JPH1135461A - Therapeutic agent for somnipathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine enhancing phase variation of a circadian rhythm induced from a light and useful for prevention and/or remedy for somnipathy by using a specific alkylene dioxybenezene derivatives as an active component. SOLUTION: This prophylactic and/or therapeutic agent is obtained by formulating an alkylene dioxybenzene derivative of the formula (m) is 2-5; (n) is 1-3} or its pharmaceutically permissible salt, or its hydrate or solvate as an active component. As a compound of the formula, especially 5-[3- (2S)-(1,4- benzodioxan-2-yl methyl)amino}propoxy]-1,3-benzodioxole is optimum. About somnipathy, the medicine is especially effective for a circadian rhythm somnipathy such as a time differential variation area syndrome. The medicine can also be auxiliary used for enhancing a remedy effect in performing a physiotherapy such as a high luminous intensity light therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament useful for treating and / or preventing sleep disorders. For more information,
A medicament comprising a specific alkylenedioxybenzene derivative as an active ingredient, which is useful for the prevention and / or treatment of sleep disorders, for example, circadian rhythm sleep disorders such as staggered band shift syndrome, shift work sleep disorder, or delayed sleep phase syndrome. The invention relates to the invention of

[0002]

2. Description of the Related Art Circadian rhythm sleep disorder is a disease in which a person's main complaint or main symptom is that normal sleep cannot be obtained at night. In some cases, sleep disorders interfere with normal social behavior. is there. The disease can be exogenous acute syndromes such as staggered band shift syndrome or shift work sleep disorders,
It encompasses a variety of conditions, such as intrinsic chronic syndromes such as delayed sleep phase syndrome caused by impairment of the biological clock or its synchronizing mechanism. Various drug treatments have been attempted for circadian rhythm sleep disorders, but it is known that benzodiazepine-based sleeping pills do not provide sufficient therapeutic effects (see “Circadian rhythm sleep disorder”). For a review of disease states and treatment methods, see Shigeru Ozaki and Masako Okawa,
"Sleep Disorders and Biological Rhythm", Special Issue on Temporal Pharmacology-New Medication Guidelines, Molecular Medicine, Vol. 34 (3), pp. 355-36
5, 1997).

[0003] A variety of synchronizing factors of the biological clock are known, and among them, light is known to be the factor having the strongest phase adjusting action. There are also reports that high-intensity light therapy is effective for treating circadian rhythm sleep disorders. Therefore, a compound that enhances the phase regulating effect of light on the circadian rhythm may be a useful therapeutic agent for circadian rhythm sleep disorder. For example, it is known that vitamin B12 is effective for the treatment of delayed sleep phase syndrome (Takahashi et al. Pp. 369-382 in Evolution).
of circadian clock (1994), Hokkaido University Pre
ss) has been reported to enhance the circadian rhythm phase advancing effect of light in rats (Ikeda et al. Experimen
tia, 52 (1996) 691-694).

On the other hand, the following equation:

Embedded image (Wherein m represents an integer of 2 to 5, and n represents an integer of 1 to 3), which are known (JP-A-3-264528 and JP-A-4-264528). No. 288072). In these publications, the alkylenedioxybenzene derivative represented by the above general formula binds to the serotonin 1A receptor subtype, exhibits an anti-conflict effect, and has anxiety disorders, schizophrenia, and manic depression. It is disclosed to be useful for the treatment of

More specifically, m = 3; n = 2; meta-substituted compound (No. 1), m = 3; n = 2; meta-substituted compound (No. 2), m = 3; n = 3; meta-substituted compound (No. 3), m = 4; n = 1; meta-substituted compound (No. 4), m = 4; n = 3; meta-substituted compound (N
o. 6), m = 5; n = 1; meta-substituted compound (No.
7), m = 3; n = 1; ortho-substituted compound (No. 1)
Regarding 3), the affinity (Ki value) for the serotonin 1A receptor subtype is disclosed. In addition, the publication discloses the above-mentioned No. Compound No. 1 Compound No. 2
It is disclosed that the three compounds have an anti-conflict effect and are useful for treating anxiety disorders, schizophrenia, manic depression and the like. However, these publications do not suggest or teach the therapeutic potential of the above compounds for circadian rhythm sleep disorders.

