JP2002128773A - Tricyclic compound and medicinal composition containing the compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tricyclic compound having excellent melatonin receptor(ML1) affinity, and to provide a medicinal composition containing the compound. SOLUTION: This composition includes (S)-N-[2-(1,6,7,8-tetrahydro-2H- indeno[5, 4-b]furan-8-yl)ethyl]acetamide or its prodrug.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic compound having excellent affinity for melatonin receptor (ML ₁ ) and a pharmaceutical composition containing the compound.

[0002]

2. Description of the Related Art Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted mainly by the pineal gland of the brain, and increases in a dark environment and decreases in a bright environment. Melatonin acts on pigment cells and female gonads in an inhibitory manner, and is involved in photoperiodic signaling to act as a biological clock synchronizing factor. Therefore, melatonin is considered to be used for treating diseases related to melatonin activity, such as reproductive and endocrine disorders, sleep-wake rhythm disorders, jet lag, and various disorders associated with aging. Also, recently, it has been revealed that the amount of melatonin produced decreases with aging, and it has been reported that aging itself can be prevented by maintaining the amount of melatonin [Annals of the New York Academy of Sciences (Ann NY Acad. Sci.), Volume 719, pages 456-460 (199).
4)]. However, melatonin is easily metabolized by metabolic enzymes in the living body [Clinical test 38,
11, pp. 282-284, 1994], which is not sufficient as a drug.

[0003] As a tricyclic melatonin receptor agonist having a sleep disorder prevention / treatment effect, N- [2- (1,6,6) is used.
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] acetamide is described in WO97 /
32871. Also, (S) -N- [2
-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and at least one selected from zolpidem, zopiclone, triazolam and brotizolam. A sleep disorder prophylactic / therapeutic agent is described in WO 99/63977.

[0004]

The structure is different from melatonin.
High affinity for melatonin receptor
Melatonin agonists with excellent behavioral and metabolic stability,
Can be expected to be more therapeutically effective than melatonin
Wear. This melatonin receptor is ML₁And ML ₂Minute
ML₁Is involved in the inhibition of adenylate cyclase
I do. At present, melatonin receptor agonistic activity,
Qualitative and those that are sufficiently satisfactory in terms of brain transfer
Not found. So, better melatonin receiving
Has agonistic or antagonistic activity, sufficient for pharmaceuticals
The development of satisfactory compounds is eagerly needed.

[0005]

The present inventors have conducted various studies and found that the formula

Embedded image (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8 represented by
- yl) ethyl] acetamide, or the first time succeeded in creation of a prodrug thereof, further has excellent properties as melatonin agonist Again compound unexpectedly excellent particularly important ML ₁ receptor selectivity, They have found that they are sufficiently satisfactory as pharmaceuticals because of their excellent metabolic stability, and completed the present invention based on these findings. That is, the present invention relates to (1) (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide or a mixture thereof. (2) crystals of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide; ) A pharmaceutical composition comprising the compound according to the above (1); (4) the above (3), which is a melatonin receptor affinity composition
(5) the composition according to the above (3), which is a biological rhythm regulator; (6) the composition according to the above (3), which is a sleep / wake rhythm regulator; (7) a jet lag regulator (8) The composition according to (3), which is a therapeutic agent for sleep disorder; (9) the composition according to (3), which is a therapeutic agent for circadian rhythmic sleep disorder; (10) (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [4-b] furan-8-yl)
[Ethyl] acetamide or a prodrug thereof and a prophylactic / therapeutic agent for sleep disorders comprising a combination of zolpidem, zopiclone, triazolam, brotizolam, and zaleplon; Use of the compound according to (1) in the manufacture of a syndrome (jet lag) regulator, a therapeutic agent for sleep disorder or a therapeutic agent for circadian rhythmic sleep disorder; (12) administration of the compound according to (1). (13) a method for treating a sleep disorder, which comprises administering the compound according to (1); and (14) a method for treating a sleep disorder. And a method for treating circadian rhythmic sleep disorder, which comprises administering a compound of formula (I).

