JP2014024800A - Hypnosis or sedation potentiator, and pharmaceuticals containing hypnosis or sedation potentiator - Google Patents

Abstract

A novel sleep action enhancer or sedation enhancer is provided.
A sleep action or sedation enhancer comprising a compound represented by formula (I) as an active ingredient.
[Selection] Figure 1

Description

  The present invention relates to a novel sleep action or sedation enhancer, a preparation containing the sleep action or sedation enhancer, and a method for enhancing the sleep action or sedation.

In modern society, the number of people who suffer from insomnia due to stress and 24-hour lifestyle tends to increase. According to a report by the Ministry of Health, Labor and Welfare, which started in 2003, the “Sleep Guidelines Review Committee for Health Promotion” accounted for 21.4% of the people who were in trouble with insomnia, a serious problem. Therefore, the number of people who want a comfortable sleep will increase more than ever, and in parallel there will be an increasing demand for drugs that improve insomnia. The currently used hypnotics are mainly benzodiazepines, non-benzodiazepines, antihistamines, barbiturates, and the like (see Patent Document 1).
Japanese translation of PCT publication 2007-510733

  However, many of the above-mentioned hypnotics are accompanied by side effects such as headache after awakening, discomfort, and physical dependence when administered at a dose for obtaining sufficient sleep action, so it is not always possible to obtain natural sleep. Absent. Moreover, when the dosage of the sleeping pill is decreased in order to suppress the side effects, there is a problem that a sufficient sleeping action as a main effect cannot be obtained.

  Therefore, it is an important matter to develop a therapeutic agent capable of obtaining a more comfortable sleep while suppressing side effects caused by the sleeping pill.

  In order to solve the above-mentioned problems, the present invention mainly aims to provide a novel sleep action and sedation enhancer.

  The present inventors have studied active ingredients to achieve the above object, and found that safranal, an essential oil component contained in saffron, has an effect of enhancing sleep action and sedation, and based on such knowledge The present invention has been completed.

  Item 1. Formula (I):

The sleep action or sedation action enhancer which contains the compound represented by these as an active ingredient.

  Item 1-1. Item 2. The sleep action or sedation enhancer according to Item 1, wherein the content ratio of the compound represented by formula (I) is 0.01 to 100% by weight.

  Item 2. Formula (I):

A preparation comprising a combination of the compound represented by formula (1) and an active ingredient having a sleep action or a sedative action.

  Item 2-1. The content of the active ingredient having a sleep action or a sedative action is the general formula (I):

The sleep improving agent of claim | item 2 which is 1-100 weight part with respect to 100 weight part of compounds represented by these.

  Item 3. Formula (I):

Item 3. The preparation according to Item 2, having a form in which a compound represented by the above and an active ingredient having a sleep action or a sedative action are administered separately.

  Item 3-1. Formula (I):

Item 4. The preparation according to Item 3, which has a form in which a sleeping action or sedative action enhancer comprising a compound represented by formula (I) as an active ingredient and a composition containing an active ingredient having a sleeping action or sedation are administered separately.

  Item 3-2. General formula (I) in a sleep or sedation enhancer:

Item 3. The preparation according to Item 3-1, wherein the content of the compound represented by the formula is 0.01 to 100% by weight.

  Item 3-3. Item 3. The preparation according to Item 3-1, wherein the content of the active ingredient in the composition containing the active ingredient having a sleep action or a sedative action is 0.1 to 100% by weight.

  Item 4. Formula (I):

The formulation of claim | item 2 containing the compound represented by these, and the active ingredient which has a sleep action or a sedative action.

  Claim | item 4-1. Formula (I):

Item 5. The preparation according to Item 4, wherein the content ratio of the compound represented by is 0.1 to 50% by weight in the preparation.

  Item 4-2. Item 5. The preparation according to Item 4, wherein the content of the active ingredient having a sleep action or a sedative action is 0.1 to 50% by weight in the preparation.

  Item 4-3. Item 5. The preparation according to Item 4, wherein the content of the active ingredient having a sleep action or a sedative action is 1 to 100 parts by weight relative to 100 parts by weight of the compound represented by the general formula (I).

  Item 5. Formula (I):

A method for enhancing the sleep action or sedation action by an active ingredient having a sleep action or sedation action, which comprises the step of administering a composition comprising the compound represented by formula (except for medical practice for humans).

  Item 5-1. General formula (I) in the composition:

Item 6. The method according to Item 5, wherein the content ratio of the compound represented by the formula is 0.01 to 100% by weight.

  Item 5-2. Formula (I):

The method of claim | item 5 whose dosage of the compound represented by these is 1-10000 mg / kg / day.

  Claim | item 5-3. Item 6. The method according to Item 5, wherein a composition containing a compound represented by the general formula (I) is administered to a subject to be administered a preparation containing an active ingredient having a sleep action or a sedative action.

  Item 5-4. Item 6. The method according to Item 5, wherein the dose of the active ingredient having a sleep action or a sedative action is 0.1 to 100 mg / kg / day.

  According to the sleep action enhancing agent of the present invention, sleep can be promoted and natural and comfortable sleep can be obtained by using together with an active ingredient having a sleep action. In particular, the sleep action enhancer of the present invention can significantly extend non-REM sleep in combination with an active ingredient having a sleep action.

  Moreover, the sleep action enhancer of the present invention can sufficiently enhance the sleep action at least when the amount of the active ingredient in the sleep medicine is administered in combination with the active ingredient having the action. Therefore, side effects caused by excessive intake of sleeping pills can be suppressed.