[0006]

SUMMARY OF THE INVENTION The present invention provides a sleep disorder,
For example, it is an object to provide a medicament useful for preventing and / or treating circadian rhythm sleep disorder. More specifically, it is an object of the present invention to provide a medicament capable of effectively preventing and / or treating endogenous circadian rhythm sleep disorder such as delayed sleep phase syndrome or extrinsic sleep disorder.

[0007]

The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a specific alkylenedioxybenzene derivative markedly enhances the phase adjusting effect of light on the circadian rhythm, and the biological effect of the present invention is improved. Was found to have an action of synchronizing with a biological clock. In addition, they have found that the above derivatives are useful for prevention and / or treatment of sleep disorders including circadian rhythm sleep disorders. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula (I):

Embedded image (In the formula, m represents an integer of 2 to 5, and n represents an integer of 1 to 3.) An alkylenedioxybenzene derivative or a pharmaceutically acceptable salt thereof, or a hydrate or It is intended to provide a preventive and / or therapeutic agent for sleep disorders containing such a solvate as an active ingredient.

In a preferred embodiment of the present invention, the above-mentioned prophylactic and / or therapeutic agent wherein the sleep disorder is a circadian rhythm sleep disorder; the circadian rhythm sleep disorder is a staggered band change syndrome, a shift work sleep disorder, or a sleep phase depression. The above preventive and / or therapeutic agent which is a syndrome; for prevention and / or treatment of various symptoms (eg, delirium and night wandering) associated with senile circadian rhythm sleep disorder caused by aging-related circadian rhythm abnormality. The above-mentioned prophylactic and / or therapeutic agent used; and the above-mentioned prophylactic and / or therapeutic agent used for high-intensity light therapy are provided. As a further preferred embodiment, a compound wherein n is 1 in the above formula (I) [particularly preferred is 5- [3-
[(2S)-(1,4-benzodioxan-2-ylmethyl) amino] propoxy] -1,3-benzodioxole] or a physiologically acceptable salt thereof, or a hydrate or solvate thereof The present invention provides a preventive and / or therapeutic agent for the above-mentioned sleep disorder, which comprises a substance as an active ingredient.

In another preferred embodiment, the prevention and / or
Alternatively, the therapeutic agent is provided in the form of a pharmaceutical composition containing an alkylenedioxybenzene derivative represented by the above formula (I), which is an active ingredient, and a pharmaceutical additive. According to still another aspect of the present invention, there is provided an alkylenedioxybenzene derivative represented by the above formula (I) for the manufacture of a prophylactic and / or therapeutic agent for the sleep disorder, preferably a circadian rhythm sleep disorder. Use of a substance selected from the group consisting of physiologically acceptable salts thereof and hydrates and solvates thereof; and an alkylenedioxybenzene derivative represented by the above formula (I) and a physiologically acceptable salt thereof. Preventing and / or preventing sleep disorders, comprising administering to a mammal, including a human, a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of acceptable salts and hydrates and solvates thereof. A method for treatment, preferably for preventing and / or treating circadian rhythm sleep disorders, is provided.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The prophylactic and / or therapeutic agent of the present invention comprises an alkylenedioxybenzene derivative represented by the above formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate thereof. It is characterized by containing a solvate as an active ingredient. The alkylenedioxybenzene derivatives represented by the general formula (I) are known, for example, JP-A-57-108088 and JP-A-58-219.
Since it is disclosed in JP-A-114-114 and JP-A-3-264528, those skilled in the art can easily obtain it. Among the alkylenedioxybenzene derivatives included in the above formula (I), a derivative in which n is 1 is preferable. The bonding position of the aminoalkyleneoxy group substituted on the phenyl group may be either the ortho position or the meta position with respect to one oxygen atom of the alkylenedioxy group, but is preferably the meta position.

As the active ingredient of the medicament of the present invention, physiologically acceptable salts thereof may be used in addition to the free form alkylenedioxybenzene derivative represented by the general formula (I). Such salts include, for example, hydrochloride,
Mineral salts such as phosphates or sulfates; organic acid salts such as acetates, formates, citrates, or paratoluenesulfonates. Further, a free form compound or any hydrate or solvate of the above salt may be used as an active ingredient of the medicament of the present invention. The solvent capable of forming a solvate is not particularly limited as long as it is a physiologically acceptable solvent, and examples thereof include methanol, ethanol, isopropanol, acetone, and ethyl acetate. Among them, an ethanol solvate can be preferably used.

