JPS6072816A - Sleep adjusting and psychoneurotic agent - Google Patents

Abstract

PURPOSE:The titled agent, containing 4-methyl-5-hydroxyhexanoic acid or a derivative thereof, and having tranquilizing and antistress action, and further hyphotic action close to natural sleep. CONSTITUTION:A sleep adjusting and psychoneurotic agent containing a compound selected from 4-methyl-5-hydroxyhexanoic acid of formula I and a salt thereof and delta-lactone of formula II which is a lactone derivative thereof as an active constituent. The daily dose of the treating agent for adults is 200- 1,000mg, and 10-20mg for injection. The agent is effective for treating various sympotms such as sleeplessness and somnipathy, neurosis accompanying anxiety and conflict, abnormality of living body rhythm, e.g. desynchronization due to time zone change, autonomic imbalance, menopausal disorder, spasm and psychosomatic diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel sleep regulating neuropsychiatric agent, more specifically,
4-methyl-5-hydroxyhexanoic acid (hereinafter MHA)
The active ingredient is 1-lactone (hereinafter abbreviated as MHAL), its salt or its lactone (abbreviated as MHAL), and has a sleep regulating effect, an anti-stress (5tress) effect, an autonomic nervous imbalance regulating effect, and a tranquilizing effect. Concerning psychotropic neuromodulating agents.

Mental illnesses such as neuroses and psychosomatic disorders, physical illnesses in the field of psychosomatic medicine, and mental and physical symptoms caused by stress are all caused by psychological symptoms such as anxiety, fear, nervousness, and sleep disorders. It occupies an important part of the pathological condition (Shunji Ishiyama et al., eds., Today's Treatment Guidelines, pp. 227-243, Igaku Shoin, 1983). Additionally, it is widely known that autonomic nervous system dysfunction is a major factor in the onset of various stress-related symptoms (
Ishikawa (ed.), Psychosomatic Medicine, pp. 404-406, Kokusai Isho Publishing, 1978).

Dysfunction of the autonomic nervous system caused mainly by stress can lead to gastrointestinal disorders such as gastric ulcer formation and irritable colitis (Young, S.
, J., Gastroenterology, Vol. 70, pp. 1162-166, 1976), circulatory disorders such as hypertension (Naka Ishikawa, ed., Psychosomatic Medicine, pp. 404-406,
Kokusai Isho Publishing, 1978) and is known to cause reproductive system disorders such as impotence (Yamamura Yu, ed., Shinen Science, Vol. 5, pp. 163-164, Nanzando, 196
Year).

Furthermore, disorders of the endocrine system caused by stress stimuli are well known, and include growth arrest, infertility, lactation arrest, and impotence (Nishibu Ikemi, ed., Theory and Practice of Psychosomatic Medicine, General Review, pp. 96-141). , Igaku Shoin, 1962), menopausal disorders (Hiroyuki Nakao et al., Modern Psychiatry, pp. 229-230, Asakura Shoten, 1976) and insomnia (Atsushi Mori, Modern Medicine, vol. 38, p. 448) 〜453 pages, 198
5 years) etc. are also known to occur.

The stress, autonomic nervous system disorders, endocrine system disorders, sleep disorders, etc. mentioned above, while maintaining an organic relationship with each other, form the symptoms of many neuropsychiatric diseases and psychosomatic disorders.

For the treatment of the above-mentioned diseases, pharmacotherapy is currently widely used in addition to psychological therapy, and the drugs used for this purpose are generally called tranquilizers, anxiolytics, or autonomic nervous system ameliorating agents.

Sedatives have anti-anxiety, anti-spasmodic, muscle-relaxing, autonomic nervous imbalance-improving, and hypnotic effects, and these effects relieve patients' anxiety, tension, and fatigue, and improve sleep. This will facilitate its introduction.