(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8
-Yl) ethyl] acetamide [hereinafter abbreviated as compound (I)] may be a hydrate or a non-hydrate. Examples of the “hydrate” include 0.5 hydrate to 5.0 hydrate. Of these, hemihydrate,
Preferred are 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate. Particularly preferred is 1.5 hydrate.

Compound (I) is represented by (±) -N- [2-
It can be obtained by separating (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide using an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, a racemic substance is added to a chiral column such as Ceramosphere series (manufactured by Shiseido), ENANTIO-OVM (manufactured by Tosoh) or CHIRAL series (manufactured by Daicel), and water, a buffer solution (eg,
Phosphate buffer), organic solvents (eg, hexane, ethanol, methanol, isopropanol, acetonitrile,
Trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate optical isomers. For example, in the case of gas chromatography, CP-Chirasil-DeX CB
(Manufactured by GL Scientific) and a method using a chiral column. (±) -N- [2-
(1,6,7,8-Tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide is produced by a method described in WO97 / 32871 or the like or a method analogous thereto. .

Compound (I) can also be synthesized by the method described below.

Embedded image Compound (I) is synthesized by reacting compound (II) with acetic acid, acetate, or a reactive derivative thereof in the presence of a deoxidizing agent, if necessary. As the acetate, an alkali metal salt such as sodium acetate, potassium acetate and lithium acetate, an amine salt such as ammonium acetate and the like are used.
Reactive derivatives of acetic acid include acid halides (eg, acid chlorides, acid bromides), acid amides (eg, acid amides with pyrazole, imidazole, benzotriazole, etc.), acetic anhydride, mixed acid anhydrides (eg, monomethyl Carbonic acid, monoethyl carbonic acid, monoisopropyl carbonic acid, etc.),
Acid azide, active ester (e.g., diethoxy phosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole And active thioesters (eg, 2-pyridylthioester, 2-benzothiazolylthioester, etc.). Examples of the deacidifying agent include sodium carbonate, potassium carbonate, inorganic bases such as sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine,
It is desirable to add tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine. When acetic acid or acetate is used, a suitable condensing agent may be used. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-disubstituted carbodiimides such as 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and N, N′-carbonyldiimidazoles. Azolides, N-ethoxycarbonyl-2
Dehydrating agents such as -ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene; and 2-halogenopyridinium salts such as 2-chloromethylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide. . The acetic acid, acetate or a reactive derivative thereof is generally used in an amount of about 0.8 to 1 with respect to 1 mol of compound (II).
0 mol, preferably about 1.0 to 2.0 mol is used. This reaction is advantageously performed using a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, and N, N-dimethyl. Amides such as formamide, N, N-dimethylacetamide, dichloromethane,
Solvents such as halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is about 5 minutes to 72 hours, preferably about 10 minutes to 20 hours, and the reaction temperature is about -20 to 200 hours.
° C, preferably about 0-100 ° C. The compound (I) thus obtained can be isolated from the reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization distillation and chromatography. Further, compound (I) can be obtained as crystals by the recrystallization distillation or the like. Compound (II) can be synthesized by the method described in WO97 / 32871 and JP-A-11-140073. The prodrug of the compound (I) is a compound that is converted into the compound (I) by a reaction with an enzyme or a stomach acid under physiological conditions in a living body, that is, the compound (I) is oxidized, reduced, hydrolyzed, etc. Or a compound which undergoes hydrolysis or the like by gastric acid or the like to change to compound (I). As a prodrug of compound (I), the imino group of compound (I) is acylated,
Alkylated and phosphorylated compounds (eg, compound (I)
Is an eicosanoyl group, an alanyl group, a pentylaminocarbonyl group, (5-methyl-2-oxo-1,
3-dioxolen-4-yl) methoxycarbonylation,
Tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.). These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is available from Hirokawa Shoten 1990
Annual Development of Pharmaceuticals, Volume 7, Molecular Design, 163 pages to 19
It may be a compound that changes to compound (I) under physiological conditions as described on page 8. The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