  Furthermore, the compound represented by the general formula (I) contained in the sleep action enhancer of the present invention has an excellent sedative action enhancing effect in addition to the above excellent sleep action enhancing effect. . Therefore, it is also useful as a sedative effect enhancer that enhances the sedative effect when used in combination with an active ingredient having a sedative effect.

2 is a typical polygraph record of mice treated with pentobarbital (PENT mice) after administration of Vehicle (FIG. 1A) or safranal 360 mg / kg (FIG. 1B) in Test Example 1 and corresponding hypnograms (sleep progress diagram). It is a graph which shows each sleep latency when pre-administering Vehicle, safranal 90, 180, and 360 mg / kg, diazepam 3 mg / kg, and pentobarbital 20 mg / kg in Test Example 1. Non-REM sleep amount (upper figure) and time course of wakefulness when pre-administering Vehicle, safranal 90, 180, and 360 mg / kg, diazepam 3 mg / kg and pentobarbital 20 mg / kg in Test Example 1 It is a graph which shows a change (below figure). It is a graph which shows the cumulative amount of non-REM sleep for 3 hours after pre-administering Vehicle, safranal 90, 180, and 360 mg / kg, diazepam 3 mg / kg, and pentobarbital 20 mg / kg in Test Example 1. It is a graph which shows the frequency | count of appearance of the non-REM sleep of 3 hours after administering pre-administration of Vehicle, safranal 90, 180, and 360 mg / kg, diazepam 3 mg / kg, and pentobarbital 20 mg / kg in the test example 1. It is a graph which shows the average duration of 3 hours after pre-administering Vehicle, safranal 90, 180, and 360 mg / kg, diazepam 3 mg / kg, and administering pentobarbital 20 mg / kg in Test Example 1. Vehicle, safranal 90, 180, and 360 mg / kg and diazepam 3 mg / kg in Test Example 1 were pre-administered, and the number of non-REM sleep episodes (left figure) relative to the time after administration of pentobarbital 20 mg / kg, and the time after administration It is a graph which shows the number of awakening episodes (right figure). Vehicle, safranal 90, 180, and 360 mg / kg and diazepam 3 mg / kg in Test Example 1 were pre-administered, and the number of stage transitions from awake to non-rem sleep after administration of pentobarbital 20 mg / kg (Left figure) and the number of stage transitions from non-REM sleep to REM sleep and from REM sleep to non-REM sleep (right figure) after administration. It is a graph which shows the electroencephalogram output density with respect to the frequency band of the electroencephalogram after pre-administering Vehicle, safranal 360 mg / kg, diazepam 3 mg / kg, and pentobarbital 20 mg / kg in Test Example 1. FIG. 4 is a photomicrograph of the appearance of c-Fos in the ventral lateral preoptic area (VLPO) and nodular papillary nucleus (TMN) of PENT mice administered with Vehicle, Safranal 90, 180, 360 mg / kg in Test Example 2. FIG. FIG. 3A is a photomicrograph of the appearance of c-Fos of VLPO in the Vehicle group, and FIG. 3E is an enlarged photo of FIG. 3A. FIG. 3B is a photomicrograph of the appearance of c-Fos of VLPO in the group administered with safranal 360 mg / kg, and FIG. 3F is an enlarged photo of FIG. 3B. FIG. 3C is a photomicrograph of the appearance of C-Fos of TMN in the Vehicle group, and FIG. 3G is an enlarged photo of FIG. 3C. FIG. 3D is a photomicrograph of TMN c-Fos appearance in the group administered with safranal 360 mg / kg, and FIG. 3H is an enlarged photo of FIG. 3D. 3 is a graph showing the number of c-Fos occurrences of VLPO in PENT mice administered with Vehicle, Safranal 90, 180, 360 mg / kg, and the lower right diagram of FIG. 3 shows Vehicle, Safranal 90, It is a graph which shows the c-Fos appearance number of TMN of the PENT mouse | mouth administered 180, 360 mg / kg.

<Sleep or sedation enhancer>
The sleep action or sedation action enhancer of the present invention has the general formula (I):

The compound represented by these is included as an active ingredient.

  The compound represented by the general formula (I) is known as safranal and can be obtained by the following general production method. In addition, safranal may be a commercially available product.

  As a manufacturing method of the compound represented by the said general formula (I), it can prepare by, for example, extracting and isolating a plant, more specifically, a saffron or gardenia (Yamakiko) as a raw material.

  It can also be obtained by hydrolyzing picrocrocin contained in saffron.

  Saffron used as a raw material can be obtained, for example, as saffron for medicinal or edible plants cultivated in Takeda City, Oita Prefecture.

  When saffronal is isolated and prepared from saffron, plant saffron (Crocus sativus L) can be used as it is as saffron, but plant saffron (Crocus sativus L) pistil is collected and dried. It is preferable to use the same. The safranal can be prepared through a process of extracting and fractionating the saffron pistil with a solvent containing an organic solvent.

  More specifically, dry saffron (saffron pistil) is refined, extracted with an organic solvent at room temperature for about 1 to 5 days, and then filtered to concentrate the filtrate. Safranal can be obtained by separating by combining various column chromatography. Here, examples of the organic solvent include methanol, ethanol, butanol, acetone, and ethyl acetate. Preferred organic solvents are methanol, ethanol, butanol and the like. Further, extraction with water, a mixed solution of water and these organic solvents, or the like is also possible.

  Examples of column chromatography include open column chromatograph, high performance liquid chromatograph (HPLC), preparative recycle HPLC, etc., and various column chromatograph carriers such as phase silica gel, reverse phase silica gel (ODS). ), Gel filtration (Sephadex), ion exchange resin (Diaion HP-20), and the like. Preferred column chromatography combinations include ion exchange resin (Diaion HP-20), normal phase silica gel, reverse phase silica gel (ODS), gel filtration (Sephadex, GS), etc. for open column chromatograph, preparative recycling Examples of HPLC include gel filtration (Sephadex, GS), and HPLC includes reverse phase silica gel (ODS).

