FI86733C - ANALOGIFICATION OF THERAPEUTIC PREPARATION OF THERAPEUTIC ANALYSIS OF PIPERAZINKARBOXYLSYRA - Google Patents

Description

1 86733

An analogous method for preparing a therapeutically useful piperazinecarboxylic acid GB Patent Application 2,157,685 describes 4-subs-5-substituted 2-piperazinecarboxylic acids which have an effect on the central nervous system.

It has been found that one compound in this class, not previously presented, has a particularly potent effect on the central nervous system, is well tolerated and is long-acting.

This invention relates to an analogous process for the preparation of [R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazinicarboxylic acid of formula I.

15 <? H

= P °

ί OH

cv 20

H 'COOH

or pharmaceutically acceptable salts thereof with a compound of formula I and its salts have use as a medicament.

The process according to the invention for the preparation of a compound of the formula I or a salt thereof is characterized in that the alkyl groups are removed from the compound of the formula II.

/ 0R

S (II) α-H'COOH-2,86733 wherein R is (C14) -alkyl or aryl (C14) alkyl, and if desired a salt thereof is formed.

The method can be carried out in a known manner. For example, removal of the alkyl can be accomplished by silylation and subsequent hydrolysis of the silyl ester formed. The silylation can be carried out, for example, with bromotrimethylsilane in an organic solvent such as dichloromethane or chloroform at ambient temperature. Subsequent hydrolysis can be performed under mild conditions.

When R is aryl () alkyl, aryl is a suitably optionally substituted phenyl group having suitable substituents lower alkyl or lower alkoxy groups.

A compound of formula I in the form of its hydrates, in particular the monohydrate. Hydrates, especially monohydrate, are also part of the invention.

The compound of formula II can be prepared as shown in the following reaction formula: 3 86733? H2C6H5 ^ H2C6H5 | / Nn | Π (') -reolitolj ^' \ y / 3 c ^ N ^ C00C-Hc 2) diastereoiso-

-3 <c 5 meer separator- 'COOKj ^^ N

CH 2 Cl 2 H 5 requires CH 2 Cl 2

I [H] CH-

t0R W

10 if n ° r S cmh3 I + CnX <h!

8r H -COO * Q

15 CH, T (C2H5 ¥

?, JXL

20>

"^ c! l.T

^ ch3

The compound of formula I may form cationic and acid addition salts. Such salts are prepared: 30 easily by general methods. Cationic salts include, but are not limited to, ammonium, sodium, potassium, calcium, piperidinium, morpholinium, or pyrrolidinium salts. Acid addition salts include, but are not limited to, those formed with hydrochloric, hydrobromic, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and trifluoroacetic acids.

4,86733

The hydrate of the compound of formula I, in particular the monohydrate, has particularly interesting physicochemical and other properties, e.g. in terms of solubility, ease of purification and stability. Hydrate 5 can be obtained by crystallization of a compound of formula I from an aqueous medium, e.g. as described in Example (e), e.g. water / methanol.

In the following examples, all temperatures are given in degrees Celsius and are uncorrected. / ä7 ^ ° values are also uncorrected.

Example; / R- (E) 7-4- (3-phosphono-2-propenyl) -2-piperazinecarboxylic acid___________ a) (R) -1,4-Bis (phenylmethyl) -2-piperazinecarboxylic acid (1R, 2S , 5R) -5-methyl-2- (1-methylethyl) cyclohexyl ester

To a solution of 761 g of 1,4-dibenzyl-2-piperazinecarboxylic acid ethyl ester (prepared according to

E. Jucker and E. Rissi, Helv. Chim. Acta 45 (1962) 2383, mu-20) and 458 g of (-) - menthol, 15 g of NaH are added at 45 ° C.

