I

1),

2) if diastereoisomer B

- The compound of formula I can form cmphonic salts and acid addition salts - these salts can be prepared easily by classical methods. Cationic salts include, but are not limited to, ammonium, sodium, potassium, calcium, piperidinium, lv: .orfolinc or pyrrolidinium salts. Cs oa: .s of acid addition inc.lv. but without being limited to this, the salts formed with hydrochloric, hydrobromic, silphonic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and trifluoroacetic acids.

The hydrate of the compound of formula I, in particular and the monohydricate of such a compound, has particularly interesting physico-chemical properties, and other properties, for example propr. * Dates relating to solubility, ease of purification Sc and stability. The hydrate can be obtained by the crystallization of the compound of formula Γ to 'O - ir from an aqueous medium, for example such a color is described in point e) below, for example in water / methanol.

In the following xemplce, the temperatures are indicated in degrees elsius and are yet to be corrected, their values Ζ * are also corrected:?.

'' 7E ‘- ', PL0; Wfo; io-2-propyl) -2-piperazinoarboxylic acid

a) * ((R) -j, 4-bimneaylmethyl) -2-piperazinocarboxylic acid (R, 2%, 5-R) ~ 5-methyl-2-methyl (2-methyl) -cyclohexyl

To a solution made up of 1,4-dibenzyl-2-piperazinocarboxylic acid ethyl ester (prepared according to. Jucker and H. Sissi, xelv »Chim · Acta 45, (1962) 23837 and 45c g of (-) - menthol is added at 45 ° t

g of Ra (dispersion at 55 / - 6C /) and 1 liter of toluene. Then, 7CG ml of the solvent is slowly removed by distillation, which is continually replaced by new portions of toluene (the reaction is controlled by chromatography 010, with 1: 3 etRlacetate / hexane). The mixture is then cooled to room temperature, treated with 1.25 liters of aqueous XI 2Π and 6 liters of diethyl ether and the whole is stirred perfectly for 1 hour. The crystalline precipitate is filtered off and washed with diethyl ether and aqueous RC 1 C, 1R. The crude product is recrystallized from ethanol / aqueous 0.21 J1, with which the hydrated hydrochloride of the title compound, F-1 ^ * ⁺ (c ~ 1.2 in C-ICl), is obtained, which is used - Perform the following step with further purification.

b) (R) -2-piperazinecarboxylic acid (IR, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl ester

Hydrogenate, for 7 hours at room temperature and under normal pressure, 210 g of the slap product a) in 2 liters of ethanol and 10.5 g of Td / O (at 10%), then filter and evaporate under reduced pressure, the residue is rinsed with .01 otanilic, the precipitate is filtered off and washed with ethanol / diethyl ether (lily). The product was recrystallized in water / methanol / ethyl ace.tato to give the dihydrochloride of the title compound with a melting point of 225-226 ° ~ 52 = C (C = 1.34 in water ), the dihydrochloride is fracted with diethyl ether / aqueous ammonia, and the organic phase is evaporated to dryness, with which the title compound is obtained with a wear point of 52-52 °, ZA_7p ° “-56 , 7 ° (c = 1.05 βπ: ·? .1.).

- c) ^ ster (IR, 23, 5R.) - 5-methyl-2- (1 * acid methyl / cyclohexflicp / T- (2 ^ 7--4- (3-detoxifosphenyl-2-propenyl) -2- pyrazine carboxylic

To a stirred solution consisting of 11.3 β of the free base obtained in '.tap .. b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran are added, at -3C ^S , within 30 rinates, 7 g of 3-broro-propen-2-yl-phosphonic acid diethyl ester (prepared according to K. 1 * akano, cashimoto and TZamiya, Chem. Charm. Sull 30 (1982), 111) in 45 ml of tetrahydrofuran. Continue to stir the mixture at -25 I ² · for 20 hours Bepois filtration of the precipitate, concentrated under reduced pressure sol solution and the resulting syrup was cxomatcgrafa on silica gel using dichloromethane strain adding a mixture 1: 19 of concentrated aqueous ammonia / ethanol in a concentration that increases until reaching, after 2 hours, 1G 7.

