TW200800160A - Prophylactic or therapeutic agent for sleep disorder - Google Patents

Abstract

By combining one or more drugs selected from the group consisting of sedative antidepressants and antihistamines with (S)-N-[1, 6, 7, 8-tetrahydro-2H-indeno[5, 4-b] furan-8-y1)ethy1]propionamide, there is provided a prophylactic or therapeutic agent for sleep disorder that induces natural sleep, shortens sleep latency, increases deep sleep, is excellent in maintaining sleep, and exerts to attain appropriate sleep duration.

Description

200800160 - IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a preventive or therapeutic agent for sleep disorders. [Prior Art] θ , —, , (S)_N—[2_(1,6, 7, tetra-argon-deazolo[5,4-b]furan-8-yl)ethyl, which is disclosed in 卯97/32871 [Propylamine (common name: Ramelteon (hereinafter, sometimes referred to as Compound A)) is a kind of melatonin stimulating effect and is expected to be _ kind of induction = extreme sleep A preventive or therapeutic agent for sleep disorders. w Prevention or treatment of sleep disorders must have several characteristics, such as induction. 'Natural sleep, get short sleep latency, increase deep sleep (eg, extended wave sleep (SWS) duration), maintain sleep, and achieve proper sleep ^ Continued period. f Although benzodiazepine or non-benzodiazepines acting on the amino acid butyric acid type A (GABA-A) receptor are mainly used as a preventive and therapeutic agent for sleeping abnormalities, calming resistance Depressions are also sometimes used to treat insomnia (eg, RoehrsT·' et al., SleepMed 5(5): 463'-6.

Sep. 2004). On the other hand, antihistamines are also used as counter sales (0TC) drugs for the treatment of mild insomnia. These drugs have properties such as increased deep sleep, but when used alone, they are not effective as a therapeutic drug for sleep disorders. SUMMARY OF THE INVENTION The problem to be solved by the present invention. The above-mentioned compound A, even when it is used alone, is expected to satisfy the demand of 318554 5 200800160 - etc., but it is necessary to develop a drug which is more suitable for such a demand. The purpose of the present invention is to provide a preventive and therapeutic agent for a sleep disorder which induces natural sleep, shortens sleep latency, and increases deep sleep. • The drug is excellent in maintaining sleep and serves to maintain sleep persistence. [Means for Solving the Problem] As a result of the present invention, the present inventors have found that the use of a more anti-depressant agent and/or an antihistamine having an increased deep sleep characteristic, combined (combination preparation, mixing (Mended) a compounding agent or a concomitant preparation) an extremely excellent sleep abnormality prevention and treatment agent for inducing natural sleep - Compound A, which can attenuate sleep latency, increase deep sleep, excellent sleep duration, and maintain proper sleep duration The present invention is thus completed. The present invention provides: [1] A pharmaceutical composition for preventing or treating sleep abnormalities, comprising: [^(1,6,7,8-tetrahydro-2H_茚[5,4_b]c-c-8-yl) Ethyl]propanamide, and one or more drugs selected from the group consisting of calming antidepressants and antihistamines; [2] - a pharmaceutical composition for preventing or treating sleep abnormalities, including [(1'6' 7, 8 tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide combined with doxepin; [3] — species (S)-N- [2-(l,6,7,8-tetrahydro-2H-indeno[5,4_b]furanyl)ethyl]propanol and one selected from the group consisting of anti-anxiety agent and anti-group Or the use of a combination of drugs for the manufacture of a pre-318554 200800160 - a pharmaceutical composition for preventing or treating sleep abnormalities; [4] a (8)-condition-[2-(1,6,7,8-tetrahydrogen) -211-indole[5,4-1)]furoxan-8-yl)ethyl]propanamide combined with doxepin for the manufacture of a pharmaceutical composition for preventing or treating sleep abnormalities ; , [5] A method for preventing or treating sleep abnormalities, comprising administering (S)-N-[2-(1,6, 7, 8-tetrahydro-2H-indole[5, 4-b] to an individual. Fur a combination of -8-ylethylideneamine and one or more drugs selected from the group consisting of calming antidepressants and antihistamines; and 10 [6] a method for preventing or treating sleep abnormalities, comprising Administration of (S)-N-[2_(l,6, 7, 8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide with multiple individuals The combination of peace. [Embodiment] Specific examples of the calming anti-allergic agent used in the present invention include doxepin, trazodendron, nefaxone (nefas〇d〇ne), paroxetine (paroxetine) ), amitriptyl ine, maprotiline, mianserin, fluvoxamine, trimipramine, setiptiline, Desipramine, imipramine, and mirtazapine 0rg-4420 (sinirtazapine), the sedative anti-depression agent used in the present invention is, for example, a tricyclic anti-depression agent. Depressants (eg, doxepin, amitriptyline, trimethoprim, desipramine, and imipramine). As the tricyclic antidepressant, the compound or its salt represented by this chemical formula is the best: 318554 7 200800160

