WO2007034778A1 - Prophylactic/therapeutic agent for sleep disorder - Google Patents

Prophylactic/therapeutic agent for sleep disorder Download PDF

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Publication number
WO2007034778A1
WO2007034778A1 PCT/JP2006/318503 JP2006318503W WO2007034778A1 WO 2007034778 A1 WO2007034778 A1 WO 2007034778A1 JP 2006318503 W JP2006318503 W JP 2006318503W WO 2007034778 A1 WO2007034778 A1 WO 2007034778A1
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Prior art keywords
sleep
compound
combination
therapeutic agent
group
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PCT/JP2006/318503
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French (fr)
Japanese (ja)
Inventor
Keisuke Hirai
Masaomi Miyamoto
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Takeda Pharmaceutical Company Limited
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Priority claimed from JP2006117524A external-priority patent/JP2008303146A/en
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2007034778A1 publication Critical patent/WO2007034778A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a prophylactic and therapeutic agent for sleep disorders.
  • 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.
  • SWS slow-wave sleep
  • 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).
  • 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
  • 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.
  • 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.
  • compound A which is an extremely excellent sleep disorder preventive therapeutic agent that induces natural sleep.
  • 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.
  • a prophylactic / therapeutic agent for sleep disorders in which the sleep induction effect is maintained even after long-term administration is provided.
  • a preventive / therapeutic agent for sleep disorders in which rebound after administration stop is suppressed.
  • 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.
  • 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]
  • 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.
  • R is a C alkyl group substituted with a dimethylamino group, or dimethylamino.
  • 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.
  • antihistamine used in the present invention examples 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.
  • antihistamines exemplified here are known compounds, all of which are commercially available, or can be easily synthesized according to known methods.
  • the strong sedative antidepressant and / or antihistamine 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.
  • 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.
  • the strong salt is not particularly limited as long as it is a pharmacologically acceptable salt.
  • 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
  • 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.
  • 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.
  • 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).
  • 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
  • tablets, fine granules and capsules are particularly preferred.
  • 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.).
  • sleep disorders include, for example,
  • Endogenous sleep disorders e.g., psychophysiological insomnia
  • extrinsic sleep disorders e.g., and circadian rhythm disorders (e.g., time zone change syndrome (time difference blur), shift work sleep disorder, irregular type)
  • 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);
  • 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.
  • sleep disorder includes sleep deprivation disorder, mid-wake awakening, early morning awakening, and combinations thereof.
  • 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.
  • the sleep disorder preventing / treating agent of the present invention maintains the sleep induction effect even when administered for a long period of time.
  • 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).
  • S sedative antidepressants and antihistamines S
  • 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.
  • sleep disorder for example,
  • Endogenous sleep disorders e.g., psychophysiological insomnia
  • extrinsic sleep disorders e.g., and circadian rhythm disorders (e.g., time zone change syndrome (time difference blur), shift work sleep disorder, irregular type)
  • 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);
  • 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.
  • Compound A can be used effectively for antiemetics and the like.
  • 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).
  • insomnia eg, M-100907, ACP-103, A PD-125, Org-50081, Mirtazapine, Org-4420 (s-mirtazapine), Pull
  • 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.
  • 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).
  • 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.
  • 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
  • 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.
  • the dose of compound A is, for example, once a day.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • EEG data was acquired using Synafit2500 from NEC Saneisha.
  • Sleep Sign Ver.2.0 a program for sleep analysis research by Kissei Comtech Co., Ltd., was used.
  • 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.
  • 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.
  • 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).
  • an increase in the power spectrum in the low frequency region 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.
  • 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.

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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

明 細 書  Specification
睡眠障害予防治療剤  Sleep disorder preventive and therapeutic agent
技術分野  Technical field
[0001] 本発明は、睡眠障害予防治療剤に関する。  [0001] The present invention relates to a prophylactic and therapeutic agent for sleep disorders.
背景技術  Background art
[0002] 特許文献 1に記載されている、 (S) -N- [2- (l, 6, 7, 8—テトラヒドロー 2H—ィ ンデノ [5, 4— b]フラン一 8—ィル)ェチル]プロピオンアミド（一般名：ラメルテオン（ 以下、化合物 Aと称する場合がある））は、優れたメラトニンァゴ-スト作用を有し、自 然な睡眠を誘発する極めて優れた睡眠障害予防治療剤として期待されている化合 物である。  [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.
睡眠障害の予防'治療剤の特性としては、例えば、自然な睡眠が誘導されること、 睡眠潜時が短いこと、深い睡眠を増加させること (すなわち、徐波睡眠（SWS、 Slow- wave sleep)時間を延長させること）、睡眠を維持すること、および適切な睡眠時間を 獲得できること、が望まれている。  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.