The fraction, eluted with 200: 1: 19 dichloromethane / aqueous concentrated anonymous / ethanol (rf - 9.35), is isolated and concentrated under reduced pressure, with which the title compound is obtained in the form of an oil, 7 - ~ -55.9 ° (e = »1.3 in: ci 2N) · -or treatment of the product with ethanolic / ether, the dihydrochloride is obtained with a melting point k of 157-153 °, £ \ _7 ? ° «-48.2 ° (c 1.4 er ... 1 23) ·

d) / * - (c27 ~ 4 * (3-detoxifosfinyl-2-p £ opsnil' — 2- / iperazinocarboxylic acid)

To a stirred solution of 5,79 g of the product obtained in the tape,

c) in 58 ml of C: ₂ 01 _the absolute is added, at -3%, for 30 minutes, 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane Approximately 2,2 ') · The reaction mixture is heated for one hour at -25 ° and then

for 3 ½ hours at C °. Then, at 5 ° C, 5 ml of water are added and the mixture is neutralized by the addition of aqueous TaCH 2: i, divided between FgC and C. dgClg · The aqueous phase evaporates to dryness under pressure reduced, and the residue taken up in CHClCl, filtered, dried ( ¹ hgSO ^) and evaporated to dryness under reduced pressure, thus obtaining the title compound, which is used in ta ·· pa next without further purification.

An analytical sample is purified by chromatography -71 (S Sucleosil R3 'J C ₂ / C ^:.: C ^_3:: 3: 2), with 0 cual obtains a foam / - -17 »0 ° (c - 1 , 1 in Ά1 C, 5 '.') ·

36C 7Hz ^ - Nuclear icgnétioa resonance (TZ SC, 1 ”C- ° C):

1.24 (61 ;, t, J - 7.0 7z), 2.25 (17, dxdxd, J «11.3 x 9.0 x 3.3 7z), 2.35 (1.» dxd, J * 11.3 <7.6 z), 2.52 -

2.58 (1: m), 2.77 (17, dxdxd, T = 12.1 x 9, C x 3.3 z),

2.83 (II, dxdxd, J - 11.3 x 3.3 x 1.7: z), 2.99 (17, dxt, -J «12.1 x 3.9 iz), 3.10 - 3.15 (2, m), 3.33 (17, dxd,. = 6.6 x 3.3 z), 3.97 (47, dxq, T = 5.6 x 7.0 .z), 5.50 (27, broad), 5.88 '17, dxdxt, J = 21.5 x 17.1 x 2.1 iz),

5.52 (II, dxdxt, T == 22.0 x 17.1 x 5.6 7z).

acid. £ & - (Ί7-4- (3 "phosphono-2-proijenyl) -2-piperazinocarbon xylum

In 3CC ml of absolute SigClg, 3.9 pounds of the crude compound obtained in step d) was dissolved, the solution was treated

9.6 ml of bromotrimethylsilane, at room temperature, and stir for 16 hours. The reaction mixture is vaporized, the residue is collected and the mixture is filtered for 1 hour. Adjust the p; of the solution to the cell with the addition of Jo> vex 1x4 (form 07) and the mixture is placed on top of a column containing 7o wx 1x4 (acetate form). after elution with a gradient of aqueous acetic acid (C, C5 to C, 25 7) and from concentration to dryness under reduced pressure, a foam is obtained. crystallize such septum in

, 0 -1 and er recrystallize. --gwGg ^ C. for ^ C / CJÍ title compound in the form of the monohydrate, with a melting point of 20S ° (decomposition), C- ^ J ^ ~ -21.9 ° obtain the (c = 1.1 in .91 2; F ). The absolute configuration is deduced by a chemical correlation with -asparagine and confirmed by a structure analysis with rays /.

The compound of formula I has a valuable pharmacological activity and is therefore suitable for use as a medicine, for example in therapy *: in particular, the compound has an inflammatory activity on the secretion of luteinizing hormone (7). and on the secretion of testosterone, as indicated by the following test:

Male, adult, rat rat (SIV, Kissley, RPA, weighing 2CC to 300 g) receive the test compound intraperitoneally. Two hours later, the animals are sacrificed by decapitation and blood samples are collected. 'luteinizing horr.ona serum (!;' *} which is based on the production of testosterone by dispersed interstitial Leydig cells from rats treated for collagenase; such cells are exposed to a serum containing luteinizing hormone or to a standard rat luteinizing hormone, testosterone is hedged in a radio-immunological study (125 — To, Ci8, edipro eufen, Switzerland), / of * t * dei Pozo, A. Dodestá, A * Cclano, J * Calaf »1. arkó, in .iorhythms and Stress in the hysicpatology of Reproduction, Γ» faacheri and _ · fiche11a (ds), emisphere fullisching go. 'Ashington, 339-328 (1988/7 · compound of formula I inhibits significantly the secretion of the luteinizing horrible (.) and significant the secretion of testosterone in a dose of 3 »2 mg / kg, administered intraperitoneally. C (+) - 4- (3-phosphono-2-propylene) - 2-piperazinocarboxylic (hereinafter OfT-ene), ie the corresponding racorate of the compound of formula I, does not

exerts alt * a..a saber on secrecy. ona fought clsante (PI) and weakly inhibits testosterone secretion.