  In addition, the structural isomer comprehensively contained in the said general formula (I) is also contained in the compound shown by the said general formula (I) used as an active ingredient of a sleep action or a sedative action enhancer.

  The sleep action or sedation action enhancer of the present invention may be composed of only the compound represented by the general formula (I), but depending on the form of use, a filler, a bulking agent, and a binder that are usually used. Carriers or additives such as moisturizers, disintegrants, surface active agents, and lubricants may be used. These carriers or additives can be appropriately selected.

  In the sleep action or sedation action enhancer of the present invention, the content ratio of the compound represented by the general formula (I) includes the use form of the sleep action or sedation action enhancer, the degree of expected effect, the user As an example, the compound represented by the general formula (I) is about 0.01 to 100% by weight, preferably about 100 to 100% by weight, preferably based on the total weight of the sleep action or sedation enhancer The ratio which becomes about 0.1 to 10 weight% is mentioned.

  The sleep action or sedation action enhancer of the present invention can be used, for example, as a pharmaceutical application. Further, the administration form / form of the sleep action or sedation action enhancer may be either oral administration or parenteral administration. Examples of the orally administered agent include solid agents such as powders, granules, capsules, tablets and chewable agents; liquid agents such as solutions and syrups; and parenteral agents include injections and sprays. Is mentioned. A preferred dosage form is oral administration such as tablets and capsules.

  In molding into a tablet form, various carriers conventionally known in this field can be widely used as carriers. Examples thereof include excipients such as lactose, glucose, sucrose, mannitol, sodium chloride, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch Liquid, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate Disintegrating agents such as stearic acid monoglyceride, starch, lactose, sodium alginate; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium base, lauryl sulfate Absorption promoters such as thorium; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol Etc. can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets, and multilayer tablets.

  When forming into the form of a pill, those conventionally known in this field can be widely used as the carrier. Examples thereof include excipients such as lactose, glucose, sucrose, mannitol, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, etc., binders such as starch, sodium alginate, gum arabic powder, tragacanth powder, ethanol, laminaran In addition, disintegrants such as agar can be used.

  When forming into powder form, excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl cellulose and the like It can be produced using a binder, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosages because they are easy to administer. When producing tablets and capsules, a solid carrier is used.

  Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.

  When prepared as a syrup, water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, preservatives such as alkyl parahydroxybenzoate, strawberry -Flavors such as flavor and peppermint can be used.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.

  The dosage of the sleep action or sedation enhancer is appropriately selected depending on the usage, administration form, patient age, sex and other conditions, the degree of disease, etc., but is generally represented by the general formula (I), which is an active ingredient It is administered so that the amount of the compound is about 1 to 10,000 mg / kg / day, preferably about 10 to 1000 mg / kg / day, more preferably about 100 to 1000 mg / kg / day. Moreover, the administration time is usually from immediately before sleeping to 6 hours, more preferably from immediately before to 5 hours.

  The sleep action or sedative action enhancer of the present invention is administered to enhance the sleep action or sedative action by an active ingredient having a sleep action or sedation action.

  In addition, the sleep action or sedation action enhancer may be administered before, during, or after administration of a preparation containing an active ingredient having the sleep action or sedation action described below.

  When the sleep action or sedative action enhancer is administered first, after administration of the sleep action or sedation action enhancer, it is usually immediately after about 3 hours, preferably immediately after about 1.5 hours. Alternatively, it is preferable to administer a preparation containing an active ingredient having a sedative action.

  In addition, when administering a preparation containing an active ingredient having a sleep action or a sedative action first, after administration of the preparation, usually immediately after about 3 hours, preferably immediately after about 1.5 hours, It is preferable to administer a sleep action or sedation enhancer.

<Method of enhancing sleep action or sedation action>
The method for enhancing the sleep action or sedation action of the present invention relates to a method for enhancing the sleep action or sedation action by an active ingredient having a sleep action or sedation action, and has the general formula (I):

Administering a composition comprising a compound represented by:

  As the compound represented by the general formula (I), those mentioned in the above <Sleep or sedation enhancer> can be used.

  The content ratio of the compound represented by the general formula (I) in the composition varies depending on the use form, the degree of expected effect, the gender and age of the user, etc., but as an example, the total weight of the composition In contrast, the proportion of the compound represented by the general formula (I) is about 0.01 to 100% by weight, preferably about 0.1 to 10% by weight.

  As a composition containing the compound shown by general formula (I), forms, such as food-drinks, may be sufficient, for example.

  Examples of the food and drink include the compound itself represented by the general formula (I), or a preparation prepared by adding the above diluent or excipient to the compound represented by the general formula (I) (for example, powder, (Eg, granules, tablets, capsules, liquids, drinks, etc.), and the like. For example, supplements can be mentioned, and the compounds represented by the above general formula (I) can be blended with general foods and drinks. Functional foods (including foods for specific health use and foods for specified health use with conditions) can be listed as examples. These functional foods contain the compound represented by the above general formula (I) and are characterized by enhancing the sleep action or sedation action by an active ingredient having a sleep action or sedation action. In addition, a food or drink with a display indicating that it is used to obtain sleep improvement or sedation is included.