However, the currently frequently used benzodiazepines (b
While drugs such as enzodiazepjne ) derivatives and barbylic acid salt conductors have remarkable sedative and anti-stress effects, their hypnotic effects are due to the paradoxical sleep essential for the human body (Guyton, translated by Koji Uchizono et al. Physiology of the Human Body, pp. 590-595, Kouyo Shoten, 1976), and in some cases may actually reduce paradoxical sleep. In sleep disorders associated with mental illness or stress, it is important to consider not only quantitative changes such as lengthening of sleep onset latency and shortening of sleep duration, but also changes in the incidence of each sleep stage, that is, qualitative changes (
Takeo Ishiguro et al., Metabolism, vol. 17, pp. 651-661, 19
1980), it is particularly important to maintain the incidence of paradoxical sleep. Paradoxically, lack of sleep causes changes in biological rhythms such as fatigue, difficulty concentrating, emotional instability, neurosis, decreased learning ability, and jet lag, as well as illusions and hallucinations (Takeo Ishiguro et al., Metabolism, 17). Vol., pp. 651-661, 1980).

In addition, with conventional drugs, insomnia and nightmares have been observed due to discontinuation of taking them (Pra-ag, translated by Makoto Kato, Psychotropic Drugs, pp. 372-379, Seiwa Shoten, 19
(1979), and the resulting development of drug dependence. These facts cast doubt on the therapeutic effects of the above-mentioned existing drugs in a fundamental sense.

In view of the above circumstances, the present inventors conducted research for many years to find a drug that has tranquilizing and anti-stress effects and paradoxically increases the amount of sleep.
We discovered that hyaluronan, its salts, and its lactone form MHAL have tranquilizing and antistress effects, as well as a one-sleep effect similar to natural sleep, and are therefore useful as sleep-regulating psychoneurotic agents. Completed the invention.

MI(A (11 and MHAL+II)), which is the active ingredient of the therapeutic agent of the present invention, is a known compound having the following chemical structural formula.

(I) [I[) MHA can be in the form of a pharmacologically acceptable salt. The salt form is sodium salt (hereinafter referred to as MHA-Na).
), metal salts such as potassium salts and lithium salts, organic base salts such as dimethylamine and ammonium salts, and amino acid salts such as glycine salts, lysine salts, and arginine salts.

Table 1 shows MHA%MHA-Na and MHAL of the present invention.
The physicochemical properties of

Table 1 Physicochemical properties Table 1 continued The therapeutic dose of the therapeutic agent of the present invention for an adult per day is 200 to 1
000”P, and 10 to 20 capes for injection,
The dosage can be increased or decreased as appropriate depending on the administration route and symptoms.

Furthermore, the therapeutic agent of the present invention can be prepared into a pharmaceutical preparation by a conventional method together with any conventional pharmaceutical carrier, base, or excipient.

Orally administered preparations include oral liquid preparations, soft capsules or syrups, intrarectally administered preparations include rectal suppositories, injections include MHA and MHA-Na, water-soluble injections, and MHAL. can be made into an emulsified injection.

Hereinafter, MHAlMHA, which is an active ingredient of the therapeutic agent of the present invention, will be described.
-The production method, efficacy, safety, usage, and therapeutic agent production method of Na and MHAL will be described.

Production example, MHA1MH human-Manufacture of Na and MHAL 1
) 100 g of 2-methyl-acetoacetic acid ethyl ester (Aldrich) dissolved in 260 g of ether,
55rrf! 9,72 dissolved in 95% ethanol
g of potassium hydroxide was added, and to this mixture was added 376 mt of 20 thiacrylic acid ethyl ester (Wako Tsumugi) at 15°C.
The solution was added dropwise over 90 minutes. The reaction solution was stirred at room temperature for 2 hours, poured into ice water, acidified with dilute hydrochloric acid, extracted with ether, washed with water, dried under reduced pressure, and purified with a silica gel column (chloroform eluent) to give 4-ethoxycarbonyl-4-methyl-
Ethyl 5-oxyhexanoate was obtained (colorless oil).

Yield: 167 g, Yield: 98.6 cm.

NMR (δ: CDCl,)t263H (t, 73Hz)
.

