JPH0624968A - Therapeutic agent for disturbance of consciousness - Google Patents

Abstract

PURPOSE:To obtain a therapeutic agent for disturbance of consciousness containing a schisandrin compound as an active ingredient, having action of retaining awareness of brain cortex and reduced in side effects. CONSTITUTION:This therapeutic agent contains a compound of the formula as an active ingredient. The compound of the formula is useful as a medicine for normalizing lethargic pattern of brain wave exhibited when brain stem reticular formation is broken. The compound of the formula is prepared in the form of tablet, capsule, granule, suppository, injection, ointment, liquid for external use, etc. The agent is administered divided in several portions in a daily dose of 5-50mg/adult based on weight of the compound of the formula in the cases of oral agents and daily 0.5-100mg/adult in the cases of parenteral agents. The compound of the formula is obtained by extracting Schizandrae Fructus with petroleum ether, etc., under heating, removing the solvent, dissolving the resultant residue in water, subjecting the solution to steam distillation and then purifying the distillate.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a consciousness disorder therapeutic agent having the action of maintaining the awake state of the cerebral cortex.

[0002]

2. Description of the Related Art Consciousness disorder generally means the following 4
It is divided into stages. The first stage is indifference, which is the lightest disturbance of consciousness, lack of concentration in the surroundings, and the condition of becoming sick. The second stage is drowsiness, which is a state of being awakened by a stimulus and responding correctly, but falling asleep again. The third stage is a stupor, which is similar to a coma in which a strong stimulus causes a short-term mental reaction, and food intake is also difficult. The fourth stage is a coma, a state in which the cornea does not respond to any strong stimuli and may leave the corneal pupillary reflex but the reflex is absent.
[Nanzando Medical University Dictionary]

On the other hand, there are an ascending reticular activation system and a hypothalamic activation system in the nervous system that regulates the level of consciousness. The ascending reticular activation system exists in the brainstem reticular body, and this brainstem-like system is present. Extensive projection from the body to the cerebral cortex activates the cerebral cortex.
The hypothalamic activation system exists in the hypothalamus and activates the limbic system by adjusting impulses and humoral stimuli from the internal organs in the hypothalamus. The nervous system that activates this cerebral cortex or limbic system causes consciousness disorder when the brainstem reticular formation is destroyed by cerebrovascular disorder, for example, and the cerebral cortex cannot maintain a wakeful state and sleep pattern It will show brain waves.

[0004] Drug therapy for consciousness disorder uses a drug that promotes metabolism of the brain damaged by some factor or has a stimulus to the conscious center. Currently, various cerebral metabolism stimulants are used, but among them, the drugs listed as drug prices for consciousness disorder are only three of meclofenoxate hydrochloride, citicoline, and protirelin tartrate. However, they are not always effective in terms of medicinal effect. As side effects, meclofenoxate hydrochloride and citicoline are associated with hypersensitivity, insomnia, excitement, blood pressure fluctuations, etc., and protirelin tartrate is associated with hypersensitivity, fever, sweating and the like. Therefore, there has been a demand for the development of a therapeutic agent for consciousness disorders, which has remarkable drug effects and has few side effects.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, found that the compounds shown below have an action of maintaining the awake state of the cerebral cortex, The present invention has been completed.

[0006] The compounds of formula I have an acetylcholinergic neurostimulatory effect in the cerebral cortex and subcortex and increase acetylcholine release. It has been known that it is useful for diseases caused by central acetylcholine function decline such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's chorea, and Pick's disease (JP-A-1-31).
6313, a brain function improving agent), has not been known to have an action of maintaining the awake state of the cerebral cortex.

The present invention improves the level of consciousness of maintaining the wakefulness of the cerebral cortex and regulates the activation of brain cells.

That is, the present invention provides the following formula I The present invention relates to a therapeutic agent for consciousness disorder, which comprises a compound represented by (hereinafter referred to as a compound of formula I) as an active ingredient.

The compound of formula I is the compound called by the generic name cissandrin, which is described, for example, in the literature [Y. Ikey
a, H.A. Taguchi, I .; Yoshioka and
H. Kobayashi, Chem. Pharm. Bu
ll. , 27 (6), 1383 (1979)].

That is, the northern schisandra is petroleum ether, n-
Extract with warm hydrocarbons such as hexane and benzene at warm temperature,
The solvent-free residue of this extract was dissolved in water, and the non-essential oil portion from which essential oil had been removed by steam distillation was subjected to chromatography on silica gel, using n-hexanebenzene, acetone or a mixed solvent thereof. It can be obtained by expanding. Specific examples for the preparation of compounds of formula I are as follows.

Specific example 1.38 kg of northern schizandra was crushed into petroleum ether 3
Reflux extraction with 1 for 8 hours was repeated 4 times. From the obtained extract, petroleum ether extract was removed under reduced pressure to obtain 188 g of petroleum ether extract. This petroleum ether extract was suspended in 450 ml of water and steam distillation was carried out for 3 hours to remove the essential oil. The residue is ether 200
After extraction with ml four times, the ether was removed to obtain 179 g of a petroleum ether-soluble non-essential oil portion (hereinafter, referred to as A fraction).

[0012] Next, after extraction with petroleum ether, northern schisandra was extracted with 3 liters of methanol three times each for 8 hours while warm, and the resulting extract was concentrated to give methanol extract 3
83 g were obtained. The methanol kiss was dissolved in 580 ml of water and extracted with 850 ml of ethyl acetate by shaking three times. The obtained ethyl acetate extract was concentrated under reduced pressure to obtain 78 g of extract. This extract was dissolved in methanol and subjected to column chromatography [Celite 535 (Johns-Ma.
300 g] manufactured by nville). It was developed with 2 l of n-hexane and the eluate was concentrated under reduced pressure to obtain 20.8 g of an extract (hereinafter referred to as B fraction).

Fraction A (179 g) and fraction B (20.8 g)
g) were combined and subjected to column chromatography (silica gel 1200 g as a carrier), and the eluate parts of benzene: acetone (7: 3) and benzene: acetone (3: 2) were combined and concentrated to give 8.3 g of residue. Got The residue was again subjected to column chromatography (using 180 g of silica gel as a carrier) and developed with a mixed solvent of n-hexane and acetone. The eluate of n-hexane: acetone (22: 3) was crystallized from n-hexane-ether to obtain 3.5 g of the compound of formula I (yield 0.25%).

Next, the usefulness of the compound of formula I as a therapeutic agent for consciousness disorder will be described with reference to experimental examples. In the present experiment, destruction of the brainstem reticulum required for arousal of the cerebral cortex is described. Electroencephalogram was used as an index for the functional changes of the cerebral cortex.

Experimental Example 1 Male Wistar rats were used.
Under anesthesia with Nembutal (50 mg / kg, ip), it was fixed to a stereotaxic apparatus and the scalp was incised to expose the skull. EEG measurement screw electrodes were attached to the left and right frontal regions. A stainless electrode for reticular destruction was attached according to the brain chart. The screw electrode was guided into the socket with a cord and fixed with dental cement. After the operation, a recovery period was set and the preencephalogram of the reticular destruction was measured. After the electroencephalogram measurement, Nembutal (50 mg / kg, i.p.
p. ) Under anesthesia, the reticulate body was destroyed with a direct current (5 mA, 30 sec). After disruption, the compound of formula I was dissolved in 0.5% carboxymethylcellulose and this was administered twice daily (3 times once).
(0 mg / kg) was orally administered, and 0.5% carboxymethyl cellulose was administered as a control group. These were recorded on a data recorder 1, 3 and 7 days after destruction.

The transition of the arousal level of the brain can be objectively grasped by measuring the electroencephalogram. The EEG shows a regular sequence of α waves when awake and resting, and the fast wave becomes dominant when the eyes are opened or when nervous. When the tension resolves and becomes sleepy, a slow wave begins to appear in the brain waves, and the spindle waves characteristic of sleep repeatedly appear.

With reference to the drawings, the effects of the compound of the formula I on the somnolence pattern of cortical EEG due to the destruction of the reticular formation and the somnolence pattern of the cortical EEG due to the destruction of the reticular formation will be described.

[0018]

[Figure 1]

[0019]

[Fig. 1] As shown in Fig. 1, the EEG is predominantly the fast wave before the reticular disruption, whereas the slow wave begins to appear from the first day after the disruption, and the spindle wave changes to the somnolence pattern on the seventh day. You can see that

Next, by administering the compound of formula I, the somnolence pattern of cortical EEG was normalized. this

FIG. 2 shows.