  The target food and drink is not particularly limited, but ice confectionery such as ice cream, ice milk, lacto ice, sherbet, ice confectionery; milk drink, lactic acid bacteria drink, soft drink (including fruit juice), carbonated drink Beverages such as fruit juice drinks, vegetable drinks, vegetable / fruit drinks, sports drinks and powdered drinks; alcoholic drinks such as liqueurs; tea drinks such as coffee drinks and tea drinks; soups such as consomme soup and potage soup; custard Pudding such as pudding, milk pudding, pudding with fruit juice; desserts such as jelly, bavaroa and yogurt; gums such as chewing gum and bubble gum (plate gum, sugar-coated grain gum); coated chocolate such as marble chocolate, Flavors such as strawberry chocolate, blueberry chocolate and melon chocolate Chocolate such as added chocolate; hard candy (including bonbon, butterball, marble, etc.), soft candy (including caramel, nougat, gummy candy, marshmallow, etc.), drop, toffee and other caramel; hard biscuits, cookies Baked confectionery such as oysters and rice crackers; fruit wine such as red wine; and other processed foods and drinks such as various side dishes.

  The dose of the compound represented by the general formula (I), which is the active ingredient of the composition, is administered in the same amount as the dose mentioned in the above <Sleep action or sedation enhancer>. The administration time is usually 1 to 6 hours before going to bed, more preferably 2 to 5 hours.

  Administration of the composition containing the compound represented by the general formula (I) may be performed before, during or after administration of a preparation containing an active ingredient having a sleeping action or sedative action described below. As for the administration time, the administration time mentioned in the above <Sleep or sedation enhancer> can be applied.

  The dosage of the preparation containing the active ingredient having the sleep action or sedative action is appropriately selected depending on the usage, administration form, patient age, gender and other conditions, the degree of disease, etc. The amount of the active ingredient is about 0.1 to 100 mg / kg / day, preferably about 0.5 to 50 mg / kg / day.

  Since the administration of the composition containing the compound represented by the general formula (I) can enhance the sleep action or sedation action by the active ingredient having a sleep action or sedation action, insomnia, hypersomnia, sleep phase It is useful for patients having sleep disorders such as regression syndrome and postmenopausal insomnia, and patients having anxiety such as panic disorder, anxiety disorder, and stress disorder (PTSD, acute stress disorder).

<Formulation>
The preparation of the present invention is characterized by combining the compound represented by the general formula (I) with an active ingredient having a sleep action or a sedative action. The form of the preparation may be a form in which the compound represented by the general formula (I) and an active ingredient having a sleep action or a sedative action are administered separately (hereinafter also referred to as preparation A), The compound may contain a compound represented by the general formula (I) and an active ingredient having a sleep action or a sedative action (hereinafter also referred to as formulation B).

  The preparation of the present invention is used as a sleep improving agent when the compound represented by the general formula (I) and an active ingredient having a sleep action are combined, and the general formula (I) Is used as a sedative agent in combination with an active ingredient having a sedative action.

  Here, “sleep improvement agent” is used to induce a good sleep state by inducing a good sleep by improving sleepiness when waking up, smoothing sleep, reducing arousal during sleep, etc. Is.

  A “sedative” is used to relax or improve sleep by sedating the spirit of a person or animal.

<Formulation A>
Formulation A has a form which administers separately the compound represented by the said general formula (I), and the active ingredient which has a sleep action or a sedative action.

  Examples of the compound represented by the general formula (I) include the same compounds as those represented by the general formula (I) included in the above-mentioned <sleeping action or sedation enhancing agent>.

Active ingredients having sleep or sedation include GABA _A receptor, α-2 adrenergic receptor, melatonin receptor, histamine receptor, acetylcholine receptor, GABA _B receptor / GHB receptor, orexin receptor, and Ingredients that act on receptors such as N-methyl-D-aspartate (NMDA) receptors.

Ingredients that act on the GABA _A receptor include amobarbital, aprobarbital, allobarbital, etororubinol, etalobarbital, cyclobarbital, secbutabarbital, secobarbital, tarbutal, thiamylal, thiopental, barbital, vinylbital, Bimbarbital, phenylethylmalonamide, phenobarbital, butabarbital, butarbital, butobarbital, proxybarbital, primidone, hexobarbital, heptabarbital, pentobarbital, metalbital, methylphenobarbital, methohexital, mehobarbital, reposal and their Barbituric acid compounds such as salts and barbiturates
Estazolam, oxazepam, oxazolam, camazepam, quazepam, clonazepam, clobazam, chlorazepate, chlordiazepoxide, ketazolam, sinorazepam, tetrazepam, temazepam, demethyldiazepam, delorazepam, dexazepamazepam, doxefazepam Benzodiazepines, such as fludiazepam, fltoprazepam, flunitrazepam, flurazepam, bromazepam, brotizolam, midazolam, medazepam, methyldiazepinone, methylnitrazepam, ethyl loflazepate, loprazolam, lorazepam, and lormetazepam;
Thienodiazepines such as etizolam, brotizolam, clothiazepam;
Dialkylphenols such as fospropofol, propofol and thymol;
Indiplon, eszopiclone, osinapron, salpidem, zaleplon, zolpidem tartrate, sprocron, sulcron, zopiclone, zolpidem, catopidem, pagocron, padinaclone, triazolopyrazine (CL-218872), (R) -5α-[(1R) -5α- [ -2- (p-tolylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-1α-yl] -4,5-dihydro-2 (3H) -furanone (ROD-188), 6,7-dimethyl- 2,4-di-1-pyrrolidinyl-7H-pyrrolo [2,3-D] pyridine hydrochloride (U-898, 43A),
11-chloro-5- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -2,3-dihydrodiimidazole [1,5-a: 1 ′, 2′-c] quinazoline (U-90042), 6-benzyl-3- (5-methoxy-1,3,4-oxadiazol-2-yl) -5,6,7,8-tetrahydro-1,6-naphthyridine-2 ( Non-benzodiazepines such as 1H) -one (SX-3228);
Piperidine screw drugs such as glutethimide, metiprilone, pyrityldione, piperidione;
Quinazolinones such as afroqualone, chloroqualone, diproqualone, ethaquaron, mebroqualone, mecrocarone, metacarone, methylmetacarone;
Iminostilbene drugs such as oxcarbazepine, opipramol, carbamazepine, eslicarbazepine;
Acebrocol, allopregnanolone, alphadrone, alphaxalone, ertanolone, ganazolone, hydroxydione, minaxolone, (2β, 3α, 5β) -21-chloro-3-hydroxy-2-morpholin-4-ylpregnane-20- Neurostimulators or steroids such as ON (Org 20599), 3α-hydroxy-2β- (2,2-dimethylmorpholino) -5α-pregna-11,20-dione (Org 21465), tetrahydrodeoxycorticosterone Can be mentioned.