睡眠障害治療剤としては主に GABA-A受容体に作用するべンゾジァゼピン系、非 ベンゾジァゼピン系の薬剤が用いられている力 不眠などに対して鎮静性抗うつ薬 が用いられることがある（例えば、非特許文献 1)。一方、軽症の不眠に対して店頭販 売医薬品として抗ヒスタミン薬もしばしば用いられる。これらの薬剤の特徴として、深 い睡眠を増やすといった特徴はあるが、これらの薬剤は単剤としては睡眠障害治療 薬としての薬効が不十分である。  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.
特許文献 1：国際公開第 97Z32871号パンフレット  Patent Document 1: Pamphlet of International Publication No. 97Z32871
非特許文献 l : Roehrs T et al, Sleep Med. 2004 Sep;5(5):463- 6  Non-Patent Document l: Roehrs T et al, Sleep Med. 2004 Sep; 5 (5): 463-6
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] 上記化合物 Aは単独でもこれらの要求に答えるものであると期待されている力 更 に高度にこれらの要求を満たす薬剤の開発が求められて 、る。 [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.
したがって、本発明は、自然な睡眠を誘導し、睡眠潜時を短くし、深い睡眠を増加 させ、睡眠の維持に優れ、および適切な睡眠時間を獲得できる睡眠障害の予防'治 療剤を目的とする。 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.
課題を解決するための手段 Means for solving the problem
本発明者らは、種々検討した結果、深!ヽ睡眠を増やす特徴を有する鎮静性抗うつ 薬および Zまたは抗ヒスタミン剤と、自然な睡眠を誘発する極めて優れた睡眠障害予 防治療剤である化合物 Aとを組み合わせて (合剤、配合剤または併用剤等として)用 いることにより、睡眠潜時を短くし、深い睡眠を増加させ、睡眠の維持に優れ、かつ適 切な睡眠時間を獲得できることを見出し、本発明を完成するに至った。  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.
即ち、本発明は、  That is, the present invention
[l] (S) -N- [2- (l, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8 —ィル)ェチル]プロピオンアミドと鎮静性抗うつ薬および抗ヒスタミン剤力もなる群か ら選択される 1種以上の薬剤とを組み合わせてなる睡眠障害の予防または治療剤； [2] (S) -N- [2- (l, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8 ィル)ェチル]プロピオンアミドとドキセピンとを組み合わせてなる睡眠障害の予防 または治療剤；  [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]睡眠障害の予防または治療用の医薬組成物の製造のための、 (S) -N- [2— ( 1, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8—ィル）ェチル]プロピ オンアミドの、鎮静性抗うつ薬および抗ヒスタミン剤力 なる群力 選択される 1種以 上の薬剤との組み合わせにおける使用；  [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]睡眠障害の予防または治療用の医薬組成物の製造のための、 (S) -N- [2— ( 1, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8—ィル）ェチル]プロピ オンアミドの、ドキセピンとの組み合わせにおける使用；  [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—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8 —ィル)ェチル]プロピオンアミドを、鎮静性抗うつ薬および抗ヒスタミン剤力もなる群 力 選択される 1種以上の薬剤との組み合わせにおいて、対象に投与することを含む 、睡眠障害の予防または治療方法;および  [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—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8 —ィル)ェチル]プロピオンアミドを、ドキセピンとの組み合わせにおいて、対象に投 与することを含む、睡眠障害の予防または治療方法等を提供するものである。 [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.
発明の効果  The invention's effect
[0005] 本発明によれば、自然な睡眠を誘導し、睡眠潜時を短くし、深 、睡眠を増加させ、 睡眠の維持に優れ、および適切な睡眠時間を獲得できる睡眠障害の予防'治療剤 が提供される。  [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.
また、本発明によれば、長期間の投与においても睡眠導入効果が維持される睡眠 障害の予防'治療剤が提供される。  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.
また、本発明によれば、投与停止後のリバウンドが抑制された睡眠障害の予防'治 療剤が提供される。  Moreover, according to the present invention, there is provided a preventive / therapeutic agent for sleep disorders in which rebound after administration stop is suppressed.
図面の簡単な説明  Brief Description of Drawings
[0006] [図 1]REM時間、 SWS時間、および総睡眠時間を示すグラフである。 [0006] Fig. 1 is a graph showing REM time, SWS time, and total sleep time.
[図 2]化合物 A単独群の、 SWS期間中のパワースペクトラムを示すグラフである。  FIG. 2 is a graph showing the power spectrum of the compound A single group during the SWS period.
