JPS63203691A - Pyperadine carboxylic acid, its production and pharmaceutical composition containing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to piperazine carboxylic acid, a method for producing the same, and a pharmaceutical composition containing the same.

(Prior Art) GB 2,157,685 discloses 4-substituted 2-piperazinecarboxylic acids with activity in the central nervous system.

Arrangements of the Invention Among this class of compounds, one hitherto undisclosed compound has been found to have strong activity, particularly in the central nervous system, and to have well-tolerated and long-lasting activity.

[R-(E)]-4-(3-phosphono-2-
The present invention relates to propenyl)-2-piperazinecarboxylic acid, its pharmaceutically acceptable salts, its production process, pharmaceutical compositions containing it, and its use as a drug.

The compound of formula I is a compound of the formula
I-4) It can be produced by dealkylating a compound represented by the formula (I-4) which is alkyl.

The above method can be performed by a known method. For example, dealkylation can be carried out by silylation followed by hydrolysis of the resulting silyl ester. The silylation can be carried out using, for example, 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 aryl(C+□)alkyl, aryl is preferably an optionally substituted phenyl group, where preferred substituents include lower alkyl or lower alkoxy groups.

The compounds of formula I and their salts can also be obtained in the form of their hydrates, especially monohydrates. Hydrates, especially monohydrates, form part of this invention.

The compound represented by formula (1) can be produced as shown in the reaction formula below.

CH.

Compounds of formula I are capable of forming cationic salts and acid addition salts. Such salts are readily prepared by standard methods. Cationic salts include, but are not limited to, ammonium, sodium, potassium, calcium, piperidinium, morpholinium or pyrrolidinium salts. Acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfone L p
- including, but not limited to, acid addition salts formed with toluenesulfonic acid and trifluoroacetic acid.

Hydrates, especially monohydrates, of compounds of formula I have physicochemical and other properties of particular interest, such as those relating to solubility, ease of purification and stability. Hydrates can be obtained, for example, by crystallizing a compound of formula (1) from an aqueous medium, such as water/methanol, as shown in example e).

In the examples below, all temperatures are in degrees Celsius and uncorrected. The value of “[a]” is uncorrected.

(Example) A) (R)-1,4-bis(phenylmethyl)-2-piperazinecarboxylic acid (l R,2S,5R)-5=methyl-2-(1-methylethyl)cyclohexyl ester 1.4-Dibenzyl-2-piperazinecarboxylic acid ethyl ester (Ni Nickel and Nin Ridge, Helv.

Chim, Acta), Vol. 45 (1962), p. 2383) and (-
) - 15 g of NaH (dispersion, 55%-60%) and toluene IQ were added to a solution consisting of 458 g of menthol at 45°
Added at C. Approximately 700 mQ of solvent was then slowly removed by distillation and then replaced with fresh toluene (
The reaction was monitored by TLC using ethyl acetate/hexane 1:3). The resulting mixture was cooled to room temperature, treated with 1.25Q of 2N aqueous MCI and 6Q of diethyl ether, and stirred for 1 hour. The clear precipitate was filtered and diluted with diethyl ether and 0. Washed with IN aqueous HCI solution.

The crude product was recrystallized from a 10.2N MCI aqueous solution in ethanol to obtain the hydrochloride hydrate of the title compound ([ty
]o'=+18.5° (c=1.2 in CHC13)
).

This was used in the next step without further purification.

b) (R)-2-piperazinecarboxylic acid (lR, 2s.

5R)-5-Methyl-2-(l-methylethyl)cyclohexyl ester The product 2109 obtained in step a) was treated in ethanol 2Q and 10.5 g of Pd/C (10%) for 7 hours at room temperature and normal pressure. Hydrogenated, then filtered and concentrated in vacuo. The residue was treated with ethanolic HCI and the precipitate was filtered and washed with ethanol/diethyl ether (1:1). The obtained product was recrystallized from water/methanol/ethyl acetate to obtain the dihydrochloride salt of the title compound (m, p, 225-
226°C, [α]Δ0−-52.0° (c=1.
34)). The obtained dihydrochloride was treated with diethyl ether/ammonia aqueous solution, and the organic layer was concentrated to dryness to obtain the title compound (m, p, 50-52 °C, [σ] Otsu' = -
56.7' (c=1.05 in CHCl)).

c) [R-(E)]-4-(3-jethoxyphosphinyl-2-propenyl)-2-piperazinecarboxylic acid (l
R,2S,5R)-5-Methyl-2-(l-methylethyl)cyclohexyl A solution of 11.3 g of the free base obtained in Nissche step b) and 5.9 mQ of triethylamine was dissolved in tetrahydrofuran 9011Q with stirring. ,
Tetrahydro 7 run 45ma to 3-promopropene-
2-yl-phosphonic acid diethyl ester Takeno Chi, Hashimoto M and Kamya Ty, Chemical and Pharmaceutical Bulletin (C
heIn. Pharm. Bull), Volume 30 (1
982), page 111) 10.