In female rats, the compound of formula 1 inhibits spontaneous luteinizing hormone-dependent ovulation (I) in the following assay. , 'arkó and woolckiger, euroendocrinology 3, 220-231 (198027 ·'

Female rats, instar rats (SIV, .issley, RFA, 200 to 30C g) with regular 4-day cycles, receive the test substance intra.eritoneally during the proestrus at 13.00 and 15, - 0 o'clock, next night, at 0 o'clock o'clock, the rats are in estrus, they are sacrificed, the ovlducts are examined microscopically. eggs are counted. It is considered as an inhibition of ovulation ONLY the total absence of eggs. Administered intraperitoneally in doses of 2 x 3.2 mg / kg, (at 13> 00 hours, 3.2 mg / kg via

i.p. and at 15.00 hours 3.2 mg / kg i.p.), the compound of formula I (tested in the form of its ronohydrate) significantly inhibits spontaneous ovulation. Due to the same experimental conditions, CPP-ene, when administered in doses of 2 x 3.2 mg / kg intraperitoneally, very weakly inhibits ovulation.

Therefore, the compound of formula X is indicated to be used in the treatment of disorders that have an etiology associated with or modulated by the secretion of luteinizing hormone (LC) or that have an etiology in which the physiological regulation of LC secretion is involved, for example in the treatment of prostate hypertrophy, in the treatment of menopausal syndrome, as well as in the treatment of breast and prostate carcinomas. For the treatments mentioned here, a daily dosage is between approximately 1 and 800 mg of the compound, administered conveniently in divided doses, 2 to 4 times a day, in the form of a single dose containing, for example, approximately < *, 25 to agre

ximad arreading 4C0 ing of the compound, or else under delayed release.

The compound ô and formula \ aduinictrad intravenously in dosages epreprehensible e..tre 1 and <cg / ^ g exerts an axial activity loose the muscles in the eciaclente ujalho J, j.escheadorf et al., Drch. -. · narm ^ cul. 266, 467 * 430 (197Q7 · .'In this assay, the .. «the compound of the formula compound» causes an inhibition of> C / of muscle t & ius, after administration of C,? 2 'g / M intravenously, en-

i.as long as the 'C.T-cne, add intravenous stripe -enie nu., at 5ose dc c, 5 og / xg, i-iil? the total of 47. ; v with., roto ãu ídr ^ ula 'is, therefore, aprcxl. · mL ·. between 25 vc: you are more active than the breed. corresponding act.

<: compound l and formula I is i..dic .- / 'o, therefore, to be used in the treatment of an increase in muscle tone, for? x · ur.plo to the treatment of attributable painful muscle spasms .. static disorders and functional of the style. » cervical the lumbar ii then ... the tr-. _: ; post-operative fear and in the treatment of spasticity, for example due to multiple ... scl-ros * ·, d; - spinal cord disease, cerebrovascular accidents, brain trauma or a parai.sac reboai .

For the aforementioned uses, one of the indicated daily allowances is between approximately 1 and approximately two mg of the compound, administered conveniently in divided doses, 2 to <1 times a day, under the unit dosage form containing, for example, from approx. 25 µl aprexisadameate 4-C mg of the compound, or so in the form of delayed release.

