JP3018123B2 - Sleep enhancer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sleep enhancer, and more particularly to a sleep enhancer for deepening paradoxical sleep and slow wave sleep.

[0002]

2. Description of the Related Art Conventionally, sleep has a change of shallow / deep, but is generally a single continuous state, and is considered to be a simpler state than when awake. However, recent studies have shown that sleep has at least two states: slow-wave sleep (so-called normal sleep) and paradoxical sleep (deepest sleep), both of which are included in the overnight sleep course 90-90.
It is known that a cycle of about 100 minutes exists.

[0003] The sleep state is characterized by changes in brain waves. That is, the brain wave usually forms a high-amplitude slow wave during slow-wave sleep, and forms a low-amplitude fast wave during paradoxical sleep similar to when awake.

[0004] On the other hand, although the quality of sleep varies among individuals,
Depending on the time from the time you try to sleep until you actually fall asleep and the number of times you awake, you can divide into the "sleep-good" and "insomnia". It is known that the “insomnia type” has a feature that the paradoxical sleep time is significantly shorter than that of the “sleep sleep type”.

[0005]

The "insomnia type" is defined as a sleep course lacking a stable appearance of paradoxical sleep, and its personality characteristics include a neurotic tendency.
In other words, they are introverted, highly anxious and nervous, depressive, sensitive to physical upsets, and prone to dissatisfaction.

Therefore, in order to correct such a tendency and restore a stable mental state in daily life, it has been desired to develop a sleep enhancer which can prolong the paradoxical sleep time.

[0007]

The inventors of the present invention have conducted intensive studies in view of such circumstances, and as a result, a specific phthalide derivative which was previously reported as a consciousness lowering agent (Japanese Patent Laid-Open No. 2-184683) is surprising. It has been found that paradoxical sleep time is significantly increased, and the present invention has been completed.
That is, the present invention provides the following general formula (1)

[0008]

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[0009] (wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a methoxy group, an amino group or a dimethylamino group, R ² and R ³ each represent a hydrogen atom, or a methoxy group, R ⁴
Represents a hydrogen atom, an amino group or a dimethylamino group;
⁵ represents a hydrogen atom, an alkyl group, or an alkoxyl group. The present invention provides a sleep enhancer comprising at least one phthalide derivative represented by the formula (1) as an active ingredient.

[0010] Here, sleep enhancers include slow-wave sleep as a normal sleep state and paradoxical sleep as the deepest sleep state.
Of the latter, it refers to a composition having the function of increasing the time.

Some of the phthalide derivatives represented by the general formula (1) used in the present invention can be extracted from rhizomes or roots of Umbelliferae plants. Further, for example, it can be synthesized by a known method in which a dialkylcadmium or the like is reacted with phthalic anhydride (JP-A-2-167216).
No.).

In the phthalide derivative of the general formula (1), the alkyl group of R ⁵ is preferably one having 3 to 16 carbon atoms, and the straight-chain alkyl group is, for example, propyl, butyl, pentyl, hexyl, heptyl, Octyl, decyl, dodecyl and hexadecyl groups are mentioned, and examples of the branched alkyl group are isopropyl, isobutyl and isoamyl. The alkoxyl group represented by R ⁵ is preferably an alkoxyl group having 3 to 4 carbon atoms, such as isopropoxy, propoxy and butoxy groups. Further, among the phthalide derivatives of the general formula (1), compounds in which R ⁵ is an alkyl group or an alkoxyl group, for example, 3-butylphthalide, 3-isoamylphthalide, 3-heptylphthalide, 3-propoxyphthalide and the like are exemplified. Particularly preferred.

The phthalide derivative (1) has the effect of increasing slow-wave sleep and paradoxical sleep, particularly paradoxical sleep time, as shown in the examples below, and has the effect of deepening sleep rather than introducing sleep. Further, this compound has an acute toxicity (intraperitoneal administration) of 1 g / kg or more to rats and is highly safe.

The phthalide derivative (1) can be administered as it is or together with a conventional pharmaceutical carrier. The administration form is not particularly limited, and examples thereof include oral preparations such as tablets, capsules, granules, powders, and liquids; and parenteral preparations such as injections and suppositories. Also, phthalide derivatives (1)
Can also be used as an inhalant because it is effective even by inhalation. In preparing solid preparations such as tablets and capsules, for example, ingredients such as excipients, binders, disintegrants, lubricants, coatings, coloring agents, flavoring agents, and flavoring agents may be added as necessary. Can be. In preparing injections and the like, solvents, stabilizers, preservatives, solubilizing agents, surfactants, soothing agents, buffers and the like can be added as necessary. In preparing an inhalant, an organic solvent, an oil, a compounded flavor, a flavoring product, and the like can be added.