(55% to 60% dispersion) and 1 L of toluene. About 700 ml of solvent is then slowly removed by distillation and replaced continuously with the addition of new portions of toluene (the reaction is monitored by thin layer chromatography, ethyl acetate / hexane 1: 3). The mixture is cooled to ambient temperature, treated with 1.25 liters of 2N aqueous HCl and 6 liters of diethyl ether and stirred thoroughly for 1 hour. The crystalline precipitate is filtered off and washed with diethyl ether and 0.1 N aqueous HCl. The crude product is recrystallized from ethanol / 0.2 N aqueous HCl to give the hydrochloride hydrate of the title compound, / a72 ^ = + 18/5 ° (c = 1.2 in CHCl3), which is used without further purification in the next step. : b) (R) -2-Piperazinecarboxylic acid (1R, 2S, 5R) -35 5-methyl-2- (1-methylethyl) cyclohexyl ester 210 g of the product of step (a) in 2 liters of ethanol and 10.5 g The Pd / C (10%) is hydrogenated for 7 hours at ambient temperature and normal pressure, then filtered and evaporated in vacuo. The residue is treated with HCl diluted with ethanol, the precipitate is filtered off 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, m.p. 225-226 ° C, λ max = -52.0 ° (c = 1.34 in water). The dihydrochloride is treated with diethyl ether / aqueous ammonia, the organic phase is evaporated to dryness to give the title compound, m.p.

50 DEG-52 DEG C., [.alpha.] D @ 20 = -56.7 DEG (c = 1.05 in CHCl3).

c) / R- (E27-4- (3-Diethoxyphosphinyl-2-propenyl) -2-piperazinecarboxylic acid (1R, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl ester

To a stirred solution of 11.3 g of the free base of step (b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran is added 10.7 g of 3-bromopropene-2- diethyl ester of ylphosphonic acid (prepared according to K. Hemmi, H. Takeno, M. Hashimoto and T. Kamiya, Chem. Pharm. Bull 30 (1982), 111) in 45 ml of tetrahydrofuran. Stirring is continued at -25 ° C for 20 hours. After filtration of the precipitate, the solution is concentrated under reduced pressure and the resulting syrup is chromatographed using silica gel and dichloromethane with increasing concentration of concentrated ammonia-25 / ethanol 1:19, reaching 10% after 2 hours.

The fraction eluting with dichloromethane / concentrated ammonia / ethanol 200: 1: 19 (rf = 0.35) is isolated and concentrated in vacuo to give the title compound as an oil, [α] D = -56.0 ° (c = 1 , 3 in 2 N aqueous HCl). Treatment of the product with ethanolic HCl / ether gives the dihydrochloride, m.p. 157-163 ° C, λ max = -48.2 ° (c = 1.4 in 2N HCl).

d) / R- (E27-4- (3-Diethoxyphosphinyl-2-propenyl) -2-piperazinecarboxylic acid To a stirred solution of 5.79 g of the product of step (c) in 58 ml of absolute CH 2 Cl 2 is added -30 ° C 6 86733 over 22 minutes 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane (about 2.2 M) The reaction mixture is stirred for 1 hour at -25 ° C and for 3.5 hours at 0 ° C. At 0 [deg.] C., 50 ml of water and the mixture are neutralized by adding 5N aqueous NaOH and partitioned between 1N and

Cf ^ C ^ jn. The aqueous phase is evaporated to dryness in vacuo, the residue taken up in CHCl 3, filtered, dried (250250) and evaporated to dryness in vacuo to give the title compound which is used without further purification in the next 10 steps.

The assay sample is purified by HPLC (Nucleosil RP-8, 1 O / CH 2 OH 3: 2) to give foam / a = -18.0 ° (c = 1.1 in 0.5 N HCl).

360 MHz 1 H-NMR (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, dxdxd, 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 -20 8.6 x 3.3 Hz), 3.97 (4H, dxq, J = 8 , 6 x 7.0 Hz), 5.50 (2H, broad), 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 7-4- (3-phosphono-2-propenyl) -2-piperazinecarboxylic acid 3.9 g of the crude compound of step (d) are dissolved in 300 ml of absolute C 9.6 ml of bromotrimethylsilane at ambient temperature and stirred for 16 hours, the reaction mixture is evaporated, the residue is taken up in H2O, stirred for 1 hour and filtered.