1.28 3H (t, z; Hz), 1353Hs,
2.174.20 2H (q, 71Hz).

2) Ethyl 4-ethoxycarbonyl-4-methyl-5-oxo-hexanoate 2.0 g f dissolved in 10 ml of ethanol, 2.16 g dissolved in 10 ml of distilled water
of potassium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was stirred at 80°C for 1 hour. The residue was extracted with ether, washed with brine, dried under reduced pressure, and purified using a silica gel column (elution: 1% methanol-chloroform) to obtain 4-methyl-5-oxyhexanoic acid.

Yield: 1.2g, Yield: 100cm.

NMR (δ: CDC11) 1.15 3H(-cj,
7.0Hz).

2.18 3Hs, 11.20 1HΣ.

5) To 4-methyl-5-oxo-hexanoic acid, add 15.75 m of sodium hydroxide solution, then 36 g of boron hydride solution (Wako Tsumugi Pharmaceutical),
Stirred at ~60°C for 2 hours.

After cooling, the pH was adjusted to 1 with dilute hydrochloric acid, heated for 2 hours, extracted with ether, dried under reduced pressure, and purified with a silica gel column (chloroform eluent) to obtain 1MHAL.

The thus obtained MHAL was stirred with an equivalent amount of aqueous sodium hydroxide solution at room temperature to obtain MHA-Na.

Moreover, MHA was obtained by adding a roaring acid to this MHA-Na.

Experimental Example 1゜Anticonvulsant effect Method of Swinyard et al. (Swinya red,
E, A, et al., J., Pharmacol, Exp, T.
herap, vol. 106, pp. 319-530, 195
2 years). Pliers wrench tracy for mouse /l/
(Pen thylenetetrazole),
120 W/9 was administered intraperitoneally, and the onset time of clonic convulsions, tonic extension, and death was observed. The test drug was dissolved in a solution of 5-thiarabic gum in distilled water and orally administered 1 hour before administration of benchlentitrazole. The results are shown in Table 2.

The average onset time of convulsion and death induced by benchlentitrazole was
The antispasmodic effect was observed.

Table 2 Dose Average onset time (@MHA 100 124 182 193MHA-Na
100 110 231 227MHAL 100
151 298 195 Diazepam 3 271 29
5 215 Experimental Example 2゜ Muscle Relaxation Effect Nakamen et al.'s method (Nalkanishi, M. et al., Arz.
neim.

Forsch, vol. 22, pp. 1000-1914, 1
972). The test drug was orally administered to mice.
The presence or absence of muscle relaxing effect was determined after SO minutes. Animals that slipped down a 45° inclined plate or those that were unable to hook their hind limbs to a wire (diameter 1 dragon) stretched at a height of 50 tx within 10 seconds were judged to be positive for muscle relaxation. The results are shown in Table 3.

Table 3 Dose Muscle relaxant positive rate (special control OQ MHA 100 20 4 Q MHA-Na 100 20 40 MHAL 50 0 20 100 40 60 Diazepam 10 100 100 By administration of MHA, MHA-Na and MI-I A L , muscle relaxing effects were observed.

Experimental Example 3 Anti-electric shock stress effect Method of Kaln et al. (Kaln, A., U. et al., Arch.
Int.

Pharmacodyn, vol. 151, pp. 466-47
4, 1964). Seven rats were used per group. The rats were placed on a metal grid, and a current of 5+ rA was applied at a rate of 2 seconds per minute for 90 minutes to apply electric shock stress. Immediately after the electric shock was completed, blood was collected by decapitation and plasma free fatty acid concentration was determined. The test drug was orally administered 1 hour before the start of electric shock. The results are shown in Table 4.

Table 4 Comparison α28 0.39 MHA 100 (129α34 MHA-Na100 α3o α36 MHAL 100 rLsl (L36 300 α32 α31) The increase in plasma free fatty acid concentration induced by electric shock stress was due to the administration of MHA, MHA-Na, and MHAL. Well, it was suppressed.