The dose of the sleep enhancer of the present invention varies depending on symptoms, body weight, administration method, etc., but it is usually administered as a phthalide derivative (1) in a dose of 5 to 300 mg / time in one or several doses. Is preferred. The phthalide derivative (1) is preferably incorporated in the above-mentioned various dosage form compositions in an amount of 0.1 to 90% by weight.

[0016]

EXAMPLES The present invention will be specifically described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 (Method) A few days before recording, a recording cord was attached to the electrode of the rat head and put into a box (400 × 200 × 400) with a wheel (φ: 300, W: 120). The animals were fully adapted to the measurement environment. During the measurement period, the animals were kept in contact with the animals without any contact with water. 0.1 g of 3-butylphthalide was impregnated into the floor of the measurement box and exposed for 30 minutes, and the floor was replaced after the exposure. For the measurement of electroencephalograms and electromyograms, an electroencephalograph manufactured by Nihon Kohden Co., Ltd. was connected to the electrodes via an electrode box, and the sleep state was classified into slow wave sleep and paradox sleep from the chart and analyzed. The outline of the experiment is shown in FIG. In the recording, the recovery period was 1 day after the exposure day, with the control group being 2 days before the exposure (control 1 on the day before the control and control 2 on the previous day).

(Results) The significance test of the obtained data is as follows.
By Student's t-test. FIG. 2 shows the results of measuring the slow-wave sleep time in the total sleep time for each of Control 1, Control 2, exposure to 3-butylphthalide, and the recovery period. As the total sleep time increases, the slow wave sleep time due to exposure to 3-butylphthalide increases (for example, sleep time 8).
(About 1.27 times in time).

FIG. 3 shows the results of measuring the paradoxical sleep time during the total sleep time for each of Control 1, Control 2, exposure to 3-butylphthalide, and the recovery period. As total sleep time increases, 3
It can be seen that the paradoxical sleep time due to -butylphthalide exposure is significantly increased (about 1.51 times over 8 hours of total sleep time). Moreover, it was revealed that the paradoxical sleep time increasing effect due to the exposure to 3-butylphthalide continued to a considerable extent even after 1 day (83 to 94% in 3 to 8 hours of total sleep time).

Example 2 A tablet having the following composition was prepared. Weight (%) 3-hexylphthalide 0.3 dextrose 80.0 gelatin 7.5 gum arabic 11.4 peppermint oil 0.5 flavor 0.3 100.0

Example 3 A liquid preparation having the following composition was prepared. Weight (%) 3-octylphthalide 1.0 Olive oil 97.0 Spearmint oil 1.0 Fragrance 1.0 100.0

Example 4 An injection having the following composition was prepared. Weight (%) 3-propoxyphthalide 5.0 Sesame oil 5.0 Benzyl alcohol 9.0 Distilled water for injection 81.0 100.0

Example 5 An inhalant having the following composition was prepared. Weight (%) 3-butylphthalide 5.0 dipropylene glycol 90.0 fragrance 5.0 100.0 All of the sleep enhancers obtained in Examples 2 to 5 were found to increase paradoxical sleep time.

[0024]

The sleep-enhancing agent of the present invention comprises a slow-wave sleep time,
And has the effect of increasing the paradoxical sleep time. In particular,
It has a remarkable effect on increasing the paradoxical sleep time, corrects the neurotic tendency due to “insomnia type”, and contributes to a stable mental state recovery.

[Brief description of the drawings]

FIG. 1 is a diagram showing an outline of an experiment in Example 1.

FIG. 2 is a graph showing the slow-wave sleep time during the entire sleep time in Example 1.

FIG. 3 is a bluff showing paradoxical sleep time during the entire sleep time in Example 1.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-184683 (JP, A) Food Sci. , 43 (1), p. 143-144 (1978) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/343 A61P 25/20 C07D 307/88 C07D 307/89 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a methoxy group, an amino group or a dimethylamino group, R ² and R ³ each represent a hydrogen atom or a methoxy group, and R ⁴ represents a hydrogen atom, an amino group, Or a dimethylamino group, and R ⁵ represents a hydrogen atom, an alkyl group or an alkoxyl group.) A sleep enhancer comprising at least one phthalide derivative represented by the following formula: