WO2007034778A1

WO2007034778A1 - Prophylactic/therapeutic agent for sleep disorder

Info

Publication number: WO2007034778A1
Application number: PCT/JP2006/318503
Authority: WO
Inventors: Keisuke Hirai; Masaomi Miyamoto
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2005-09-20
Filing date: 2006-09-19
Publication date: 2007-03-29
Also published as: AR056076A1

Abstract

A prophylactic/therapeutic agent for sleep disorder comprising a combination of at least one substance selected from the group consisting of a sedating anti-depressant agent and an anti-histamine agent and (S)-N-[2-(1,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethyl]propionamide. The prophylactic/therapeutic agent can induce a spontaneous sleeping, shorten the sleep latency time, increase the depth of sleeping, is excellent in sleep-maintaining property, and provide an appropriate sleeping duration.

Description

Specification

Sleep disorder preventive and therapeutic agent

Technical field

[0001] The present invention relates to a prophylactic and therapeutic agent for sleep disorders.

Background art

[0002] (S) -N- [2- (l, 6,7,8-tetrahydro-2H-indeno [5,4-b] furan-1-8-yl) ethyl described in Patent Document 1 ] Propionamide (generic name: ramelteon (hereinafter sometimes referred to as compound A)) has an excellent melatoninagost action and is expected to be an extremely excellent sleep disorder preventive and therapeutic agent that induces natural sleep. Compound.

The characteristics of the preventive / therapeutic agent for sleep disorders include, for example, that natural sleep is induced, sleep latency is short, deep sleep is increased (ie, slow-wave sleep (SWS)) It is desirable to extend the time), maintain sleep, and obtain appropriate sleep time.

As therapeutic agents for sleep disorders, benzodiazepine and non-benzodiazepine drugs that mainly act on GABA-A receptors are used. Sedative antidepressants may be used for insomnia (for example, Non-patent document 1). On the other hand, antihistamines are often used as over-the-counter drugs for mild insomnia. These drugs are characterized by increasing deep sleep, but these drugs are not sufficient as single drugs to treat sleep disorders.

Patent Document 1: Pamphlet of International Publication No. 97Z32871

Non-Patent Document l: Roehrs T et al, Sleep Med. 2004 Sep; 5 (5): 463-6

Disclosure of the invention

Problems to be solved by the invention

[0003] The above-mentioned compound A alone is expected to respond to these demands, and there is a demand for the development of a drug that satisfies these demands.

Therefore, the present invention induces natural sleep, shortens sleep latency and increases deep sleep The purpose of this treatment is to prevent sleep disorders that are excellent in maintaining sleep and acquiring appropriate sleep time.

Means for solving the problem

As a result of various investigations, the present inventors have found that sedative antidepressants and Z or antihistamines that have the feature of increasing deep sleep and compound A which is an extremely excellent sleep disorder preventive therapeutic agent that induces natural sleep. In combination (as a combination, combination or concomitant) to shorten sleep latency, increase deep sleep, maintain sleep, and obtain adequate sleep time The present invention has been completed.

That is, the present invention

[l] (S) -N- [2- (l, 6, 7, 8—tetrahydro-2H-indeno [5,4-b] furan-8 —yl) ethyl] propionamide and sedative antidepressants And a prophylactic or therapeutic agent for sleep disorders in combination with one or more drugs selected from the group that also has antihistamine potency; [2] (S) -N- [2- (l, 6, 7, 8-tetrahydro 1H—Indeno [5, 4— b] Furan 1-8 yl) ethyl] propionamide and doxepin for the prevention or treatment of sleep disorders;

[3] (S) -N- [2— (1, 6, 7, 8—Tetrahydro-1H—indeno [5, 4— b] for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders Use of sedative antidepressants and antihistamines in combination with one or more selected drugs;

[4] (S) -N- [2— (1, 6, 7, 8—Tetrahydro-1H—indeno [5, 4— b] for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders 1-fur) ethyl] propionamide in combination with doxepin;

[5] (S) -N- [2- (l, 6, 7, 8—tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is a sedative antidepressant A group force also comprising a drug and an antihistamine, a method of preventing or treating sleep disorders comprising administering to a subject in combination with one or more selected drugs; and

[6] (S) -N- [2- (l, 6, 7, 8—tetrahydro-1 2H—indeno [5, 4— b] furan 8 —yl) ethyl] propionamide in combination with doxepin In The present invention provides a method for preventing or treating a sleep disorder, and the like.