The pH of the solution is adjusted to 6 by adding Dowex 1 x 4 (0H form) and the mixture is placed on top of a column containing Dowex 1 x 4 (acetate form). Elution with an aqueous acetic acid gradient (0.05 to 0.25 N) gives, after concentration in vacuo to dryness, a foam. Foam 35 was crystallized from H 2 O / CH 2 OH solution and recrystallized from 7,86733 H 2 O / C 2 H 5 OH solution to give the title compound as a monohydrate, m.p. 206 ° C (decomposition). [.alpha.] D @ 20 = -21.6 DEG (c = 1.1 in 2N HCl). The absolute configuration is deduced from the chemical correlation with D-asparagine 5 and confirmed by X-ray structure analysis.

The compound of formula I shows valuable pharmacological activity and is therefore recommended for use as a pharmaceutical agent, e.g. for therapeutic purposes. In particular, the compound has an inhibitory effect on luteinizing hormone 10 (LH) and testosterone secretion in the following test: Adult male rats of Wistar strain (SIV, Kissleg, West Germany, 200-300 g) receive the test compound intraperitoneally. 2 hours later, the rats are taped by cutting the neck and taking blood samples. Serum LH is determined using an animal assay based on the production of testo-20 steron from fragmented, collagenase-treated rat intermediate Leydig cells exposed to the LH-containing serum or rat LH standard; serum testosterone is determined by radioimmunoassay (125-J-T, cis, Medipro Teufen, Switzerland) / cf. E. del Pozo, A. Podesta, A. Solano, J. Calaf, M. Marko in Biorythms and Stress in the Physio-Pathology of Reproduction, P. Pancheri and L. Zichella 25 (eds.), Hemisphere Publishing Co. Washington, 389 - 398 (19881 ?.

The compound of formula I significantly inhibits the secretion of LH and testosterone at a dose of 3.2 mg / kg i.p. (+) - 4- (3-phosphono-2-propenyl) -2-piperazinecarboxylic acid (hereinafter referred to as CPP-ene), with the corresponding racemate of the compound of formula I, not at a dose of 3.2 mg / kg i.p. has no effect on LH secretion and only weakly inhibits testosterone secretion.

In female rats, compound 35 of formula I inhibits LH-dependent spontaneous ovulation in the following experiment / cf. M. Marko and E. Fluckiger, Neuroendocrinology 30, 228-231 (19801 ?: 8 86733

Female Wistar strains (SIV, Kissleg, West Germany, 200-300 g) with regular 4-day cycles receive test substance during the proestrus phase at 13.00 hours and 15.00 hours, intraperitoneally. . The next day, at 9.00 h, when the rats are in the estrus stage, they are sacrificed, the fallopian tubes are examined under a microscope, and the eggs are counted. Ovulation is considered to be inhibited only if no ova were detected at the time of counting. Compound 10 of formula I (tested as a monohydrate) significantly inhibits spontaneous ovulation when administered at doses of 2 x 3.2 mg / kg i.p. (at 13.00 hours 3.2 mg / kg i.p. and at 15.00 hours 3.2 mg / kg i.p.). CPP inhibits spontaneous ovulation very weakly when administered at doses of 2 x 3.2 mg / kg i.p. under the same experimental conditions.

The compound of formula I is therefore recommended for use in the treatment of diseases whose etiology involves or is influenced by LH secretion or whose etiology involves the physiological regulation of LH secretion, for example in the treatment of prostate hyperplasia, menopausal Rome and breast and prostate cancer. in trust. For this purpose, a daily dose in the range of about 1 to about 800 mg of compound is recommended, suitably administered in divided doses 2 to 4 times daily in unit dosage form containing, for example, about 0.25 to about 400 mg of compound, or in sustained release form.

The compound of formula I shows muscle relaxant activity in a conscious rabbit at a dose of 0.01 to 0.05 mg / kg i.v. (HJ Teschendorf et al., Arch. Exp. Pharmacol. 266, 467-468 (1970)) · In this experiment, the monohydrate reflective-muscle tension of a compound of formula I is inhibited by 50% when administered at 0.02 mg / kg iv , whereas CPP, on the other hand, inhibits reflective-35 muscle tension by 47% when administered at 0.5 mg / kg in 1 year, the compound of formula I is thus about 25 times more active than the corresponding racemate.