[図 3]ドキセピン単独群の、 SWS期間中のパワースペクトラムを示すグラフである。  FIG. 3 is a graph showing the power spectrum of the doxepin single group during the SWS period.
[図 4]化合物 Aとドキセピンの併用群の、 SWS期間中のパワースペクトラムを示すグラ フである。  FIG. 4 is a graph showing the power spectrum during the SWS period for the combination group of Compound A and doxepin.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 本発明で用いられる鎮静性抗うつ薬としては、具体的には、例えばドキセピン、トラ ゾドン、ネファゾドン、ノ ロキセチン、アミトリプチン、マプロチリン、ミアンセリン、フルボ キサミン、トリミプラミン、セチプチリン、デシプラミン、イミプラミン、ミルタザピン (Mirtaz apine、 Org-4420 (s- mirtazapine) )が挙げられる。本発明で用いられる鎮静性抗うつ 薬として、好ましくは、例えば、三環系抗うつ薬 (例、ドキセピン、アミトリプチン、トリミ プラミン、デシブラミン、イミブラミン）が好ましい。当該三環系抗うつ薬としては、式 [化 1] [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]
Figure imgf000004_0001
[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、および硫黄力 選択される 1個以上のへテロ原子を構成原子として有する 7 員複素環を、 Rは、ジメチルァミノ基で置換された C アルキル基、またはジメチルァ
Figure imgf000004_0001
[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.
1 -4  14
ミノ基で置換された C アルキリデン基を、 =は一重結合または二重結合を示す。 ]  In the C alkylidene group substituted with a mino group, = represents a single bond or a double bond. ]
1-4  1-4
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。  Or a tricyclic antidepressant which is a salt thereof is preferred.
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、 Miodo wnik, 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。  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.
[0008] 本発明で用いられる抗ヒスタミン剤としては、具体的には、例えばジフェンヒドラミン 、ドキシラミン、ァザタディン、ブロムフエ二ラミン、セティラジン、クロルフエ二ラミン、ク レマスティン、シプロヘプタディン、ディスロラタディン、デスク口フエ二ラミン、ディメンヒ ドリネート、フエクソフェナディン、ヒドロキシジン、口ラタディン、フェニンダミンが挙げら れる。本発明で用いられる抗ヒスタミン剤として、好ましくは、例えばヒスタミン HI拮抗 薬である。 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.
ここで例示した抗ヒスタミン剤は、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、公知の方法に準じて容易に合成することができる。  The antihistamines exemplified here are known compounds, all of which are commercially available, or can be easily synthesized according to known methods.
これらの鎮静性抗うつ薬および/または抗ヒスタミン剤は、単独で用いてもよぐ 2種 以上を組み合わせて用いてもょ 、。力かる鎮静性抗うつ薬および/または抗ヒスタミ ン剤として好ましくは、三環系抗うつ薬とヒスタミン HI拮抗薬の性質を併せ持つもの である。中でも、ドキセピンが好ましい。  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.
本発明で用いる化合物 Aは、例えば W097Z32871に記載の方法、またはそれに 準じた方法により製造される。  Compound A used in the present invention is produced, for example, by the method described in W097Z32871 or a method analogous thereto.
[0009] 本明細書において、化合物または薬剤は特に記載の無い限り、フリー体もしくは塩 、または無水和物もしくは水和物のいずれであってもよぐラセミ体または光学活性体 のいずれであってもよい。力かる塩としては、薬理学的に許容される塩であれば特に 限定されないが、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸 との塩、塩基性または酸性アミノ酸との塩などがあげられる。無機塩基との塩の好適 な例としては、例えばナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、 マグネシウム塩などのアルカリ土類金属塩、ならびにアルミニウム塩、アンモニゥム塩 などが挙げられる。有機塩基との塩の好適な例としては、例えばトリメチルァミン、トリ ェチルァミン、ピリジン、ピコリン、 2, 6—ルチジン、エタノールァミン、ジエタノールァ ミン、トリエタノーノレアミン、シクロへキシルァミン、ジシクロへキシノレアミン、 N, N，ージ ベンジルエチレンジァミンなどとの塩があげられる。無機酸との塩の好適な例としては 、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。有機酸との 塩の好適な例としては、例えばギ酸、酢酸、トリフルォロ酢酸、フタル酸、フマル酸、 シユウ酸、酒石酸、マレイン酸、クェン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベン ゼンスルホン酸、 p—トルエンスルホン酸などとの塩があげられる。塩基性アミノ酸との 塩の好適な例としては、例えばアルギニン、リジン、オル-チンなどとの塩が挙げられ 、酸性アミノ酸との塩の好適な例としては、例えばァスパラギン酸、グルタミン酸などと の塩があげられる。 [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] 本発明の睡眠障害予防治療剤においては、有効成分のすべてが一製剤中に含ま れていてもよぐまた有効成分のそれぞれまたは一部が別々に製剤化されていてもよ い。すなわち、本発明の睡眠障害予防治療剤は、有効成分である、鎮静性抗うつ薬 および抗ヒスタミン剤からなる群力 選択される 1種以上の薬剤と化合物 Aとを、例え ば（1)公知の製剤学的製造法に準じ、所望により適宜製剤学的に許容され得る賦形 剤等と共に製剤化した単一剤であってもよぐ (2)同時または時差を設けて組み合わ せて使用（併用）するように、それぞれを所望により製剤学的に許容され得る賦形剤 等を用いて製剤化した製剤であってもよく、または（3)それぞれを常法により適宜賦 形剤と共にそれぞれ製剤化したものを組み合わせたセット (キット剤等)であってもよ い。  [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.