  Examples of components that act on the α-2 adrenergic receptor include α- such as 4- (1-naphthalen-1-ylethyl) -1H-imidazole (4-NEMD), clonidine, dexmedetomidine, lofexidine, medetomidine, romifidine, and xylazine. An adrenergic agonist is mentioned.

  Ingredients that act on the histamine receptor or acetylcholine receptor include amitriptyline, diphenhydramine hydrochloride, cyproheptadine hydrochloride, promethazine hydrochloride, bromodiphenhydramine erzasonane hydrochloride, eltoprazine, orphenadrine, carbinoxamine, dimenhydrinate, diphenhydramine, scopolamine, doxylamine, doxepamine , Antihistamines and anticholinergic agents such as trazodone, niaprazine, nefazodone, hydroxyzine, pyrilamine, phenyltoloxamine, propiomazine, perillamine, chlorpheniramine maleate, mianserin, mirtazapine and the like.

Components that act on GABA _B receptor / GHB receptor include 1,4-butanediol, 4-acetoxybutanoic acid, aminooxybutyric acid (GABOB), γ-hydroxybutyric acid, γ-butyrolactone, γ-valerolactone, etc. Can be mentioned.

  The components that act on the orexin receptor include almorexant, suvorexant, 1- (2-methylbenzoxazol-6-yl) -3- (1,5-naphthyridin-4-yl) urea (SB-334,867). ), N- (6,8-difluoro-2-methyl-4-quinolinyl) -N ′-[4- (dimethylamino) phenyl] urea (SB-408,124), N-([(2S) -1 -([5- (4-Fluorophenyl) -2-methyl-4-thiazolyl] carbonyl) -2-piperidinyl] methyl) -4-benzofurancarboxamide (SB-649,868), (2S) -1- (3 , 4-Dihydro-6,7-dimethoxy-2 (1H) -isoquinolinyl) -3,3-dimethyl-2-[(4-pyridinylmethyl) amino] -1-butanone hydrochloride (TCS-OX2-2) ) Orexin receptor antagonists, such as and the like.

  Specific examples of the NMDA receptor antagonist include, for example, acamprosate, amantadine, carisoprodol, ketamine, ketobemidone, dizocilpine, dextranolphan, levalorphan, dextropropoxyphene, dextromethorphan, dextrorphan, Examples include tramadol, haloperidol, ferbamate, pethidine meperidine, milnacipran, meprobamate, methadone, memantine, lacosamide, levomethorphan, levororphanol and the like.

  In addition to the above components, for example, acetylglycinamide chloral hydrate, chloral hydrate, chloraldol, dichlorar phenazone, paraaldehyde, petrichloral, trichloroethanol, urethane, ethochlorbinol, ethinamate, hexapropimate, methyl pentyl Nord, carbamate, meprobamate, carisoprodol, cibamate, metocarbamol, procymate, 2-methyl-2-butanol, acecarbromar, acetophenone, apronal, bromvalerylurea, carbomar, chloralose, chromethiazole, embutramide, etomidate, Eboxine, phenadiazole, gaboxadol, lorecresol, mefenoxaline, sulfonemethane, trichloroethanol, triclophos, sey Ukanokosou, valnoctamide include active ingredients, such as herbal medicines showing the sleep promoting effects.

  These active ingredients may be used individually by 1 type, and may mix and use 2 or more types.

  In the preparation (A), the content ratio of the active ingredient having a sleeping action or sedative action varies depending on the use form, the expected degree of effect, the sex and age of the user, etc., but as an example, the preparation (A The active ingredient having a sleep action or sedative action is about 0.01 to 100% by weight, preferably about 0.1 to 10% by weight, based on the total weight of

  The compounding amount of the active ingredient having the sleep action or sedative action varies depending on the type and use form of the active ingredient, but is preferably preferably 100 parts by weight of the compound represented by the general formula (I). It is prepared to be about 1 to 100 parts by weight, more preferably about 2 to 50 parts by weight. By setting the content of the hypnotic drug to 1 part by weight or more, an effect that the sleep improvement or sedation effect by the sleep action or sedation enhancer is sufficiently obtained can be obtained. Moreover, the effect that the side effect by the active ingredient which has a sleep action or a sedative action can be reduced by setting content of a sleeping pill to 100 weight part or less is acquired.

  The form of the composition (sleeping or sedative enhancer) containing the compound represented by formula (I) as an active ingredient is any of the forms mentioned in the above <Sleep or sedative enhancer>. May be. Moreover, as a form containing the active ingredient which has a sleep action or a sedative action, according to a use form, a filler, a bulking agent, a binder, a moistening agent, a disintegrating agent, a surface active agent, a lubricant agent are used normally Carriers or additions such as may be used. These carriers or additives can be appropriately selected, and those similar to those mentioned above can be used.