In addition, the compound of formula T reduces neural damage induced by isi.uer.ia, as corresponding symptoms in the occlusion model in the cerebral cerebral artery (UCA) were rats, when administered subcutaneous

eã of ' _w e. · from 1 to 37' - particular color via, limU-oporl · · toaiai in a dosage ue 2 x 1 ^ · t - - í .. · d VC, j L. C ϋ · - · - Ο », · ÍAjA. <W ίί.ΐΐ »* H

j. Gereb »vlood A-lou \ etabcl. 1, 53-50 (1X1) 7, * '-. . previous, f. ? udin, -iroke 17, 1221 * 123 '; 1X áj * stinks with infarcted tissue, eci..re walking or'a;'. X-rim image ^ MCX ^ XXinvolved by T.cagix .ieserch ”n.) E.„ 5 sections-m: · hurXomtait. with a thickness of 2C hi: dry _: C ^ t .A 'ijí) aA>JÍ-tUL,' tf J ^ -ÁA ww ÍA ^ h .los e /

colored and violet by cresilo. The total volume of the brain that is present therein: bone is determined from the 5 areas obtained from the 5 sections. hearty, which is deVrXn a cerebral veXan artery after the ti-at core wind al (the first blast was healthy CA, the sogu .-. da and to have: · te 1 .. · hours --osteriorea adi

The arem of. n 5 days after the occlusion of the X), it is reduced in rials ~ c 20 0. <10 mg / Ag via ioteraforltone *; ost immed Xtamento after the occlusion injection to the S, rorp ^ etivane / i to the occlusion A.

• 3, u

The co .. post is indicated, by coarepul t:., To be used in prcX 1XX and oa t ^ rv-Mier. of conditions associated with = cerebral ischemia ·, -. for example, stroke. For this purpose, the daily indicated dodaspen is c οχ> r hanging between a.-roxim adameate 25 c aproKÍ., A <X v.ze X 'r. „G dv behaviour administered conveniently w. divided doses 2 4 voices a day, in the form of a single dose containing, for example, approximately: · between 5 to approximately 4'X mg of the compound, or otherwise under force; the retylated release »cc.-compound of formula I azvrue, aLL. In addition, a potent antugoXsta action on otivm and co-xtitivu covers XGA receptors (Î ± -AXyl -'- aspóXieoh 'mst? ... in the? xperi * 'icie of the bone marrow x the rat / \ 1. .errli .g, XuooscXncK 11, 417—12-5 (195517 color ur pL value 4e 6.8, ov?> ene color u; value of 5.2 · thus, the compound of fomila T has a »a .etivbXX 'jksA-odanento 4 time and swim with the corresponding racornate, is acid (^) - 3- (2-0Λ.Λν .4 ^ 1ρ:; Γ..ζ1ηο- · 4-ίΙ) - ρ3? Ο ^ _? Ί1 ->. Ίθ8.ν .. · ι ^? .Θ0 · (* ??) _t gu Be the conp .; is highlighted when ordering .'Ό1ο.ο jiilo 2 15?? 25 has u: r pA ^ e 5.3 value,

..., the experience of effiuxão o e sedie in * -urida by .1 jA (acidic. V <xoc. Aati ,, Acad. Lei -A 78, 32ÍÁ- · 3234 ^ IjAlp ?, o: .. o..hydrate cb coaiposto of formula 1 presents Uw v,;. Lux · pA _? Úe A.5 and the „dd-ene a pâ _? cl · * value 5.2, with the cut ... post of fÓrt-ú-a * a ^ tvity of approximately two flows which are already corrospondent. 1 ?? u _tea: pA value> S, C..

The selectivity of the. ... Ά a.ntago-.lsta action is shown and the one that is inactive, the cosine that the - ^ IC-ene and GGA water in the assay <the sodium eXLuxSo induced by · qulsquaLuto and the kainate, up to a concentration of 1 a, * the result of yours. a ^ r- tagmirmo the three reception ·· toi The DA (methyl-L-aspartic acid), .posto c ind formula I is carr EADO s ^r r comes used ..?. vto of anxiety, schizophrenia and depression cu degenerative disorders ^are:. nerv ^ sc central stema such Acuitingtoii run of the disease, the Axaneimer -or ar.inson, .the such AIF 'is an indicated daily doso ^ ccnrr between eudida I approximated n.reãte 25 and approximately CAG mg of the compound, administered in divided doses, 2 to 4 verts a day, in the form of du ;. · act as a unit, counting by exercise approximately at approximately 4 "0 r .: g of the compound, or otherwise delayed release.