The invention's effect

[0005] According to the present invention, the prevention and treatment of sleep disorder that induces natural sleep, shortens sleep latency, increases depth and sleep, is excellent in maintaining sleep, and can acquire appropriate sleep time. An agent is provided.

Further, according to the present invention, a prophylactic / therapeutic agent for sleep disorders in which the sleep induction effect is maintained even after long-term administration is provided.

Moreover, according to the present invention, there is provided a preventive / therapeutic agent for sleep disorders in which rebound after administration stop is suppressed.

Brief Description of Drawings

[0006] Fig. 1 is a graph showing REM time, SWS time, and total sleep time.

FIG. 2 is a graph showing the power spectrum of the compound A single group during the SWS period.

FIG. 3 is a graph showing the power spectrum of the doxepin single group during the SWS period.

FIG. 4 is a graph showing the power spectrum during the SWS period for the combination group of Compound A and doxepin.

BEST MODE FOR CARRYING OUT THE INVENTION

[0007] Specific examples of the sedative antidepressant used in the present invention include doxepin, trazodone, nefazodone, loroxetine, amitriptine, maprotiline, mianserin, fluvoxamine, trimipramine, cetipitrine, desipramine, imipramine, mirtazapine (Mirtaz apine, Org-4420 (s- mirtazapine)). The sedative antidepressant used in the present invention is preferably, for example, a tricyclic antidepressant (eg, doxepin, amitriptin, trimipramine, desibramin, imibramin). The tricyclic antidepressant is represented by the formula [Chemical 1]

[Wherein, ring A and ring C each have a 6-membered aromatic ring, ring B has a 7-membered carbocyclic ring, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur as constituent atoms. In the 7-membered heterocyclic ring, R is a C alkyl group substituted with a dimethylamino group, or dimethylamino.

14

In the C alkylidene group substituted with a mino group, = represents a single bond or a double bond. ]

1-4

Or a tricyclic antidepressant which is a salt thereof is preferred.

The sedative antidepressants exemplified here are known compounds, all of which are commercially available. Stach K. et al, Monatsh. Chem., 1967, 93, 896, USP3354155, Miodo wnik , A. et al, Synth. Commun., 1981, 11, 241 and the like.

Specific examples of the antihistamine used in the present invention include diphenhydramine, doxylamine, azatadine, bromofenilamine, cetirazine, chlorfenilamine, cremastine, cyproheptadine, disloratadine, desk mouth Lamin, dimenhydrinate, fuexofenadine, hydroxyzine, oral latadin, phenindamine. The antihistamine used in the present invention is preferably a histamine HI antagonist, for example.

The antihistamines exemplified here are known compounds, all of which are commercially available, or can be easily synthesized according to known methods.

These sedative antidepressants and / or antihistamines may be used alone or in combination of two or more. The strong sedative antidepressant and / or antihistamine is preferably a compound having both the properties of a tricyclic antidepressant and a histamine HI antagonist. Among these, doxepin is preferable.

Compound A used in the present invention is produced, for example, by the method described in W097Z32871 or a method analogous thereto.

[0009] In the present specification, unless otherwise specified, a compound or a drug is either a free form or a salt, a racemic form or an optically active form, which may be an anhydrate or a hydrate. Also good. The strong salt is not particularly limited as long as it is a pharmacologically acceptable salt. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic salt Or the salt with an acidic amino acid etc. are mention | raise | lifted. Suitable salts with inorganic bases Specific examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine. N, N, -dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid. And salts with p-toluenesulfonic acid. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, orthine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid and glutamic acid, for example. Can be given.