  The administration form / dosage form of the active ingredient having the sleep action or sedation action may be either oral administration or parenteral administration, and these have any of the forms mentioned above. Also good.

  The dosage of the compound represented by the general formula (I) in the preparation is appropriately selected depending on the usage, administration form, patient age, sex and other conditions, disease severity, etc. The dose can be the same as the dose of the compound represented by formula (I). Moreover, the administration time of the above-mentioned <sleep action or sedation action enhancer> can be applied as the administration time. As the dose of the preparation containing an active ingredient having a sleep action or sedation action, the amount mentioned in the above <Method for enhancing sleep action or sedation action> can be applied.

  The order of administration of the compound represented by the general formula (I) and the active ingredient having a sleep action or sedative action is not particularly limited, and the compound represented by the general formula (I) is administered first. However, the active ingredient having a sleep action or sedative action may be administered first, and the compound represented by the general formula (I) and the active ingredient having a sleep action or sedative action may be administered simultaneously. Also good.

  Examples of the administration time include the same time as the above-mentioned <Sleep or sedation enhancer>.

<Formulation B>
Formulation B has a form containing the compound represented by general formula (I) and the active ingredient which has a sleep action or a sedative action.

  Examples of the compound represented by the general formula (I) include the same compounds as those represented by the general formula (I) included in the above-mentioned <sleeping action or sedation enhancing agent>.

  In addition, as specific examples of the active ingredient having a sleep action or a sedative action, those mentioned in the above <Formulation A> can be used.

  As content of the active ingredient which has the said sleep action or sedative action, the amount similar to the compounding quantity of the active ingredient which has the said sleep action or sedative action in said <formulation A> is mentioned.

  The content of the compound represented by the general formula (I) in the preparation B is preferably about 0.1 to 50% by weight, more preferably about 0.1 to 30% by weight. Moreover, as a content rate of the active ingredient which has a sleep action or a sedative action, about 0.1 to 50 weight% is preferable and about 0.1 to 30 weight% is more preferable.

  As the form of the preparation B, a diluent or excipient such as a filler, a bulking agent, a binder, a moistening agent, a disintegrating agent, a surface active agent, or a lubricant, which are usually used, is used depending on the form of use. May be. These diluents or excipients can be appropriately selected, and those similar to those mentioned above can be used. In addition, the administration form / dosage form of the preparation B may be either oral administration or parenteral administration, and these forms can be the same as those mentioned above.

  Examples of the doses of the compound represented by the general formula (I) in the preparation B and the active ingredient having the sleep action or sedative action include the <sleep action or sedation enhancer>, and <sleep action or The amount mentioned in the method for enhancing the sedative action> can be applied.

  EXAMPLES Hereinafter, although an Example etc. are given and this invention is demonstrated in detail, this invention is not limited to these.

1. Experimental animals 11-12 week old C57BL / 6J mice were used for the experiments. The mouse has a temperature of 22 ± 0.5 ° C., a humidity of 60 ± 2%, a light / dark cycle of 12 hours (light period time 7:00 to 19:00, illuminance 100 lux), and an environment in which samples and water can be freely ingested Raised.

2. The sample safnal solution was manufactured by Sigma-Aldrich and diluted with paraffin oil.

3. Electroencephalogram / myoelectric potential measurement electrode placement surgery An electrode for electroencephalogram / myoelectric potential measurement was implanted in a mouse under 5% chloral hydrate (360 mg / kg, ip) anesthesia. To measure electroencephalogram (EEG), according to the brain map of Franklin & Paxinos (1997), the cerebrum at a position of 1.5 mm to the right and 1 mm to the front from each of the cross stitch (Bregma) and human character stitch (Lambda) A stainless steel screw with a diameter of 1 mm was embedded up to the cortex. In order to measure myoelectric potential (EMG), a silver wire insulated by Teflon (registered trademark) processing was exposed only at the tip, and one wire was inserted into each of the left and right trapezius muscles. All electrodes were connected to microconnectors and fixed to the mouse skull with dental cement. After a 10-day recovery period from surgery, the mice were transferred to individual recording cages and connected to cables. Polygraph recording started 2 hours after connecting to the cable.

  In order to effectively observe the sleep effect of the sample, the test was performed in the dark period when the wakefulness time of the mouse was long. The electroencephalogram and myoelectric potential were recorded for 24 hours from the time 19:00 of the dark period start. The electroencephalogram and myoelectric potential were recorded after A / D conversion at a sampling rate of 128 Hz after processing an amplification filter (EEG: 0.5 to 30 Hz, EMG: 20 to 200 Hz). The electroencephalogram analysis uses the software SleepSign to set the data for 4 seconds to 1 epoch, and automatically determines whether each epoch is awake, non-REM sleep, or REM sleep according to standard criteria, and then visually confirms and corrects if necessary did.

<Test Example 1>
Safranal was adjusted immediately before use and was orally administered into the stomach of 6 mice each at a dose of 90, 180, 360 mg / kg at 20:00 (safranal administration group). Diazepam was diluted in physiological saline and administered into the stomach of 5 mice at a dose of 3 mg / kg (diazepam administration group). In the Vehicle group, physiological saline was administered into the mouse stomach.

  Pentobarbital was dissolved in physiological saline and administered into the abdominal cavity of the mice in each administration group at a dose of 20 mg / kg that did not reach sleep at 21:00.

Results and Discussion FIG. 1 shows a typical polygraph record of mice treated with pentobarbital (PENT mice) after administration of Vehicle or safranal 360 mg / kg and the corresponding hypnogram (sleep diagram). FIG. 1A is a typical polygraph record of a PENT mouse after administration of Vehicle and a corresponding hypnogram, and FIG. 1B is a typical polygraph record of a PENT mouse after administration of safranal 360 mg / kg. Hypnogram to do.