本発明の睡眠障害予防治療剤の形態は、特に限定されないが、患者に経口的に 投与しうる剤形 (例えば錠剤、細粒剤、カプセル剤、顆粒剤等)や経皮的に吸収させ ることのできる剤形 (例えばパッチ剤等）が好ましい。中でも錠剤、細粒剤及びカプセ ル剤等が特に好ましい。  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] 力かる本発明製剤は、自体公知の手段 (例えば、 日本薬局方記載の方法等)また はそれに準じて製造され、一般的に使用されている薬理学的に許容される担体が適 宜、適量用いられる。 [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.
本発明の睡眠障害予防治療剤は、哺乳動物 (例えば、ヒト、ネコ、ィヌ、サル等)の 睡眠障害 (不眠)の予防，治療に有効に使用することができる。かかる睡眠障害として は、例えば、  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)内在因性睡眠障害 (例、精神生理性不眠)、外在因性睡眠障害、および概日リズ ム障害 (例、時間帯域変化症候群 (時差ボケ)、交代勤務睡眠障害、不規則型睡眠 覚醒パターン、睡眠相後退症候群、睡眠相前進症候群、非 24時間睡眠覚醒)等の 睡眠異常；  (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)睡眠時随伴症；  (2) Sleep-related complications;
(3)内科または精神科障害 (例、慢性閉塞性肺疾患、アルツハイマー病、パーキンソ ン病、脳血管性痴呆、統合失調症、うつ病、不安神経症）に伴う睡眠障害が挙げられ る。  (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).
なお、本明細書において、睡眠障害 (不眠）は、入眠障害、途中覚醒、早朝覚醒、 およびこれらの組み合わせを含む。  In the present specification, sleep disorder (insomnia) includes sleep deprivation disorder, mid-wake awakening, early morning awakening, and combinations thereof.
また、本発明の睡眠障害予防治療剤を用いることにより、自然な睡眠を誘導し、睡 眠潜時を短くし、深い睡眠を増加させ、睡眠の維持に優れ、および適切な睡眠時間 を獲得できるため、夜間の覚醒が少なくなる。さらに、夜間覚醒が少なくなること、およ び夜間覚醒が起こった場合でも夜間覚醒時に起立した際の転倒が起こりにくくなるこ とから、打撲 ·骨折などの発生を減少させることができる。  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.
また、本発明の睡眠障害予防治療剤は、長期間の投与においても睡眠導入効果 が維持される。  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.
また、本発明の睡眠障害予防治療剤は、投与停止後のリバウンドが抑制されている さらに、鎮静性抗うつ薬および抗ヒスタミン剤カゝらなる群カゝら選択される 1種以上の 薬剤と（S)— N— [2— (1, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8—ィル)ェチル]プロピオンアミドとを組み合わせてなる医薬組成物は、睡眠障害の 他に、季節的憂鬱病、生殖および神経内分泌疾患、老人性痴呆、アルツハイマー病 、老化に伴う各種障害 (例えば、老化防止など)、脳循環障害 (脳卒中など)、頭部外 傷、骨髄損傷、ストレス、てんかん、痙攣、不安、うつ病、パーキンソン病、高血圧、緑 内症、癌、糖尿病、頭痛、夜間頻尿、過敏性腸症候群など]の予防または治療ならび に免疫調節、向知能、精神安定または***調整 (例、避妊）に対しても有効である。 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] なお、化合物 Aは、鎮静性抗うつ薬および Zまたは抗ヒスタミン剤と組み合わせな い単独使用においても、哺乳動物 (例えば、ヒト、ネコ、ィヌ、サル等)の睡眠障害 (不 眠)の予防 ·治療に有効に使用することができる。かかる睡眠障害としては、例えば、 [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,
(1)内在因性睡眠障害 (例、精神生理性不眠)、外在因性睡眠障害、および概日リズ ム障害 (例、時間帯域変化症候群 (時差ボケ)、交代勤務睡眠障害、不規則型睡眠 覚醒パターン、睡眠相後退症候群、睡眠相前進症候群、非 24時間睡眠覚醒)等の 睡眠異常； (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)睡眠時随伴症；  (2) Sleep-related complications;
(3)内科または精神科障害 (例、慢性閉塞性肺疾患、アルツハイマー病、パーキンソ ン病、脳血管性痴呆、統合失調症、うつ病、不安神経症）に伴う睡眠障害が挙げられ る。  (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).