* wherein ring A and ring C represent a six-membered aromatic ring, and ring B represents a seven-membered carbocyclic ring or a seven-membered heterocyclic ring having one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Ring, R represents a Ci-4-alkyl group substituted with a dimethylamino group or a Ci-4 alkylene group substituted with a dimercaptoamine group, and = represents a single 10- or double bond. The calming antidepressants described herein are known compounds, each of which is commercially available or readily synthesized by known methods. The method is described in Stach K. et aL, Monatsh. Chem., 1 967, 93 , 896; USP 3354155; Miodownik, A. et al., Synth· Commun., 1981, 11, 241; Specific examples of the antihistamines used in the present invention include diphenhydramine, doxy 1 amine, azatadine, brompheniramine, cetirizine ( Cetirazine), chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexchlorpheniramine, dimenhydrinate ), fexofenadine, hydroxyzine, loratadine, phenindamine. Preferably, the antihistamine used in the present invention is, for example, a histamine H1 antagonist. 8 318554 200800160 • The antihistamines exemplified herein are known compounds and are all commercially available from commercial products or readily synthesized by methods known in the art. ‘ These calming antidepressants and/or antihistamines may be used alone or in combination of two or more. Preferably, the antidepressant and/or antihistamine is a tricyclic antidepressant and a histamine H1 antagonist. Especially with Doxepin is preferred. The compound A used in the present invention can be produced according to the method described in W097/32871 or the like. In the present specification, unless otherwise stated, the compound or drug may be either a salt or a salt thereof, or a non-hydrate or a hydrate, or may be any of a foreign substance or an optically active compound. Such salts are not limited to pharmaceutically acceptable salts of X, and examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and acids or bases. Amine-based salts. Preferred examples of the inorganic base salt include, for example, alkali metal salts such as sodium salts and potassium salts, such as alkaline earth metal salts of calcium salts and magnesium salts, aluminum salts, ammonium salts, and the like. Preferred examples of the organic base salt include, for example, tridecylamine, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, cyclohexylamine, 2,6-dimethylpyridine, ethanolamine, and A salt such as dicyclohexylamine or N,N'-diphenylethylenediamine. Preferred examples of the inorganic alkali acid include, for example, salts with hydrochloric acid, bromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples with organic alkali acids include 'for example, with citric acid, acetic acid, trifluoroacetic acid, benzoic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, apples Salts such as acid, a sister, benzoic acid, and benzoic acid. Preferred examples of the salt of a basic amino acid include, for example, a salt with arginine, lysine, 318554 9 200800160 ornithine. Salts with basic amino acids _ good examples include salts with aspartic acid, face acid and the like. In the prevention or treatment of the abnormality of the sleeping subject of the present invention, the human component of the active ingredient may be contained in the preparation, or each of the active ingredients may be mixed with different preparations. The preventive or therapeutic agent for sleep abnormality of the present invention may be a single preparation in which an active ingredient, for example, one or more selected from the group consisting of anti-analgesics and antihistamines