9 86733

The compound of formula I is therefore recommended for use in the treatment of increased muscle tension, e.g. due. For this purpose, a daily dose in the range of about 1 to about 800 mg of compound is recommended, suitably administered in divided doses 2 to 4 times daily in unit dosage form containing, for example, about 0.25 to about 400 mg of compound, or in sustained release form.

In addition, the compound of formula I reduces neuronal damage and associated symptoms caused by local anemia in a middle cerebral artery (MCA) obstruction model in rats at a dose of 1-30 mg / kg s.c. and in particular 3 x 10 mg / kg i.p. / Cf. A.

20 Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981), A. Sauter, M. Rubin, Stroke 17, 1228-1324 (1986-7). The area of tissue damaged by infarction is measured using MCID image analysis software (developed by Imaging Research Inc.), 5 horizontal 20-μm-thick slices cut from several levels and stained with cresyl violet The total volume of brain showing hematopoietic damage is estimated by summing the 5 areas obtained from the five-slice 5 days after MCA occlusion, the histologically determined infarct size over 30 20% when treated with 3 x 10 mg / kg ip monohydrate of a compound of formula I (first injection immediately after MCA occlusion, second after 8 and third after 16 hours).

The compound is therefore recommended for use in the prevention and treatment of conditions associated with local anemia of the brain, e.g., paralysis.

ίο 86 733 For this purpose, a daily dose in the range of about 25 to about 800 mg of compound is recommended, suitably administered in divided doses 2-4 times daily in unit dosage form / containing, for example, about 6 to about 400 mg of compound, or in sustained release form.

In addition, the compound of formula I has a potent, selective and competitive antagonistic effect on NMDA (N-methyl-D-aspartic acid) receptors. Thus, the monohydrate of the compound of formula I inhibits NMDA-induced depolarizations in an experiment performed using the isolated spinal cord of a frog /P.L. Herrling, Neuroscience 14, 417-426 (1985-7 having a pA2 value of 6.8, CPP having a pA2 value of 6.2, so that the compound of formula I is about 4 times as active as the corresponding racemate.

CPP with /(+)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid.7, the compound of GB Patent Application 2,157,685, has a pA2 of 5.8.

NMDA-induced sodium efflux in experimental rat brain sections (Luini A., Goldberg O. + Teichberg VI, Proc. Natl. Acad. Sci. USA 78, 3250-3254 (1981)) is a compound of formula I monohydrate pA2- a value of 6.5 and a pA2_ value of 6.2 for the CPP ene, so that the compound of formula I is about twice as active as the corresponding racemate 25. The pA2_aro of the CPP is 6.0.

The selectivity of the antagonistic effect on NMDA is demonstrated by the fact that the compound is ineffective, as is CPP-ene and CPP, in the assay for sodium efflux caused by quisqualate and kainate to a concentration of 1 mM to -30.

Due to its antagonistic effect on the NMDA receptor, the compound of formula I is recommended for use in the treatment of anxiety, schizophrenia and depression or degenerative diseases of the central nervous system, such as Huntington's, Alzheimer's or Parkinson's disease. For this use, a daily dose of 11,86733 in the range of about 25 to about 800 mg of compound is suitably administered, suitably administered in divided doses 2-4 times daily in unit dosage form containing, for example, about 6 to about 400 mg of compound, or in slow release form.

Due to its antagonistic effect on the NMDA receptor, the compound of formula I is further recommended for use in the treatment of ringing in the ears. For this purpose, a daily dose of about 25 to about 800 mg of compound is preferably recommended, suitably administered in divided doses 2 to 4 times daily in unit dosage form containing, for example, about 6 to about 400 mg of compound, or in sustained release form.