. As a result of your antapc going to the GAGA receptor, the color of the formula. it is also indicated for use in the treatment of tinitis. ..for this purpose, a daily dosage indicated is between approximately 25 and approx. -i. ·: 'mg of the compound, conveniently administered in divided doses 2 to 4 times a day, in the form of unit dosage containing for example of approximately

• exit 6 α uprcximalameatc · 41 'r cou_o.-to. or ions under the late-release pattern,

In addition, the set of formula 1 allows an actlvi · ...... to be a.iticonva.isiva in the convulsions induced by rat shock in the rat Λ. v./inyara,,. Am. Jcarm. ..cesc it. iclexi d. 38, 2vl (1941) and; * .-. Hamcol. 'xpti. iherap, le6, 319 (1952 ^ 7 · such an assay ,. male rats, (the> _ groups of 6 anisal at a time) (from 18 to 2..J -.//-1, Sand. -z,. .asileiaj receive the substance of the test via i: itra _-- erito; .eal * To fictions 1, 2 and 4 ho ..... air, it is applied to rats,; a obcr.uc at 5 / ra \, c; .. iua

I duration of 2 ms, with e-lsctrodo-s oornoaie lara dos dos coe. · _An ol of electrolytes · even supra-naximal shock produces convulsions and tonic tensors of all extrec, 'daà? <* / Inhibition of the hind paw extension - '' • onsidsrada as uc o protec ·. tora · After investing several dose levels, the limit dose, A ds * · - limit, is evaluated at 1 hour, or is the dose necessary to inhibit jet extension. back * ra * <1 ic / '- S adn> © Administered by coming intruporytoneal for the compound of formula I (monohydrate) and between 3 n 1.' mp., -. / o / d ilsiro / ·; via Antrap ^ riton ··. al for 0 õdo-en · ?, The limit, i / dicated in the lite- »break for 0 '/? /, is K-i &,: _t adcinivtrads. by saw L-itraperito salt.

la / abela seruinte, inhibition of extension of the hind legs with color. The compound is used in 7, except in the form of the corresponding racer:

I of the shock inhibition? eloctr :. roses co induced on the itension of the trawler patm m: /. i.p i.p. In 2L 4h oaohydrate Ίο

formula 1 color stand 83 * . 67 * 33 _w 83 * 67 * _ 3__ ............ 11-0 * 1-> X ».jv. ' cj

TC

shock inhibition induced electric about . oses to paw ecter-are transassi- LOL. ag / ug i.p. Ih 2n 4 am 1 2- ^; * çq ΟΓ rn- ·. 1 33 & Ϊ * dr.-ene 3 1C 67 * 17 ass -ssaic of Plsher, product of cvntrolo vs. u group

of substances, * _Λ 'P <»v, v5

The chorus can be removed from the table, the compound of formula I occurs until its iconvulsive activity is higher than the corresponding racerate when they are tested against convulsions induced by electric shock and: straight.

• the compound of formula I furthermore inhibits the convulsions induced by «-methyl *, - aspartic acid (Rd Rd) in the rat. : 'this test, carried out with color: groups of ca.the time 5 female rats (from 18 to 26 g, CR-1, going #''-asiloia), the animals are treated preventively with the test substance administered via intraper1toneal. 3C minutes late, excite the animals by subcutaneously injecting them 4ΑΓ mg / kg of RRA in the cervical region, after which they are only observed: the rats for 30 minutes. Reg 'stam-sr the latencies for the disclosure of the first signs of seizures, for the first tonic seizures and for the occurrence of death. * Grandfather phosphorylation of any differences is carried out by the ^r-Pann Áitnoy SLegel test Pon-parametric itatisties, Rcbrnv - '' yl, N 'Rork' 1956 · · · The bid dose is the dose which occurs infer t a significant inhibition of seizure symptoms. The limit dose for the compound of formula X (o, given as its monohydrate) is approximately 5 mg / ag, administered intraperitoneally. CC ?? administered intraperitoneally at a dose of 10 mg / kg.

Thanks to its anticonvulsant activity, the compound of formula I is indicated for use in the treatment of epilepsy, for this purpose, a daily dosage indicated is between approximately 25 and approximately 800 mg of the compound, administered conveniently and i: divided doses, 2 to 4 times a day, in unit dosage form containing, for example, approximately 6 to approximately 400 mg of the compound, or else in the form of delayed release.

The compound of the formula presents later.

in vitro, an analgesic activity in the dorsal spinal cord (back and tail) isolated in the rat, using capsaicin depolarization at the ventral root / Γ. anpisava et al., furopean J. Phaimacol · 1C1, 1444231-239 ÍDD1717 * fu ^ the concentration of 10, the hydrochloride of the compound of formula T reduces the chemical stimulus by 75-30%.