In combination with a suitable «upper acceptable formulation, according to known manufacturing methods for formulating pharmaceutical preparations, (2) a plurality of preparations, wherein each of the active ingredients, for example, one or more selected from the group consisting of calming anti-anxiety agents and anti-tissue a drug consisting of a group of amines, and a compound A, together with an appropriate pharmaceutical: acceptable excipient, etc., if necessary, to facilitate simultaneous simultaneous (in combination; eQmbineduse), or (8) combined group of preparations (Cup product, etc.) 'Each of the active ingredients is appropriately formulated by a conventional method together with an excipient. The dosage form of the prophylactic or therapeutic agent for sleep abnormality of the present invention is not particularly limited, and is preferably a dosage form which can be administered orally (for example, a tablet, a fine granule, a capsule, a granule, etc.) and a transdermal application (for example, Patch, etc.). Among them, tablets, granules and capsules are preferred. The preparation of the present invention can be used by a method known per se (for example, the method described in Japanese Pharmacopoeia or the like) or the like, and a suitable amount of a pharmaceutically acceptable carrier conventionally used can be suitably used. . The prophylactic or therapeutic agent for sleep abnormality of the present invention can be effectively used for preventing and/or treating sleep of mammals (e.g., humans, baboons, dogs, monkeys, etc.) 318554 10 200800160, disorder (insomnia). Such sleep disorders include: (1) sleep disorders (dyssomnia) such as endogenous sleep disorders (such as psychophysiological insomnia), exogenous sleep disorders, and circadian rhythm disorders (eg, time zone change syndrome (time difference), Shi ft-work sleep disorder, irregular sleep-wake mode, delayed sleep-phase syndrome, advanced sleep-phase syndrome, It 24,J , sleep in the eyes of the people - wake up abnormalities; 10 (2) outsomnia (parasomnia); (3) with medical / mental disorders (eg, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, multiple Sleep disorders associated with infarct dementia, schizophrenia, depression, and anxiety disorders. In addition, in this specification, sleep disorders (insomnia) include difficulty falling asleep (si eep-onset insomnia), awakening during sleep, and

Arrousals and awakenings during sleep (sleep maintenance insominia), early-morning awakening, and combinations thereof. Further, by using the pharmaceutical composition for preventing and treating sleep disorders of the present invention, natural sleep is shortened, sleep latency is shortened, deep sleep is increased, sleep is excellent, and proper sleep persistence is maintained, and nighttime waking is reduced. Furthermore, because the nighttime waking is reduced, the occurrence of hangs and fractures can be reduced, and, in the event of waking at night, it is difficult to occur outside the land when standing up. In addition, the pharmaceutical composition for preventing and treating sleep disorders of the present invention 318554 11 200800160 can maintain its sleep induction effect under long-term administration. In the pharmaceutical composition for preventing and treating sleep disorders of the present invention, the recurrence phenomenon after the administration of _ is suppressed.

In addition, Compound A can be effectively used alone, that is, it is not used in combination with calming antidepressants and antihistamines for the prevention of sleep abnormalities (insomnia) in mammals (eg, humans, juveniles, dogs, monkeys, etc.) / or treatment. These sleep disorders include: (1) sleep abnormalities (dyss〇mnia) such as endogenous sleep disorders (such as psychophysiological insomnia), exogenous sleep disorders, and circadian rhythm abnormalities (eg, time zone change syndrome (time difference), shift shift sleep Obstacle, irregular sleep-wake mode, delayed sleep syndrome, early sleep syndrome, non-24-hour sleep-wake abnormality; 2' contains a group selected from calming anti-anxiety and antihistamines A multi-drug and a pharmaceutical composition of (8)|[2_(1,6,7,8-tetrahydropyrene and \4-bK-anthranyl)ethyl]-propyl, which can effectively prevent and treat except for sleep-ten / or treatment of seasonal depression, reproductive and neurological, bleeding diseases, Alzheimer's disease, Alzheimer's disease, aging related to various adjustments (such as aging prevention, etc.), cerebral blood flow abnormalities (stroke, etc.), head Trauma, myelopathy, stress, epilepsy, paralysis, anxiety, depression, Parkinson's disease, blood, glaucoma, cancer, diabetes, headache, nocturnal urinary tract, intestinal irritation, etc. Smart tropism (inte 11 ectual tr〇p Ism), mental stability and ovulation regulation (eg, contraception). (2) parasomnia; (3) with medical/pseumatic abnormalities (eg chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, multiple infarct dementia, schizophrenia, depression, 318554 12 200800160 . Anxiety disorders) related to sleep disorders. In addition to this, the compound A can be effectively used as an antiemetic agent or the like. Furthermore, in order to obtain a higher quality sleep in the prevention or treatment of such sleep abnormalities (insomnia), Compound A may suitably be combined with a serotonin 2A antagonist (for example, M-100907, ACP- 103, APD-125, Org-50081, Mirtazapine (Org-4420 (s-miltazapine)), Purvanserin, El ivanserin, Quetiapine , Clozapine, Risperidone, Sertindole, Olanzapine, Ziprasidone 'asenapine, Oka faction Ocaperidone, Paliperidone, R167154, I oper idone, Ar ipiprazole, desmethylclozapine (ACP-104, N- Remove clozapine). As regards the above-mentioned invention, specific examples thereof may be, for example, (1) a single preparation in which a serotonin 2 A antagonist and a compound A are formulated together with a suitably pharmaceutically acceptable excipient, if necessary, based on Known manufacturing methods for formulating pharmaceutical preparations; (2) various preparations in which each of the active ingredients is formulated together with a pharmaceutically acceptable excipient, if necessary, for simultaneous use or combined use at different times; A combined use of a preparation (set product, etc.), wherein each of the active ingredients is appropriately prepared by a conventional method together with an excipient. The above serotonin 2A antagonists are known compounds and are commercially available from commercial products or can be produced by methods known in the art. 13 318554 200800160 , M-100907 can be described, for example, in Medicinal Chemistry