A solution containing 7 g was added over a period of 30 minutes at -30°C. Stirring was continued for 20 hours at -25°C. Retirement of sediment,
The filtrate was concentrated under reduced pressure, and the resulting syrup-like material was purified on silica gel using dichloromethane while gradually increasing the concentration of a concentrated aqueous ammonia solution/ethanol (1:19) mixture to 10% after 2 hours. Chromatographically processed. The fraction eluted with dichloromethane/concentrated aqueous ammonia/ethanol (200:1:19 (c=1.3 in 2N MCI aqueous solution). The resulting product was purified by ethanolic H
Treatment with CI/ether gave the dihydrochloride salt (m.p.
.

157~163°O, [σ]Otsu'=-48.2°(2
c=1.4) in N HCl).

d) [R-(E)]-4-(3-jethoxyphosphinyl-2-propenyl)-2-piperazinecarboxylic acid 5.799 of the product obtained in step C) was dissolved in anhydrous CH.

Cli58i (l,2-
22.8 ml of a solution of boron trichloride in dichloroethane (approximately 2.2 M) was added at -30° C. for 30 minutes.

The reaction mixture was stirred at -25°C for 1 hour and at 0°C for 3.5 hours. At 0°C, add 50 mQ of water and add 2
Neutralize by adding aqueous NaOH solution of N, H2O and C
H2Cl, partitioned between.

The aqueous layer was concentrated to dryness in vacuo and the residue was dissolved in CHCl. NazSO. and concentrated to dryness in vacuo to give the title compound. The obtained compound was used in the next step without further purification.

Analytical samples were analyzed using HPLC (Nucleosil).
os i l) RP-8, II, O/CH30H (3:
2)) to obtain a spongy substance ([a]M'-
-1 8.0° (0.

c=1. in 5N HCl. l)).

360MHz 'H-NMR (DMSO, l 5
0°C): 1, 24 (6H, L, J = 7.0Hz), 2.26 (l
H.

axdxd, J-1 1.3x9. ox3.3Hz),
2.

35 (l H, aXd, J=1 1.3X8.6Hz)
, 2.

5 2-2.5 8 (L H, m), 2.77 (I
H, dxdxd% J=12. lX9. OX3.3H
z), 2.8 3(IH, dXdXd.J=l 1.3
X3.3X1.7Hz), 2,99(IH,aXt,J
-12. lX3.9Hz), 3,10~3.15(
2H, m), 3.33 (L H, dxdS J=8.
6X3.3Hz), 3.97 (4H, dXq1J=8.
6X7. OHz), 5.50 (2H, broad),
5, 88 (IH, dxdxtl J-21.5X17.
lX2. lHz), 6.52(lH,dXdXL,J
=22.

OX17. 1×5.6Hz).

e) [R-(E)]-4-(3-phosphono-2-
Brobenyl)-2-piperazinecarboxylic acid 3.9 g of the crude compound obtained in step d) was added to anhydrous CH2CH
Bromotrimethylsilane 9 dissolved in 2C1z300
, 6 mQ at room temperature and stirred for 16 hours.

The reaction mixture was concentrated and the residue was taken up in H,O, stirred for 1 hour and filtered. Dowex lx
The filtrate was adjusted to pH 6 by the addition of 4 (OH form) and the resulting mixture was purified with Dowex l
acetate form).

A spongy material was obtained by eluting with acetic acid aqueous solution in gradients (0.05 to 0.25 N) and concentrated to dryness in vacuo. The resulting spongy material was treated with H,O/CH.

OHi: J: Ri crystallizes, H! Recrystallization from O/C, H, OH gave the monohydrate of the title compound (m, p.

206°C (decomposition)). [a1g'=-21,6°(2N
c-1,1) in HCl. The absolute configuration was estimated by chemical correlation using D-asparagine and confirmed by X-ray structural analysis.

Compounds of Formula I possess significant pharmaceutical activity, e.g., exhibiting utility as therapeutic agents.

