JP4213639B2 - Copolyvidone-containing preparation - Google Patents

Description

  The present invention relates to a preparation excellent in storage stability, particularly a pharmaceutical preparation, which is coated with a coating agent containing copolyvidone.

  Tablets that are common as oral preparations are molded using various additives such as diluents, binders, lubricants, and disintegrants. Depending on the active compound, there is a concern about stability to light in a normal distribution and storage state, and a film that gives a light shielding effect is often applied to the active compound by film coating. It is also a useful means to apply a film to prevent the bitter taste of drugs. This film consists of hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC) as a water-soluble coating agent, polyethylene glycol (PEG) as a plasticizer, titanium oxide as a light-shielding agent, and, if necessary, a colorant such as iron sesquioxide. The composition containing is common.

In the tablet, the addition of a plasticizer is essential for enhancing the film strength, improving the spreadability in the process, and improving the appearance, and polyethylene glycol is generally used as the plasticizer for the water-soluble coating agent.
However, depending on the active compounds such as pharmaceutically active ingredients, the addition of polyethylene glycol deteriorates the stability of the active ingredient against heat and light, and the activity cannot be maintained for a sufficient period even under normal storage conditions in the medical field. There is a problem in the formulation.

〔式中、Ｒ¹は置換基を有していてもよい炭化水素基、置換基を有していてもよいアミノ基または置換基を有していてもよい複素環基、
Ｒ²は水素原子または置換基を有していてもよい炭化水素基、
Ｒ³は水素原子、置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、
ＸはＣＨＲ⁴、ＮＲ⁴、ＯまたはＳ（Ｒ⁴は水素原子または置換基を有していても
よい炭化水素基を示す。）、
ＹはＣ、ＣＨまたはＮ（但し、ＸがＣＨ₂を示す場合、ＹはＣまたはＣＨである）、
---- は単結合または二重結合、
Ａ環は置換基を有していてもよい５ないし７員の酸素原子を含む複素環、
Ｂ環は置換基を有していてもよいベンゼン環、および
ｍは１ないし４の整数を示す。〕で表される化合物またはその塩である上記（１）記載の製剤、
（６）ポリエチレングリコール含有製剤で不安定な薬物が式

〔式中、Ａｒは置換基を有していてもよい芳香族基を示し、Ｘ’は−Ｏ−、−Ｓ−、−ＣＯ−、−ＳＯ−、−ＳＯ_２−および−ＣＯＯ−から選ばれる２価の基を１または２個含んでいてもよい２価のＣ_１−６脂肪族炭化水素基を示し、Ｙ’は２価のＣ_１−６脂肪族炭化水素基を示し、Ｒ’およびＲ”は、各々、同一または異なって、水素原子または置換基を有していてもよいＣ_１−６アルキルを示し、Ａ’環はさらに置換基を有していてもよいベンゼン環を、Ｂ’環はさらに置換基を有していてもよい４ないし８員環を示す。〕で表される化合物またはその塩である上記（１）記載の製剤、
（７）ポリエチレングリコール含有製剤で不安定な薬物が、Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］アセチルアミド、Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、６−（４−ビフェニリル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、６−（４−ビフェニリル）メトキシ−２−（Ｎ，Ｎ−ジメチルアミノ）メチルテトラリン、６−（４−ビフェニリル）メトキシ−２−（Ｎ，Ｎ−ジプロピルアミノ）メチルテトラリン、２−（Ｎ，Ｎ−ジメチルアミノ）メチル−６−（４’−メトキシビフェニル−４−イル）メトキシテトラリン、（＋）−６−（４−ビフェニリル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、（＋）−６−（４−ビフェニリル）メトキシ−２−［２−（Ｎ，Ｎ−ジエチルアミノ）エチル］テトラリン、（＋）−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］−６−（４’−メチルビフェニル−４−イル）メトキシテトラリン、（＋）−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］−６−（４’−メトキシビフェニル−４−イル）メトキシテトラリン、（＋）−６−（２’，４’−ジメトキシビフェニル−４−イル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、（＋）−６−［４−（１，３−ベンゾジオキソール−５−イル）フェニル］メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、（＋）−６−（３’，４’−ジメトキシビフェニル−４−イル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、その光学活性体およびその塩から選ばれる上記（１）記載の製剤；
（８）ポリエチレングリコール含有製剤で不安定となる薬物をコポリビドンを含有する被覆剤で被覆することを特徴とする製剤の安定化方法；
（９）ポリエチレングリコール含有製剤で不安定となる薬物を安定化するためのコポリビドン含有被覆剤の使用；
（１０）ポリエチレングリコール含有製剤で不安定となる薬物を安定化するため被覆剤におけるコポリビドンの使用；
（１１）ポリエチレングリコール含有製剤で不安定となる薬物を安定化するための被覆剤における上記（１０）記載のコポリビドンの使用；などを提供する。 In order to solve the above-mentioned problems, the present inventors diligently studied a plasticizer as an alternative to polyethylene glycol. Based on this finding, the present invention was completed based on the finding that it is a useful plasticizer that is not allowed to be used and can be used in place of polyethylene glycol.
That is, the present invention
(1) A stable preparation obtained by coating a labile drug with a polyethylene glycol-containing preparation with a copolypydone-containing coating (not containing polyethylene glycol);
(2) The preparation according to (1) above, wherein the drug is an unstable drug in a preparation coated with a polyethylene glycol-containing coating;
(3) The preparation according to (1) above, wherein the coating agent contains a water-soluble polymer;
(4) The preparation according to the above (1), wherein the coating agent further contains a light-shielding agent;
(5) Formulas containing unstable drugs in polyethylene glycol-containing preparations

[In the formula, R ¹ is a hydrocarbon group that may have a substituent, an amino group that may have a substituent, or a heterocyclic group that may have a substituent,
R ² represents a hydrogen atom or an optionally substituted hydrocarbon group,
R ³ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
X represents CHR ⁴ , NR ⁴ , O or S (R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent),
Y is C, CH or N (provided that when X represents CH ₂ , Y is C or CH),
---- is a single bond or a double bond,
Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent,
Ring B is an optionally substituted benzene ring, and m is an integer of 1 to 4. ] The preparation according to the above (1), which is a compound represented by the formula:
(6) The unstable drug in the polyethylene glycol-containing preparation is of the formula

[In the formula, Ar represents an aromatic group which may have a substituent, and X ′ is selected from —O—, —S—, —CO—, —SO—, —SO ₂ — and —COO—. Represents a divalent C _1-6 aliphatic hydrocarbon group which may contain one or two divalent groups, Y ′ represents a divalent C _1-6 aliphatic hydrocarbon group, R ′ And R ″ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl which may have a substituent, and the A ′ ring represents a benzene ring which may further have a substituent, The ring B ′ represents a 4- to 8-membered ring which may further have a substituent.] The preparation according to the above (1), which is a compound represented by the formula:
(7) An unstable drug in a polyethylene glycol-containing preparation is N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetylamide N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (1,6,7, 8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetralin, 2- (N, N-dimethyl Amino) methyl-6- (4′-methoxybiphenyl-4-yl) methoxytetralin, (+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin, (+)-2- [2- (N, N-dimethylamino) ethyl] -6 -(4'-methylbiphenyl-4-yl) methoxytetralin, (+)-2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methoxybiphenyl-4-yl) methoxytetralin , (+)-6- (2 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- [4- ( 1,3-Benzodioxo Ru-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- (3 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2 -[2- (N, N-dimethylamino) ethyl] tetralin, an optically active substance thereof, and a preparation according to the above (1) selected from a salt thereof;
(8) A method for stabilizing a preparation, which comprises coating a drug that becomes unstable in a preparation containing polyethylene glycol with a coating agent containing copolyvidone;
(9) Use of a copolyvidone-containing coating to stabilize a drug that becomes unstable in a polyethylene glycol-containing preparation;
(10) Use of copolyvidone in a coating to stabilize a drug that becomes unstable in a polyethylene glycol-containing preparation;
(11) Use of the copolyvidone according to (10) above in a coating agent for stabilizing a drug that becomes unstable in a polyethylene glycol-containing preparation;

The preparation of the present invention is stable against light, particularly ultraviolet rays and heat, and has excellent storage stability. In addition, according to the present invention, various coatings including film coating are possible without destabilizing the drug. Since the surface of the coated stable preparation of the present invention is uniform, for example, engraving or the like. Processing is easy and the finish is beautiful. Furthermore, the pharmaceutical preparation also helps to prevent bitterness when the drug is bitter, and no adhesion to the esophageal mucosa is observed during administration.
The coating agent of this invention is useful as a raw material which does not contain polyethyleneglycol for manufacturing the formulation excellent in storage stability as mentioned above. Moreover, since this coating agent is excellent in intensity | strength and a spreadability, it is excellent in operativity and uniform coating | cover is possible.

The “copolyvidone” used in the present invention is listed in pharmaceutical regulations and the European Pharmacopoeia, and is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, and the weight ratio thereof is 3: 2. Copolyvidone is commercially available [Prasidone S-630 (trade name) ISP, Kollidon VA64 (trade name) BASF).
The content of “copolyvidone” in the coating agent is, for example, about 5 to about 50% by weight, preferably about 10 to about 30% by weight, more preferably about 10 to about 20% by weight.

The “coating agent” used in the present invention includes a coating base in addition to “copolyvidone”. The content of the coating base in the coating is an amount used for production of general preparations. The “coating agent” may further contain additives that do not adversely affect the coating agent and the pharmaceutical preparation, if desired.
Further, the “coating agent” may be a liquid obtained by dissolving or dispersing each of the above components in water or an organic solvent. The kind of the organic solvent is not particularly limited, and for example, alcohols such as methanol, ethanol and isopropyl alcohol; ketones such as acetone can be used. Moreover, the liquid mixture of water and an organic solvent can also be used.

Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.
As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co., Ltd.], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Rohm Pharma Co.], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]; Examples include natural products such as shellac.
Examples of sustained-release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Rohm Pharma) are listed.
Two or more of the coating bases described above may be mixed and used at an appropriate ratio.
As the coating agent, from the viewpoint of working environment and the like, the coating agent is preferably water-soluble, and preferably contains a water-soluble polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose.

Examples of the additive described above include a light-shielding agent, a colorant, a fragrance, and the like.
Examples of the light shielding agent include inorganic oxides such as titanium oxide, iron sesquioxide, and zinc oxide. The light-shielding agent is preferably a metal oxide, more preferably titanium oxide. It is also preferable to use talc or barium sulfate as a light-shielding agent instead of titanium oxide.
Examples of the colorant include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (the above-mentioned water-soluble edible tars) And aluminum pigments), natural pigments (eg, β-carotene, chlorophyll, etc.).
Examples of the flavor include lemon oil, orange, dl- or l-menthol.

The “coating agent” in the present invention is produced, for example, by mixing the above-mentioned “copolyvidone” and a coating base after optionally adding the above-mentioned additives.
The “coating agent” is also produced by dissolving or dispersing the above components in water or the above organic solvent, and a uniform coating can be obtained by such a production method.

The “formulation” of the present invention is a preparation, particularly a pharmaceutical preparation, obtained by coating “an unstable drug in a polyethylene glycol-containing preparation” with the above-mentioned coating agent. The “unstable drug in a polyethylene glycol-containing preparation” may be “drug” alone or a mixture of “drug” and a conventional “formulation component” used in the preparation of the preparation.
Examples of drug dosage forms include tablets, powders, granules, fine granules, and pills.