Manufactured by Research, 1 996, 6, ρρ· 1-10 or the like. ACP-103 can be manufactured as described, for example, in WO 2001/66521 or the like. ♦ APD-125 can be made by the methods described, for example, in WO 2005/12254 or the like.

Org-50081 can be made by the methods described, for example, in EP0373998 or the like. Lu Org-4420 can be made by the methods described, for example, in U.S. Patent 4,066,848 or the like. Pruvanserin can be made by the methods described, for example, in WO 2001/07535, or the like. Eplivanserin can be made by methods described, for example, in WO 2005/ 05410 or the like. Asenapine can be made by the methods described, for example, in U.S. Patent 4,145,434 or similar. Ocaperidone can be produced by the methods described, for example, in EP 4453042A or the like. Paclironone (P a 1 i p e r i d ο n e ) can be produced by a method described, for example, in U S 515 8 9 5 2 or the like. R-167154 can be made by methods such as W0 97/38991 and W0 99/19317 or the like. Iloperidone can be produced by methods described, for example, in WO 93/09102 or the like. 14 318554 200800160 clozapine) can be produced by the methods described, for example, in WO 2004/064753 or the like. The pharmaceutical composition for preventing or treating a sleep disorder of the present invention is low in toxicity and can be orally administered to a mammal, such as a human. The pharmaceutical composition for preventing or treating sleep abnormality of the present invention can be administered at the time of bedtime, nighttime waking, and/or early morning waking up according to the type of sleep disorder (insomnia). Further, similarly, when Compound A is used alone, the pharmaceutical composition containing Compound A can be administered at the time of bedtime, nighttime waking, and/or early morning waking up according to the type of sleep disorder (insomnia) described above. The dosage of the pharmaceutical composition for preventing or treating sleep abnormality of the present invention varies depending on the individual to be administered, the route of administration, the disease, the kind of the active ingredient to be used, and the like, such as the amount of each of the following active ingredients (referred to as a dose) It can be administered to a sleeping abnormal adult (weight about 6 〇 kg) in a single dose or in divided doses per day (preferably, a single daily dose). Preferably, each component is #30 minutes apart. The combination was administered at different times up to 3 hours. The invention relates to a pharmaceutical composition for preventing or treating sleep disorders comprising U, 疋 "depressant and antihistamine", when combined with a compound & a group or a plurality of drugs; from: the use of the drug, the dose of each of the drugs is different::,,,, and the early individual contains a drug selected from the group consisting of: preventing or treating sleep disorders or A variety of drugs: =:: = ° anti-tissue coffee ^ eight combination, compound eight daily single-dose 318,554 15 200800160 • agent 篁 is about 0.05 mg (mg) to the example, preferably about !亳...: 克一古尤, in the case of oral preparations in the case of transdermal preparations, preferably j, and a single dose. 4 is from about pg to about 10 mg as • In addition, selected from calming anti-worry # The dosage of the drug-drug may be appropriate according to the type of the drug = two, for example, in the early administration of the mother, the dose is usually about 0. Preferably, it is 5 mg to _mg as a single dose. m_, compared to ~ two : the specific compound dose of doxepin, for example, in each dose: a single dose (four). 1 mg to about 200 milligrams Preferably, it is 〇5 mg, more preferably from about 1 mg to about 2. mg, and particularly preferably from about 13⁄4 g to 10 mg. The pharmaceutical composition for preventing or treating sleep disorders according to 1 2 is self-stabilizing The combination ratio of the antidepressant and the antihistamine to the compound (coinbinati〇nra = usually 1:1 〇〇 to 60:1 (weight ratio), preferably 1:2 〇 4 is 1 · 10 To a ratio of 20:1 (weight ratio). For a more specific compound, the ratio of 'doxepin to compound eight is 4', for example, '1:50 to 30:1 (weight ratio), preferably 1:20 to 1 (Weight ratio) 'More preferably 1:10 to 5:1 (weight ratio). The field uses two doses of t drug from a group of anti-depressants and antihistamines, compared to single use One of these drugs, each of the 318554 16 200800160 'group J into the two sleep disorders of the medical component combination and combined use. Other