  In the Vehicle group, it became clear from FIG. 1A that the awakening time is longer than the sleeping time from 21:00 to 10:00. On the other hand, it became clear from FIG. 1B that the safranal administration group began to sleep in a short time and the sleep time was longer than that of the subject group. In addition, since it was longer than the sleep time after the safranal administration until the pentobarbital treatment, it was revealed that the sleep action is enhanced by the combined use of safranal and penbarbital. Similar changes were observed in mice administered with safranal 180 mg / kg.

  In Test Example 1, the sleep latencies of the vehicle group, the safranal administration group, and the diazepam administration group were measured. FIG. 1C shows sleep latencies of the vehicle group, the safranal administration group, and the diazepam administration group. In FIG. 1C, “Veh” indicates a vehicle group, “Saf” indicates a safranal administration group, and “DZ” indicates a diazepam administration group (hereinafter, “Veh”, “Saf”, and “DZ”). Means the same). It should be noted that the sleep onset latency was defined as the time from the administration of vehicle or safranal to the first appearance of non-REM sleep that lasted for 20 seconds or more. * Indicates p <0.05 vs. Vehicle group, ** is p <0.01 vs. The vehicle group is represented (hereinafter the same) (hereinafter, “*” and “**” have the same meaning).

From FIG. 1C, the safranal administration group significantly shortened the sleep latency to non-REM sleep. In the vehicle group, the sleep onset latency was 3.47 minutes, whereas in mice administered with safranal 180 mg / kg, 360 mg / kg and diazepam 3 mg / kg, respectively, significantly increased at 1.61, 1.86 and 1.04 minutes, respectively. Decreased (F _(4.28) = 3.808, P <0.05). However, even when safranal or diazepam was administered to PENT mice, no change was observed in the sleep latency of REM sleep. The short sleep onset latency to non-REM sleep in the safranal administration group clearly shows that safranal accelerates the onset of non-REM sleep in PENT mice.

  FIG. 1D shows temporal changes in the amount of non-REM sleep and wakefulness for 3 hours after administration of pentobarbital in the vehicle group, safranal administration group, and diazepam administration group in Test Example 1, and FIG. 1E shows cumulative non-REM sleep amount ( (Upper diagram) and cumulative arousal amount (lower diagram). Also, ## is p <0.01 vs. Represents safranal (90 mg / kg).

From FIG. 1D, compared with the Vehicle group, the cumulative non-REM sleep amount for 3 hours was significantly increased in the safranal 360 mg / kg administration group. In addition, the awakening time decreased with an increase in sleep time. Similar results were seen in the low-dose safranal administration group, but the sleep effect was small and lasted only 1-2 hours after administration. The total amount of non-REM sleep 3 hours after administration of safranal or diazepam to PENT mice was calculated, and compared to the vehicle group, safranal 180 mg / kg, 360 mg / kg, diazepam 3 mg / kg administration group were 62.6%, 109.7% and 117.5% increased significantly. In the safranal administration group, no significant change was observed in REM sleep after administration. According to ANOVA analysis, safranal increased non-REM sleep (F _(4.28) = 21.316, P <0.01), and the effect of administration of safranal 360 mg / kg is stronger than administration of safranal 90, 180 mg / kg. (P <0.01, vs. safranal 360 mg / kg), no significant difference from the effect of administration of diazepam 3 mg / kg was observed (P> 0.05). From the above results, it is considered that safranal increases non-REM sleep in PENT mice.

  In Test Example 1, the number of appearances of wakefulness, REM sleep, and non-REM sleep for 3 hours after administration of pentobarbital in the vehicle group, the safranal administration group, and the diazepam administration group was measured.

  FIG. 2A shows the number of non-REM sleep appearances in Test Example 1, and FIG. 2B shows the average duration. 2A and 2B, “Wake” indicates “wakefulness”, “NRem” indicates “non-REM sleep”, and “Rem” indicates “REM sleep”. Furthermore, * indicates p <0.05 vs. Vehicle group, ** is p <0.01 vs. Represents the Vehicle group.

  From FIG. 2A and FIG. 2B, changes in the number of non-REM sleep appearances and average duration were confirmed by administration of safranal, but no change was observed in REM sleep. In particular, when safranal 180 and 360 mg / kg were administered, non-REM episodes were increased 2.7 times and 1.9 times, respectively. Administration of safranal 360 and 180 mg / kg to PENT mice reduced the mean duration of non-REM sleep for 3 hours from administration.

  FIG. 2C shows the number of non-REM sleep episodes with respect to the time after administration of pentobarbital in Test Example 1 (left diagram) and the number of arousal episodes with respect to the time after administration (right diagram).

  2D shows the number of stage transitions from non-REM sleep after pentobarbital administration in Test Example 1 to waking and from waking to non-REM sleep (left figure), and from non-REM sleep to REM sleep and REM sleep to non-REM after administration. The number of stage transitions to sleep (right figure) is shown.

  From FIG. 2D, safranal 180, 360 mg / kg increased the number of stage transitions from awakening to non-REM sleep and from non-REM sleep to awakening. On the other hand, there was no change in the stage transition from non-REM sleep to REM sleep and from REM sleep to awakening.

  From FIG. 2C, in the high dose safranal (180, 360 mg / kg) administration group, the number of non-REM sleep episodes of 4-16, 16-32, 32-64, 64-128 seconds, 4-16, 16-32, The number of awakening episodes between 32 and 64 seconds increased. Similarly, in the diazepam administration group, the number of non-REM sleep episodes of 32-64, 64-128, and 128-256 seconds increased, and the number of arousal episodes of 16-32, 256-512 seconds decreased.