[0010] In the agent for preventing and treating sleep disorders of the present invention, all of the active ingredients may be contained in one preparation, or each or a part of the active ingredients may be separately formulated. That is, the agent for preventing or treating sleep disorders according to the present invention comprises, as an active ingredient, one or more drugs selected from the group consisting of a sedative antidepressant and an antihistamine and compound A, for example (1) a known preparation (2) Use in combination at the same time or with a time difference (concurrent use). Thus, each may be a formulation formulated with a pharmaceutically acceptable excipient or the like, if desired, or (3) each may be formulated with an appropriate excipient by a conventional method. It may be a set (kits etc.) that combines things.

The form of the sleep disorder preventing / treating agent of the present invention is not particularly limited, but it can be orally administered to a patient (for example, tablets, fine granules, capsules, granules, etc.) or percutaneously absorbed. A dosage form that can be used (eg, a patch) is preferred. Of these, tablets, fine granules and capsules are particularly preferred.

[0011] The powerful preparation of the present invention can be obtained by means known per se (for example, the method described in the Japanese Pharmacopoeia, etc.) Is produced according to the above, and a generally used pharmacologically acceptable carrier is appropriately used in an appropriate amount.

The agent for preventing or treating sleep disorders of the present invention can be effectively used for the prevention and treatment of sleep disorders (insomnia) in mammals (eg, humans, cats, dogs, monkeys, etc.). Such sleep disorders include, for example,

(1) Endogenous sleep disorders (e.g., psychophysiological insomnia), extrinsic sleep disorders, and circadian rhythm disorders (e.g., time zone change syndrome (time difference blur), shift work sleep disorder, irregular type) Sleep abnormalities such as sleep-wake patterns, sleep phase regression syndrome, sleep phase advance syndrome, non 24-hour sleep awakening);

(2) Sleep-related complications;

(3) Sleep disorders associated with internal medicine or psychiatric disorders (eg, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety).

In the present specification, sleep disorder (insomnia) includes sleep deprivation disorder, mid-wake awakening, early morning awakening, and combinations thereof.

Furthermore, by using the sleep disorder preventive / therapeutic agent of the present invention, natural sleep is induced, sleep latency is shortened, deep sleep is increased, sleep maintenance is excellent, and appropriate sleep time can be acquired. Therefore, nighttime awakening is reduced. In addition, the occurrence of bruises and fractures can be reduced because nighttime awakening is reduced, and even when nighttime awakening occurs, it is difficult for the body to fall when standing up at nighttime.

In addition, the sleep disorder preventing / treating agent of the present invention maintains the sleep induction effect even when administered for a long period of time.

Further, the sleep disorder preventive / therapeutic agent of the present invention suppresses rebound after the administration is stopped, and further comprises one or more drugs selected from the group consisting of sedative antidepressants and antihistamines (S ) — N— [2— (1, 6, 7, 8-tetrahydro-1 2H-indeno [5, 4-b] furan-1-yl) ethyl] propionamide in combination with sleep Besides disorders, seasonal depression, reproductive and neuroendocrine diseases, senile dementia, Alzheimer's disease Various disorders associated with aging (for example, prevention of aging), cerebral circulation disorder (such as stroke), head injury, bone marrow damage, stress, epilepsy, convulsions, anxiety, depression, Parkinson's disease, hypertension, glaucoma, Cancer, diabetes, headache, nocturia, irritable bowel syndrome, etc.] and also effective for immune regulation, intelligence, mental stability or ovulation regulation (eg, contraception).

[0013] It should be noted that Compound A can be used in mammals (eg, humans, cats, dogs, monkeys, etc.) for sleep disorders (insomnia) even when used alone in combination with sedative antidepressants and Z or antihistamines. Can be used effectively for prevention and treatment. As such sleep disorder, for example,

(2) Sleep-related complications;

In addition, Compound A can be used effectively for antiemetics and the like.