/Phenlose component, calming anti-anxiety agent and /H lysine, and compound A are obtained as pharmaceutical compositions (for example, ingot, sputum, sputum, body-to-head method) 1 "1 powder, fine granules, capsules (including Soft capsules, liquid preparations, patches, injections, elixirs, and sputum compositions can be administered, or various garments prepared by the 5-weekly method of 酉 酉 锸 锸 拗叮 门 门 门 门 门 门 门 门Μ Μ 或 或 或 不同 不同 不同 不同 。 。 。 。 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本Can be changed under 0 Preparation Example 1 8.0 g 8 · 0 g 60 · 0 g 35 · 0 g 3.0 g 2.0 g (1) Doxepine

(2) Compound A (3) Lactose

(4) Corn starch (5) Gelatin (6) Magnesium stearate... 8.4 grams of oxime flat, compound A u gram, lactose 60.0 g and corn starch = · 0 g mixture 'Use % ml of gelatin to open the knee) 1 Mouth 〇 里 里 溶液 溶液 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The resulting fine granules were mixed with 2 g of stearic acid and the mixture was compressed. The obtained core ingot was coated with sugar, and an aqueous suspension of titanium oxide and mica gum arabic was coated with sugar. The coated ingot was thrown with yellow bee 318554 17 200800160 to produce 100 pieces of coated ingot. Experiment 1 The animals used in the test were bred in a 12-hour light-dark cycle (lighting time from 7 am to 7 pm) (4). The electrode used to record the brain wave map under pentobarbital anesthesia is divided into the frontal lobe, frontal lobe and hippocampus of the cerebral cortex. The electrode used to record the ocular wave map is implanted in the bone of the frame. The track radio wave H (four) is implanted in the dorsal neck muscle. Use antibiotics to prevent bacterial infections. In order to measure the EEG map, the reincarnation was started in the cage 3 to 4 days after the operation, and the electroencephalogram was measured at 2 weeks after the remnant. The vector and the drug to be administered are contained in a capsule - and then forcedly administered by the mouth. Each group of the experimental group consists of 10 animals' and a crossover experiment is performed [drug administration group] ' (1) Vector (0· 5% methylcellulose aqueous solution) (2) Compound Α (0·1 mg/kg) _ (3) Doxepin (〇·3 mg/kg) Doxepin (0·3 mg/cm (4)) (Compound α (〇·1 mg/kg) + kg)) After attaching the measuring electrode, put the jug into the test box order from about 8:3 in the morning. The drug administration was performed at approximately 10:00 in the morning, and the sleep brainwave map was measured 8 hours after the administration. The data of the electroencephalogram was obtained by NEC Synafit 25 and the analysis was performed using the Kissei CQmtec c. · LTD.'s sleep analysis research program Sleep Sign Ver.2.0. As a characteristic parameter, the 4 wave is set to 318554 18 200800160 , and the wave type '0 wave obtained from the cerebral cortex is set as the wave pattern obtained from the hippocampus. Every 20 seconds, the following method is used to analyze this parameter (if~then meth〇d), while awake, slow wave sleep, and rapid eye movement sleep are automatically judged. In addition, after the automatic judging is completed, visual judgment is made. If the judgment of the sleep state is significantly different, the result of the judgment will be corrected. [Automatic evaluation of sleep brainwave map] aSEMG score 00—is “awake” i No® 20$5% time SlOO& £EMG score is “slow wave sleep” 4 No 25$θ% time £1〇〇&〇 SEMG points <c- is "rapid eye movement sleep" i no 3$ fast wave % time $1 〇〇 - is "awake" I no first grievances (reporting immediately prior sleep judgment), b, c should be Depending on the appropriate value for each individual, Figure 1 shows the results of Compound A alone administered to the combination of Compound 4 and Doxepin. It can be clearly seen from this figure that the combination of Compound A and Doxepin was compared with Compound A alone, and the total slow wave sleep time and total sleep duration were extended by about 30 minutes, with significant differences. Experiment 2 [Frequency Analysis] In Beiyiyi, using Sleep Sign Ver· 2· 0 (KISSEI COMTEC), only the period judged to be slow wave sleep will be extracted.