In particular, this compound showed luteinizing hormone (LH) and testosterone secretion inhibitory activity in the following tests: Adult male rats of the Wistar strain (S
Test compounds were administered intraperitoneally (IV, Kisleg, West Germany, 200-300 g). After 2 hours, the rats were sacrificed by dissection and blood samples were collected. Serum LH was measured by a bioassay based on the production of testosterone by dispersed and collagenase-treated rat stromal Leydig cells exposed to LH-containing serum or rat LH-standards.

Serum testosterone was determined by radioimmunoassay (125-
J-T.

[E. del Pozzo, A. Bodest, A. Solan, J. Kara7, M. Marco, Biorhythms.
- Stress in the Physiopathology of Reproduction (Biorhythms and
5tress in the Physiopathy
389-398 (1988)].

The compound represented by formula ■ has a dosage of 3, 2111 g/
Intraperitoneal administration of ky L)(- and testosterone- secretion was very well inhibited. The corresponding racemic form of the compound of formula ■, (±)-4-(3-phosphono-2-propenyl)-2 -piperazinecarboxylic acid (hereinafter referred to as CPP-
When administered intraperitoneally at a dose of 3 or 2 my/by, it had no effect on LH secretion and did not significantly suppress testosterone secretion.

In female rats, the compound of formula I was tested [M. Marco and E. 7.
30, pp. 228-231 (19
In female Wistar rats (S I
V.

Test substances were administered intraperitoneally during proestrus in regularly scheduled 4-day cycles at 13:00 and 15:00 hours. At 9 o'clock the day after the rats entered estrus, the rats were sacrificed, the oviducts were examined under a microscope, and the number of eggs was counted.

Ovulation was considered suppressed only when there were no eggs.

The compound of formula I (tested as monohydrate) is
When administered intraperitoneally at a dose of 2 x 3.2 mg/ky (1
3,21119/by was administered intraperitoneally at 3 o'clock, 15
(3,211 g/#9 administered intraperitoneally) suppressed natural ovulation very well. CPP-ene did not significantly inhibit spontaneous ovulation when 9 was administered intraperitoneally to 2 x 3.2+19/ under the same test conditions.

Accordingly, compounds of formula I may be useful in treating diseases whose etiology involves physiological regulation of LH secretion, such as the treatment of prostatic hypertrophy. , treatment of menopausal syndrome,
It exhibits utility in the treatment of breast and prostate cancer. In this use, the daily index dosage is approximately 1 ml of the compound.
to about 800 mg, preferably in unit dosage form or sustained release form containing, for example, about 0.25 to about 400 my of the compound, administered in two to four divided doses per day.

The compound represented by the formula ■ exhibited muscle relaxing activity in conscious rabbits when administered intravenously at doses of 0.01 to 0.05 mg/kg [H. Verimental Pharmacology (Arch, Exp, Pharmacol)
), Vol. 266, pp. 467-468 (1970
Year)]. In this test, the monohydrate of the compound of formula I inhibited reflex muscle tone by 50% after intravenous administration of 0.02 myi/kg, whereas CPP-ene
After intravenous administration of 0.5119/kg, reflex muscle tension decreased to 47
% suppressed. The activity of the compound of formula I was 25 times that of the corresponding racemate.

The compounds of formula I are therefore suitable for the treatment of muscle hypertonia, for example for the treatment of painful muscular spasms resulting from static and functional disorders of the lungs or cervical spine or after surgery or for example in multiple sclerosis. , has utility in the treatment of spasticity due to diseases of the spinal cord, seizures, cerebral damage or cerebral palsy.

In this application, the daily index dosage is within the range of 1 to about 8001119 ml of the compound, preferably in unit dosage form or sustained release form containing, for example, 0.25 to about 400 ml of the compound. Administer in divided doses 2 to 4 times a day.

Furthermore, the compound of formula I may be administered at a dose of 1 to 30 my
subcutaneous administration of /7 and especially 3X10Il+g/hg
Intraperitoneal administration of 20% reduced ischemia-induced neuronal damage and its symptoms in a rat central sulcus artery (MCA) occlusion model [A. Tamura et al., Journal on Cerebral Blood-7o--Metabolism. (J, Cereb, BloodFlow Me
tabol, ), Volume 1, pp. 53-60 (198
1), A. Souter, M. Rudin, S Lroke, Volume 17, pp. 1228-12
See p. 34 (1986). 1° The infarcted tissue area was cut at multiple levels and five horizontal 20μ thick sections stained with cresyl violet were analyzed using MCID image analysis software (Imaging Research Incorporated). (developed by). The total brain volume showing ischemic damage was assessed by summing 5 areas obtained from 5 slices. The infarct size measured 5 days after occlusion of the MCA was determined by intraperitoneal administration of the monohydrate of the compound of formula I at 3 x l 0119/9 (first injection immediately after MCA occlusion; After 8 hours and 1
after treatment with the second and third injections after 6 hours, respectively), the reduction was more than 20%.