[0014] It should be noted that Compound A is used for the purpose of giving a higher quality sleep in the prevention and treatment of such sleep disorders (insomnia) (eg, M-100907, ACP-103, A PD-125, Org-50081, Mirtazapine, Org-4420 (s-mirtazapine), Pullvanserin, Eplivanserin, Taetiapine, Clozapine, Risperidone, Cell Chindol (Sertindole), Olanzapine, Ziprasidone, Asenapine, Ocaperidone, Noriperidone, R-167154, Iloperidone, Aripiprazole, Aripiprazole It can also be suitably used in combination with desmethylclozapine (ACP-104, N-desmethylclozapine). In the same manner as in the present invention, for example, serotonin / antagost is used in accordance with (1) Compound A and known pharmacological production methods, and excipients that can be appropriately pharmaceutically acceptable as desired. (2) To be used in combination (with simultaneous) or with a time difference These can be formulated by using pharmaceutically acceptable excipients, etc., if desired, or (3) combined with each appropriately formulated with excipients according to conventional methods. It can be a set (kits, etc.).

The serotonin-antagost exemplified above is a known compound, and is commercially available or can be produced according to a known method.

M-100907 is produced, for example, by the method described in Medicinal Chemistry Research, 1996, 6 (ppl-10), or a method analogous thereto.

ACP-103 is produced, for example, by the method described in International Publication Pamphlet WO2001Z66521 or a method analogous thereto.

APD-125 is produced, for example, by the method described in International Publication Pamphlet WO2005Z12254 or a method analogous thereto.

Org-50081 is produced, for example, by the method described in European Patent Publication EP0373998 or a method analogous thereto.

Org-4420 is produced, for example, by the method described in US Patent Publication US4062848 or a method analogous thereto.

Purvanserin is produced by, for example, the method described in WO2001Z07435 or a method analogous thereto.

Eplivanserin is produced, for example, by the method described in International Publication Pamphlet WO2005Z05410 or a method analogous thereto.

For example, asenapine is produced by the method described in US Pat. No. 4,145,434 or a method analogous thereto.

Ocaperidone is produced, for example, by the method described in European Patent Publication EP453042, or a method analogous thereto.

Noriperidone is produced, for example, by the method described in US Patent Publication US5158952, or a method analogous thereto.

R-167154 is produced, for example, by the method described in International Publication Pamphlet W097Z38991 and International Publication Pamphlet W099Z19317, or a method analogous thereto. Iloperidone is produced by the method described in International Publication Pamphlet WO 93/09102 or a method analogous thereto.

Desmethylclozapine (ACP-104, N-desmethylclozapine)) is produced by the method described in International Publication Pamphlet WO2004Z064753 or a method analogous thereto. The agent for preventing or treating sleep disorders of the present invention has low toxicity and can be safely administered orally to mammals such as humans. Administration of the sleep disorder preventive / therapeutic agent of the present invention can be performed before going to bed, at night awakening, and at Z or early morning awakening, depending on the type of sleep disorder (insomnia). Similarly, when compound A is used alone, depending on the type of sleep disorder (insomnia), the pharmaceutical composition containing compound A before bedtime, at night awakening, and at Z or early morning awakening, etc. Administration can be performed.

The dosage of the sleep disorder preventive and therapeutic agent of the present invention varies depending on the administration subject, administration route, disease, type of active ingredient used, etc., but each active ingredient is administered to an adult with sleep disorder (body weight of about 60 kg). Each component should be administered once or several times a day (preferably once a day). The components can be combined at the same time or with a time difference of 30 minutes to 3 hours. They should be administered together.

When the sleep disorder preventive and therapeutic agent of the present invention comprising a combination of one or more drugs selected from the group consisting of sedative antidepressants and antihistamines and compound A is used, the sedative antidepressant and These doses may be reduced as compared with the case where the drug selected from the group consisting of antihistamines and Compound A are used alone, respectively. For example, in the case of an agent comprising a combination of one of the drugs selected from the group consisting of a sedative antidepressant and an antihistamine and compound A, the dose of compound A is, for example, once a day. About 0.05 mg to about 50 mg per dose, particularly for oral administration, preferably about lmg to about 20 mg per dose, and for transdermal agents, preferably about 0.1 mg to about 1 per dose. Omg.