The compound of formula I is therefore indicated to be used to supply pain. For this purpose, the indicated daily dosage is between approximately 25 and approximately c-CC mg of the compound, administered conveniently in divided doses, 2 to 4 times a day, in the form of dosa.-er. unit containing, for example, approximately 6 to approximately 400 mg of the compound, or else in the form of delayed release.

In addition, the compound of formula Γ, as the corresponding racemate, does not exert any effects on blood pressure or heart rate in the anesthetized rat at a dose of up to 10 ir / kg intravenously, in pilot toxicity experiments with dogs, carried out for more than 4 weeks with doses of 3 mg / 2% per day, administered intravenously, the T-form compound is well tolerated.

:: οπο o demonstrate the results of the tests described above, the high inhibitory activity of the separation of luteinizing hormone (LI), the marked increase (.. '5 times higher) of the relaxing activity of the muscles, as well as the antagonistic activity of. Two to four times higher than the compound of formula I - compared to the corresponding racemate * is not accompanied by a similar increase in side effects, for example in cardiovascular effects.

The compound of formula I can be administered as such or in the form of its pharmaceutically acceptable salts. These salts exhibit the same order. of the activity that the compound of formula.

The present invention furthermore offers pharmaceutical compositions comprising the compound of formula I or a pharmaceutically acceptable salt of the same, in association with a pharmaceutically acceptable carrier or diluent.

The compound of formula I can be administered in any of the classic ways, in particular by heart, preferably oral or parenteral. The compound of formula ^w 'can be administered as is or in combination with pharmaceutically acceptable carriers, eg for oral administration, for example in the form of tablets or capsules, the compound of formula I can be mixed with the usual, pharmaceutically acceptable excipients, for example with inert diluents, such as lactose, mannitol, calcium sulfate, micro-crystalline cellulose; with disintegrating agents, for example starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, alginic acid, crospovidone; binding agents, such as cellulose derivatives (methylcellulose, hydroxylethylcellulose, hydroxypropylethylcellulose, povidone, gelatin; lubricating agents, for example silicon dioxide, stearic acid, magnesium or calcium stearate; hydropeped oils, . such as castor oil, and edulcoruntes agents may be .Tímidos with Gs, -or coating or be coated according strain known techniques fi * delay disintegration and absorption in the gastrointestinal tract _and, therefore, to provide a delayed action over a long period of time. For parenteral administration, the compounds are preferably in the form of a sterile, aqueous, i.at. solution. Such aqueous solutions will have to be adequately buffered, if necessary, and isotonic turns with sufficient sodium chloride solution, if necessary, a preserving agent, such as bensyl alcohol, may be added.

The pharmaceutical compositions can be prepared according to conventional techniques.

For the manufacture of tablets, one can mix the compound of formula I with lactose and granulated with water it with sodium innate al C, 5, or with a solution of 5 ^w / hydroxy methylcellulose. ..and dry the granules into tablets in the presence of approximately 2 g of corn starch and 1 mg of magnesium stearate. .. 'roc Jendo in this way, we obtain, for example »tablet: .- having the following composition:

Ingredients

Compound of formula I, lactose hydrochloride

Idroxypropylcetylcellulose corn acid

Magnesium petearate

Silicon dioxide> suppressed

Weight (mg)

4C

1C

2CC _ such tablets, provided with a groove to facilitate division, can be administered orally in a dosage between half a tablet and a tablet, two to four times a day.

The capsules may contain the active substance alone or in combination with color: an inert, solid excipient, for example as previously described.

The capsules containing the following ingredients, can be prepared by conventional techniques and are administered in a dose of one capsule, two to four times a day,

I

Ingredients .... Capsule desp ...... (mg)

Compound of formula I, monohydride 10 'x solid container, i.ert (starch, lactose, aerosil, magnesium stearate) 290

In a similar manner, tablets and capsules containing 25 θ 10C rg of the compound of formula I * can be prepared

The next injectable solution is formulated with | active substance in the quantities indicated above, using conventional techniques. The solution for injection is suitable for administration once a day.

Solution for injection, sterile

Ingredients Weight (mg / ml) Compound of formula monohydrate 25 Sodium chloride 7.0 Pihldrogen-potassium phosphate 3.53 disodium idrogen-phosphate 5.68 Benzilic alcohol 9, C Water for injections q.s. to 1 ml

The solutions can be filtered through a sterile filter of C, 2 and introduced into acidic ampoules. The ampoules are married with carbon dioxide.