Accordingly, the compounds exhibit utility in the prevention and treatment of symptoms associated with cerebral ischemia, such as stroke. In this use, the daily index dosage ranges from about 25 to about 800119 of the compound, preferably from 2 to about 2 to about 800119 per day in unit dosage form or sustained release form containing, for example, about 6 to about 4001119 of the compound. Administer in 4 divided doses.

Furthermore, the compound represented by formula (1) has an effective, selective and competitive antagonistic effect on the NMDA (N-methyl-D-aspartate) receptor.

For example, the monohydrate of the compound of formula I can be used in isolated frog bone marrow assays [P.L. pAz
CPP-ene had a pAt of 6.8 and CPP-ene had a pAt of 6.2.

The compound of formula I was about 4 times more active than the corresponding racemate. The key compound disclosed in UK Patent Application No. 2157685, (±)-3-(2-carboxypiperazin-4-yl)-propyl-I-phosphonic acid (CPP), had a pA of 25-8. .

NMDA-induced sodium efflux assay in rat brain slices [Luini A, Goldbarb O, Teachbarb B, I, Proceedings of the National Academy of Sciences on Science, N. Varnish 5--(Proc, Natl,
Acad, Sci, USA), Volume 78, No. 3
250 to 3254 (1981) J, the monohydrate of the compound represented by the formula ■ has a pA of 26.5, the CPP-ene has a pAx of 6.2, and the compound represented by the formula ■ is approximately twice the activity of the corresponding racemate;
. CPP had pAz6-0.

As for the selectivity of NMD A antagonism, the concentration is 1mM.
It was shown to be as inactive as CPP-ene and CPP in sodium efflux tests induced by quisqualate and kainate.

Due to their NMDA receptor antagonism, compounds of Formula I exhibit utility in the treatment of CNS degenerative diseases such as anxiety, schizophrenia and depression; Huntington's disease, Alzheimer's disease or Parkinson's disease.

In these applications, the daily index dosage ranges from about 25 to about 800+1 g of the compound, preferably from about 6 to about 40 g of the compound (1 g in unit dosage form or sustained release form containing h++9). Administer in divided doses 2 to 4 times a day.

Because of this NMDA receptor antagonism, compounds of Formula I further exhibit utility in the treatment of tinnitus. In this application, the daily index dosage ranges from about 25 to about 8001R9, preferably from about 6 to about 40 doses of the compound (e.g., in unit dosage form or sustained release form containing Jray) per day. Administer in 2 to 4 divided doses.

Furthermore, the compound of formula ■ exhibited antispasmodic activity in electrical shock-induced convulsions in mice [E.N. Swinyard, Journal Op.
American 7 Armathematics Association Scientific Education (J.
Am, Pharm, As5oc.

5cienL, Ed,), Volume 38, Page 8201 (1
949) and Journal of Pharmacology and Experimental Therapeutics (J.
Phar+aaco1. Exptl, Thera
p.), vol. 106, p. 319 (1952)]. In this study, six male mice (18-26 g, 0
The test substance was administered intraperitoneally to groups consisting of F-1° Sand Basel). After 12 and 4 hours, 200 mA at 50 mA was applied using a corneal electrode coated with electrolyte jelly.
Shocked during Wls. This supermaximal shock produced tonic extensor spasm of all extremities. As a protective response, hindlimb extension is inhibited. After studying several dosage levels, efficacy was evaluated. The dosage required to suppress hindlimb elongation in one hour is the dosage of the compound represented by formula I (
less than 1 my/kyc i.p. for monohydrate) and 3 to 9 l Omg/kyc for CPP-ene
(intraperitoneal administration). The dosage of CPP according to the literature is 10rtrg/kg (intraperitoneal administration).