この他、化合物 Aは制吐等に有効に使用することができる。  In addition, Compound A can be used effectively for antiemetics and the like.
[0014] なお、化合物 Aは、かかる睡眠障害 (不眠)の予防'治療において、より質の高い睡 眠を与える目的のために、セロトニン ΠΑアンタゴ-スト（例、 M-100907、 ACP-103、 A PD- 125、 Org- 50081、ミルタザピン（Mirtazapine)、 Org- 4420 (s- mirtazapine)、プル バンセリン（Pruvanserin)、ェプリバンセリン（Eplivanserin)、タエチアピン（Quetiapine) 、クロザピン（Clozapine)、リスペリドン（Risperidone)、セルチンドール（Sertindole)、ォ ランザピン（Olanzapine)、ジプラシドン（Ziprasidone)、ァセナピン（Asenapine)、ォカ ペリドン（Ocaperidone)、ノ リペリドン（Paliperidone)、 R- 167154、イロペリドン（Iloperid one)、ァリピラゾール（Aripiprazole)、デスメチルクロザピン（ACP- 104、 N- desmethylc lozapine) )とも好適に組み合わせて使用することができる。その態様は、本発明と同 様に、例えば、セロトニン ΠΑアンタゴ-ストとを（1)化合物 Aと公知の製剤学的製造 法に準じ、所望により適宜製剤学的に許容され得る賦形剤等と共に製剤化した単一 剤であってもよぐ (2)同時または時差を設けて組み合わせて使用（併用）するように 、それぞれを所望により製剤学的に許容され得る賦形剤等を用いて製剤化した製剤 であってもよぐまたは（3)それぞれを常法により適宜賦形剤と共にそれぞれ製剤化 したものを組み合わせたセット (キット剤等)であってもよ 、。 [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.).
上記で例示したセロトニン ΠΑアンタゴ-ストは、公知の化合物であり、市販品にて 入手可能であるか、または公知の方法に準じて製造することができる。  The serotonin-antagost exemplified above is a known compound, and is commercially available or can be produced according to a known method.
M— 100907は、例えば Medicinal Chemistry Research, 1996, 6 (ppl— 10)に記載の方法、またはそれに準じた方法により製造される。  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は、例えば、国際公開パンフレット WO2001Z66521に記載の方法、 またはそれに準じた方法により製造される。  ACP-103 is produced, for example, by the method described in International Publication Pamphlet WO2001Z66521 or a method analogous thereto.
APD—125は、例えば、国際公開パンフレット WO2005Z12254に記載の方法、 またはそれに準じた方法により製造される。  APD-125 is produced, for example, by the method described in International Publication Pamphlet WO2005Z12254 or a method analogous thereto.
Org— 50081は、例えば、欧州特許公報 EP0373998に記載の方法、またはそれ に準じた方法により製造される。  Org-50081 is produced, for example, by the method described in European Patent Publication EP0373998 or a method analogous thereto.
Org— 4420は、例えば米国特許公報 US4062848に記載の方法、またはそれに 準じた方法により製造される。  Org-4420 is produced, for example, by the method described in US Patent Publication US4062848 or a method analogous thereto.
プルバンセリンは、例えば、 WO2001Z07435〖こ記載の方法、またはそれに準じ た方法により製造される。  Purvanserin is produced by, for example, the method described in WO2001Z07435 or a method analogous thereto.
ェプリバンセリンは、例えば、国際公開パンフレット WO2005Z05410に記載の方 法、またはそれに準じた方法により製造される。  Eplivanserin is produced, for example, by the method described in International Publication Pamphlet WO2005Z05410 or a method analogous thereto.