318554 200800160 "And provide for Fast Fourier Transform (FFT) analysis, then the functional spectral values for each frequency will be measured. The results are not as good as the second figure (in this figure, ♦ carrier characterization person A), Three figures (in this figure, ♦ carrier □ multi-level), the fourth picture (in this figure, ♦ carrier □ combined with compound A and doxepin) (respectively after administration, 〇 to 2 hours, 2 to 4 hours, 4 to 6 hours). From this figure, it can be proved that the phase father is separately administered in compound A, and the compound a and the doxepin group are observed for about 2 hours after administration, and the power spectrum can be observed in the low frequency region. There is an increase. As a result, it has been found that the combination of Compound A and Doxepin is used to make the sleep deeper. [Industrial Applicability] / According to the present invention, a pharmaceutical group for preventing or treating sleep disorders is provided. Natural sleep, shortening sleep latency, increasing deep sleep, and being excellent for maintaining sleep, and exhibiting appropriate sleep persistence. Further, according to the present invention, a pharmaceutical composition for preventing or treating sleep disorders is provided, which is long-term Further, the sleep-inducing effect can be maintained. φ Furthermore, according to the present invention, a w-drug composition for preventing or treating a sleep disorder is suppressed from recurring after discontinuation of administration. [Fig. 1] A graph showing rapid eye movement (REM) time, sws time, and total sleep duration. Fig. 2 is a graph showing the period of the compound A alone administered to the group. Fig. 3 is a graph showing the doxepin alone administration group. Power spectrum diagram during sfs. 318554 20 200800160 Figure 4 is a power spectrum diagram showing the SWS during the combination of Compound A and Doxepin.

21 318554

Claims (1)

200800160 • Ten, apply for a patent garden: 1. A pharmaceutical composition for preventing or treating sleep disorders, including [2 one (1,6,7,8-four-one-211-茚[5,4-1)] Furan-8-yl)ethyl•13⁄4 amine with one or more drugs selected from the group consisting of calming antidepressants and antihistamines. , a pharmaceutical composition for preventing or treating sleep disorders, comprising [2-(1,6' 7, 8-tetrahydro-2H-unit[5,4_b]furan-8-yl)ethylpropanthene Combination of amine and doxepin. Use of a combination of a compound or a plurality of drugs selected from the group consisting of a calming anti-anxie # agent and an antihistamine, and a use thereof A pharmaceutical composition for preventing or treating sleep disorders. 4. Use of a combination of (8)-N-[2-(1,6,7-8-tetrahydro-2H-pyrene[5,4_bbufuran8-yl)ethyl]propanamide and doxepin It is used to manufacture a pharmaceutical composition for preventing or treating sleep disorders. # 5. _ A method for preventing sleep disorders in silk therapy, which comprises administering (S)-N-[2-(l,6, 7, 8-tetrahydro-2H-gange[5, 4_b] to the subject individual A combination of one or more drugs selected from the group consisting of calming antidepressants and antihistamines. 6. A method for preventing or treating a sleep disorder comprising administering to a subject individual (S)-N-[2-(l,6,7' 8-tetrahydro-2H-indole[5,4-b] Combination of furan-8-yl)ethyl]propanamide with doxepin. 318554 22