JP2008255058A - Somnipathy-preventing and treating agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a somnipathy-preventing or treating agent inducing natural sleep, shortening sleeping latency, increasing deep sleep, excellent in maintaining the sleep and obtaining appropriate sleeping time. <P>SOLUTION: This somnipathy-preventing or treating agent is provided by combining ≥1 kind of a medicine selected from the group consisting of a sedative antidepressant and an antihistamine agent with (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an agent for preventing or treating sleep disorders.

(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (described in Patent Document 1) General name: Ramelteon (hereinafter sometimes referred to as compound A) is a compound that has an excellent melatonin agonist action and is expected as an extremely excellent sleep disorder preventive and therapeutic agent that induces natural sleep.
The characteristics of a prophylactic / 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, Slow-wave sleep)) It would be desirable to extend the time), maintain sleep, and obtain adequate sleep time.
Benzodiazepines and non-benzodiazepines that act mainly on GABA-A receptors are used as therapeutic agents for sleep disorders, but 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 insufficient in efficacy as therapeutic agents for sleep disorders as a single agent.
International Publication No. 97/32871 Pamphlet Roehrs T et al, Sleep Med. 2004 Sep; 5 (5): 463-6

The compound A alone is expected to meet these requirements, but there is a demand for the development of a drug that satisfies these requirements to a higher degree.
Therefore, the present invention is directed to a preventive / therapeutic agent for sleep disorders that induces natural sleep, shortens sleep latency, increases deep sleep, is excellent in maintaining sleep, and can acquire appropriate sleep time. To do.

As a result of various investigations, the present inventors have combined a sedative antidepressant and / or antihistamine having the characteristic of increasing deep sleep with Compound A, which is an extremely excellent sleep disorder preventive and therapeutic agent that induces natural sleep. (As a combination, a combination drug or a combination drug), the sleep latency is shortened, deep sleep is increased, sleep maintenance is excellent, and appropriate sleep time can be obtained. It came to be completed.
That is, the present invention
[1] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and a sedative antidepressant and A prophylactic or therapeutic agent for sleep disorders, comprising a combination of one or more drugs selected from the group consisting of antihistamines;
[2] A combination of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and doxepin. Preventive or therapeutic agent for sleep disorders;
[3] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders Furan-8-yl) ethyl] propionamide in combination with one or more agents selected from the group consisting of sedative antidepressants and antihistamines;
[4] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders Furan-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 as a sedative antidepressant And 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 and an antihistamine; and [6] (S) -N- [2- (1 , 6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide in combination with doxepin to prevent sleep disorders or It provides treatment methods and the like.

According to the present invention, a prophylactic / therapeutic agent for sleep disorders that induces natural sleep, shortens sleep latency, increases deep sleep, is excellent in maintaining sleep, and can acquire appropriate sleep time is provided. The
In addition, 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 this invention, the prophylactic / therapeutic agent of the sleep disorder | damage | failure by which the rebound after administration stop was suppressed is provided.

［式中、環Ａおよび環Ｃは、それぞれ６員芳香環を、環Ｂは、７員炭素環、または窒素、酸素、および硫黄から選択される１個以上のヘテロ原子を構成原子として有する７員複素環を、Ｒは、ジメチルアミノ基で置換されたＣ_１−４アルキル基、またはジメチルアミノ基で置換されたＣ_１−４アルキリデン基を、---は一重結合または二重結合を示す。］で表される化合物またはその塩である三環系抗うつ薬が好ましい。
ここで例示した鎮静性抗うつ薬は、公知の化合物であり、いずれも市販品にて入手可能であるか、Stach K. et al, Monatsh. Chem., 1967, 93, 896、USP3354155、Miodownik, A. et al, Synth. Commun., 1981, 11, 241等に記載の公知の方法に準じて容易に合成することができる。 Specific examples of the sedative antidepressant used in the present invention include, for example, doxepin, trazodone, nefazodone, paroxetine, amitriptine, maprotiline, mianserin, fluvoxamine, trimipramine, cetiptiline, desipramine, imipramine, mirtazapine (Mirtazapine, Org-4420) (S-mirtazapine)). As the sedative antidepressant used in the present invention, for example, a tricyclic antidepressant (eg, doxepin, amitriptin, trimipramine, desipramine, imipramine) is preferable. Such tricyclic antidepressants include formulas

[Wherein, ring A and ring C each have a 6-membered aromatic ring, ring B has a 7-membered carbon ring, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur as constituent atoms. R is a C _1-4 alkyl group substituted with a dimethylamino group or a C _1-4 alkylidene group substituted with a dimethylamino group, --- represents a single bond or a double bond . ] Or a tricyclic antidepressant which is a salt thereof is preferable.
The sedative antidepressants exemplified here are known compounds, all of which are commercially available. Stach K. et al, Monatsh. Chem., 1967, 93, 896, USP 3354155, Miodownik, It can be easily synthesized according to a known method described in A. et al, Synth. Commun., 1981, 11, 241, etc.

Specific examples of the antihistamine used in the present invention include diphenhydramine, doxylamine, azatadine, brompheniramine, cetirazine, chlorpheniramine, clemastein, cyproheptadine, disloratadine, descropheniramine, dimenhydride. Nate, fexofenadine, hydroxyzine, loratadine, and phenindamine. The antihistamine used in the present invention is preferably a histamine H1 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. Such sedative antidepressants and / or antihistamines preferably have both the properties of tricyclic antidepressants and histamine H1 antagonists. Among these, doxepin is preferable.
Compound A used in the present invention is produced by, for example, the method described in WO97 / 32871 or a method analogous thereto.

  In the present specification, unless otherwise specified, the compound or drug may be any of a free form or a salt, an anhydrate or a hydrate, and may be a racemate or an optically active form. Such a 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, basic or Examples include salts with acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, 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 salt. 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 the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. It is done.

In the agent for preventing or treating sleep disorders of the present invention, all of the active ingredients may be contained in one preparation, and each or a part of the active ingredients may be separately formulated. That is, the sleep disorder preventive / therapeutic agent of the present invention comprises, as an active ingredient, one or more drugs selected from the group consisting of sedative antidepressants and antihistamines and compound A, for example, (1) known pharmacology It may be a single agent formulated with excipients that are appropriately pharmaceutically acceptable according to the manufacturing method, if desired. (2) Use (combination) simultaneously or in combination with a time difference In addition, each may be a preparation formulated with a pharmaceutically acceptable excipient or the like if desired, or (3) each of which is respectively formulated with an appropriate excipient by a conventional method. A combined set (such as a kit) may be used.
The form of the agent for preventing or treating sleep disorders 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 (for example, a patch) is preferred. Of these, tablets, fine granules and capsules are particularly preferred.

  Such a preparation of the present invention is produced by a method known per se (for example, a method described in the Japanese Pharmacopoeia, etc.) or a pharmacologically acceptable carrier generally used in an appropriate amount, and an appropriate amount is appropriately used.

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.). As such sleep disorder, for example,
(1) Endogenous sleep disorders (eg, psychophysiological insomnia), extrinsic sleep disorders, and circadian rhythm disorders (eg, time zone change syndrome (time difference blur), shift work sleep disorder, irregular sleep Sleep abnormalities such as wakefulness pattern, 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, awakening in the middle, awakening in the early morning, and combinations thereof.
In addition, by using the sleep disorder preventive and 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. , Less awakening at night. Furthermore, the occurrence of bruises, fractures, etc. can be reduced because night awakening is reduced, and even when night awakening occurs, a fall when standing up at night awakening is less likely to occur.
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.
Moreover, the rebound after a stop of administration of the sleep disorder preventing / treating agent of the present invention is suppressed.
In addition, one or more drugs selected from the group consisting of sedative antidepressants and antihistamines and (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4- b] furan-8-yl) ethyl] propionamide in combination with sleep disorders, seasonal depression, reproductive and neuroendocrine diseases, senile dementia, Alzheimer's disease, various types of aging Disorders (eg anti-aging), cerebral circulation disorders (stroke, etc.), head trauma, bone marrow injury, stress, epilepsy, convulsions, anxiety, depression, Parkinson's disease, hypertension, glaucoma, cancer, diabetes, bipolar Disorder, asthma, reflux esophagitis (GERD), headache, nocturia, irritable bowel syndrome, etc.] or associated sleep disorders as well as immune regulation, intelligence, mental stability or ovulation regulation (eg, It is also effective against contraception.

Compound A is effective for the prevention and treatment of sleep disorders (insomnia) in mammals (eg, humans, cats, dogs, monkeys, etc.) even when used alone without being combined with sedative antidepressants and / or antihistamines. Can be used. As such sleep disorder, for example,
(1) Endogenous sleep disorders (eg, psychophysiological insomnia), extrinsic sleep disorders, and circadian rhythm disorders (eg, time zone change syndrome (time difference blur), shift work sleep disorder, irregular sleep Sleep abnormalities such as wakefulness pattern, 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 addition, Compound A can be used effectively for antiemetics and the like.

  Compound A is a serotonin IIA antagonist (eg, M-100907, ACP-103, APD-125, Org-) for the purpose of giving higher quality sleep in the prevention and treatment of such sleep disorders (insomnia). 50081, mirtazapine, Org-4420 (s-mirtazapine), purvanserin, eplivanserin, quetiapine, clozapine, risperidone, sertindole, Olanzapine, Ziprasidone, Asenapine, Ocaperidone, Paliperidone, R-167154, Iloperidone, Aripiprazole, Desmethylclozapine (ACP-104, N- desmethylclozapine))). In the same manner as in the present invention, for example, a serotonin IIA antagonist is formulated according to (1) Compound A and a known pharmacological production method, together with excipients that can be appropriately pharmaceutically acceptable as required. (2) Each was formulated with a pharmaceutically acceptable excipient or the like, if desired, so as to be used in combination (in combination) with simultaneous or time difference It may be a preparation, or (3) may be a set (kit or the like) in which each is formulated together with an appropriate excipient by a conventional method.

The serotonin IIA antagonists exemplified above are known compounds, and are commercially available, or can be produced according to known methods.
M-100907 is produced, for example, by the method described in Medicinal Chemistry Research, 1996, 6 (pp1-10) or a method analogous thereto.
ACP-103 is produced by, for example, the method described in International Publication Pamphlet WO2001 / 66521 or a method analogous thereto.
APD-125 is produced, for example, by the method described in International Publication Pamphlet WO2005 / 12254 or a method analogous thereto.
Org-50081 is produced, for example, by the method described in European Patent Publication EP 0373998 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 WO2001 / 07435 or a method analogous thereto.
Eplivanserin is produced by, for example, the method described in International Publication Pamphlet WO2005 / 05410 or a method analogous thereto.
Asenapine is produced, for example, 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.
Paliperidone is produced, for example, by the method described in US Pat. No. 5,158,952, or a method analogous thereto.
R-167154 is produced, for example, by the method described in International Publication Pamphlet WO97 / 38991 and International Publication Pamphlet WO99 / 19317, 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 WO2004 / 064753 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, and / or at early morning, depending on the type of sleep disorder (insomnia). Similarly, when compound A is used alone, depending on the type of sleep disorder (insomnia), administration of a pharmaceutical composition containing compound A before bedtime, at night awakening, and / or at early morning awakening, etc. Can be performed.
Although 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., the dosage of each active ingredient for adults with sleep disorder (body weight of about 60 kg). The following amount may be administered once to several times a day (preferably once a day), and each component may be administered simultaneously or in combination with a time difference of 30 minutes to 3 hours It is good to do.
A group consisting of a sedative antidepressant and an antihistamine 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 a sedative antidepressant and an antihistamine and Compound A is used Each of these doses may be reduced as compared with the case where each of the drug selected from the above and Compound A is used alone.
For example, in the case of an agent obtained by combining one compound selected from the group consisting of a sedative antidepressant and an antihistamine with Compound A, the dose of Compound A is, for example, once a day. About 0.05 mg to about 50 mg per dose, particularly in the case of oral administration, preferably about 1 mg to about 20 mg per dose, and in the case of a transdermal agent, preferably about 0.1 mg to about 10 mg per dose.
In addition, the dose of one kind of drug selected from the group consisting of sedative antidepressants and antihistamines may be selected according to the type, for example, once a day, usually 1 About 0.1 mg to about 3000 mg per time, preferably about 5 mg to about 900 mg per time.

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 per dose, Preferably it is about 1 mg to about 20 mg, and particularly preferably about 1 mg to about 10 mg per dose.
The combination ratio (administration ratio) of one type of drug selected from the group consisting of sedative antidepressants and antihistamines and compound A in the sleep disorder preventive and therapeutic agent of the present invention 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), and particularly preferably 1:10 to 20: 1 (weight ratio).
For more specific compounds, the combination ratio (dose ratio) of doxepin and compound A is, for example, 1:50 to 30: 1 (weight ratio), preferably 1:20 to 10: 1 (weight ratio). Is 1: 10-5: 1 (weight ratio).
It induces natural sleep, shortens sleep latency, increases deep sleep, maintains sleep, acquires appropriate sleep time, and has the effect of having little or no carryover to the next day For the purpose, the daily dose is preferably 8 mg of Compound A and about 1 mg to about 6 mg (eg, 1 mg, 3 mg, 6 mg) of Doxepin, more preferably about 8 mg of Compound A and about 1 mg of Doxepin. About 3 mg (eg, 1 mg, 3 mg).
Each dose when two or more drugs selected from the group consisting of sedative antidepressants and antihistamines are used can be reduced as compared with the case of using only one drug.
Furthermore, the prophylactic and therapeutic agent for sleep disorders of the present invention may be used in combination with other active ingredients as long as the excellent properties are not substantially impaired. The other active ingredient, sedative antidepressant and / or antihistamine and compound A are mixed according to a method known per se, and a pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule), liquid, Patch preparations, injections, suppositories, sustained-release preparations, etc.) or separately may be administered to the same subject at the same time or with a time difference as in the preparation of the present invention.

  The present invention is further explained in detail by the following test examples and formulation examples, which are merely examples and are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. May be.

Formulation Example 1
(1) Doxepin 8.0g
(2) Compound A 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
A mixture of 8.0 g of doxepin, 8.0 g of compound A, 60.0 g of lactose and 35.0 g of corn starch was granulated through a 1 mm mesh sieve using 30 ml of a 10% by weight aqueous gelatin solution (3.0 g as gelatin), and 40 ° C. And dried 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. The coated tablets are polished 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 (light period from 7 am to 7 pm) was used. Under pentobarbital anesthesia, an electroencephalogram recording electrode was embedded in the frontal lobe, parietal lobe and hippocampus of the cerebral cortex, an electrooculogram electrode was embedded in the orbital bone, and an electromyographic recording stainless wire electrode was embedded in the dorsal cervical muscle. Antibiotics were administered to prevent bacterial infection. Acclimatization to an electroencephalogram cage was started from 3 to 4 days after the operation, and electroencephalogram measurement was performed 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 mice per group, and a crossover test was conducted.
[Drug administration 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))
After about 8:30 am, the cats were fitted with measurement electrodes and then placed in the experiment box. Administration was performed around 10:00 am, and sleep electroencephalogram was measured 8 hours after the administration.
The electroencephalogram data was acquired using Synafit 2500 from NEC Saneisha. For the analysis, Sleep Sign Ver.2.0, which is a sleep analysis research program of Kissei Comtech, was used. We set δ (delta) wave in the waveform derived from the cortex and θ (Theta) wave in the waveform derived from the hippocampus as characteristic parameters, and perform analysis every 20 seconds from this parameter by the following If to Then method. Slow wave sleep and REM sleep were automatically determined. After completion of these automatic determinations, visual determination was performed, and when the sleep stage determination was clearly different, the determination was corrected.
[Automatic determination of sleep EEG]
a ≦ EMG Integral ≦ 100 → Yes “Awakening”
↓ No
20 ≤ Delta% time ≤ 100 & 0 ≤ EMG Integral <b → Yes “SWS”
↓ No
25 ≦ Theta% Time ≦ 100 & 0 ≦ EMG Integral <c → Yes “REMS”
↓ No
3 ≦ Fast wave% Time ≦ 100 → Yes “Awakening”
↓ No
Previous stage (reflect the previous sleep judgment)
* The values of a, b, and c were 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 combined group of Compound A and doxepin, the total slow wave sleep time and the 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, using SleepSign Ver.2.0 (Kissei Comtech), only the epoch determined to be slow wave sleep was extracted and subjected to FFT analysis, and the power spectrum value at each frequency was obtained.
The results are shown in FIG. 2 (in the figure, ◆ vehicle, □ Compound A), FIG. 3 (in the figure, ◆ vehicle, □ doxepin), and FIG. 4 (in the figure, ◆ Compound A, □ Compound A and □ Compound A and doxepin combined). (0-2 hr, 2-4 hr, 4-6 hr after dosing, 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 (near 2 Hz) was observed from about 2 hours after administration compared to Compound A alone. From this result, it can be seen that sleep is deep in the combination group of Compound A and doxepin.

  According to the present invention, a prophylactic / therapeutic agent for sleep disorders that induces natural sleep, shortens sleep latency, increases deep sleep, is excellent in maintaining sleep, and can acquire appropriate sleep time is obtained. .

It is a graph which shows REM time, SWS time, and total sleep time. It is a graph which shows the power spectrum in SWS period of the compound A single group. It is a graph which shows the power spectrum in SWS period of a doxepin single group. It is a graph which shows the power spectrum in SWS period of the combined use group of a compound A and doxepin.

Claims (6)

  (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and a sedative antidepressant and antihistamine A prophylactic or therapeutic agent for sleep disorders, comprising a combination of one or more drugs selected from the group.   (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide in combination with doxepin Prophylactic or therapeutic agent.   (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8 for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders -Il) ethyl] propionamide in combination with one or more drugs selected from the group consisting of sedative antidepressants and antihistamines.   (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8 for the manufacture of a pharmaceutical composition for the prevention or treatment of sleep disorders -Yl) ethyl] propionamide in combination with doxepin.   (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide from sedative antidepressants and antihistamines 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:   (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.

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