[0021]

[Fig. 2]

[0022]

FIG. 2 shows that the electroencephalogram is predominantly fast wave after reticular disruption as before disruption, and by administration of the compound of formula I,
It can be seen that the somnolence pattern is normalized. Thus, the compound of formula I is useful as a consciousness disorder improving agent.

[0023] Then place the acute toxicity test by oral administration of the compounds of Formula I were performed using male SD rats, LD ₅₀
Was 1137 mg / kg. Thus, the active ingredient of the present invention has low toxicity and high safety.

Formulation of the compound of formula I is described below. The compounds of formula I can be administered to animals and humans neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral agents such as tablets, capsules and granules, and parenteral agents such as suppositories and injections.

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but it is usually 5 to 50 by weight of the active ingredient of the present invention in adults.
It seems appropriate to take 0 mg in several divided doses a day.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used for the production according to a conventional method.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a corrigent, a coloring agent, a perfume and the like may be used in addition to the above-mentioned excipients. You can Specific examples of each are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

In order to exert a desired effect as a parenteral preparation, it depends on the patient's age, body weight or degree of disease, but is usually 0.5 m per day as the weight of the compound of formula I in adults.
Intravenous injection, intravenous drip injection, subcutaneous injection, and intramuscular injection of g to 100 mg are considered appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol or polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent, etc. may be added appropriately.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method. Next, examples of the preparation of the present invention will be described.

Example 1 Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Compound of formula I obtained in a specific example 10 g Total 100 g

According to the above formulation, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each). 20 mg of the active ingredient of the present invention is contained in one tablet, and 3 to 10 tablets for adults are to be taken in several divided doses per day.

Example 2 Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound of formula I obtained in a specific example 10 g Total 100 g

According to the above formulation, a part of and was uniformly mixed, compression-molded, crushed, and the remaining amount of and was added and mixed, and compression-molded by a tableting machine to give one tablet.
A 00 mg tablet was obtained. This tablet contains 20 mg of the compound of the formula I, and 3 to 10 tablets for adults are to be taken in several divided doses per day.

Example 3 Crystalline cellulose 79.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound of formula I obtained in a specific example 10 g Total 145 g

According to the above formulation, and were uniformly mixed, and the mixture was kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and then mixed, and compressed by a tableting machine. It was molded to obtain a tablet of 200 mg each. This tablet contains 20 mg of the compound of the formula I, and 3 to 10 tablets for adults are to be taken in several divided doses per day.

Example 4 Corn starch 84 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound of formula I obtained in a specific example 10 g Total 100 g

According to the above formulation, the components (1) to (4) are uniformly mixed, compression-molded by a compression molding machine, and then crushed by a crusher,
Sieve to obtain granules. 1 g of this granule contains 100 mg of the compound of the formula I, and an adult daily dose of 0.6-2
Take g in several divided doses.

Example 5 Crystalline cellulose 86.5 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound of formula I obtained in a specific example 10 g Total 131.5 g

According to the above recipe, the ingredients (1) to (4) were uniformly mixed and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule has the formula I
Contains 100 mg of the compound of
Take ~ 2g in divided doses.

Example 6 Cornstarch 89.5 g Light anhydrous silicic acid 0.5 g Compound of formula I obtained in a specific example 10 g Total 100 g

According to the above-mentioned formulation, 1 to 3 were mixed uniformly, and 200 mg was filled in a No. 2 capsule. One capsule of this capsule contains 20 mg of the compound of the formula I, and 3 to 10 capsules per day for adults are to be taken in several divided doses.

[Example 7] Distilled water for injection 89.5 g Soybean oil 5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound of formula I obtained in a specific example 1 g Total amount 100 g

According to the above-mentioned prescription, was dissolved in and, and a solution of and was added and emulsified to obtain an injection.

[0051]

[Brief description of drawings]

FIG. 1 is an electroencephalogram showing changes caused by reticular destruction.

[0052]

FIG. 2 is an electroencephalogram showing the effect of schisandrin on changes caused by reticular destruction.

Claims (1)

[Claims] 1. The following formula I A therapeutic agent for consciousness disorder, which comprises a compound represented by [0001]