In addition, the sedative antidepressant and the anti-histamine drug can also be selected as an appropriate dose depending on the type of the selected drug. For example, once a day, 1 About 0.1 mg to about 3000 mg per dose, preferably about 5 mg to about 900 mg per dose. [0017] For more specific compounds, the dosage of doxepin is, for example, once a day, usually about 0.1 mg to about 200 mg per dose, preferably about 0.5 mg to about 30 mg, more preferably about 1 mg to about 20 mg, and even more preferably about 1 mg to about 10 mg per dose.

The combined ratio (administration ratio) of one of the drugs selected from the group consisting of a sedative antidepressant and an antihistamine in the sleep disorder preventive and therapeutic agent of the present invention and compound A is usually 1: 100 to 60: 1. (Weight ratio), preferably 1:20 to 30: 1 (weight ratio), more preferably 1:10 to 30: 1 (weight ratio), particularly preferably 1:10 to 20: 1 (weight ratio). is there.

For more specific compounds, the combination ratio (dose ratio) of doxepin and compound A is, for example, 1: 50-30: 1 (weight ratio), preferably 1: 20-10: 1 (weight ratio). It is preferably 1:10 to 5: 1 (weight ratio).

Each dose when using two or more drugs selected from the group consisting of sedative antidepressants and antihistamines can be reduced compared to using only one drug.

Furthermore, the sleep disorder preventive / therapeutic agent of the present invention may be used in combination with other active ingredients as long as the superior properties are not substantially impaired. The other active ingredient, sedative antidepressant and Z or antihistamine and compound A are mixed according to a method known per se, and a pharmaceutical composition (for example, tablet, powder, granule, capsule (soft capsule) Or liquid preparations, patches, injections, suppositories, sustained-release preparations, etc.) or separately, and are administered to the same subject at the same time or with a time difference as in the preparation of the present invention. You can do it.

Example

[0018] The present invention is further illustrated in detail by the following test examples and formulation examples, which are merely examples and do not limit the present invention and do not depart from the scope of the present invention. You can change the range!

[0019] Formulation Example 1

(1) Doxepin 8. Og

(2) Compound A 8. Og

(3) Lactose 60. Og (4) Corn starch 35. Og

(5) Gelatin 3. Og

(6) Magnesium stearate 2. Og

Doxepin 8.0g, Compound A8. Og, 孚 L Sugar 60. Og and Corn Starch 35. Use a mixture of Og and 10% gelatin aqueous solution 30ml (3.0g as gelatin) and granulate through 1mm mesh sieve. After drying, it was dried at 40 ° C and sieved again. The obtained granules are mixed with 2.0 g of magnesium stearate and compressed. The obtained central tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. Extract coated tablets with beeswax to obtain 1000 coated tablets.

Test example 1

As an experimental animal, a cat reared in an environment of a 12-hour light-dark cycle (7 am force, 7 pm light period) was used. Under pentobarbital anesthesia, electrodes for EEG recording were implanted in the frontal lobe, parietal lobe and hippocampus of the cerebral cortex, electrooculogram electrodes in the orbital bone, and stainless steel electrodes for electromyogram recording in the dorsal neck muscle. It is. Antibiotics were administered to prevent bacterial infection. Acclimatization to an electroencephalogram cage was started from 3 to 4 days after the operation, and electroencephalogram was measured 1 to 2 weeks after acclimatization.

Solvents and drugs to be administered were filled into capsules and administered by oral gavage. The administration group was 10 animals per group, and a crossover test was conducted.

[Drug group]

(1) Vehicle (0.5% methylcellulose aqueous solution)

(2) Compound A (0.1 mg / kg)

(3) Doxepin (0.3 mg / kg)

(4) Concomitant use (compound A (0.1 mg / kg) + doxepin (0.3 mg / kg))

From around 8:30 am, the cat was fitted with a measurement electrode and then placed in the experiment box. Administration was performed around 10:00 am, and sleep electroencephalograms were measured 8 hours after dosing.