ァセナピンは、例えば、米国特許公報 US4145434に記載の方法、またはそれに 準じた方法により製造される。  For example, asenapine is produced by the method described in US Pat. No. 4,145,434 or a method analogous thereto.
ォカペリドンは、例えば、欧州特許公開公報 EP453042に記載の方法、またはそ れに準じた方法により製造される。  Ocaperidone is produced, for example, by the method described in European Patent Publication EP453042, or a method analogous thereto.
ノ リペリドンは、例えば、米国特許公報 US5158952に記載の方法、またはそれに 準じた方法により製造される。  Noriperidone is produced, for example, by the method described in US Patent Publication US5158952, or a method analogous thereto.
R— 167154は、例えば、国際公開パンフレット W097Z38991および国際公開 パンフレット W099Z19317に記載の方法、またはそれに準じた方法により製造され る。 イロペリドンは、国際公開パンフレット WO93/09102に記載の方法、またはそれ に準じた方法により製造される。 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.
デスメチルクロザピン (ACP- 104、 N- desmethylclozapine) )は、国際公開パンフレツ ト WO2004Z064753に記載の方法、またはそれに準じた方法により製造される。 本発明の睡眠障害予防治療剤は低毒性であり、安全にヒト等の哺乳動物に経口投 与することができる。本発明の睡眠障害予防治療剤の投与は、上記の睡眠障害 (不 眠)の種類に応じて、就寝前、夜間覚醒時、および Zまたは早朝覚醒時等に行なうこ とができる。なお同様に、化合物 Aを単独で使用する場合も、睡眠障害 (不眠)の種 類に応じて、就寝前、夜間覚醒時、および Zまたは早朝覚醒時等に化合物 Aを含有 する医薬組成物の投与を行なうことができる。  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.
本発明の睡眠障害予防治療剤の投与量は、投与対象、投与ルート、疾患、使用す る有効成分の種類等によって異なるが、睡眠障害の成人 (体重約 60kg)に対し、各 有効成分の投与量として、次の量が 1日に 1〜数回に分けて投与 (好ましくは 1日に 1 回で投与）されればよぐ各成分は同時または 30分〜 3時間の時差を設けて組み合 わせ投与するのがよい。  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.
鎮静性抗うつ薬および抗ヒスタミン剤からなる群カゝら選択される 1種以上の薬剤と化 合物 Aとを組み合わせてなる本発明の睡眠障害予防治療剤を使用した場合、鎮静 性抗うつ薬および抗ヒスタミン剤からなる群カゝら選択される薬剤、およびィ匕合物 Aをそ れぞれ単独で用いる場合に比べ、それぞれ、これらの投与量を減量してもよい。 例えば、鎮静性抗うつ薬および抗ヒスタミン剤カゝらなる群カゝら選択される薬剤の 1種 と化合物 Aとを組み合わせてなる剤の場合、化合物 Aの投与量は、例えば、 1日 1回 投与で、 1回当たり約 0. 05mg〜約 50mg、特に経口投与剤の場合、好ましくは 1回 当たり約 lmg〜約 20mg、また経皮剤の場合、好ましくは 1回当たり約 0. lmg〜約 1 Omgである。  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.
また、鎮静性抗うつ薬および抗ヒスタミン剤力もなる群力 選択される薬剤の 1種の 投与量は、その種類によって適当な量を選択すればよいが、例えば、 1日 1回投与で 、通常、 1回当たり約 0. lmg〜約 3000mg、好ましくは 1回当たり約 5mg〜約 900m gである。 [0017] より具体的な化合物については、ドキセピンの投与量は、例えば、 1日 1回投与で、 通常、 1回当たり約 0. lmg〜約 200mg、好ましくは 1回当たり約 0. 5mg〜約 30mg 、更に好ましくは約 lmg〜約 20mg、特に更に好ましくは 1回当たり約 lmg〜約 10m gである。 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.
本発明の睡眠障害予防治療剤における、鎮静性抗うつ薬および抗ヒスタミン剤から なる群力 選択される薬剤の 1種と化合物 Aとの組み合わせ比率 (投与割合）は、通 常 1： 100〜60： 1 (重量比）、好ましくは 1： 20〜 30： 1 (重量比）、更に好ましくは 1： 1 0〜30： 1 (重量比）、特に好ましくは 1： 10〜20： 1 (重量比）である。  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.
より具体的な化合物については、ドキセピンと化合物 Aとの組み合わせ比率 (投与 割合）は、例えば 1： 50-30： 1 (重量比）、好ましくは 1： 20-10： 1 (重量比）更に好 ましくは 1： 10〜5： 1 (重量比）である。  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).