In addition, the compound of formula I shows anticonvulsant activity in electric shock-induced convulsions in the mouse /E.A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952j_7 · In this experiment, groups of 6 male mice (18-26 g, OF-1, Sandoz Basle) receive test substance 20 intraperitoneally. After 1, 2, and 4 hours, a 200 ms shock 50 mA shock is administered to the corneal electrodes. This over-maximal shock causes tonic extensor muscle spasms in all limbs.A hindrance to hind limb straightening is considered a protective effect.After studying several dose levels, a threshold dose is assessed.Nreshold dose at 1 hour, dose, to prevent hindlimb extension, the compound of formula I (monohydrate) has <1 mg / kg ip and the CPP-ene is between 30 and 10 mg / kg ip According to the literature, the threshold for CPP is nos 10 mg / kg ip

The following table shows the inhibition of hindlimb straightening, expressed as a percentage, by the compound of formula I compared to the corresponding racemate: 12 86733

Dose Inhibition of posterior mg / kg limb straightening by electric shock i.p. In% _1 hours 2 hours 4 hours

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

Fisher test, control against group of substances, * p <= 0.05.

As can be seen from the table, the anticonvulsant activity of the compound of formula I is greater than that of the corresponding racemate when tested for electric shock convulsions in mice.

The compound of formula I further inhibits N-methyl-D-aspartic acid (NMDA) seizures in mice. In this experiment, groups of 6 female mice (18-26 g, OF-1, 20 Sandoz Basle) were pre-injected with the test substance intraperitoneally. Thirty minutes later, they were given 400 mg / kg s.c. NMDA to the neck area and were monitored for 30 minutes. Latency times for the onset of the first signs of seizures, the first 25 tonic seizures, and the occurrence of death were noted. The significance of possible differences was examined using the Mann-Whitney U-test / S. Siegel, Non-parametric Statistics, McGraw-Hill, New York 19567 · The threshold dose is the lowest dose at which there is significant inhibition of seizure symptoms.

The threshold dose of a compound of formula I (tested as a monohydrate) is approximately 5 mg / kg i.p., CPP 10 mg / kg i.p.

Due to its anticonvulsant activity, the compound of formula I is recommended for use in the treatment of epilepsy. For this use, a daily dose in the range of about 25 to about 800 mg of 13,867,733 compounds, suitably administered in divided doses 2-4 times daily in unit dosage form containing, for example, about 6 to about 400 mg of compound, or in slow release form, is recommended.

The compound of formula I further exhibits analgesic activity in the isolated rat spinal cord in vitro using capsaicin (0.8-1 μM) as a chemical deleterious stimulus causing depolarizing anterior root reactions / M. Yanagisawa 10 et al., European J. Pharmacol. 106, 231-239 (1984 | 7 * The monohydrate of the compound of formula I reduces the chemical stimulus by 75 to 80 at a concentration of 10.

The compound of formula I is therefore recommended for use in the treatment of pain. For this use, a daily dose in the range of about 25 to about 800 mg of compound is suitably administered in divided doses 2 to 4 times daily in unit dosage form containing, for example, about 6 to about 400 mg of compound, or in sustained release form.

In addition, the compound of formula I, like the corresponding racemate, has no effect on blood pressure and heart rate in an anesthetized cat at a dose of 10 mg / kg i.v. until. In preliminary toxicity tests in dogs, 3 mg / kg / day i.v. compound of formula I well.

As can be seen from the above experimental results, the compound of formula I has no significant (25-fold) increase in muscle relaxant effect compared to the corresponding racemate compared to the corresponding racemate, nor a double or quadruple NMDA receptor antagonistic effect. associated with a similar increase in side effects, e.g., cardiovascular effects.

The compound of formula I may be administered as such or as pharmaceutically acceptable salts thereof. Such salts have the same order of activity as the compound of formula I.