Experimental Example 4 Suppression of stress-induced intestinal transport capacity Stress-induced intestinal transport capacity state considered to be a model of autonomic nervous system ataxia (Haruo Onishi et al., Japanese Pharmacological Journal, Vol. 78, 13)
9-144, 1981) were used in groups of 7 rats. Rats that had been fasted for 18 hours in advance were placed in a metal stress cage and immersed in a constant temperature bath with water at a temperature of 25°C. 2
After being immersed in water for 5 hours, 500 Mf/rp of nine charcoal powder suspended in a distilled aqueous solution of gum arabic was orally administered, and the rats were immediately re-restrained and immersed in water for 10 minutes again. Immediately after completion of the water immersion, the rats were sacrificed, the intestine from the pylorus to the ileocecal region was removed, and the transfer rate of charcoal powder relative to the entire length of the removed intestine was measured. The test drug was orally administered to the rats 1 hour before water immersion. The results are shown in Table 5.

Although MHA, MHA-Na, and MHAL had no effect on the charcoal powder transport ability of normal rats, the restoration of charcoal powder transport ability caused by water immersion restraint stress was suppressed by these drugs.

Table 5 Comparison 57.1 75.4 MHA 100 56,7 65.2 MHA-Na 100 59.1 64.5MHAL
100 5a0 619 Experimental Example 5゜Calming effect Tedeschi et al.'s method (Tedeschi, R, E, et al., J.

Pharmacol, Exp, Ther, , 125
Vol., pp. 28-54.

(1959). One group of 5 pairs of mice was used. 1
A pair of mice was placed on a metal grid, electrical stimulation of 3 mA and 60 V was applied for 3 minutes at a rate of 5 times per second, and the number of fight responses produced was measured. The test drug was orally administered 2 hours before the start of electrical stimulation. The results are shown in Table 6.

Table 6 Dosage Average number of fights Control 100 MHA 10ro 43 MHA-Na 100 58 MHAL 30 3q 100 55 Diazepam 10 36 By administration of MHA, MHA-Na and MHA L,
A calming effect was observed in both cases.

Experimental Example 7゜Bendoparbital (Pentobarbi)
tal) sleep-enhancing effect Gray et al.'s method (Gray, W, D, et al., Arch
, Int.

Pharmacodyn, vol. 125, p. 101-12
0, p. 1960). One hour after oral administration of the test drug, Bendoparbital Nat'J Lam (Pent
o-barbital sodium) 5019/Q
was administered intraperitoneally.

Sleep time was then measured using loss of righting reflex as an index. The results are shown in Table 7.

Prolongation of sleep time was observed in all of MHA, MHA-Na, and MHAI.

(Situation) % MHA 100 1/>9 MHA-Na 100 175 MHAL 100 181 Experimental Example 7 Adjustment effect on stress-induced sleep disorder One group of 6 rats implanted with chronic electrodes (electrodes for cortical electroencephalography and electromyography) were Using. Rats were forcibly immersed in a water tank with a water temperature of 28°C for 5 hours to stress them. After water immersion, the animals were placed in a transparent observation box and cortical electroencephalograms and electromyograms were recorded without anesthesia or restraint. Determine wakefulness, slow wave sleep and paradoxical sleep,
It was expressed as the percentage of each sleep phase in the total recording time from 1 hour after the completion of water immersion to 4 hours after completion of water immersion. The test drug was orally administered immediately after water immersion. The results are shown in Table 8.

In rats subjected to water immersion stress, slow wave sleep increased and paradoxical sleep decreased compared to normal rats. on the other hand,
MHA after water immersion stress loading.

In rats administered MHA-Na and MHA L,
Paradoxical sleep was restored compared to the control group. No significant changes were observed in slow wave sleep.

However, diazepam (D), a benzodiazepine tranquilizer,
Administration of iazepam) did not affect slow-wave sleep, but a marked decrease in paradoxical sleep was observed.