  FIG. 2E shows the electroencephalogram output density with respect to the electroencephalogram frequency band after administration of pentobarbital in Test Example 1.

  In the safranal 360 mg / kg administration group, the EEG output density of non-REM sleep increased at 0.5 to 0.75 Hz and 2.0 to 2.5 Hz, but decreased at 8.5 to 23.25 Hz. In the diazepam administration group, the electroencephalogram output density of non-REM sleep decreased in the frequency band of 2 to 3.5 Hz. In the safranal 180, 360 mg / kg administration group, the ratio of the average slow activity of non-REM sleep increased in a frequency band of 0.25-4 Hz. These results suggest that safranal may increase EEG power density and slow activity in non-REM sleep.

<Test Example 2 (c-Fos immunohistochemistry)>
Four groups of mice were prepared, and either vehicle, safranal 90, 180, or 360 mg / kg was orally administered into the stomach at time 20:00. One hour later, at 21:00, all mice received 20 mg / kg of pentobarbital intraperitoneally. Ninety minutes after administration of pentobarbital, anesthetized with 10% chloral hydrate, and perfused with physiological saline through the heart, followed by ice-cold 4% paraformaldehyde-0.1M phosphate buffer (pH 7.4). I let you. The brain was then removed and re-fixed with 4% paraformaldehyde for 6 hours and soaked in 30% sucrose overnight. Using a frozen microtome, frozen sections were prepared with a coronal surface of 30 μm. Sections were stored in an antifreeze solution at −20 ° C. for histological analysis. Immunohistological examination was performed according to the free float method. Sections are fixed with 4% paraformaldehyde for 10 minutes and then incubated with 0.3% hydrogen peroxide for 15 minutes to suppress endogenous peroxidase activity. Next, it was placed in a blocking solution at 37 ° C. in 0.01 M phosphate buffered saline (PBS, pH 7.2) containing 10% normal rabbit serum and 0.3% Triton X-100 for 30 minutes. The polyclonal antibody was incubated in a solution diluted 2000 times with PBS containing 1% normal rabbit serum and 0.3% Triton X-100 at 4 ° C. for 24 hours. The next day, it was incubated with a biotinylated goat anti-rabbit secondary antibody diluted 200-fold for 1 hour, and then incubated with avidin-biotin-peroxidase diluted 200-fold for 1 hour at 37 ° C. The peroxidase reaction was visualized with 0.1 M phosphate buffer containing 0.05% DAB and 0.01% hydrogen peroxide. The sections were placed on a slide, dried and covered with a cover.

  In addition, as a control group, in order to confirm that non-specific staining does not occur, the adjacent antibody was not treated with the primary antibody. Moreover, the section | slice was observed under bright field illumination using the Leica DMLB2 microscope, and image | photographed with the Cool SNAP-Proof digital camera.

<Results and discussion>
To examine the effects of safranal on ventral lateral preoptic area (VLPO) and nodular papillary nucleus (TMN) of PENT mice, VLPO and TMN c-Fos positive nerves were counted. 3A to 3H show photomicrographs of the appearance of c-Fos of VLPO and TMN of PENT mice administered with Vehicle, Safranal 90, 180, 360 mg / kg.

  FIG. 3A is a photomicrograph of C-Fos appearance of VLPO in the vehicle group, and FIG. 3E is an enlarged photo of FIG. 3A. FIG. 3B is a photomicrograph of the appearance of c-Fos of VLPO in the group administered with safranal 360 mg / kg, and FIG. 3F is an enlarged photo of FIG. 3B. FIG. 3C is a photomicrograph of the appearance of C-Fos of TMN in the Vehicle group, and FIG. 3G is an enlarged photo of FIG. 3C. FIG. 3D is a photomicrograph of TMN C-Fos appearance in the group administered with safranal 360 mg / kg, and FIG. 3H is an enlarged photo of FIG. 3D.

From the analysis of the number of nuclei that immunoreacted with c-Fos from FIG. 3, the appearance of c-Fos increased with VLPO in the safranal 180, 360 mg / kg group compared with the Vehicle group (F _{(3, 19)} = 25. .753; P <0.01), decreased with TMN (F ₍ 3,19 ₎ = 4.691; P <0.05). From these results, it is considered that safranal increased non-REM sleep in PENT mice by activating the VLPO sleep center and inhibiting the TMN arousal center.

Formulation Example 1: Tablets are prepared according to the following composition by a conventional tablet method.
Safranal 200mg
Lactose 60mg
Potato starch 30mg
Polyvinyl alcohol 2mg
Magnesium stearate 1mg
Tar pigment Trace amount Formulation example 2: Powder A powder is prepared according to the following composition by a conventional method.
Safranal 200mg
Lactose 275mg

  The compound represented by the general formula (I) of the present invention can be used as a sleep action enhancer or a sedative action enhancer, and can be used as a sleep improving agent or a sedative in combination with a sleep pill or sedative. Can do.

Claims (5)

Formula (I):

The sleep action or sedation action enhancer which contains the compound represented by these as an active ingredient. Formula (I):

A preparation comprising a combination of the compound represented by formula (1) and an active ingredient having a sleep action or a sedative action. Formula (I):

The formulation of Claim 2 which has a form which administers separately the compound represented by these, and the active ingredient which has a sleep action or a sedative action. Formula (I):

The formulation of Claim 2 containing the active ingredient which has the compound represented by these, and a sleep action or a sedative action. Formula (I):

A method for enhancing the sleep action or sedation action by an active ingredient having a sleep action or sedation action, which comprises the step of administering a composition comprising the compound represented by formula (except for medical practice for humans).

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