The alkylenedioxybenzene derivative represented by the general formula (I) has one asymmetric carbon and has two kinds of optical isomers. The production method of such an optical isomer and its pharmaceutical use are described in JP-A-4-28807.
No. 2, the two optical isomers are available to those skilled in the art. As an active ingredient of the medicament of the present invention, any of optical isomers of the above-mentioned alkylenedioxybenzene derivatives in optically pure form, or any mixture of optical isomers may be used. When an optical isomer is used, it is preferable to use an S-isomer. Further, a racemic form which is a mixture of equal amounts of optical isomers may be used.

The alkylenedioxybenzene derivatives suitable as the active ingredient of the medicament of the present invention are exemplified below, but the active ingredient of the medicament of the present invention is not limited to the following derivatives.

[0015]

Embedded image

[Table 1]

[0016]

Embedded image

[Table 2]

Of the compounds exemplified in Tables 1 and 2 above, No. 1 is a particularly preferred compound. Compound 1 is described in JP-A-3-2645.
No. 28 and JP-A-4-288072. JP-A-3-264528 and JP-A-4-2888072 disclose that the alkylenedioxybenzene derivative of the formula (I), which is an active ingredient of the present invention, has a high affinity for the serotonin 1A receptor subtype. And has been shown to have an anti-conflict effect. In addition, these publications disclose that the alkylenedioxybenzene derivatives are useful for treating anxiety disorders, schizophrenia, manic depression, and the like. For example, there is no suggestion or teaching that it is useful for treating circadian rhythm sleep disorders.

Without wishing to be bound by any particular theory, the medicament of the present invention significantly enhances the action of light to advance the phase of the circadian rhythm under constant dark conditions, and The effect of the light tuned to can be significantly enhanced. Therefore, the medicament of the present invention is useful for prevention and / or treatment of endogenous circadian rhythm sleep disorders, for example, delayed sleep phase syndrome and senile circadian rhythm sleep disorder, and aging-related circadian rhythms It can be used for prevention and / or treatment of symptoms associated with sleep disorders caused by abnormalities, such as delirium and wandering at night.

The medicament of the present invention is also useful for the prevention and / or treatment of extrinsic circadian rhythm sleep disorders caused by changes in the environment, for example, staggered band shift syndrome and shift work sleep disorders. Furthermore, the medicament of the present invention
It is also useful for prevention and / or treatment of various sleep disorders other than circadian rhythm sleep disorders. The medicament of the present invention may be used in combination with other pharmacotherapy performed for the purpose of preventing and / or treating sleep disorders, and in order to enhance the therapeutic effect when performing physical therapy such as high-intensity light therapy. May be used as a supplementary drug.

The above-mentioned substances selected from the group consisting of the alkylenedioxybenzene derivatives and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof can be administered to mammals including humans. In general, it is preferable to prepare a pharmaceutical composition containing one or two of the above-mentioned substances as active ingredients and a pharmaceutical additive and to administer the composition to a patient. Such pharmaceutical compositions include, for example, formulations for oral administration such as tablets, capsules, fine granules, powders, pills, troches, sublinguals, or liquids, or injections, drops, suppositories, Preparations for parenteral administration, such as transdermal absorbents, transmucosal absorbents, inhalants, and transdermal patches can be mentioned.

Tablets or capsules for oral administration are usually provided as unit doses, binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents, or wetting agents. It can be produced by using a usual pharmaceutical additive such as Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrrolidone, a starch derivative, or sodium starch. It may be produced using a disintegrant such as glycolate; a lubricant such as magnesium stearate; a wetting agent such as sodium lauryl sulfate.

Liquid preparations for oral administration include, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs, as well as frozen ones which can be dissolved by adding water or a suitable aqueous medium before use. It can be provided as a dry preparation in the form of a dried product or the like. Such solutions include the usual pharmaceutical additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; lecithin, sorbitan monooleate Non-aqueous media such as almond oil, rectified coconut oil, oily esters (eg, esters of glycerin), propylene glycol, ethyl alcohol (which may also include edible oils); p-hydroxybenzoic acid And a preservative such as methyl ester, ethyl ester, or propyl ester, or sorbic acid; and a usual flavoring agent or coloring agent, if necessary.

Preparations for oral administration can be manufactured by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive compounding operation. Preparations for parenteral administration such as injections and infusions are generally provided as unit dose preparations containing the above-mentioned active ingredients and a sterile vehicle. And then sterile-filtered, and then filled in a suitable vial or ampoule and sealed, to produce a product. To enhance the stability, the composition may be filled into vials after freezing and the water removed under vacuum. Suspensions for parenteral administration are produced in substantially the same manner as for parenteral solutions, but can be suitably produced by suspending the active ingredient in a vehicle and sterilizing with gas such as ethylene oxide. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.