The compound (I), which is an optically active form (S form),
Or a prodrug thereof (hereinafter abbreviated as “compound of the present invention”).
May be noted) is a high parent for melatonin receptors
Shows compatibility, especially ML₁High selectivity for the receptor.
S-form is ML compared to racemic form ₁Selectivity for the receptor
Higher (approximately 2.7 times), more selective than R-form
The sex is remarkable. Therefore, compound (I) is ML₂Derived from
Possible side effects such as impaired movement or memory after awakening
It has the advantage of low expression for use. Metabolic stability
It is also excellent in sex and transfer to the brain. Less toxic,
Moreover, it has few side effects and is useful as a pharmaceutical. Sa
Further, by obtaining the present compound (I) as a crystal, manipulation of the preparation can be achieved.
Providing better medicines in terms of workability, purity, stability, etc.
be able to. Note that the ML-1 selective operability is
Research (Brain Research), 1989, 505
No. 157-159, Vanesek
According to these methods, CHO cells containing the human ML-1 receptor
Forskolin-induced cAMP production using vesicles
By being suppressed, the ML-1 receptor agonist
Can be evaluated. The compounds of the present invention can be used in mammals (eg,
For example, mice, rats, hamsters, rabbits, cats,
, Cattle, sheep, monkeys, humans, etc.)
Act as agonists or antagonists
Tonin receptor affinity composition, especially melatonin receptor operation
It is useful as a composition,
Diseases that can be affected by ratonin, such as
Sleep disorders [eg, primary insomnia, circadian rhythm disorders (eg,
Modulation of physical condition due to shift work, time band change syndrome (time difference
Blur, etc.), sleep-wake rhythm disorder], seasonal depression, reproductive organs
Dysfunction, endocrine disorders, senile dementia, Alzheimer's disease,
Various aging disorders, cerebral circulation disorders (eg, stroke, etc.), head
Trauma, spinal cord injury, epilepsy, anxiety, depression, manic depression, spirit
Schizophrenia, alcoholism, Parkinson's disease, hypertension
Disease, arteriosclerosis, arrhythmia, premenstrual tension syndrome, glaucoma,
Safe prevention and / or treatment of cancer, AIDS, diabetes, etc.
It can be carried out. Anti-aging, immune regulation, ovulation regulation
(Eg, contraception, etc.) can also be used effectively.

The compound of the present invention has a low toxicity, and it is a pharmaceutical composition containing a pharmacologically acceptable carrier as it is or according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powders, Granules, capsules (including soft capsules), liquids, injections, suppositories,
It can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as a sustained release agent, patch, or even chewing gum. The content of the compound of the present invention in the preparation of the present invention is about 0.01 to 100% by weight of the whole preparation. The dose varies depending on the administration subject, administration route, disease and the like. For example, when administered as an oral agent to an adult (body weight of about 60 kg) as a therapeutic agent for sleep disorders, the compound of the present invention as an active ingredient is used. It is about 0.0005 to 2 mg / kg body weight, preferably about 0.001 to 1 mg / kg body weight, more preferably about 0.001 to 0.5 mg / kg body weight, but usually 0.01 kg to 0.6 mg / kg body weight. kg. 1 per day
It can be administered in several divided doses. Preferably about 0.1 to about 100 mg, more preferably about 0.3 to about 64 mg, even more preferably about 1 to about 16 mg of the compound
It is preferable to prepare a formulation containing g.

The pharmacologically acceptable carriers which may be used in the preparation of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients in solid preparations, lubricants and the like. Agents, binders, disintegrants; solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. Also, if necessary,
Conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Excipients include, for example, lactose, sucrose, D-mannitol, starch,
Corn starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polypinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. As a disintegrant,
For example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L
-Hydroxypropylcellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-
Mannitol, benzyl benzoate, alcohol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like can be mentioned. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like. Examples of the light stabilizer include titanium oxide.