鎮静性抗うつ薬および抗ヒスタミン剤からなる群カゝら選択される薬剤を 2種以上用い る場合の各投与量は、 1種のみを用いる場合よりも減少させることができる。  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.
更に、本発明の睡眠障害予防治療剤は、その優れた性質を実質的に害さない限 度において、他の活性成分と組み合わせて併用してもよい。該その他の活性成分と 鎮静性抗うつ薬および Zまたは抗ヒスタミン剤とィ匕合物 Aとを自体公知の手段に従つ て混合し、医薬組成物 (例えば錠剤、散剤、顆粒剤、カプセル剤 (ソフトカプセルを含 む)、液剤、パッチ剤、注射剤、坐剤、徐放剤等)として、あるいは別途、製剤化したも のを、本発明の製剤と同様に同時にまたは時間差をおいて同一対象に投与してもよ い。  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.
実施例  Example
[0018] 本発明は、更に以下の試験例および製剤例によって詳しく説明されるが、これらの 例は単なる実施であって、本発明を限定するものではなぐまた本発明の範囲を逸脱 しな 、範囲で変化させてもよ!、。  [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] 製剤例 1  [0019] Formulation Example 1
(1)ドキセピン 8. Og  (1) Doxepin 8. Og
(2)化合物 A 8. Og  (2) Compound A 8. Og
(3)乳糖 60. Og (4)コーンスターチ 35. Og (3) Lactose 60. Og (4) Corn starch 35. Og
(5)ゼラチン 3. Og  (5) Gelatin 3. Og
(6)ステアリン酸マグネシウム 2. Og  (6) Magnesium stearate 2. Og
ドキセピン 8. 0g、ィ匕合物 A8. Og、孚 L糖 60. Og及びコーンスターチ 35. Ogの混合 物を 10重量％ゼラチン水溶液 30ml (ゼラチンとして 3. 0g)を用い、 1mmメッシュの 篩を通して顆粒ィ匕した後、 40°Cで乾燥し再び篩過した。得られた顆粒をステアリン酸 マグネシウム 2. 0gと混合し、圧縮する。得られた中心錠を、蔗糖、二酸化チタン、タ ルク及びアラビアゴムの水懸濁液による糖衣でコーティングする。コーティングが施さ れた錠剤をミツロウで艷出して 1000錠のコート錠を得る。  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.
試験例 1  Test example 1
実験動物として、 12時間明暗サイクル (午前 7時力 午後 7時まで明期）の環境下で 飼育したネコを使用した。ペントバルビタール麻酔下、大脳皮質前頭葉、頭頂葉およ び海馬に脳波記録用電極を、眼窩骨に眼電図用電極を、背側頸部筋肉内に筋電図 記録用ステンレス線電極を各々埋め込んだ。細菌感染を防ぐために抗生物質を投与 した。術後 3〜4日から脳波測定用ケージへの馴化を開始し、馴化 1〜2週間後に脳 波測定を行った。  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.
溶媒および投与薬物をカプセルに充填し、強制経口投与した。投与群は 1群 10匹と して、クロスオーバー試験を行った。  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.
[薬物投与群] [Drug group]
(1)ビヒクル（0.5%メチルセルロース水溶液）  (1) Vehicle (0.5% methylcellulose aqueous solution)
(2)化合物 A (0.1 mg/kg)  (2) Compound A (0.1 mg / kg)
(3)ドキセピン（0.3 mg/kg)  (3) Doxepin (0.3 mg / kg)
(4)併用（化合物 A (0.1 mg/kg) + ドキセピン（0.3 mg/kg))  (4) Concomitant use (compound A (0.1 mg / kg) + doxepin (0.3 mg / kg))
午前 8:30頃からネコに測定用電極を装着させた後、実験ボックスに入れた。投与は 午前 10 : 00前後に行い、投薬後 8時間の睡眠脳波を測定した。  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.
脳波データは NEC三栄社の Synafit2500を用いて取得した。解析はキツセィコムテツ ク社の睡眠解析研究用プログラムである Sleep Sign Ver.2.0を用いた。皮質から誘導 した波形で δ (デルタ)波を、海馬から誘導した波形で 0 (シータ)波を特徴パラメ一 ターとして設定し、このパラメーターより下記の If〜 Then方式で 20秒ごとの解析を行 い、覚醒、徐波睡眠、レム睡眠を自動判定した。これらの自動判定終了後、目視判定 を行い、明らかに睡眠ステージ判定が異なる場合は判定を修正した。 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.
[睡眠脳波の自動判定] [Automatic determination of sleep EEG]
a≤ EMG Integral≤100→ Yes "覚醒，，  a≤ EMG Integral≤100 → Yes "Awakening, ...