EEG data was acquired using Synafit2500 from NEC Saneisha. For the analysis, Sleep Sign Ver.2.0, a program for sleep analysis research by Kissei Comtech Co., Ltd., was used. Δ (delta) wave with a waveform derived from the cortex and 0 (theta) wave with a waveform derived from the hippocampus. Using this parameter, the analysis was performed every 20 seconds using the following If-Then method, and wakefulness, slow wave sleep, and REM sleep were automatically determined. After these automatic judgments were completed, visual judgments were made, and when the sleep stage judgments were clearly different, the judgments were corrected.

[Automatic determination of sleep EEG]

a≤ EMG Integral≤100 → Yes "Awakening, ...

I No

20≤Delta% time≤100 & 0≤ EMG Integral <b → Yes "SWS"

i No

25≤Theta% time≤100 & 0≤ EMG Integral <c → Yes "REMS"

i No

3≤fast wave% Time≤ 100 → Yes "Awakening"

i No

Previous stage (reflect the previous sleep judgment)

* The values of a, b, and c are determined appropriately for each individual.

The results for the compound A alone group and the combination group of compound A and doxepin are shown in FIG. As is clear from this figure, in the combination group of Compound A and doxepin, the total slow wave sleep time and total sleep time were both extended by about 30 minutes compared with Compound A alone, and a significant difference was observed.

Test example 2

[Frequency analysis]

In Test Example 1, SleepSign Ver.2.0 (Kitssey Comtech) was used to extract only the epoch determined to be slow wave sleep, and FFT analysis was performed to determine the power spectrum value at each frequency.

The results are shown in Figure 2 (in the figure, ♦ vehicle, oral compound A), Figure 3 (in the figure, ♦ vehicle, rhodoxepin)

And FIG. 4 (in the figure, ♦ Compound A, oral compound A and doxepin in combination) (0 to 2 hr, 2 to 4 hr, and 4 to 6 hr after administration, respectively). As is clear from these figures, in the combination group of Compound A and doxepin, an increase in the power spectrum in the low frequency region (around 2 Hz) was observed from about 2 hours after administration compared to Compound A alone. From this result, the compound A and doxepin It can be seen that in the combination group, sleep is deep.

Industrial applicability

According to the present invention, it is possible to obtain a therapeutic agent for preventing or treating sleep disorders that induces natural sleep, shortens sleep latency, increases deep sleep, is excellent in maintaining sleep, and can acquire appropriate sleep time. .

Claims

The scope of the claims

[1] (S) — N— [2- (1, 6, 7, 8—tetrahydro-2H-indeno [5, 4-—b] furan-8-yl) ethyl] propionamide and sedative antidepressants In addition, a group agent that also has antihistaminic ability. A prophylactic or therapeutic agent for sleep disorders, which is combined with one or more selected drugs.

[2] (S) -N- [2- (1, 6, 7, 8—tetrahydro-1H-indeno [5,4-b] furan-1-yl) ethyl] propionamide combined with doxepin An agent for the prevention or treatment of sleep disorders.

[3] (S) -N- [2- (l, 6,7,8-tetrahydro-2H-indeno [5,4-b] furan for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders 8-yl) ethyl] propionamide in combination with one or more drugs selected from the group consisting of sedative antidepressants and antihistamines.

[4] (S) -N- [2- (l, 6,7,8-tetrahydro-2H-indeno [5,4-b] furan for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders 8-yl) ethyl] propionamide in combination with doxepin.

[5] (S) -N- [2- (1, 6, 7, 8—tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is a sedative antidepressant A method for preventing or treating sleep disorders, comprising administering to a subject in combination with one or more drugs selected from the group consisting of drugs and antihistamines.

[6] (S) -N- [2- (1, 6, 7, 8—tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide in combination with doxepin A method for preventing or treating sleep disorders, comprising administering to a subject.