The present invention offers, in addition to said, the compound of formula I or a pharmaceutically acceptable salt for use with the drug, for example for use in the treatment of disorders associated with the secretion of luteinizing hormone in the treatment of thioius increased muscle; in the treatment of conditions associated with cerebral ischemia; in the treatment of anguish, schizophrenia, de. healthy reits, or degenerative disorders of the central nervous system; in the treatment of tinitis; in the treatment of epilepsy cu to suppress der.

The invention therefore provides a method for treating disorders associated with the secretion of the luteinizing hormone (1); the treatment of increased muscle tone; the treatment of conditions associated with color: · cerebral ischemia; the treatment of anxiety, schizophrenia, depression or degenerative disorders of the central nervous system; the treatment of tinnitus; the treatment of epilepsy or for the suppression of pain in a human being, a method that includes the administration of the compound using formula I or a pharmaceutical salt thereof:. · an acceptable entity, in a torvnuttically effective concentration, to a patient in need such treatment,

The present invention further offers the compound of formula I or a pharmaceutically acceptable salt of nnsrrx for use in the manufacture of a pharmaceutical composition for use in the treatment of disorders associated with LH secretion, increased muscle tone, conditions associated with ischemia cerebral, anguish, schizophrenia, depression, degenerative disorders of the central nervous system, tinnitus or epilepsy, or for the suppression of pain

The invention also comprises a process for preparing a pharmaceutical composition, a process according to which between C, 1 and 99.9% of the compound of formula I or a pharmaceutically acceptable color salt is mixed. a pharmaceutically acceptable carrier or diluent.

Claims (6)

process for the preparation of acid / n- (27 ·· 1 · <· -4- (3-phosphono-2-propenyl) -2-piperazinecarboxylic formula I (I) οα a salt thereof, usable in the treatment of disorders associated with. the secretion of luteinizing hormone (L.), increased muscle tone, conditions associated with cerebral ischemia, anguish, schizophrenia, depression, degenerative disorders of the centi ..x nervous system, "tinnitus" or epilepsy , or in the suppression of pain, characterized by the fact that a compound of formula IE is dealkylated in which R means an alkyl group in a compound. optionally, sc ^ '1-4 ^{oa & r will} form a salt of this 2 ~. Process for the preparation of a compound according to claim 1, characterized in that the acid is obtained in the form of its ..onohiylrate or in the form of a salt of such a compound. 3-. - Process for the preparation of a compound according to color. claim 1 or 2, characterized by the fact that the acid is obtained in the form of: onohldratc or a pharmaceutically acceptable salt of that compound suitable for use as a drug. 4- ·. - Process for the preparation of a pharmaceutical composition, characterized by the fact that co. - understanding to mix a coconut compound claimed in claims 1 or 2 or a furmacoutica salt thereof; : is it acceptable with ..: a suitable pharmaceutically acceptable vehicle or diluent. 5X - ^ rocesse for the preparation of a pharmaceutical composition comprising the compound of formula I in free form or, where appropriate, in the form of a pharmaceutically acceptable salt, characterized in that they mix between 0.1 / 99, 9 'by weight of that compound with an acceptable pharmaceutical carrier or diluent. 6 ». - Method for treating disorders in human beings associated with:. L secretion, increased muscle tone, color-associated conditions .; cerebral ischemia, anguish, schizophrenia, depression, degenerative disorders of the central nervous system, 'tinnitus' or epilepsy or to suppress pain, in the treatment of disorders associated with the secretion of the lueinizing hormone (I :) or increased muscle mass, characterized by the fact that these humans are administered a pharmaceutical composition containing the compound of formula I prepared according to color. claim 1 and which is preferably used in one of the following daily dosages: a) to obtain an effect: of treatment of the increased muscle tone, between about 1 and about SCC mg of active substance, and conveniently administered in 2 to 4 individual doses per day, each with about G, 25 mg a about 4CC mg of active substance, or in a delayed form; b) to obtain a protective and therapeutic effect of conditions associated with cerebral ischemia, u ... treatment effect of angstia, schizophrenia, depression, degenerative disorders of the central nervous system, tinnitus, epilepsy or suppression of pain, about 25 mg to about 8CC mg of active substance, we conveniently administer in 1 to 4 individual doses per day, each with about 5 mg to about 4CC of active substance, or as a delayed action #