The mechanism of the destabilization is unclear in “polyethylene glycol-containing preparations”, but it is destabilized in polyethylene glycol-containing preparations, especially preparations coated with polyethylene glycol-containing coatings. For example, among the following drugs, drugs whose drug content is reduced by 0.5% by weight or more of the content immediately after production when stored at 60 ° C. in the dark for 4 weeks are included. . A more unstable drug means a drug that decreases by 2% or more by storage under the same conditions. Alternatively, such unstable drugs include drugs in which an increase of 0.2% by weight or more of the total related substances or 0.2% by weight or more of the total unknown degradation substances appears.
Examples of such drugs include nourishing tonics, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodic drugs, central nervous system drugs, brain metabolism improving drugs, antiepileptic drugs. Sympathomimetic, gastrointestinal drug, antacid, anti-ulcer agent, antitussive expectorant, antiemetic, respiratory accelerator, bronchodilator, antiallergic agent, dental oral agent, antihistamine, cardiotonic agent, arrhythmic agent, diuretic Drugs, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia treatments, antibacterials, antibiotics, chemotherapeutics, diabetes treatments, osteoporosis treatments, skeletal muscle One or more components selected from a relaxing agent, an antidepressant, a hormone agent, an alkaloid narcotic, a sulfa agent, a gout treatment agent, a blood coagulation inhibitor, an antineoplastic agent, an Alzheimer treatment agent and the like can be mentioned.
The content of the “drug” in the “formulation” may be an effective amount of the “drug”.

Hereinafter, specific examples of the above-mentioned drugs will be described. However, since the degree of destabilization varies depending on the combination of individual drugs and other formulation components, the following specific examples include those that do not require stabilization. There may be cases.
For example, vitamin A, vitamin D, vitamin E (such as d-α-tocopherol acetate), vitamin B ₁ (such as dibenzoylthiamine, fursultiamine hydrochloride), vitamin B ₂ (such as riboflavin butyrate) Vitamin B ₆ (such as pyridoxine hydrochloride), vitamin C (such as ascorbic acid, sodium L-ascorbate), vitamin B ₁₂ (such as hydroxocobalamin acetate); minerals such as calcium, magnesium, iron; proteins, amino acids, oligos Examples include sugar and herbal medicine.
Antipyretic analgesic and anti-inflammatory agents include, for example, aspirin, acetaminophen, etenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscabine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine , Serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolol, pentazocine and the like.
Examples of the psychotropic drug include chlorpromazine, reserpine and the like.
Examples of the anxiolytic drug include alprazolam, chlordiazepoxide, diazepam and the like.
Examples of the antidepressant include imipramine, maprotiline, amphetamine and the like.

Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like.
Examples of antispasmodic agents include scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, and the like.
Examples of the central nervous system drug include citicoline and rotilenin.
Examples of brain metabolism improving agents include idebenone, vinpocetine, meclofenixate hydrochloride, 8- [1-oxo-3- [1- (phenylmethyl) piperidin-4-yl] propyl] -2,3,4,5. -Tetrahydro-1H-1-benzazepine or a salt thereof.
Examples of the antiepileptic agent include phenytoin and carbamazepine.
Examples of the sympathomimetic agent include isoproterenol hydrochloride.
Examples of the gastrointestinal agent include gastrointestinal agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, and cinnamon oil; and intestinal agents such as perperine hydrochloride, resistant lactic acid bacteria, and bifidobacteria.
Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like.
Examples of the anti-ulcer agent include benzimidazole compounds (eg, lansoprazole, omeprazole, rabeprazole, pantoprazole), famotidine, cimetidine, ranitidine hydrochloride, and the like.

Examples of the antitussive expectorant include cloperastine hydrochloride, dextromelt fan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, and codeine phosphate.
Examples of the antiemetic include diphenidol hydrochloride and metoclopramide.
Examples of the respiratory accelerator include levallorphan tartrate.
Examples of bronchodilators include theophylline and salbutanol sulfate.
Examples of antiallergic agents include amlexanox and seratrodast.
Examples of the dental and oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.
Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipentyl hydrochloride, dl-chlorpheniramine maleate, and the like.
Examples of the cardiotonic agent include caffeine and digoxin.
Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like.
Examples of diuretics include isosorbide and furosemide.
Examples of antihypertensive agents include delapril hydrochloride, captopril, hexamethonium bromide, hydralazine hydrochloride, lapetalol hydrochloride, manidipine hydrochloride, canexartan cilexetil, methyldopa, losartan, valsartan, eprosartan, irbesartan, tasosartan, telmisartan, pomisartan, folisartan, folasar Examples include sultan.

Examples of the vasoconstrictor include phenylephrine hydrochloride.
Examples of the coronary vasodilator include carbochromene hydrochloride, molsidomine, and perapamil hydrochloride.
Examples of peripheral vasodilators include cinnarizine.
Examples of the therapeutic agent for hyperlipidemia include selivastatin sodium, simvastatin, pravastatin and the like.
Examples of the bile agent include dehydrocholic acid and trepeptone.
Antibiotics include, for example, cephem antibiotics such as cephalexin, amoxicillin, pipmecillin hydrochloride, cefotiam hydrochloride, cefozopran hydrochloride, cefmenoxime hydrochloride, cefthrozin sodium; Agents; monobactam antibiotics such as carmonam sodium; penem antibiotics and carpapenem antibiotics.
Examples of the chemotherapeutic agent include sulfamethizole hydrochloride and thiazosulfone.
Examples of the therapeutic agent for diabetes include tolbutamide, voglibose, thiazolidinedione derivatives (eg, pioglitazone hydrochloride, troglitazone, 5-[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazoline. Dione), acarbose, miglitol, emiglitate and the like.
Examples of the osteoporosis therapeutic agent include ipriflavone.
Examples of the skeletal muscle relaxant include metocarpamol.
Examples of the antidepressant include meclizine hydrochloride and cymenhydrinate.

Examples of hormone agents include liotinin sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
Examples of alkaloid narcotics include opium, morphine hydrochloride, tocone, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like.
Examples of the sulfa drugs include sulfamine and sulfamethizole.
Examples of anti-gout drugs include allopurinol and colchicine.
Examples of the blood coagulation inhibitor include dicumarol.
Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like.
Examples of the Alzheimer's disease therapeutic agent include idebenone, vinpocetine, 8- [1-oxo-3- [1- (phenylmethyl) piperidin-4-yl] propyl] -2,3,4,5-tetrahydro-1H-1 -Benzazepine or a salt thereof.

〔式中、Ｒ¹は置換基を有していてもよい炭化水素基、置換基を有していてもよいアミノ基または置換基を有していてもよい複素環基、
Ｒ²は水素原子または置換基を有していてもよい炭化水素基、
Ｒ³は水素原子、置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、
ＸはＣＨＲ⁴、ＮＲ⁴、ＯまたはＳ（Ｒ⁴は水素原子または置換基を有していても
よい炭化水素基を示す。）、
ＹはＣ、ＣＨまたはＮ（但し、ＸがＣＨ₂を示す場合、ＹはＣまたはＣＨである）、
---- は単結合または二重結合、
Ａ環は置換基を有していてもよい５ないし７員の酸素原子を含む複素環、
Ｂ環は置換基を有していてもよいベンゼン環、および
ｍは１ないし４の整数を示す。〕で表される化合物またはその塩（以下、単に化合物（Ｉ）と称する場合がある）である。 The “unstable drug in a polyethylene glycol-containing preparation” is more preferably a formula

[In the formula, R ¹ is a hydrocarbon group that may have a substituent, an amino group that may have a substituent, or a heterocyclic group that may have a substituent,
R ² represents a hydrogen atom or an optionally substituted hydrocarbon group,
R ³ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
X represents CHR ⁴ , NR ⁴ , O or S (R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent),
Y is C, CH or N (provided that when X represents CH ₂ , Y is C or CH),
---- is a single bond or a double bond,
Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent,
Ring B is an optionally substituted benzene ring, and m is an integer of 1 to 4. Or a salt thereof (hereinafter sometimes simply referred to as Compound (I)).

In the compound (I), R ¹ represents a hydrocarbon group which may have a substituent, an amino group which may have a substituent, or a heterocyclic group which may have a substituent.
Examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ include an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, an aromatic hydrocarbon group, and the like. And those having 1 to 16 carbon atoms are preferred. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and an aryl group are used.
The “alkyl group” is preferably a lower alkyl group, for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, etc. The
The “alkenyl group” is preferably, for example, a lower alkenyl group, for example, C _2-6 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl and isobutenyl are generally used.
The “alkynyl group” is preferably, for example, a lower alkynyl group, for example, C _2-6 alkynyl groups such as ethynyl, propargyl and 1-propynyl are widely used.
The “cycloalkyl group” is preferably, for example, a lower cycloalkyl group, for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc.
The “aryl group” is preferably a C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like, and for example, a phenyl group is generally used.

Examples of the substituent that the “hydrocarbon group” of the “hydrocarbon group that may have a substituent” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group , A cyano group, a hydroxy group, an optionally halogenated lower alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl) , Pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5 , 5-trifluoro-pentyl, hexyl, 6,6,6-which may be halogenated such as trifluoroacetic hexyl C _1-6 alkyl Group), a lower alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, and the like C _1-6 alkoxy group such as hexyloxy), an amino group, a mono - lower alkylamino group (e.g. Mono-C _1-6 alkylamino groups such as methylamino and ethylamino), di-lower alkylamino groups (eg, di-C _1-6 alkylamino groups such as dimethylamino and diethylamino), carboxyl groups, Lower alkylcarbonyl group (for example, C _1-6 alkyl-carbonyl group such as acetyl and propionyl), lower alkoxycarbonyl group (for example, C _1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) Group), carbamoyl group, thiocarbamoyl Groups, mono-lower alkylcarbamoyl groups (for example, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl and ethylcarbamoyl), di-lower alkylcarbamoyl groups (for example, di-C such as dimethylcarbamoyl, diethylcarbamoyl and the like) _1-6 alkyl-carbamoyl groups, etc.), arylcarbamoyl groups (eg, C _6-10 aryl-carbamoyl groups such as phenylcarbamoyl, naphthylcarbamoyl etc.), aryl groups (eg, C _6-10 aryl groups such as phenyl, naphthyl etc.) Etc.), aryloxy groups (eg C _6-10 aryloxy groups such as phenyloxy, naphthyloxy etc.), lower alkylcarbonylamino groups which may be halogenated (eg acetylamino, trifluoroacetylamino etc.) an optionally halogenated C _1-6 alkyl - carbonylamino group), an oxo group, or the like is used. The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” has 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the hydrocarbon group. When the number of substituents is 2 or more, each substituent may be the same or different.

Preferred examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ¹ include an alkyl group (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl and the like). Group), alkenyl group (eg, C _2-6 alkenyl group such as vinyl), alkynyl group (eg, C _2-6 alkynyl group such as ethynyl), cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, etc.) , C _3-6 cycloalkyl groups such as cyclohexyl) and aryl groups (eg, C _6-14 aryl groups such as phenyl), etc., in particular alkyl groups (eg, C _1-6 alkyl groups such as methyl, etc.) and A cycloalkyl group (for example, C _3-6 cyclopropyl such as cyclopropyl) is generally used. The “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” are, for example, substituents that the above “hydrocarbon group” may have (preferably fluorine or the like). 1 to 5 and preferably 1 to 3 halogen atoms.

The “amino group optionally having substituent (s)” represented by R ¹ may have one or two of the above-mentioned “hydrocarbon group optionally having substituent (s)” as a substituent, for example. Examples include a good amino group. Preferred examples of the substituent which this “amino group” may have include 1 or 2 of a lower alkyl group which may have a substituent and an aryl group which may have a substituent. In particular, one lower alkyl group which may have a substituent is used. Examples of the “lower alkyl group” include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The “lower alkyl group” may have, for example, 1 to 3 substituents and the like which the above “hydrocarbon group” may have. As the “aryl group”, for example, a C _6-10 aryl group such as a phenyl group is used. The “aryl group” is, for example, a substituent which the above “hydrocarbon group” may have (preferably a halogen atom such as fluorine or chlorine, a C _1-6 alkoxy group such as methoxy or ethoxy). Or 5 to 1 and preferably 1 to 3. The “optionally substituted amino group” is, for example, a phenylamino group substituted with 1 to 3 lower alkoxy groups (eg, C _1-4 alkoxy group such as methoxy), or the like, A monoalkylamino group substituted with an alkyl group (eg, a C _1-4 alkyl group such as methyl, ethyl, propyl, butyl, tert-butyl, etc.) is generally used.