In Table 1 below, the inhibition of hindlimb elongation exerted by the compound of formula I is shown in % and compared with that of the corresponding racemate: Table 1 Formula I 1 67 67 *
2.5 of 33 compounds 83* 8
3 67 monohydrate 3 100*1
00ne 83*CPP-en 1205025
3 33 -67* 17 I0 67 lines 80 lines 80 lines Finnyer's test, control vs. substance group, middle <-0,05° As can be seen from Table 1 above, a test on convulsions induced by electric shock in mice. In the case of , the compound of formula ■ has higher antispasmodic activity than the corresponding racemate.

Furthermore, the compound of formula I has N-
Suppresses spasticity induced by methyl-0-asparagine* (NMDA). For this study, groups of 6 female mice (18-26 g, 0F-1° Sand Basel) were pretreated intraperitoneally with the test substance. After 30 minutes, the neck region was challenged with subcutaneous administration of 400 my/bg of NMDA and observed for 30 minutes. The appearance of the first signal of spasticity, the latency of the first tonic spasticity and the occurrence of death were recorded. Mann-Whitney
Knee test [Niss-Siegel, non-parametric]
Status (Mouse (Non-parametric)
Statistics), McGraw-Hill, New York, 1956]. The effective dosage was the minimum dosage, and the spasmodic symptoms were sufficiently suppressed at this effective dosage. The active dose of the compound of formula I (tested as monohydrate) was approximately 511,497 kg (intraperitoneal administration) and the CPP was 1 Omg/kg (intraperitoneal administration);
.

Due to its antispasmodic activity, compounds of formula ■ have shown utility in the treatment of epilepsy. In this application, the daily index dosage ranges from about 25+ig/bg to about 8 ig/bg of the compound.
001119/kg, preferably in unit dosage form containing, for example, from about 6 to about 4001119 of the compound; administered in sustained release form in 2 to 4 divided doses per day.

In addition, the compound of formula I has been shown to be effective against cabsaicin (0,8
~ lμM) isolated in vitro in rats showed analgesic activity in the cauda medullary [M. Yanagisawa et al., European Journal on.
Pharmacology (Eur.

pean J, Pharmacol, ), No. 106
Vol., pp. 231-239 (1984)]. The monohydrate of the compound of formula I reduced the chemical irritation by 75-80% at a concentration of 10 μM.

Therefore, compounds of Formula I have exhibited utility in relieving pain. In this use, the daily index dosage ranges from about 25 to about 800 rgy/day of the compound.
ky, preferably for example about 6
Administer in unit dosage form or sustained release form containing ~400 yry in 2 to 4 divided doses per day.

Furthermore, the compound of formula I and its corresponding racemate had no effect on blood pressure and heart rate in anesthetized cats when administered intravenously up to 9 to 10n97. The compound of formula I was well tolerated in preliminary toxicity studies in dogs administered intravenously at 3 mg/kg/day for 4 weeks.

As can be seen from the results of the above tests, the compound of formula I has a strong LH secretion inhibitory activity, a significant (25-fold) increase in muscle relaxing activity and a 2-4-fold increase in NMDA receptor antagonism compared to the corresponding racemate. The activity is not accompanied by a similar increase in side effects, such as cardiovascular effects.

In the above electric shock test, regarding antispasmodic activity (
+) -5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohebutene-5,10-imine-maleic acid ester (l [synthetic NMD8-antagonist)] The hydrate of the compound of formula I has an active dosage of 10-201 Ig/kg (oral administration), compared to 0.1-0.2 mg/kg (oral administration). did. Thus, for antispasmodic indications, a compound of formula I can be administered to large mammals, e.g. humans, by a similar mode of administration at dosages about 100 times higher, e.g. from about 50 to about 300119/day. .

formula! The compounds shown can be administered neat or in their pharmaceutically acceptable salts. Such salts exhibit the same activity as the compound of formula (1).

Additionally, the invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

Compounds of formula I can be prepared by any conventional antagonism:
It can be administered in particular enterally, preferably orally or parenterally. The compound of formula (1) can be administered neat or mixed with a conventional pharmaceutically acceptable carrier.

For oral administration, e.g. in tablet or capsule form, the compounds of formula 1 may be prepared in the form of pharmaceutically acceptable conventional excipients such as lactose, calcium mannitone sulfate, inert diluents such as microcrystalline cellulose. Excipient;
For example, starch, sodium carboxymethyl starch, sodium carboxymethyl starch, alginic acid,
Disintegrants such as crospovidone: cellulose derivatives (methyl-, hydroxymethyl-, hydroxypropylmethyl-), povidone, binders such as gelatin; lubricants such as silicium dioxide, stearic acid, magnesium or calcium stearate; It can be mixed with hydrogenated oils such as castor oil, glycerol esters such as palmitostearate and/or flavoring, coloring and sweetening agents. Tablets are uncoated or slow disintegration and absorption in the gastrointestinal tract;
They may also be coated by known techniques, thereby making it possible to maintain their action for a long time. Parenteral compositions are preferably in the form of sterile injectable aqueous solutions. Such aqueous solutions can be suitably buffered, if necessary, and made isotonic with a sufficient amount of saline. If desired, preservatives such as benzyl alcohol can be added.

A unit dosage can contain from about 0.25 to about 4001119 of a compound of Formula I or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions can be manufactured according to conventional techniques.

For the manufacture of tablets, the compound of formula I can be mixed with lactose and granulated with water, 0.5% sodium alginate or 5% hydroxypropyl methylcellulose solution. Add about 2 tablespoons of cornstarch to the dried granules.
0% and magnesium stearate 1%.

In this way, for example, tablets having the following composition were obtained.

Monohydrate of the compound represented by formula ■ 5゜Lactose 97 Cornstarch
40 Hydroxypropyl methylcellulose 10 Magnesium stearate
Silicium dioxide --
These tablets with a crackline can be administered orally in dosages of half to one tablet, one to four times per day.

The capsules contain the active agent alone or mixed with inert solid excipients, such as those mentioned above.

Capsules containing the following ingredients may be manufactured by conventional techniques and may be administered in dosages of 1 to 4 capsules per day.

Monohydrate of a compound of formula I 50 Inert solid excipients (cornstarch, lactose, aerosil, magnesium stearate) 250 Tablets and capsules containing 1 g of compound 25I and 100 of formula I can be manufactured.

The injection solutions described below are formulated using conventional techniques with the indicated amounts of active agent. The injection solution is suitable for administration once a day.

Monohydrate of the compound of formula I 25 Sodium chloride 7.0 Potassium dihydrogen phosphate 3.63 Disodium hydrogen phosphate
5.68 benzyl alcohol
9.0 Water for injection Add appropriate amount and total Lrm
The resulting solution, designated Q, can be filtered through a 0.2 μm sterile filter and aseptically filled into ampoules. The ampoule is gassed with carbon dioxide.

In addition, the present invention is applicable to, for example, treatment of diseases associated with LH secretion; treatment of muscle hypertonia; treatment of symptoms associated with cerebral ischemia;
Treatment of anxiety, schizophrenia, palsy or CNS degenerative diseases;
The present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof useful as a drug for the treatment of tinnitus; the treatment of epilepsy or pain relief.

Therefore, the present invention provides formula ■ for subjects requiring treatment.
or a pharmaceutically acceptable salt thereof.
Treatment of diseases associated with H secretion; treatment of muscle hypertonia; treatment of symptoms associated with cerebral ischemia; onset of anxiety, schizophrenia, illness or CNS degenerative diseases; treatment of tinnitus; treatment of epilepsy or pain relief. Provide a method regarding cargo release.

Claims (10)

[Claims] (1) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II (In the formula, R is (C_1_-_4) alkyl or aryl (C_1_-_4) alkyl) Dealkylating the compound represented by [R-(E)]-4-(3-phosphono-2-
A method for producing (propenyl)-2-piperazinecarboxylic acid or a salt thereof. (2) A method for producing a compound represented by formula I or a salt thereof as described in the Examples. (3) A compound represented by formula I or a salt thereof produced according to the production method set forth in claim 1. (4) A compound represented by formula I or a salt thereof. (5) The compound according to claim 4 or a salt thereof, which is in the form of a monohydrate. (6) A compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof, which is useful as a drug. (7) Diseases associated with LH secretion, increased muscle tone, symptoms associated with cerebral ischemia, anxiety, schizophrenia, depression, CNS degenerative diseases,
7. A compound according to claim 6, useful for the treatment of tinnitus or epilepsy or relief of pain. (8) Diseases associated with LH secretion, muscle hypertonia, cerebral ischemia, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need of treatment. Symptoms associated with anxiety, schizophrenia, depression, CN
Methods of treating S-degenerative diseases, tinnitus or epilepsy or relieving pain. (9) Diseases associated with LH secretion, increased muscle tone, symptoms associated with cerebral ischemia, anxiety, schizophrenia, depression, CNS degenerative diseases,
Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition useful for the treatment of tinnitus or epilepsy or relief of pain. (10) A pharmaceutical composition comprising the compound according to claim 4 or 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier thereof.