Table 8 Dose Awakening Sleep (@ Normal control 4z44ao 4-6 Stressed control 55.0 6 to 61.4 MHA 100 55.7 6α53,8MHA-Na
ioo 36. B 6CL8 12MHAL 50
51.5 6[Ll 3.6100 3a6 574
4.0 Diazepam 10 35.5 64.5 [L2 Experimental Example 8. Acute toxicity test The test drug was dissolved in a 5-thium arabicum distilled water solution and administered orally, subcutaneously or intraperitoneally to mice to examine acute toxicity. Calculation of LD and θ values is based on life and death within 7 days after administration.
) method (written by Akira Sakuma, bioassay method, pages 267-269,
(University of Tokyo Press, 1964). The results are shown in Table 9.

Table 9 MHA 10,000 to 700 1.700MHA-
Na 10,000 a500 1.800MHAL1
0. ! 100 8,500 1.700 Diazepam 6
20 900 300 As is clear from the above experimental examples, MHA, MHA-N
a and MHAT are disorders of biological rhythms such as insomnia and sleep disorders, anxiety and conflict-related neurosis, jet lag, etc.
It is a safe compound with various pharmacological actions useful for the treatment of autonomic nervous system imbalance, menopausal disorders, convulsions, and psychosomatic symptoms, and as shown in Experimental Example 8, its toxicity is low and it is a safe compound. It is understood that

M of the present invention
-N a and MtlAT.

is extremely useful in clinical use in humans as a sleep-adjusting neuropsychiatric agent.

The formulations are shown below as examples, but the formulations are not limited thereto.

Example 1 Oral Liquid Preparation 1) MI-IA-N a 50 gll) Liquid Glucose 300 g 1) Sucrose 250 g Each of the above components was weighed, and purified water was added to make 1,000 gram.

Example 2゜Soft capsules 1. Add glycerin to MHAL50Og. Go.

The mixture was mixed uniformly. A 2-pack of the mixed liquid was made into soft capsules by punching using a gelatin sheet.

Example 5 Syrup 65% sucrose distilled aqueous solution was added to 500 g of MHA-Na and mixed uniformly at 1,000 m/stack. 100 portions of the mixed liquid were filled into glass containers.

Example 4 Suppositories 1) MHA-N a 100 g ll) Polyethylene glycol 1500 1111 g
m) Polyethylene glycol 4000 720g mixture
A total of 1,000 g of 1) and the base were melted and mixed, poured into a chilled suppository container, and cooled and solidified to make a 500 ml rectal suppository.

Example 5 Injection After weighing 50 g of MHA-Na and dissolving it in distilled water for injection,
Further, distilled water for injection was added to make the total volume 1,000 parts.

The aqueous solution was aseptically filtered using a membrane filter, and two containers each were filled into glass containers and freeze-dried.

This was sealed tightly to obtain a lyophilized powder preparation.

Example 6. Weigh out 100 g of ampoule injection MHA-Na, dissolve it in distilled water for injection, and then add distilled water for injection to make the total amount 2.000rr.
M! and 17. This aqueous solution was aseptically filtered using a membrane filter, and two ampoules were filled in a conventional manner into ampoules and sealed to give an ampoule injection.

Example 7 Emulsifying injection 100 g of MHAL and 200 g of polyoxyethylene sorbitan monooleate were mixed, distilled water for injection was added, the mixture was sealed at 2,000 rr, and the whole mixture was emulsified using an ultrasonic homogenizer. It was made equal. This emulsion was heated in an autoclave for 20 minutes at 110°0.1.055If/a.
After the d treatment, 2XnI! Each sample was filled into ampoules and sealed to form an emulsified injection.

patent applicant Mochida Pharmaceutical Co., Ltd. agent Yumi Sakai (1 other person) -Go to 16-

Claims (1)

[Claims] A sleep regulating psychoneurotic agent containing as an active ingredient at least one compound selected from the group consisting of 4-methyl-5-hydroxyhexanoic acid, its salts, and its lactone δ-lactone.