The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ¹ is, for example, one or two selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom 5- to 14-membered (preferably 5- to 10-membered) (monocyclic to tricyclic, preferably monocyclic or bicyclic) containing 1 to 4 (preferably 1 to 3) heteroatoms Examples include heterocyclic groups. For example 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- Or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyrazolidinyl, 2-, 4- Or a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom such as 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl; 4 5-membered cyclic groups such as 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2- 4-, 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino, 2-, 3- or 4-piperidyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- Or a 6-membered cyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, such as indolyl , Benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl Bicyclic or tricyclic condensed ring groups containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as manyl, phenothiazinyl and phenoxazinyl (preferably the above 5 to 5 6-membered ring is a group formed by condensing with 1 to 2 5- to 6-membered ring groups which may contain 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms) Etc. are used. Among these, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms is preferable.
Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ¹ include, for example, 1 to 1 selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom A 5- or 6-membered heterocyclic group containing 3 heteroatoms is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2- Piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl Etc. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl etc.) is used.

Examples of the substituent that the “heterocyclic group” of the “heterocyclic group which may have a substituent” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower Alkyl groups (for example, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), cycloalkyl groups (for example, cyclopropyl, cyclobutyl, C _3-6 cycloalkyl groups such as cyclopentyl, cyclohexyl, etc.), lower alkynyl groups (eg, C _2-6 alkynyl groups such as ethynyl, 1-propynyl, propargyl, etc.), lower alkenyl groups (eg, vinyl, allyl, iso C _2-6 alkenyl groups such as propenyl, butenyl, isobutenyl, etc.), aralkyl groups (eg benzyl, α-methylbenzyl, phenethyl) C _7-11 aralkyl group, etc.), aryl groups (eg, C _6-10 aryl groups such as phenyl, naphthyl, etc., preferably phenyl groups), lower alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy groups such as butoxy, isobutoxy, sec-butoxy and tert-butoxy), aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy), lower alkanoyl groups (eg formyl; acetyl) C _1-6 alkyl-carbonyl groups such as propionyl, butyryl, isobutyryl, etc.), arylcarbonyl (eg, C _6-10 aryl-carbonyl groups such as benzoyl group, naphthoyl group, etc.), lower alkanoyloxy groups (eg formyl) Oxy; C such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc. _1-6 alkyl-carbonyloxy group etc.), arylcarbonyloxy group (eg C _6-10 aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy etc.), carboxyl group, lower alkoxycarbonyl group (eg methoxycarbonyl) , Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, C _1-6 alkoxy-carbonyl groups such as tert-butoxycarbonyl), aralkyloxycarbonyl (for example, C _7-11 such as benzyloxycarbonyl, etc.) An aralkyloxycarbonyl group, etc.), a carbamoyl group, a mono-, di- or tri-halogeno-lower alkyl group (for example, mono- such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, Zima Or tri-halogeno-C _1-4 alkyl group), oxo group, amidino group, imino group, amino group, mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino) mono -C _1-4 alkylamino group, etc.) etc., di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di -C _1-4 alkyl such as methylethylamino An amino group, etc.), a 3- to 6-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom and one nitrogen atom (for example, Aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, pi 3 to 6-membered cyclic amino groups such as lysyl, morpholinyl, dihydropyridyl, pyridyl, N-methylpiperazinyl and N-ethylpiperazinyl), alkylenedioxy groups (eg methylenedioxy, ethylenedioxy, etc.) C _1-3 alkylenedioxy group, etc.), hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfayl group) Mono-C _1-6 alkylsulfamoyl groups such as moyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl), dialkylsulfamoyl groups (For example, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulf Di-C _1-6 alkylsulfamoyl groups such as famoyl), alkylthio groups (eg, C _1-6 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) Arylthio groups (for example, C _6-10 arylthio groups such as phenylthio and naphthylthio), lower alkylsulfinyl groups (for example, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like), an arylsulfinyl group C _1-6 alkyl, such as (e.g., C _6-10 arylsulfinyl groups such as phenylsulfinyl, naphthylsulfinyl), lower alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl Sulfonyl group, etc.), an arylsulfonyl group (e.g., phenylsulfonyl, C _6-10 arylsulfonyl groups such as naphthylsulfonyl, etc.) and the like.
The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” has 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the heterocyclic group. When the number of substituents is 2 or more, each substituent may be the same or different.

Preferred examples of the substituent of the “optionally substituted heterocyclic group” represented by R ¹ include a halogen atom (eg, chlorine, fluorine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl). Etc.), C _1-6 alkoxy groups (for example, methoxy, ethoxy and the like), aralkyloxycarbonyl groups (for example, C _7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl) and the like are used.

R ¹ may have, for example, (i) a lower alkyl group which may have a substituent, (ii) a lower cycloalkyl group which may have a substituent, and (iii) a substituent. A lower alkenyl group, (iv) an aryl group which may have a substituent, (v) a mono- or di-lower alkylamino group which may have a substituent, and (vi) an optionally substituted group. A good arylamino group or (vii) a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent is preferred.

The “lower alkyl group” is preferably a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. The “lower cycloalkyl group” is preferably a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The “lower alkenyl group” is preferably a C _2-6 alkenyl group such as vinyl, 1-propenyl, butenyl and the like. The “aryl group” is preferably a C _6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl and the like. “Lower alkylamino group” means mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, dimethylamino, diethylamino, methylethylamino, etc. Groups and the like are preferred. The “arylamino group” is preferably a C _6-10 arylamino group such as phenylamino. The “5- or 6-membered nitrogen-containing heterocyclic group” is preferably a 5- or 6-membered nitrogen-containing heterocyclic group such as 2-, 3- or 4-pyridyl. As the substituent that these groups may have, for example, 1 to 5 substituents that the “hydrocarbon group” may have are used.

More preferred examples of R ¹ are, i) halogen or C _1-6 1 not each alkoxy group to four substituents which may be C _1-6 alkyl group, ii) C _3-6 cycloalkyl group, iii) C _2-6 alkenyl groups, iv) C _1-6 alkoxy, nitro, halogeno C _1-6 alkyl-carbonylamino or C _6-10 aryl groups each optionally substituted by a halogen atom, v) mono _-Or di-C _1-6 alkylamino group, vi) a C _6-10 arylamino group optionally substituted by 1 to 3 C _1-6 alkoxy groups, or vii) a C _7-11 aralkyloxycarbonyl group. Or a 6-membered nitrogen-containing heterocyclic group which may be substituted by 1 to 2 or the like. In particular, an optionally halogenated C _1-6 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, penta Fluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5 -Trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.), C _3-6 cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) or mono-C _1-6 alkylamino group ( For example, methylamino, ethylamino, propylamino, isopropylamino, butyla Bruno, tert- butylamino, etc.), etc. are generic, inter alia, optionally halogenated C _1-6 alkyl group or a mono -C _1-6 alkylamino group, which may be especially halogenated C _1- Preferred are ₆ alkyl groups, especially C _1-3 alkyl groups (eg methyl, ethyl, propyl etc.).

R ² in the compound (I) represents a hydrogen atom or a hydrocarbon group which may have a substituent.
R ² is preferably a hydrogen atom or an optionally substituted lower (C _1-6 ) alkyl group, more preferably a hydrogen atom or a lower (C _1-6 ) alkyl group, particularly a hydrogen atom. Is widely used. The “substituent” of the “lower (C _1-6 ) alkyl group _optionally having substituent (s)” is, for example, the substituent that the above “hydrocarbon group” may have.

R ³ in the compound (I) represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent.
Preferred examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituents” represented by R ³ include alkyl groups (eg, C _1-6 such as methyl, ethyl, propyl, isopropyl and the like). Alkyl group etc.), alkenyl group (eg C _2-6 alkenyl group such as vinyl etc.), alkynyl group (eg C _2-6 alkynyl group such as ethynyl etc.), cycloalkyl group (eg cyclopropyl, cyclobutyl, etc.) C _3-6 cycloalkyl groups such as cyclopentyl and cyclohexyl) and aryl groups (eg, C _6-14 aryl groups such as phenyl), etc., especially alkyl groups (eg, C _1-6 alkyl groups such as methyl) In addition, aryl groups (for example, C _6-14 aryl groups such as phenyl) and the like are widely used. The “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” are, for example, substituents that the above “hydrocarbon group” may have (preferably fluorine or the like). 1 to 5 and preferably 1 to 3 halogen atoms.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ³ include 1 to 1 selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. A 5- or 6-membered heterocyclic group containing 3 heteroatoms is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2- Piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, etc. Is mentioned. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl etc.) is used.

Preferable substituents of the “optionally substituted heterocyclic group” represented by R ³ include, for example, a halogen atom (eg, chlorine, fluorine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl). Etc.), C _1-6 alkoxy group (eg methoxy, ethoxy etc.), aralkyloxycarbonyl group (eg C _7-12 aralkyloxy-carbonyl etc. such as benzyloxycarbonyl), amino group, mono-C _1-6 alkylamino A group (eg, methylamino, ethylamino, etc.), a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.) and the like are used.

R ³ has, for example, (i) a hydrogen atom, (ii) a lower alkyl group which may have a substituent, (iii) an aryl group which may have a substituent, and (iv) a substituent. An optionally substituted 5- or 6-membered heterocyclic group is preferred, and for example, (i) a hydrogen atom, (ii) a lower alkyl group, (iii) an optionally substituted C _6-10 aryl group, ( iv) A 6-membered nitrogen-containing heterocyclic group which may have a substituent is preferred. Examples of the substituent include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group, and a di-C _1-6 alkylamino group. More preferably, R ³ is a hydrogen atom, a phenyl group, a 2-, 3- or 4-pyridyl group. Particularly preferred is a hydrogen atom.

X in the compound (I) represents CHR ⁴ , NR ⁴ , O or S (R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent).
R ⁴ is preferably a hydrogen atom or an optionally substituted lower (C _1-6 ) alkyl group, and a hydrogen atom is generally used.
X is preferably CHR ⁴ (R ⁴ is as defined above), O or S. Alternatively, X is preferably CHR ⁴ or NR ⁴ (R ⁴ is as defined above).

  Y in compound (I) represents C, CH or N. Preferably it is C or CH.

〔式中、Ｅは（i）ＣＨ₂ＣＨ₂、（ii）ＣＨ＝ＣＨ、（iii）ＣＨ₂Ｏ、（iv）ＯＣＨ₂、（v）ＣＨ₂Ｓ(Ｏ)ｑ'（ｑ'は０ないし２の整数）、（vi）Ｓ(Ｏ)ｑ'ＣＨ２（ｑ'は上記と同意義）、（vii）ＣＨ₂ＮＨ、（viii）ＮＨＣＨ₂、（ix）Ｎ＝Ｎ、（x）ＣＨ＝Ｎ、（xi）Ｎ＝ＣＨまたは（xii）ＣＯＮＨ を示し、ｎ'は０ないし２の整数を示す。〕で表わされる環が好ましい。
Ｅは（i）ＣＨ₂ＣＨ₂、（ii）ＣＨ＝ＣＨ、（iii）ＣＨ₂Ｏ、（iv）ＯＣＨ₂、（v）ＣＨ₂ＮＨ、（vi）ＮＨＣＨ₂、（vii）Ｎ＝Ｎ、（viii）ＣＨ＝Ｎまたは（ix）Ｎ＝ＣＨが好ましく、特に（i）ＣＨ₂ＣＨ₂または（ii）ＣＨ＝ＣＨが好ましい。
具体的には、例えば２,３−ジヒドロフラン、フラン、１,３−ジオキソール、オキサゾリン、イソオキサゾール、１,２,３−オキサジアゾール、オキサゾール等の酸素原子を含む５員複素環、例えば２Ｈ−３,４−ジヒドロピラン、２Ｈ−ピラン、２,３−デヒドロ−１,４−ジオキサン、２,３−デヒドロモルホリン等の酸素原子を含む６員複素環等が好ましい。
さらに好ましくは、式

〔式中、ｎは０ないし２の整数を示し、---- は単結合または二重結合を示す。〕で表わされる環である。
具体的には、例えば、２，３−ジヒドロフラン、フラン、２Ｈ−３，４−ジヒドロピラン、２Ｈ−ピランが汎用される。 Ring A in compound (I) represents a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent.
The “heterocycle containing a 5- to 7-membered oxygen atom” means 1 to 3 (preferably 1 or 2) selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom and oxygen atom. Or 2) optionally 5 to 7 membered (preferably 5 or 6 membered) heterocyclic ring. The ring includes the formula

[In the formula, E is (i) CH ₂ CH ₂ , (ii) CH═CH, (iii) CH ₂ O, (iv) OCH ₂ , (v) CH ₂ S (O) q ′ (q ′ is 0 Or an integer of 2), (vi) S (O) q′CH2 (q ′ is as defined above), (vii) CH ₂ NH, (viii) NHCH ₂ , (ix) N = N, (x) CH = N, (xi) N = CH or (xii) CONH, and n 'represents an integer of 0 to 2. ] The ring represented by these is preferable.
E is _{(i) CH 2 CH 2,} (ii) CH = CH, (iii) CH 2 O, (iv) OCH 2, (v) CH 2 NH, (vi) NHCH 2, (vii) N = N, (Viii) CH = N or (ix) N = CH is preferable, and (i) CH ₂ CH ₂ or (ii) CH = CH is particularly preferable.
Specifically, for example, a 5-membered heterocyclic ring containing an oxygen atom such as 2,3-dihydrofuran, furan, 1,3-dioxole, oxazoline, isoxazole, 1,2,3-oxadiazole, oxazole, for example 2H Preferred are 6-membered heterocycles containing oxygen atoms such as 3,4-dihydropyran, 2H-pyran, 2,3-dehydro-1,4-dioxane, and 2,3-dehydromorpholine.
More preferably, the formula

[Wherein n represents an integer of 0 to 2, and ---- represents a single bond or a double bond. ] Is a ring represented by
Specifically, for example, 2,3-dihydrofuran, furan, 2H-3,4-dihydropyran, and 2H-pyran are widely used.

〔ｎは上記と同意義を示し、Ｒ⁵は水素原子または上記「Ａ環の好ましい置換基」で表された置換基１または２個を示す。〕等が挙げられる。中でも、Ｒ⁵が水素原子、置換基を有していてもよいＣ_1-6アルキル基であるもの、特にＲ⁵が水素原子であるもの（無置換Ａ環）が汎用される。
化合物（Ｉ）におけるＢ環は置換基を有していてもよいベンゼン環を示す。
Ｂ環の置換基としては、例えば上記「置換基を有していてもよいベンゼン環」の「置換基」が挙げられる。中でも、ハロゲン原子または置換基を有していてもよい低級（Ｃ_1-6）アルキル基が好ましく、特にハロゲン原子または低級（Ｃ_1-6）アルキル基（好ましくはメチル）が汎用される。該「置換基を有していてもよい低級（Ｃ_1-6）アルキル基」の「置換基」は例えば、上記「炭化水素基」が有していてもよい置換基を示す。
Ｂ環は該置換基を置換可能な位置に１または２個、好ましくは１個有していてもよく、置換基数が２個の場合は各置換基は同一または異なっていてもよい。
Ｂ環としては、例えば、

〔Ｒ⁶は水素原子、ハロゲン原子、置換基を有していてもよい低級（Ｃ_1-6）アルキル基または置換基を有していてもよい低級（Ｃ_1-6）アルコキシ基を示す。〕等が好ましい。Ｒ⁶は、例えば水素原子、ハロゲン原子または低級（Ｃ_1-6）アルキル基（好ましくはメチル）が好ましい。さらに好ましくは水素原子である。
化合物（Ｉ）におけるｍは１ないし４の整数を示す。ｍは１ないし３の整数が好ましい。さらに、ｍは２または３が好ましく、特に、ｍは２のときが好ましい。
上記式中、ｎは０ないし２の整数を示す。ｎは０または１の整数が好ましい。
特に、ｎは０のときが好ましい。

〔式中、Ｒ⁴'は置換基を有していてもよい炭化水素基を示し、その他の各記号は上記と同意義を示す。〕等が挙げられる。
Ｒ⁴'は好ましくは置換基を有していてもよい低級（Ｃ_1-3）アルキルである。

〔式中、各記号は上記と同意義を示す。〕等が示される。中でも、

〔式中、各記号は上記と同意義を示す。〕等が好ましい。

〔式中、各記号は上記と同意義を示す。〕等が好ましく用いられる。
このうち、

〔式中、各記号は上記と同意義を示す。〕等が好ましい。特に好ましくは

〔式中、各記号は上記と同意義を示す。〕である。
化合物（Ｉ）としては、例えば以下の構造式を有するもの等が特に汎用される。

〔式中、各記号は上記と同意義を示す。〕
化合物（Ｉ）の好ましい例として、式

〔式中、各記号は上記と同意義を示す。〕で表される化合物等が挙げられる。
また、化合物（Ｉ）の好ましい例としては、
Ｒ¹が（i）置換基を有していてもよい低級アルキル基、(ii）置換基を有していてもよい低級シクロアルキル基、(iii）置換基を有していてもよい低級アルケニル基、(iv）置換基を有していてもよいアリール基、(v）置換基を有していてもよいモノまたはジ低級アルキルアミノ基、(vi）置換基を有していてもよいアリールアミノ基または(vii）置換基を有していてもよい５または６員含窒素複素環基、
Ｒ²が水素原子または置換基を有していてもよい低級（Ｃ_1-6）アルキル基、
Ｒ³が（i）水素原子、(ii）置換基を有していてもよい低級アルキル基または(iii）置換基を有していてもよいアリール基、
ＸがＣＨＲ⁴またはＮＲ⁴（Ｒ⁴は水素原子またはオキソ基で置換されていてもよい低級（Ｃ_1-6）アルキル基を示す）、
ＹはＣ、ＣＨまたはＮ（但し、ＸがＣＨ₂を示す場合、ＹはＣまたはＣＨである）、
---- は単結合または二重結合を示し、
Ａ環が置換基を有していてもよい５ないし７員の酸素原子を含む複素環、
Ｂ環が置換基を有していてもよいベンゼン環、および
ｍが１または２である化合物等が挙げられる。 Examples of the substituent of the A ring include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, A lower alkynyl group which may have a substituent, a lower alkenyl group which may have a substituent, an aryl group which may have a substituent, a lower alkoxy group (for example, methoxy, ethoxy, propoxy, iso C _1-6 alkoxy groups such as propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy), lower alkanoyl groups (eg, formyl) ; acetyl, propionyl, butyryl, C _1-6 alkyl isobutyryl, etc. - such carbonyl group), an arylcarbonyl group (e.g., benzoyl group, naphthoquinone C _6-10 aryl such as yl group - carbonyl group), a lower alkanoyloxy group (e.g., formyloxy; acetyloxy, propionyloxy, butyryloxy, C _1-6 alkyl such as iso-butyryloxy - carbonyloxy group) Arylcarbonyloxy groups (for example, C _6-10 aryl-carbonyloxy groups such as benzoyloxy and naphthoyloxy), carboxyl groups, lower alkoxycarbonyl groups (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl) , butoxycarbonyl, isobutoxycarbonyl, C _1-6 alkoxy, such as tert- butoxycarbonyl - such carbonyl group), an aralkyloxycarbonyl (e.g., C _7-11 aralkyloxycarbonyl such as benzyloxycarbonyl - carbonyl group , Carbamoyl group, thiocarbamoyl group, mono-, di- or tri-halogeno-lower alkyl group (for example, mono-, di-, such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) Or tri-halogeno-C _1-4 alkyl group, etc.), oxo group, amidino group, imino group, amino group, mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) mono -C _1-4 alkylamino group, etc.), di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di -C _1-4 alkylamino such as methylethylamino Group, etc.), oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom and one nitrogen atom A 3- to 6-membered cyclic amino group optionally containing 1 to 3 heteroatoms such as aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, N-methylpiperazinyl, 3- to 6-membered cyclic amino groups such as N-ethylpiperazinyl), alkylenedioxy groups (for example, C _1-3 alkylenedioxy groups such as methylenedioxy and ethylenedioxy) Etc.), hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butyl Mono -C _1-6 alkylsulfamoyl group), dialkyl sulfamoyl group sulfamoyl (e.g., N, N-dimethylsulfamoyl, N, N-diethyl sulfamoyl, N, N-dipropyl Moyl, di-C _1-6 alkylsulfamoyl groups such as N, N-dibutylsulfamoyl), alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc. C _1-6 alkylthio groups, etc.), arylthio groups (eg, C _6-10 arylthio groups such as phenylthio, naphthylthio, etc.), lower alkylsulfinyl groups (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.) _1-6 alkylsulfinyl group), an arylsulfinyl group (e.g., phenyl Rufiniru, etc. C _6-10 arylsulfinyl group such as naphthylsulfinyl), lower alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc. C _1-6 alkylsulfonyl groups such as a butylsulfonyl), an arylsulfonyl group ( For example, C _6-10 arylsulfonyl groups such as phenylsulfonyl, naphthylsulfonyl, etc.) are used.
The “lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “lower cycloalkyl group”, “aryl group” are, for example, substituents that the above “hydrocarbon group” may have, etc. May be 1 to 5, preferably 1 to 3.
As the substituent for the A ring, a halogen atom, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkoxy group which may have a substituent, a hydroxyl group, a nitro group, cyano Group, an amino group optionally having a substituent, an oxo group and the like. The "optionally substituted C _1-6 alkyl group", "optionally substituted C _1-6 alkoxy group", "optionally substituted amino group" The “substituent” in the above represents, for example, a substituent that the above “hydrocarbon group” may have.
The ring A may have 1 to 4, preferably 1 to 2 substituents at the substitutable positions according to the size of the ring, and the number of substituents is 2 or more. Each substituent may be the same or different.
As the A ring, for example,

[N represents the same meaning as described above, and R ⁵ represents a hydrogen atom or one or two substituents represented by the above-mentioned “preferable substituents for the A ring”. ] Etc. are mentioned. Among them, those in which R ⁵ is a hydrogen atom or a C _1-6 alkyl group which may have a substituent, particularly those in which R ⁵ is a hydrogen atom (unsubstituted A ring) are generally used.
Ring B in compound (I) represents an optionally substituted benzene ring.
Examples of the substituent of the B ring include the “substituent” of the above “optionally substituted benzene ring”. Among them, a halogen atom or a lower (C _1-6 ) alkyl group which may have a substituent is preferable, and a halogen atom or a lower (C _1-6 ) alkyl group (preferably methyl) is particularly used. The “substituent” of the “lower (C _1-6 ) alkyl group _optionally having substituent (s)” is, for example, the substituent that the above “hydrocarbon group” may have.
Ring B may have one or two, preferably one, at the substitutable position, and when the number of substituents is 2, each substituent may be the same or different.
As the B ring, for example,

[R ⁶ represents a hydrogen atom, a halogen atom, an optionally substituted lower (C _1-6 ) alkyl group or an optionally substituted lower (C _1-6 ) alkoxy group. ] Is preferable. R ⁶ is preferably, for example, a hydrogen atom, a halogen atom or a lower (C _1-6 ) alkyl group (preferably methyl). More preferred is a hydrogen atom.
M in the compound (I) represents an integer of 1 to 4. m is preferably an integer of 1 to 3. Further, m is preferably 2 or 3, particularly preferably when m is 2.
In the above formula, n represents an integer of 0 to 2. n is preferably an integer of 0 or 1.
In particular, n is preferably 0.

[Wherein R ⁴ ′ represents a hydrocarbon group which may have a substituent, and other symbols are as defined above. ] Etc. are mentioned.
R ⁴ ′ is preferably lower (C _1-3 ) alkyl which may have a substituent.

[Wherein each symbol is as defined above. ] Etc. are shown. Above all,

[Wherein each symbol is as defined above. ] Is preferable.

[Wherein each symbol is as defined above. Etc. are preferably used.
this house,

[Wherein each symbol is as defined above. ] Is preferable. Especially preferably

[Wherein each symbol is as defined above. ].
As the compound (I), for example, compounds having the following structural formulas are generally used.

[Wherein each symbol is as defined above. ]
Preferred examples of compound (I) include compounds of the formula

[Wherein each symbol is as defined above. And the like.
Moreover, as a preferable example of compound (I),
R ¹ is (i) a lower alkyl group that may have a substituent, (ii) a lower cycloalkyl group that may have a substituent, and (iii) a lower alkenyl that may have a substituent. A group, (iv) an aryl group which may have a substituent, (v) a mono or di-lower alkylamino group which may have a substituent, and (vi) an aryl which may have a substituent A 5- or 6-membered nitrogen-containing heterocyclic group which may have an amino group or (vii) substituent,
R ² is a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent,
R ³ is (i) a hydrogen atom, (ii) a lower alkyl group which may have a substituent, or (iii) an aryl group which may have a substituent,
X is CHR ⁴ or NR ⁴ (R ⁴ represents a lower (C _1-6 ) alkyl group optionally substituted with a hydrogen atom or an oxo group),
Y is C, CH or N (provided that when X represents CH ₂ , Y is C or CH),
---- indicates a single bond or a double bond,
A heterocyclic ring containing a 5- to 7-membered oxygen atom in which ring A may have a substituent;
Examples thereof include a benzene ring optionally having a substituent in the B ring, and a compound in which m is 1 or 2.

〔各記号は上記と同意義を示す。〕
Ｂ環が

〔Ｒ⁶ａは水素原子、ハロゲン原子または低級（Ｃ_1-6）アルキル基を示す。〕、および
ｍが１または２である化合物等が挙げられる。
このうち、式

また、式

化合物（Ｉ）としては、例えば、Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５,４−ｂ］フラン−８−イル）エチル］アセトアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５,４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５,４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（３，７，８，９−テトラヒドロピラノ［３,２−ｅ］インドール−１−イル）エチル］プロピオンアミド、
Ｎ−［２−（５−フルオロ−３，７，８，９−テトラヒドロシクロペンタ［ｆ］［ｌ］ベンゾピラン−９−イル）エチル］プロピオンアミド、
Ｎ−［２−（３，７，８，９−テトラヒドロピラノ［３,２−ｅ］インドール−１−イル）エチル］ブチルアミド、
Ｎ−［２−（１，２，３，７，８，９−ヘキサヒドロピラノ［３,２−ｅ］インドール−１−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，２，３，７，８，９−ヘキサヒドロピラノ［３,２−ｅ］インドール−１−イル）エチル］ブチルアミド、
Ｎ−［２−（４−フルオロ−１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５,４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（４−フルオロ−１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５,４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
（Ｒ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］アセトアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（７，８−ジヒドロ−６Ｈ−インデノ［４，５−ｄ］−１，３−ジオキソール−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（７，８−ジヒドロ−６Ｈ−インデノ［４，５−ｄ］−１，３−ジオキソール−８−イル）エチル］ブチルアミド、
Ｎ−［２−（２，３，８，９−テトラヒドロ−７Ｈ−インデノ［４，５−ｂ］−１，４−ジオキシン−９−イル）エチル］プロピオンアミド、
Ｎ−［２−（２，３，８，９−テトラヒドロ−７Ｈ−インデノ［４，５−ｂ］−１，４−ジオキシン−９−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］ブチルアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド等が好ましいものとして挙げられる。
さらに好ましくは、Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］アセトアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（５−フルオロ−３，７，８，９−テトラヒドロシクロペンタ［ｆ］［１］ベンゾピラン−９−イル）エチル］プロピオンアミド、
Ｎ−［２−（５−フルオロ−１，２，３，７，８，９−ヘキサヒドロシクロペンタ［ｆ］［１］ベンゾピラン−９−イル）エチル］プロピオンアミド、
（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
（Ｒ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］アセトアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］ブチルアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミドである。
特に好ましくは、（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−フロ［３，２−ｅ］インドール−８−イル）エチル］ブチルアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド、
Ｎ−［２−（７−フェニル−１，６−ジヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］ブチルアミド、
Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル]アセトアミドである。
化合物（Ｉ）としては、式

〔式中、ＲはＣ_1-6アルキル基（メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル等）を示す。〕で表される化合物がとりわけ好ましく、具体的には、（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミド（以下、化合物Ａという）または（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］アセトアミド（以下、化合物Ｂという）が好ましい。
化合物（Ｉ）の塩としては、例えば薬理学的に許容される塩等が用いられる。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等が挙げられる。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、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩、並びにアルミニウム塩、アンモニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えばトリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６−ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’−ジベンジルエチレンジアミン等との塩が挙げられる。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、リン酸等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、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、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等との塩が挙げられる。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、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えばアスパラギン酸、グルタミン酸等との塩が挙げられる。
中でも薬学的に許容可能な塩が好ましく、その例としては、化合物（Ｉ）内に塩基性官能基を有する場合には、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等無機酸との塩、例えば酢酸、フタル酸、フマル酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ−トルエンスルホン酸等の有機酸との塩が挙げられ、酸性官能基を有する場合には、例えばナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩、アンモニウム塩等が挙げられる。
また、化合物（Ｉ）は、水和物であっても、非水和物であってもよい。
化合物（Ｉ）は、例えばＷＯ９７／３２８７１（日本特許第２８８４１５３号）に記載の方法またはこれに準じた方法等により得ることができる。 More preferably,
R ¹ is, i) halogen or C 1 to respectively _1-6 alkoxy group to four optionally substituted C _1-6 alkyl group, ii) C _3-6 cycloalkyl group, iii) C _2-6 alkenyl Groups, iv) C _1-6 alkoxy, nitro, halogeno C _1-6 alkyl-carbonylamino or C _6-10 aryl groups optionally substituted by 1 to 4 halogen atoms, respectively v) mono- or di- A C _1-6 alkylamino group, vi) a C _6-10 arylamino group optionally substituted with 1 to 3 C _1-6 alkoxy groups, or vii) a C _7-11 aralkyloxy-carbonyl group Two optionally substituted 6-membered nitrogen-containing heterocyclic groups, R ² is a hydrogen atom or a lower (C _1-6 ) alkyl group,
R ³ is (i) a hydrogen atom, (ii) a lower (C _1-6 ) alkyl group or (iii) a C _6-14 aryl group,
X is CHR ⁴ or NR ⁴ (R ⁴ represents a lower (C _1-6 ) alkyl group optionally substituted with a hydrogen atom or an oxo group),
Y is C, CH or N (provided that when X represents CH ₂ , Y is C or CH),
---- indicates a single bond or a double bond,
Ring A is

[Each symbol is as defined above. ]
Ring B is

[R ⁶ a represents a hydrogen atom, a halogen atom or a lower (C _1-6 ) alkyl group. And a compound in which m is 1 or 2.
Of these, the formula

Also the formula

Examples of the compound (I) include N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indol-1-yl) ethyl] propionamide,
N- [2- (5-fluoro-3,7,8,9-tetrahydrocyclopenta [f] [l] benzopyran-9-yl) ethyl] propionamide,
N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indol-1-yl) ethyl] butyramide,
N- [2- (1,2,3,7,8,9-hexahydropyrano [3,2-e] indol-1-yl) ethyl] propionamide,
N- [2- (1,2,3,7,8,9-hexahydropyrano [3,2-e] indol-1-yl) ethyl] butyramide,
N- [2- (4-Fluoro-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide;
N- [2- (4-Fluoro-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
(R) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl] propionamide,
N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl] butyramide,
N- [2- (2,3,8,9-tetrahydro-7H-indeno [4,5-b] -1,4-dioxin-9-yl) ethyl] propionamide,
N- [2- (2,3,8,9-tetrahydro-7H-indeno [4,5-b] -1,4-dioxin-9-yl) ethyl] butyramide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butyramide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide and the like are preferable.
More preferably, N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (5-fluoro-3,7,8,9-tetrahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide,
N- [2- (5-Fluoro-1,2,3,7,8,9-hexahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide,
(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
(R) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butyramide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide.
Particularly preferably, (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide,
N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butyramide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide,
N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butyramide,
N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide.
Compound (I) includes compounds of the formula

[Wherein, R represents a C _1-6 alkyl group (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). The compound represented by the formula is particularly preferred, and specifically, (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl. ) Ethyl] propionamide (hereinafter referred to as Compound A) or (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl Acetamide (hereinafter referred to as Compound B) is preferred.
As the salt of compound (I), for example, a pharmacologically acceptable salt or the like is used. Examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And 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 the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
Among them, a pharmaceutically acceptable salt is preferable. For example, when the compound (I) has a basic functional group, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, Salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc., and having an acidic functional group Examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt and the like.
Compound (I) may be a hydrate or non-hydrate.
Compound (I) can be obtained, for example, by the method described in WO97 / 32871 (Japanese Patent No. 2884153) or a method analogous thereto.

〔式中、Ａｒは置換基を有していてもよい芳香族基を示し、Ｘ’は−Ｏ−、−Ｓ−、−ＣＯ−、−ＳＯ−、−ＳＯ_２−および−ＣＯＯ−から選ばれる２価の基を１または２個含んでいてもよい２価のＣ_１−６脂肪族炭化水素基を示し、Ｙ’は２価のＣ_１−６脂肪族炭化水素基を示し、Ｒ’およびＲ”は、各々、同一または異なって、水素原子または置換基を有していてもよいＣ_１−６アルキルを示し、Ａ’環はさらに置換基を有していてもよいベンゼン環を、Ｂ’環はさらに置換基を有していてもよい４ないし８員環を示す。〕で表される化合物またはその塩（以下、化合物（ＩＩ）と称する場合がある）が挙げられる。 As another example suitable as “an unstable drug in a polyethylene glycol-containing preparation” in the present invention,

[In the formula, Ar represents an aromatic group which may have a substituent, and X ′ is selected from —O—, —S—, —CO—, —SO—, —SO ₂ — and —COO—. Represents a divalent C _1-6 aliphatic hydrocarbon group which may contain one or two divalent groups, Y ′ represents a divalent C _1-6 aliphatic hydrocarbon group, R ′ And R ″ are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl, and the A ′ ring further represents an optionally substituted benzene ring, Ring B ′ represents a 4- to 8-membered ring which may further have a substituent.] Or a salt thereof (hereinafter sometimes referred to as compound (II)).

Ar in compound (II) represents an aromatic group which may have a substituent.
As the “aromatic group” of the “optionally substituted aromatic group” represented by Ar, for example, a monocyclic aromatic group, a ring assembly aromatic group, a condensed aromatic group, and the like are used. .
As the “monocyclic aromatic group”, for example, a monovalent group formed by removing any one hydrogen atom from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring is used.
Examples of the “5- or 6-membered aromatic heterocycle” include one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (for example, 1 to 3, preferably 1 to 2). A 5- or 6-membered aromatic heterocyclic ring containing is used. Specifically, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine ring and the like are used.
Specific examples of the monocyclic aromatic group include phenyl, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 3- Alternatively, 4-pyridazinyl and the like are used, and phenyl and the like are particularly preferable.
Examples of the “ring-aggregating aromatic group” include two or more (preferably two or three) aromatic rings directly connected by a single bond, and the number of bonds directly connecting the rings is the number of ring systems. A group obtained by removing one arbitrary hydrogen atom from one less aromatic ring assembly is used. As the “aromatic ring”, aromatic hydrocarbon, aromatic heterocycle and the like are used.
Examples of the “aromatic hydrocarbon” include monocyclic or condensed polycyclic (eg, bicyclic or tricyclic) aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene, anthracene). Etc.) are used.
The “aromatic heterocycle” includes, for example, 5 to 1 containing 1 or more hetero atoms (for example, 1 to 4, preferably 1 to 2) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. A 14-membered, preferably 5- to 10-membered aromatic heterocycle is used. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxazole, iso Oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole 1 to 3 aromatic heterocycles such as isothiazole, phenothiazine, furazane, phenoxazine, phthalimide, 2-, 3- or 4-pyridone, 2-, 3 or 4-quinolone, or a ring (preferably monocyclic) thereof. A ring formed by condensation with a plurality of (preferably 1 or 2) aromatic rings (eg, benzene ring) is used.
Examples of the aromatic ring assembly in which these aromatic rings are directly connected by a single bond include, for example, 2 or 3 (preferably a benzene ring, a naphthalene ring, and a 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic ring. Is an aromatic ring assembly formed by 2). Preferred examples of this aromatic ring assembly include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazole, isothiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole, and an aromatic ring assembly composed of two or three aromatic rings selected from benzofuran, etc. Can be mentioned. More specific examples include, for example, 2-, 3- or 4-biphenylyl, 3- (1-naphthyl) -1,2,4-oxadiazol-5-yl, 3- (2-naphthyl) -1, 2,4-oxadiazol-5-yl, 3- (2-benzofuranyl) -1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazole-5- Yl, 3- (2-benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4-oxadiazol-2-yl, 3 -(2-Indolyl) -1,2,4-oxadiazol-2-yl, 4-phenylthiazol-2-yl, 4- (2-benzofuranyl) thiazol-2-yl, 4-phenyl-1,3 -Oxazol-5-yl, 5-phenylisothiazol-4-i 5-phenyloxazol-2-yl, 4- (2-thienyl) phenyl, 4- (3-thienyl) phenyl, 3- (3-pyridyl) phenyl, 4- (3-pyridyl) phenyl, 6-phenyl- 3-pyridyl, 5-phenyl-1,3,4-oxadiazol-2-yl, 4- (2-naphthyl) phenyl, 4- (2-benzofuranyl) phenyl, 4,4′-terphenyl and the like are used. In particular, biphenylyl (2-, 3- or 4-biphenylyl) is preferred.

Examples of the “condensed aromatic group” include a monovalent group formed by removing any one hydrogen atom from a condensed polycyclic (preferably 2 to 4 ring, preferably 2 or 3 ring) aromatic ring. Used. As the “condensed polycyclic aromatic ring”, a condensed polycyclic aromatic hydrocarbon, a condensed polycyclic aromatic heterocycle and the like are used.
Examples of the “fused polycyclic aromatic hydrocarbon” include condensed polycyclic (2 or tricyclic) aromatic hydrocarbons (eg, naphthalene, indene, anthracene, etc.) having 9 to 14 carbon atoms. Used.
The “fused polycyclic aromatic heterocycle” includes, for example, 9 to 14 members containing 1 or more (for example, 1 to 4) heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Preferably, a 9- or 10-membered condensed polycyclic aromatic heterocycle is used. Specifically, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalimide, etc. Aromatic heterocycles are used.
Specific examples of the above condensed aromatic group include, for example, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-benzimidazolyl, 1-indolyl. , 2-indolyl, 3-indolyl and the like, among which 1-naphthyl, 2-naphthyl and the like are preferable.

Examples of the substituent of the aromatic group represented by Ar include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), Nitro, cyano, optionally halogenated C _1-6 alkyl, C _6-10 aryloxy-C _1-6 alkyl (eg, phenoxymethyl, etc.), C _1-6 alkyl-C _6-10 aryl-C _2-6 alkenyl (eg, methylphenylethenyl, etc.), optionally halogenated C _3-6 cycloalkyl, optionally substituted C _7-16 aralkyl, _optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, optionally substituted C _6-10 aryloxy, C _{6-1 0} aryl-C _7-16 aralkyloxy (eg, phenylbenzyloxy, etc.), amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di- C _1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, etc. Is used. The “aromatic group” may have, for example, 1 to 5 and preferably 1 to 3 of the above substituents at the substitutable position of the aromatic group. When the number of substituents is 2 or more, Each substituent may be the same or different.
Of these substituents of the aromatic group represented by Ar, examples of the “C _7-16 aralkyl” of “optionally substituted C _7-16 aralkyl” include benzyl, phenethyl, naphthylmethyl, and the like. Is used.

As “C _6-10 aryloxy” of “C _6-10 aryloxy _optionally having substituent (s)”, for example, phenyloxy, naphthyloxy and the like are used. As the “substituent” of these “ _optionally substituted C _7-16 aralkyl” and “ _optionally substituted C _6-10 aryloxy”, for example, a halogen atom ( Examples, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, halogenated C _1-6 alkyl, halogen Optionally substituted C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkyl amino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di _{-C 1-6} alkylamino (e.g., dimethyl Mino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, _{C 1-6} alkyl optionally halogenated - _{carbonyl, C 1-6} alkoxy - carbonyl (e.g., methoxycarbonyl , Ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethyl) carbamoyl, ethylmethylcarbamoyl etc.), optionally halogenated _{C 1-6} alkylsulfonyl, formylamino, _{C 1-6} alkyl optionally halogenated - _{carboxamide, C 1-6} alkoxy Carboxamide (e.g., methoxy carboxamide, ethoxy carboxamide, propoxy carboxamide, such as butoxy carboxamide), C _1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl - carbonyloxy (e.g., acetoxy , Propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methyl) Carbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) 1 to 5 are used.

Among the substituents of the aromatic group represented by Ar, the “5- to 7-membered saturated cyclic amino” of the “optionally substituted 5- to 7-membered saturated cyclic amino” includes, for example, morpholino, thiomorpholino Piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethylene-1-yl and the like are used. Examples of the “substituent” of these “optionally substituted 5- to 7-membered saturated cyclic amino” include, for example, C _1-6 alkyl which may be halogenated, and substituent. Good C _6-14 aryl, _optionally substituted C _7-19 aralkyl, _optionally substituted 5- to 10-membered aromatic heterocyclic group, optionally substituted 1 to 3 of C _6-10 aryl-carbonyl, optionally halogenated C _1-6 alkyl-carbonyl, optionally halogenated C _1-6 alkylsulfonyl and the like are used.
Here, examples of “C _6-14 aryl” of “C _6-14 aryl _optionally having substituent (s)” include phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like. Is used. Preferred is phenyl. Examples of the “C _7-19 aralkyl” in the “ _optionally substituted C _7-19 aralkyl” include benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like are used, and preferably benzyl and the like. Examples of the “5- to 10-membered aromatic heterocyclic group” in the “optionally substituted 5- to 10-membered aromatic heterocyclic group” include 2-, 3- or 4-pyridyl, 1-, 2- or 3-indolyl, 2- or 3-thienyl and the like are used, and preferably 2-, 3- or 4-pyridyl and the like. Of - "carbonyl optionally having substituent _{C 6-10} aryl" - as the _{"C 6-10} aryl-carbonyl", e.g., benzoyl, 1-naphthoyl, and the like 2-naphthoyl. These “C _6-14 aryl _optionally having substituent (s)”, “C _7-19 aralkyl _optionally having substituent (s)”, “5- to 10-membered aromatic _optionally having substituent (s)” Examples of the “substituent” that each “heterocyclic group” and “optionally substituted C _6-10 aryl-carbonyl” may have include a halogen atom (eg, fluorine, chlorine, Bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated _{C 1-6} alkoxy optionally halogenated which may be _{C 1-6} alkylthio, hydroxy, amino, _{mono--C 1-6} alkylamino (e.g. Methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di -C _1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, Carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl -Carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, Methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamo) _{1-5 of} di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.).

The “acyl” in the “acyl”, “acylamino” and “acyloxy” as the “substituent” of the “aromatic group optionally having substituent (s)” represented by Ar is, for example, the formula: R ^a , —CO—OR ^a , —CO—NR ^a R ^a , —CS—NHR ^a , —SO ₂ —R ^aa or —SO—R ^aa
[Wherein, R ^a is (i) a hydrogen atom,
(Ii) A hydrocarbon group which may have a substituent, specifically, as a substituent, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _{1- 6} alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, optionally substituted 5- to 7-membered cyclic amino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl- _{carbonyl, C 1-6} alkoxy - _{carbonyl, C 6-10} aryl - _{carbonyl, C 6-10} aryloxy - _{carbonyl, C 7-16} aralkyloxy - carbonyl, mono- _{-C 1-6} alkyl - carbamoyl, di _{-C 1-6} alkyl - _{carbamoyl, C 6-10} aryl - carbamoyl, a _{C 1-6} alkylsulfonyl which may be _{halogenated, C 6-10} aryl Sulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl- Carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyl oxy, nicotinoyl oxy and _{C 6 10} substituent 1 to 5 which may have a hydrocarbon group selected from aryloxy or (iii) optionally substituted heterocyclic group, and specifically, as a substituent, a halogen Atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _{1 -6} alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, optionally substituted 5 to 5 7-membered cyclic amino, formyl, carboxy, carbamoyl, optionally halogenated _{C 1-6} alkyl - _{carbonyl, C 1-6} alkoxy - _{carbonyl, C 6-10} a Lumpur - _{carbonyl, C 6-10} aryloxy - _{carbonyl, C 7-16} aralkyloxy - carbonyl, mono- _{-C 1-6} alkyl - carbamoyl, di _{-C 1-6} alkyl - _{carbamoyl, C 6-10} aryl - carbamoyl Optionally halogenated C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _{1 -6} alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyl oxy, di _{-C 1-6} alkyl - carba Yloxy, C _6-10 aryl - indicates carbamoyloxy, nicotinoyloxy oxy and C _6-10 substituent 1 to heterocyclic group which may have five to selected from aryloxy,
R ^aa is (i) a hydrocarbon group which may have a substituent, specifically, as a substituent, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated. C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, Mono-C _1-6 alkylamino, di-C _1-6 alkylamino, optionally substituted 5- to 7-membered cyclic amino, formyl, carboxy, carbamoyl, optionally halogenated C _{1- 6} alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 arral Kiroxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, C _6-10 Arylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl -Carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl- Carbamoyloxy, nicotinoyloxy Fine C _6-10 substituent 1 to may have 1-5 amino acids substituents 1 are selected from which may have five hydrocarbon group selected from aryloxy, or (ii) a substituent Heterocyclic group that may be present, specifically, as a substituent, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, halogenated _Optionally C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, Di-C _1-6 alkylamino, optionally substituted 5- to 7-membered cyclic amino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-alkyl Rubonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _{1 -6} alkyl-carbamoyl, C _6-10 aryl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl -Carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- _{-C 1-6} A Kill - carbamoyloxy, di _{-C 1-6} alkyl - _{carbamoyloxy, C 6-10} aryl - carbamoyloxy, even to the substituents 1 are selected from nicotinoyloxy oxy and _{C 6-10} aryloxy optionally having five to A heterocyclic group which may have 1 to 5 substituents selected from the following:
R ^b represents a hydrogen atom or C _1-6 alkyl, or R ^a and R ^b may form a nitrogen-containing heterocycle together with the adjacent nitrogen atom. An acyl represented by the above formula is used.

As “a 5- to 7-membered saturated cyclic amino optionally having substituent (s)” as a substituent for R ^a and R ^aa , those similar to the above can be used.
As the hydrocarbon group represented by R ^a and R ^aa , a group obtained by removing one hydrogen atom from a hydrocarbon compound is used. For example, a chain or cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl) , Aryl, aralkyl, etc.). Of these, the following linear or cyclic hydrocarbon groups having 1 to 19 carbon atoms are preferred.
a) C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
b) C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 2-butenyl, etc.),
c) C _2-6 alkynyl (eg, ethynyl, propargyl, 2-butynyl, etc.),
d) C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), the C _3-6 cycloalkyl may be condensed with one benzene ring,
e) C _6-14 aryl (eg phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc.), preferably phenyl,
f) C _7-19 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5- Phenylpentyl and the like), preferably benzyl.

Examples of the heterocyclic group represented by R ^a and R ^aa include 1 or 2 types, 1 to 4 (preferably 1 to 3) heterocycles selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocycles containing atoms, preferably (i) 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles, (ii) 5- to 10-membered A monovalent group formed by removing any one hydrogen atom from a non-aromatic heterocyclic ring or (iii) a 7- to 10-membered heterocyclic bridged ring is used.
Examples of the “5- to 14-membered (preferably 5- to 10-membered aromatic heterocycle)” include, for example, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3 -B] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3 , 4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, One or more (preferably 1 or 2) aromatic heterocycles such as enanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine and phthalimide, or these rings (preferably monocycle). A ring formed by condensation with an aromatic ring (eg, a benzene ring).
Examples of the “5- to 10-membered non-aromatic heterocycle” include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, and the like.
Examples of the “7 to 10-membered heterocyclic bridged ring” include quinuclidine and 7-azabicyclo [2.2.1] heptane.

  The “heterocyclic group” is preferably a 5- to 10-membered (monocyclic) containing one or two, preferably 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Formula or bicyclic) heterocyclic group. Specifically, for example, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl, 4-isoquinolyl Aromatic heterocyclic groups such as, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-isoindolinyl, etc. 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino, etc. And aromatic heterocyclic groups. Among these, for example, a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom is preferred. Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-, 2 -Or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholino and the like are used.

Examples of “C _1-6 alkyl” represented by R ^b include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
Examples of the “nitrogen-containing heterocycle” formed by R ^a and R ^b together with the adjacent nitrogen atom include 1 to 3 selected from a nitrogen atom, a sulfur atom and an oxygen atom containing at least one nitrogen atom in addition to the carbon atom. A 5- to 7-membered nitrogen-containing heterocyclic ring which may contain one hetero atom is used, and examples thereof include piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine and the like.

Preferable examples of “acyl” as “substituent” of “aromatic group” represented by Ar include formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl, etc.), which may have a substituent C _6-10 aryl - carbonyl which may have a substituent C _{6 -10} aryloxy-carbonyl, _optionally substituted C _7-16 aralkyloxy-carbonyl, _optionally substituted 5-6 membered heterocyclic carbonyl, mono-C _1-6 alkyl- Carbamoyl, di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethyl Rumethylcarbamoyl), optionally substituted C _6-10 aryl-carbamoyl, optionally substituted 5-6 membered heterocyclic carbamoyl, optionally halogenated C _{1- 6} alkylsulfonyl, an optionally substituted C _6-10 arylsulfonyl, and the like.
Among these, as “C _6-10 aryl-carbonyl” of “ _optionally substituted C _6-10 aryl-carbonyl”, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like are used. . As “C _6-10 aryloxy-carbonyl” of “C _6-10 aryloxy-carbonyl _optionally having substituent (s)”, for example, phenoxycarbonyl and the like are used. As “C _7-16 aralkyloxy-carbonyl” in “C _7-16 aralkyloxy-carbonyl _optionally having substituent (s)”, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like are used. Examples of the “5- to 6-membered heterocyclic carbonyl” of the “optionally substituted 5- to 6-membered heterocyclic carbonyl” include nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3 -Furoyl, morpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl and the like are used. As “C _6-10 aryl-carbamoyl” of “C _6-10 aryl-carbamoyl _optionally having substituent (s)”, for example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like are used. Examples of the “5- to 6-membered heterocyclic carbamoyl” of the “optionally substituted 5- to 6-membered heterocyclic carbamoyl” include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2- Thienylcarbamoyl, 3-thienylcarbamoyl and the like are used. Examples of “C _6-10 arylsulfonyl” of “ _optionally substituted C _6-10 arylsulfonyl” include benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl and the like.

These “optionally substituted C _6-10 aryl-carbonyl”, “optionally substituted C _6-10 aryloxy-carbonyl”, “optionally substituted” “C _7-16 aralkyloxy-carbonyl”, “ _optionally substituted 5-6 membered heterocyclic carbonyl”, “optionally substituted C _6-10 aryl-carbamoyl”, “substituted” As the “substituent” of “optionally substituted 5-6 membered heterocyclic carbamoyl” and “optionally substituted C _6-10 arylsulfonyl”, a halogen atom, C _1-3 alkyl dioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6 alkoxy optionally, a C _1-6 alkylthio which may be halogenated, hydroxy Amino, _{mono--C 1-6} alkylamino, di _{-C 1-6} alkylamino, formyl, carboxy, carbamoyl, _{C 1-6} alkyl optionally halogenated - _{carbonyl, C 1-6} alkoxy - carbonyl, mono- -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C ₁ 1 to 5 substituents selected from _-6 alkyl-carbamoyloxy 1 to 3 are preferably used.

As the “acylamino” as the “substituent” of the “aromatic group optionally having substituent” represented by Ar above, for example, the “aromatic optionally having substituent” represented by Ar Amino substituted with 1 or 2 of “acyl” detailed in “Substituent” of “Group” is used, preferably
Formula: —NR ^c —COR ^d , —NR ^c —COOR ^da , —NR ^c —SO ₂ RR ^da or —NR ^c —CONR ^da R ^db
[Wherein, R ^c is a hydrogen atom or C _1-6 alkyl, R ^d is the same as R ^a , R ^da is the same as R ^aa, and R ^db is the same as R ^b ] Acylamino and the like are used.
_{"C 1-6} alkyl" represented by R ^c and ^{R db} is the same as the _{"C 1-6} alkyl" represented by ^{R b} are used.
As "acylamino" as the "substituent" of the "aromatic group which may have a substituent" represented by Ar, preferably, formylamino, C _1-6 alkyl optionally halogenated - carboxamide An optionally substituted C _6-10 aryl-carboxamide (eg, phenylcarboxamide, naphthylcarboxamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc. ), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.).
Examples of the “acyloxy” as the “substituent” of the “optionally substituted aromatic group” represented by Ar include the above-mentioned “optionally substituted aromatic group”. Oxy substituted by one “acyl” as detailed in “Substituent” in FIG. 5 is used, and preferably, the formula: —O—COR ^e , —O—COOR ^e or —O—CONHR ^e
[In the formula, R ^e is as defined above for R ^a ] acyloxy and the like are used.
As “acyloxy” as “substituent” of “optionally substituted aromatic group” represented by Ar, preferably C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.) ), Optionally substituted C _6-10 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, Methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyl Oxy (eg, dimethylcarbamoyloxy, diethyl carbonate) Etc. Bamoiruokishi), substituent optionally C _6-10 aryl optionally having - carbamoyloxy (e.g., phenylcarbamoyloxy, etc. naphthylcarbamoyl oxy), and nicotinoyl oxy is used. These “optionally substituted C _6-10 aryl-carboxamide”, “optionally substituted C _6-10 aryl-carbonyloxy”, and “optionally substituted” Examples of the “substituent” of “good C _6-10 aryl-carbamoyloxy” and “preferred examples” thereof include the “substituent” of “optionally substituted C _6-10 aryl-carbonyl”. Similar ones are used.
Among the above, Ar is preferably a ring-aggregated aromatic group (particularly biphenylyl such as 2-, 3- or 4-biphenylyl) which may have a substituent.

X ′ in compound (II) may contain one or two divalent groups selected from —O—, —S—, —CO—, —SO—, —SO ₂ — and —COO—. Y 'represents a divalent C _1-6 aliphatic hydrocarbon group, and Y ′ represents a divalent C _1-6 aliphatic hydrocarbon group.
As the C _1-6 aliphatic hydrocarbon group, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene and the like are used.
Examples of the C _1-6 alkylene include —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — ( In addition to linear C _1-6 alkylene such as CH ₂ ) ₆ —, C _1-3 alkylene optionally having 1 to 3 C _1-3 alkyl (eg, —CH ₂ —, — ( CH ₂ ) ₂ —, — (CH ₂ ) ₃ — and the like) are used.
Examples of the C _2-6 alkenylene include 1 to 3 C _1-3 alkyls in addition to a linear C _2-6 alkenylene such as —CH═CH— and —CH ₂ —CH═CH—. C _2-3 alkenylene (for example, —CH═CH—, —CH ₂ —CH═CH— and the like) which may be used is used.
Examples of the C _2-6 alkynylene include —C≡C—, —CH ₂ —C≡C—, —C≡C—CH ₂ —, —C≡C—CH ₂ CH ₂ —, —CH ₂ CH. _2- C≡C—, —CH ₂ —C≡C—CH ₂ —, — (CH ₂ ) ₂ —C≡C—CH ₂ —, — (CH ₂ ) ₂ —C≡C— (CH ₂ ) _{2 -, - (CH 2) 3} -C≡C-CH 2 - in addition to the linear _{C 2-6} alkynylene, such as, one to three _{C 1-3} optionally _{C 2-3} which may have an alkyl alkynylene _{(e.g., -C≡C -, - CH 2 -C≡C} -, - C≡C-CH 2 -, - C≡C-CH 2 CH 2 -, - CH 2 CH 2 -C≡C- etc. ) Is used.
As the C _1-6 aliphatic hydrocarbon group, a C _1-3 aliphatic hydrocarbon group such as C _1-3 alkylene, C _2-3 alkenylene, C _2-6 alkynylene and the like are particularly preferable.
In particular, X _1-3 is preferably C _1-3 alkylene containing one —O—, and Y ′ is preferably C _1-3 alkylene.

R ′ and R ″ in compound (II) are the same or different and each represents C _1-6 alkyl which may have a substituent.
“C _1-6 alkyl” of “C _1-6 alkyl _optionally having substituent (s)” for R ′ and R ″ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , Tert-butyl, pentyl, hexyl and the like are used, and methyl, ethyl, propyl and the like are particularly preferable.
As the “substituent” of “C _1-6 alkyl optionally having substituent (s)” represented by R ′ or R ″, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, C _1-6 alkoxy which may be halogenated, C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, optionally halogenated) isopropylamino, etc. butylamino), di _{-C 1-6} alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino Ethylmethylamino, etc.), formyl, carboxy, carbamoyl, _{C 1-6} alkyl optionally halogenated - _{carbonyl, C 1-6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl Mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), halogenated which may be _{C 1-6} alkylsulfonyl, formylamino, _{C 1-6} alkyl optionally halogenated - _{carboxamide, C 1-6} alkoxy - carboxamide (e.g., methoxy carboxamide, Etokishika Bokisamido, propoxy carboxamide, such as butoxy carboxamide), C _1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl - carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.) 1 to 5 di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted aromatic group, etc. 1 to 3 are used. When the number of substituents is 2 or more, each substituent may be the same or different.

The A ′ ring in compound (II) represents a benzene ring that may further have a substituent. That is, the A ′ ring may further have a substituent at the substitutable position in addition to the group represented by the formula Ar—X′—. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl which may be halogenated, C _1-6 alkoxy which may be halogenated. , Hydroxy, amino and the like are used. The "optionally halogenated C _1-6 alkyl optionally" and "optionally halogenated C _1-6 alkoxy optionally" means may be "halogenated detailed in the Ar C _1-6 Those similar to “alkyl” and “optionally halogenated C _1-6 alkoxy” are used respectively. As the substituent for the A ring, a halogen atom (eg, chlorine) and C _1-6 alkoxy (eg, methoxy) are particularly preferable. 1 to 3 of these substituents may be substituted at substitutable positions on the A ′ ring, and when the number of substituents is 2 or more, each substituent may be the same or different. The case where the A ′ ring is substituted only with a group represented by the group represented by the formula Ar—X′— is particularly preferred.