It is possible to prepare pharmaceutical preparations containing a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

The compound of formula I may be administered by any conventional route, in particular into the gastrointestinal tract, preferably orally, or parenterally. The compound of formula I may be administered alone or in admixture with conventional pharmaceutical carriers. For example, for oral administration, e.g. in the form of tablets or capsules, the compound of formula I may be mixed with conventional pharmaceutically acceptable excipients, e.g. inert diluents such as lactose, mannitol, calcium sulphate, fine crystalline cellulose; with disintegrants, e.g. starch, sodium carboxymethylcellulose, sodium carboxymethyl starch, alginic acid, crospovidone; with binders such as cellulose derivatives (methyl, hydroxymethyl, hydroxypropylmethyl), povidone, gelatin; lubricants, e.g. silica, stearic acid, magnesium or calcium stearate; with hydrogenated oils, such as castor oil, glycerol esters, e.g. palm tostearate, and / or flavoring, coloring and sweetening agents. The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Formulations for parenteral administration are preferably in the form of a sterile injectable aqueous solution. Such aqueous solutions should be suitably buffered, if necessary, and rendered isotonic with sufficient saline. If desired, a preservative such as benzyl alcohol may be added.

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

The pharmaceutical preparations can be prepared by conventional methods.

To prepare tablets, a 1 ° compound of formula I can be mixed with lactose and granulated with water, 0.5% sodium alginate or 5% hydroxypropylmethylcellulose solution. The dried granules are compressed into tablets in the presence of about 20% corn starch and 1% magnesium stearate. In this way, e.g.

15 tablets of the following composition:

Tablet

Ingredients Weight (mg)

Monohydrate of the compound of formula I 50 20 lactose 97 corn starch 40 hydroxypropylmethylcellulose 10 magnesium stearate 2 silica 1 25 200 These tablets, which are scored, can be administered orally in a dose of half to one tablet one to four times a day.

Capsules may contain the active ingredient alone or in admixture with an inert solid excipient, for example as mentioned above.

Capsules containing the ingredients listed below can be prepared by conventional methods and administered in a single capsule dose of 1 to 4 times a day.

16 86733

Capsule

Ingredients Weight (mg)

Compound of formula I monohydrate 50 inert solid excipient (corn starch-5 lys, lactose, aerosil, magnesium stearate) 250

In a similar manner, tablets and capsules containing 25 mg and 100 mg of a compound of formula I may be prepared.

10 The following solution for injection has been prepared using the indicated amount of active substance, using conventional methods. The solution for injection is suitable for once daily administration.

Sterile, injectable solution_

Ingredients Weight (mq / ml)

Monohydrate of the compound of formula I 25 Sodium chloride 7.0 20 Potassium dihydrogen phosphate 3.63 Disodium hydrogen phosphate 5.68 Benzyl alcohol 9.0 Sufficient water for injections up to 1 ml 25 Solutions may be filtered through a sterile 0.2 filter and placed aseptically. ampoules. The ampoules are gasified with carbon dioxide.

This compound of formula I or a pharmaceutically acceptable salt thereof according to the invention can be used as a medicament, e.g. in the treatment of diseases associated with the secretion of LH; in the treatment of increased muscle tension; in the treatment of conditions associated with local anemia of the brain; in the treatment of anxiety, schizophrenia, depression or degenerative diseases of the central nervous system; in the treatment of ringing in the ears; in the treatment of epilepsy or to relieve pain.

Claims (1)

An analogous method of a therapeutically useful [R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazinecarboxylic acid of formula I OH> 0 ^ Jl OH 10 / N. (I) for the preparation of H C 10 H 15 or a salt thereof, characterized in that the alkyl groups are removed from the compound of the formula II 0-20 Γ 0R (II) H \ 25 'COOH wherein R is (C 1-4) alkyl or aryl (C 14) alkyl, and if desired its salt. i 86 86 733 Analogs for the preparation of therapeutically active compounds [R- (E)] - 4- (3-phosphono-2-propenyl) -2-pipe-5 razinecarboxylates with the formula I OH P = ° il OH 10 ^ Cl · - H \ COOH 15 or, if the same is obtained, the alkyl group having the same alkyl group as in formula II 20 0 Il 25 (II) H \ COOH color R is (C 1-4) alkyl or aryl (C 1-4) alkyl , och, ifall 30 önskvärt, bildar ett sait därav.