The compound of the present invention may be used in combination with at least one selected from zolpidem, zopiclone, triazolam, brotizolam and zaleplon. That is, the compound of the present invention and zolpidem, zopiclone,
Triazolam, brotizolam and at least one selected from the group consisting of zaleplon and a sleep disorder prophylactic / therapeutic agent are safer than in the case of using each alone, and are more safe for recoil insomnia, memory impairment, and after awakening. It has an excellent effect as a clinically used drug, such as obtaining a very excellent effect of preventing and treating sleep disorders, with almost no occurrence of side effects such as light-headedness and drowsiness. Zolpidem is N, N, 6-trimethyl-2- (4-methyl
phenyl) -imidazo [1,2-a] pyridine-3-acetamide
For example, JP-A-63-8384 (USP)
4,794,185) or a method analogous thereto. Zopiclone is a 4-
methyl-1-piperazinecarboxylic acid 6- (5-chlorine
o-2-pyridinyl) -6,7-dihydro-7-oxo-5H-pyrr
olo [3,4-b] pyrazin-5-yl ester, which is described in, for example, JP-A-48-76892 (US Pat. No. 3,862,14).
It is produced by the method described in 9) or a method analogous thereto. Triazolam (trade name: Halcyon)
Is 8-chloro-6- (2-chlorophenyl) -1-methyl-
4H- [1,2,4] triazolo [4,3-a] [1,4] benzodia
Zepine, for example, produced by the method described in JP-B-49-40239 (USP 3,987,052) or a method analogous thereto. Brotizolam
olam, trade name: Lendormin) is 8-bromo-6- (o
-Chlorophenyl) -1-methyl-4H-s-triazolo [3,4
c] thieno [2,3e] 1,4-diazepine, for example, Japanese Patent Application Laid-Open No. Sho 51-80899 (USP 4,094,9)
84) or a method analogous thereto. Zaleplon is N- [3- (3-cyano
pyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-
ethylacetamide, for example USP 5,714,6
07, EP-A-776898 or a method analogous thereto.

When the compound of the present invention is used in combination with at least one selected from the group consisting of zolpidem, zopiclone, triazolam, brotizolam and zaleplon, for example, (1) according to a known pharmaceutical production method, and (2) each is formulated as a single preparation with a pharmaceutically acceptable excipient or the like, if desired, and used simultaneously or in combination with a time difference ( Or (3) may be prepared as a set (kit, etc.) by formulating each with an appropriate excipient according to a conventional method. When each compound is separately formulated, as long as the object of the present invention is achieved, the formulations may be separately, simultaneously or with a time lag,
It may be used for the same administration subject, and the frequency of administration of each preparation may be different. All of the active ingredients may be contained in one formulation, or each or a part of the active ingredients may be separately formulated. The content of the active ingredient in such a preparation is usually about 0.01 to about 100% by weight. The preparation may be in any form as long as it can be administered orally to a patient, and examples thereof include tablets, fine granules, capsules, and granules. Among them, tablets, fine granules, capsules and the like are preferable.

The dosage of the compound of the present invention when used in combination with other drugs varies depending on the administration subject, administration route, disease, type of active ingredient to be used, and the like. The following doses of each active ingredient may be administered once or several times a day, and the respective ingredients are preferably administered simultaneously or in combination with a time difference of 30 minutes to 3 hours. The dosage of the compound of the present invention may be about 0.05 mg to about 10 mg per dose, preferably about 0.1 mg to about 3 mg per dose. The dosage of zolpidem is about 0.2 mg to about 10 mg per dose, preferably about 0.5 mg to about 5 mg per dose. The dose of zopiclone is about 0.2 mg to about 10 mg per dose,
Preferably, the dose is about 0.5 mg to about 5 mg per dose.
The dose of triazolam is about 0.01 mg per dose
About 0.5 mg, preferably about 0.02 mg per serving
About 0.3 mg. The dose of brotizolam is from about 0.01 mg to about 1 mg per dose, preferably from about 0.05 mg to about 0.3 mg per dose. The dosage of zaleplon is about 1 mg to about 30 mg per dose, preferably about 2 mg to about 20 mg per dose. When used in combination, the combination ratio (administration ratio) of the compound of the present invention and at least one selected from zolpidem, zopiclone, triazolam, brotizolam and zaleplon is 1 part by weight of the compound of the present invention, zolpidem, zopiclone,
0.1 to 30 parts by weight of triazolam, brotizolam and / or zaleplon. Further, the compound of the present invention
Further, other active ingredients (for example, benzodiazepines such as diazepam, alprazolam and estazolam which are benzodiazepines, sleep rhythm regulators such as butactamide or a salt thereof which is a fatty acid derivative, cis-9, 10
-A sleeping substance such as octadecenoamide) may be used in appropriate combination in an appropriate amount. Zolpidem, zopiclone, and the other active ingredient and the compound of the present invention or the compound of the present invention,
At least i selected from triazolam, brotizolam and zaleplon are mixed according to a means known per se, and a pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, As a sustained release agent) or separately, and may be administered to the same subject at the same time or with a time lag similarly to the preparation of the present invention.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, Preparation Examples and Experimental Examples, but these do not limit the present invention.

EXAMPLES Example 1 (S) -N- [2- (1,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] acetamide (S) -2- (1,6,7,8-tetrahydro-2H-
Triethylamine (104.6 mL, 0.75 mo) was added to a dichloromethane solution (500 mL) of indeno [5,4-b] furan-8-yl) ethylamine hydrochloride (71.92 g, 0.3 mol).
l), dimethylaminopyridine (3.67 g, 0.03 mol) and acetic anhydride (31.2 mL, 0.33 mol) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into cold water, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and saturated saline, dried over sodium sulfate, and then purified by a small amount of silica gel column chromatography (dichloromethane).
After evaporating the solvent under reduced pressure, the obtained crystals were recrystallized from isopropyl ether / ethyl acetate to give the title compound (yield 5
3.2 g, yield 72%). FIG. 1 shows an X-ray diffraction spectrum chart of the obtained crystal. The powder X-ray diffraction was measured by RINT Ultima ⁺ 2100 manufactured by Rigaku Corporation.
It measured using. 118-120 ° C. NMR (CDCl ₃ ) δ: 1.50-1.92 (2
H, m), 1.96 (3H, s), 1.96−2.13 (1H, m), 2.19−
2.38 (1H, m), 2.67-2.95 (2H, m), 3.00-3.39 (5
H, m), 4.43-4.64 (2H, m), 5.43 (1H, br), 6.62
(1H, d, J = 7.8Hz), 6.95 (1H, d, J = 7.8Hz). Elemental analysis: C ₁₅ H ₁₉ NO ₂ Calculated: C, 73.44, H, 7.81, N, 5.71. Found: C, 73.56, H, 7.89, N, 5.86. Optical rotation: [α] _D = -59.1 ° (c = 1.0%, chloroform).

Formulation Example 1 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g A mixture of 10.0 g of the compound obtained in Example 1, 60.0 g of lactose and 35.0 g of corn starch was granulated through a 1 mm mesh sieve using 30 ml of a 10% by weight aqueous gelatin solution (3.0 g as gelatin), and then granulated. Dry at ℃ and sieved again. The granules obtained were mixed with 2.0 g of magnesium stearate and compressed. The resulting central tablet was coated with sugar coating by a water suspension wave of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain 1000 coated tablets.

Formulation Example 2 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 70.0 g (3) Corn starch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium stearate 0 g Compound 10.0 g obtained in Example 1 and magnesium stearate 3.0 g were added to an aqueous solution of soluble starch 70 ml.
(7.0 g as soluble starch), dried and mixed with 70.0 g of lactose and 50.0 g of corn starch. The mixture was compressed to give 1000 tablets.

Experimental Example 1 Inhibition of 2- [ ¹²⁵ I] iodomelatonin binding The forebrain was isolated from a 7-day-old chick (white leghorn).
Ice-cold assay buffer (50 mM Tris-HCl,
pH 7.7, 25 ° C) to prepare a homogenate,
A precipitate was obtained by centrifugation at 000 × g for 10 minutes. This was washed once with the same buffer solution, and then homogenized with an assay buffer solution to a concentration of 0.3 to 0.4 mg protein / mL to obtain a membrane sample. Test solution, membrane sample,
The ligand (80 pM 2- [ ¹²⁵ I] iodomelatonin, about 100,000 dpm) was mixed in a total volume of 0.5 mL and incubated at 25 ° C. for 90 minutes. Add 3 mL of ice-cold assay buffer and immediately add Whatman
n) Suction filtration was performed on GF / B, and the filter was further washed twice with 3 mL of ice-cooled assay buffer, and then radioactivity was measured with a γ-counter. The value obtained by subtracting the binding in the presence of 10 μM melatonin as non-specific binding was defined as specific binding. The 50% inhibitory concentration (IC ₅₀ ) was determined by log probit (lo
g-probit), and the results are shown in Table 1. [Table 1] Inhibitory effect on 2- [ ¹²⁵ I] iodomelatonin binding {Compound IC ₅₀ (nM)} {Compound of Example 1 0.28 Melatonin 0.68} From the results shown in Table 1, it can be seen that the compound (I) of the present invention has excellent melatonin receptor agonist activity.

[0019]

The compound of the present invention has excellent properties as a melatonin agonist, and is therefore a disease associated with the action of melatonin in a living body (eg, sleep disorder).
Can be provided a clinically useful prophylactic / therapeutic agent.
The compounds of the present invention is particularly excellent in ML ₁ receptor selectivity, metabolic stability, and is excellent in the migration brain. Therefore, they are useful alone or in combination with other therapeutic agents for sleep disorders to prevent and treat sleep disorders and the like.

[Brief description of the drawings]

FIG. 1 shows an X-ray diffraction spectrum chart of a crystal of the compound obtained in Example 1.

Claims (14)

[Claims] (1) (S) -N- [2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
8-yl) ethyl] acetamide or a prodrug thereof. 2. (S) -N- [2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
8-yl) ethyl] acetamide crystals. 3. A pharmaceutical composition comprising the compound according to claim 1. 4. The composition according to claim 3, which is a melatonin receptor affinity composition. 5. The composition according to claim 3, which is a biological rhythm regulator. 6. The composition according to claim 3, which is a sleep / wake rhythm regulating agent. 7. The composition according to claim 3, which is a jet lag regulator. 8. The composition according to claim 3, which is a therapeutic agent for sleep disorders. 9. The composition according to claim 3, which is a therapeutic agent for circadian rhythmic sleep disorder. 10. (S) -N- [2- (1, 6, 7, 8)
-Tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide or a prodrug thereof and a sleep disorder preventive treatment comprising a combination of zolpidem, zopiclone, triazolam, brotizolam and zaleplon Agent. 11. The compound according to claim 1 in the production of a biological rhythm regulator, a sleep-wake rhythm regulator, a time band change syndrome (lag lag) regulator, a sleep disorder therapeutic agent or a circadian rhythm sleep disorder therapeutic agent. use. 12. A method for regulating a biological rhythm, a sleep-wake rhythm, or a circadian rhythm, which comprises administering the compound according to claim 1. 13. A method for treating a sleep disorder, which comprises administering the compound according to claim 1. 14. A method for treating circadian rhythmic sleep disorder, which comprises administering the compound according to claim 1.