The dose of the medicament of the present invention may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the patient's symptoms, weight, age, sex, and the like. In this case, the amount of the active ingredient is about 0.01 mg to 1000 mg by oral administration per day for an adult, preferably about 1 to 1000 mg.
About 100 mg can be administered. Such a dose may be administered once or several times a day.

[0025]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. In Examples, No. 1 exemplified in Table 1 above as an active ingredient of the medicament of the present invention. Compound 1 (m = 3; n = 1; meta-substitution: hereinafter, abbreviated as “medicine of the present invention” in Examples).

Example 1 Hamsters were bred in breeding cages with rotating baskets under constant dark conditions. The activity rhythm of the hamster was measured daily by the number of rotations of the basket. Hamsters bred under constant dark conditions exhibited an activity rhythm (circadian rhythm) of about a 24-hour cycle. The beginning of the active period was circadian time (hereinafter abbreviated as CT) 12.
After 2 weeks of rearing, CT20 was exposed to 60-lux light for 15 days.
Irradiated for minutes. The medicament of the present invention was administered intraperitoneally 30 minutes before, 5 minutes or 60 minutes after light irradiation. The circadian rhythm advanced by 2 hours with light irradiation alone (FIG. 1). When the medicament of the present invention was administered 30 minutes before light irradiation, this phase advancing effect was enhanced in a dose-dependent manner, and a significant difference was observed at a dose of 3 mg / kg (FIG. 1).

The medicament of the present invention is administered 5 minutes after light irradiation, or 60 minutes.
The administration of the drug of the present invention at a dose of 3 mg / k without light irradiation was also observed when administered after 1 minute (FIG. 2).
No phase change was observed when the g dose was administered alone. On the other hand, tandospirone (comparative example) which is a partial agonist of serotonin 1A receptor was administered at 10 and 20 mg / k.
When g was administered, no significant difference was observed in the phase advance effect by light (FIG. 3). These results indicate that the action of the medicament of the present invention for enhancing phototuning is not solely due to the stimulation of serotonin 1A receptor.

[0028]

The medicament of the present invention enhances the phase change of the circadian rhythm due to light and is therefore useful for preventing and / or treating various sleep disorders, for example, circadian rhythm sleep disorders.

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of the pharmaceutical of the present invention on the phase advance of the circadian rhythm induced after light irradiation (administration 30 minutes before light irradiation).

FIG. 2 is a graph showing the effect of the medicament of the present invention on the phase advance of the circadian rhythm induced after light irradiation, as observed by changing the administration time. In the figure, * indicates that there is a significant difference of 5% against the control group.

FIG. 3 shows the effect of tandospirone (comparative example) on the phase advance of the circadian rhythm induced after light irradiation (light irradiation 30).
1 minute before administration).

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 407/12 319 C07D 407/12 319

Claims (8)

[Claims] 1. The following general formula (I): (In the formula, m represents an integer of 2 to 5, and n represents an integer of 1 to 3.) An alkylenedioxybenzene derivative or a pharmaceutically acceptable salt thereof, or a hydrate or A preventive and / or therapeutic agent for a sleep disorder containing such a solvate as an active ingredient. 2. An alkylenedioxybenzene derivative comprising 5
-[3-[(2S)-(1,4-benzodioxane-2
2. The prophylactic and / or therapeutic agent according to claim 1, which is -ylmethyl) amino] propoxy] -1,3-benzodioxole. 3. The preventive and / or therapeutic agent according to claim 1, wherein the sleep disorder is a circadian rhythm sleep disorder. 4. The preventive and / or therapeutic agent according to claim 3, wherein the circadian rhythm sleep disorder is a staggered band change syndrome. 5. The preventive and / or therapeutic agent according to claim 3, wherein the circadian rhythm sleep disorder is a shift work sleep disorder group. 6. The preventive and / or therapeutic agent according to claim 3, wherein the circadian rhythm sleep disorder is delayed sleep phase syndrome. 7. The prophylactic and / or therapeutic agent according to claim 1, which is used for prevention and / or treatment of symptoms associated with senile circadian rhythm sleep disorder. 8. The prophylactic and / or therapeutic agent according to claim 1, which is used for high-intensity light therapy.