I No  I No
20≤デルタ％時間≤100 & 0≤ EMG Integral <b→ Yes "SWS"  20≤Delta% time≤100 & 0≤ EMG Integral <b → Yes "SWS"
i No  i No
25≤シータ％時間≤100 & 0≤ EMG Integral <c→ Yes "REMS"  25≤Theta% time≤100 & 0≤ EMG Integral <c → Yes "REMS"
i No  i No
3≤速波 % Time≤ 100→ Yes "覚醒"  3≤fast wave% Time≤ 100 → Yes "Awakening"
i No  i No
前段階（直前の睡眠判定を反映させる）  Previous stage (reflect the previous sleep judgment)
* a、 b、 cの値は、各個体で適切な数値を定めることとした。 * The values of a, b, and c are determined appropriately for each individual.
化合物 A単独群と、化合物 Aとドキセピンの併用群についての結果を、図 1に示す 。この図から明らかなように、化合物 Aとドキセピンの併用群では化合物 A単独に比 ベ、総徐波睡眠時間及び総睡眠時間がいずれも 30分程度延長し、有意差が認めら れた。  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.
試験例 2  Test example 2
[周波数解析]  [Frequency analysis]
試験例 1において、 SleepSign Ver.2.0 (キツセィ コムテック）を用い、徐波睡眠と判 定されたエポックのみを抽出し FFT解析を行い、各周波数におけるパワースペクトル 値を求めた。  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.
結果を図 2 (図中、♦ビヒクル、口化合物 A)、図 3 (図中、♦ビヒクル、ロドキセピン） The results are shown in Figure 2 (in the figure, ♦ vehicle, oral compound A), Figure 3 (in the figure, ♦ vehicle, rhodoxepin)
、および図 4 (図中、♦化合物 A、口化合物 Aとドキセピンの併用）に示す (それぞれ 投薬後 0〜2hr、 2〜4hr、 4〜6hr)。これらの図から明らかなように、化合物 Aとドキ セピンの併用群では化合物 A単独に比べ、投薬 2時間後あたりから低周波領域 (2H z近傍)のパワースペクトラムの上昇が見られた。この結果から、ィ匕合物 Aとドキセピン の併用群では、睡眠が深くなつて ヽることが分かる。 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.
産業上の利用可能性 Industrial applicability
本発明によれば、自然な睡眠が誘導し、睡眠潜時を短くし、深い睡眠を増加させ、 睡眠の維持に優れ、および適切な睡眠時間を獲得できる睡眠障害の予防'治療剤 が得られる。  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

請求の範囲 The scope of the claims
[1] (S)— N— [2- (1, 6, 7, 8—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8—ィ ル)ェチル]プロピオンアミドと鎮静性抗うつ薬および抗ヒスタミン剤力もなる群力 選 択される 1種以上の薬剤とを組み合わせてなる睡眠障害の予防または治療剤。  [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—テトラヒドロ一 2H—インデノ [5, 4— b]フラン一 8—ィ ル)ェチル]プロピオンアミドとドキセピンとを組み合わせてなる睡眠障害の予防また は治療剤。  [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] 睡眠障害の予防または治療用の医薬組成物の製造のための、（S) -N- [2- (l , 6, 7, 8—テトラヒドロー 2H—インデノ [5, 4—b]フランー8—ィル）ェチル]プロピオ ンアミドの、鎮静性抗うつ薬および抗ヒスタミン剤からなる群カゝら選択される 1種以上 の薬剤との組み合わせにおける使用。  [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] 睡眠障害の予防または治療用の医薬組成物の製造のための、（S) -N- [2- (l , 6, 7, 8—テトラヒドロー 2H—インデノ [5, 4—b]フランー8—ィル）ェチル]プロピオ ンアミドの、ドキセピンとの組み合わせにおける使用。  [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—テトラヒドロ一 2H—インデノ [5, 4—b]フラン一 8—ィ ル)ェチル]プロピオンアミドを、鎮静性抗うつ薬および抗ヒスタミン剤力もなる群から 選択される 1種以上の薬剤との組み合わせにおいて、対象に投与することを含む、睡 眠障害の予防または治療方法。  [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—テトラヒドロ一 2H—インデノ [5, 4—b]フラン一 8—ィ ル)ェチル]プロピオンアミドを、ドキセピンとの組み合わせにおいて、対象に投与す ることを含む、睡眠障害の予防または治療方法。  [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.
PCT/JP2006/318503 2005-09-20 2006-09-19 Prophylactic/therapeutic agent for sleep disorder WO2007034778A1 (en)

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