〔式中、- - -は単結合または二重結合、
Ｚ’は（ｉ）結合手、（ii）Ｃ_１−４アルキレンまたは（iii）Ｃ_２−４アルケニレンを示す〕で表される環が挙げられる。Ｚ’は、好ましくは、Ｃ_１−３アルキレン、さらに好ましくは、エチレンである。
該「４ないし８員環」として好ましくは、式

〔式中、Ｚ’は上記と同意義を示す〕で表される環である。好ましくは、Ａ’環と縮合している部分以外には二重結合を含まず、炭素原子以外に、１個の酸素原子またはイミノを含んでいてもよい６員同素または複素環である。
Ｂ’環で示される「置換基を有していてもよい４ないし８員環」の「置換基」としては、例えば、オキソ、Ｃ_１−６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチルなど）、ヒドロキシなどが挙げられる。該置換基は置換可能な位置に１ないし３個置換されていてもよく、置換基数が２個以上の場合は各置換基は同一または異なっていてもよい。
Ｂ’環は、好ましくは、式

で表わされる基以外に置換基を有しない６員同素または複素環である。 The B ′ ring in compound (II) represents a 4- to 8-membered ring which may further have a substituent.
The 4- to 8-membered ring represented by the B ′ ring may contain one double bond in addition to the portion condensed with the A ′ ring, and from oxygen atoms, nitrogen atoms and sulfur atoms in addition to carbon atoms. Examples thereof include 4 to 8 membered allotrope or heterocyclic ring which may contain 1 to 3 heteroatoms. As a specific example, the expression

Wherein - - - is a single bond or a double bond,
Z ′ represents a ring represented by (i) a bond, (ii) C _1-4 alkylene or (iii) C _2-4 alkenylene). Z ′ is preferably C _1-3 alkylene, more preferably ethylene.
The “4- to 8-membered ring” is preferably a compound of the formula

[Wherein Z ′ is as defined above]. Preferably, it is a 6-membered allotrope or heterocycle which does not contain a double bond other than the portion fused with the A ′ ring and may contain one oxygen atom or imino other than the carbon atom.
Examples of the “substituent” of the “optionally substituted 4- to 8-membered ring” represented by B ′ ring include oxo, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, Butyl), hydroxy and the like. 1 to 3 substituents may be substituted at substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different.
The B ′ ring is preferably of the formula

A 6-membered allotrope or heterocycle having no substituent other than the group represented by

で表される環である。特にテトラリンが好ましい。
化合物（Ｉ）としては特に、６−（４−ビフェニリル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン、６−（４−ビフェニリル）メトキシ−２−（Ｎ，Ｎ−ジプロピルアミノ）メチルテトラリン、その塩およびその光学活性体など、とりわけ、（Ｒ）−（＋）−６−（４−ビフェニリル）メトキシ−２−［２−（Ｎ，Ｎ−ジメチルアミノ）エチル］テトラリン（（Ｒ）−６−［（１，１’−ビフェニル）−４−イルメトキシ］−１，２，３，４−テトラヒドロ−Ｎ，Ｎ−ジメチル−２−ナフタレンエタナミンとも称する）塩酸塩１水和物（化合物Ｃ）が好適である。 The condensed ring formed by the A ′ ring and the B ′ ring is preferably a formula

Is a ring represented by Tetralin is particularly preferable.
Especially as compound (I), 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N- Dipropylamino) methyltetralin, its salts and optically active forms thereof, among others (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] Tetralin ((R) -6-[(1,1′-biphenyl) -4-ylmethoxy] -1,2,3,4-tetrahydro-N, N-dimethyl-2-naphthaleneethanamine) hydrochloride 1 Hydrates (Compound C) are preferred.

Examples of the salt of compound (II) include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. .
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, A salt with p-toluenesulfonic acid or the like is used. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is used.
Of these salts, pharmaceutically acceptable salts are preferred. For example, when the compound (II) has an acidic functional group, an alkali metal salt (for example, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example, calcium salt, magnesium salt, barium salt, etc.), etc. Inorganic salts, ammonium salts, and the like, and when the compound (II) has a basic functional group, an inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide, or the like, Organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate, and tartrate are used.
Furthermore, compound (II) may be either an anhydride or a hydrate. In the case of a hydrate, it may have 1 to 3 H ₂ O molecules.
Compound (II) may be a prodrug similar to that described for compound (I) above.
Compound (II) may be labeled with an isotope (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).
Compound (II) can be produced according to the production method described in JP-A-11-80098. Alternatively, as an improved method, when an amide bond and an ether bond are present in the same molecule, only the ether bond is selectively cleaved in the presence of methanesulfonic acid and methionine, and then subjected to an alkylation reaction. It can also be produced by reducing the amide moiety.

Examples of the above-mentioned “formulation component” include excipients (eg, lactose, sucrose, D-mannitol, D-sorbitol, starch (corn starch, potato starch, etc.), pregelatinized starch, dextrin, crystalline cellulose, low substitution degree. Hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextran, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, etc.), binder (eg pregelatinized starch, sucrose, gelatin, gum arabic powder) , Methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, dextrin, pullulan, etc. ), Lubricant (eg, magnesium stearate, calcium stearate, talc, colloidal silica, etc.), disintegrant (eg, lactose, sucrose, carboxymethylcellulose, low-substituted hydroxypropylcellulose, starch (corn starch, potato starch, etc.) , Light anhydrous silicic acid, croscarmellose sodium, carboxymethyl starch sodium, carboxymethylcellulose calcium, cros polyvinylpyrrolidone, etc.), colorant, fragrance, flavoring agent, adsorbent, preservative, wetting agent, antistatic agent, disintegration extender Etc.
The amount used for the preparation of the general preparation may be used as the amount of the preparation component described above.

  Examples of the dosage form of the “formulation” of the present invention include tablets, capsules, powders, granules, fine granules, pills and the like. The granule contains, for example, about 90% by weight or more of particles having a particle size of about 500 to about 1410 μm and about 5% by weight or less of particles having a particle size of about 177 μm or less. The fine granule is, for example, about 75% by weight or more of particles having a particle size of about 10 to about 500 μm, about 5% by weight or less of particles having a particle size of about 500 μm or more, and about 10% by weight of particles having a particle size of about 10 μm or less. Contains the following. A preferred fine granule contains about 75% by weight or more of particles having a particle size of about 150 to about 500 μm, about 5% by weight or less of particles having a particle size of about 500 μm or more, and about 10% by weight or less of particles having a particle size of about 74 μm or less. To do.

The “formulation” of the present invention is produced by coating a “drug-containing composition” obtained by mixing the above-mentioned “drug” and “formulation component” by a conventional method with a “coating agent”.
What is necessary is just to select the usage-amount of a coating agent according to the dosage form of a formulation. The amount of coating (dry weight) used in the formulation is, for example, about 0.1 to about 30% by weight for tablets, preferably about 0.5 to about 10% by weight; 1 to about 50% by weight, preferably about 1 to about 20% by weight; for fine granules, it is about 0.1 to about 100% by weight, preferably about 1 to about 50% by weight.

As a coating method, a method known per se, such as a pan coating method, a fluid coating method, a rolling coating method, or a method combining them can be employed. Further, when the coating agent is a solution or dispersion containing water or an organic solvent, a spray coating method can also be employed as a coating method.
The temperature during coating is usually about 25 to about 60 ° C, preferably about 25 to about 40 ° C.
In addition, the time required for coating can be appropriately selected in consideration of the coating method, the characteristics and usage of the coating, the characteristics of the pharmaceutical preparation, and the like.

Since the above-mentioned compound (I) has an excellent melatonin action, has low toxicity and is safe without side effects, it can be suitably used for the preparation of the present invention.
For example, when the compound (I) or a salt thereof is used as a drug, the “formulation” of the present invention is a disease that may be affected by melatonin such as impaired biological rhythm, such as sleep-wake rhythm disorder, jet lag (jet) lag), modulation of physical condition due to three shifts, seasonal depression, reproductive and neuroendocrine diseases, senile dementia, Alzheimer's disease, various disorders associated with aging (for example, prevention of aging), cerebral circulation disorders (stroke, etc.) Can be used for prevention and treatment of head injury, bone marrow injury, stress, epilepsy, convulsions, anxiety, depression, Parkinson's disease, hypertension, glaucoma, cancer, insomnia, diabetes, etc. It is also effective for mental stability or ovulation regulation (eg, contraception). Therefore, when compound (I) or a salt thereof is used in the pharmaceutical preparation of the present invention, for example, a biological rhythm regulator, preferably a sleep disorder therapeutic agent (eg, sleep inducer), a sleep wake rhythm regulator (sleep wake rhythm) It is also used as a preventive / therapeutic agent for time zone change syndrome, so-called jet lag.
The dose of the “pharmaceutical preparation” of the present invention may be selected so that the dose as a drug is an effective dose in consideration of the type of drug, the type of target disease, symptoms, dosage form, etc. . For example, when the compound (I) or a salt thereof is used as a drug, the “pharmaceutical preparation” means that the dosage of the compound (I) or a salt thereof is about 0.01 mg to about 100 mg per day in an adult (body weight 60 kg), preferably Is administered at a dose of about 0.1 to about 30 mg, more preferably about 0.3 to about 10 mg, once or in 2 or 3 divided doses. In particular, in the case of the compounds A and B, the daily dose is administered in the range of about 0.3 mg to 64 mg.

In addition, since the compound (II) described above has an excellent amyloid β protein production / secretion inhibitory action and an excellent secretory APP secretion promoting action, and also has a β-selectase inhibitory action, it is a neurodegenerative disease; Amyloid angiopathy: Effective for prevention and treatment of cerebrovascular disorders (eg, cerebral infarction, cerebral hemorrhage, etc.), head injury, or neuropathy due to spinal cord injury.
In addition, compound (II) is low in toxicity and excellent in brain migration.
Therefore, compound (II) is preferably used in the preparation of the present invention, and safely, due to neurodegenerative diseases of mammals such as humans; amyloid angiopathy; cerebrovascular disorders (eg, cerebral infarction, intracerebral hemorrhage, etc.) As a prophylactic / therapeutic agent for neuropathy due to head trauma or spinal cord injury, and to improve various mental disorders caused by neurodegeneration and neuropathy (eg, depression, anxiety, threatening neuropathy, sleep disorder, etc.) It is also useful as an agent. Compound (II) is preferably a neurodegenerative disease (eg, Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic spinal sclerosis, diabetic neuropathy, Huntington's chorea) As a prophylactic / therapeutic agent for multiple sclerosis and the like, it can be used more preferably as a prophylactic / therapeutic preparation for neurodegenerative diseases (eg, Alzheimer's disease, Down's disease, etc.) caused by amyloid β protein. Particularly preferably, it is useful as a preventive / therapeutic agent for Alzheimer's disease.
The preparation of compound (II) may be used in combination with other anti-dementia drugs (eg, acetylcholinesterase inhibitor).
In the preparation of the present invention, the content of compound (II) is 0.1 to 100% by weight of the whole agent. The dose varies depending on the administration subject, administration route, disease and the like, but for example, about 0 as an active ingredient (compound (II)) as an oral agent for an adult (about 60 kg) as an Alzheimer's disease therapeutic agent. .1 to 500 mg, preferably about 1 to 100 mg, more preferably 5 to 100 mg, and can be administered in 1 to several times a day.

  Hereinafter, the present invention will be described more specifically by reference examples, examples, comparative examples, and test examples.

Reference example 1

Synthesis of 2,3-dihydrobenzofuran-5-carbaldehyde
2,3-dihydrobenzofuran 100.0 g (832.3 mmol) and N, N-dimethylformamide 133.8 g (1830.6 mmol) were mixed and heated, and phosphorus oxychloride 255.2 g (1643.0 mmol) was added at an internal temperature of 70-80 ° C. It was added dropwise over time. The mixture was heated at an internal temperature of 80 to 90 ° C. and stirred for 7.5 hours, then cooled, dropped into 1000 g of water and stirred at room temperature for 5 hours. The mixture was extracted with toluene, washed successively with water, saturated aqueous sodium hydrogen carbonate, and water, and the organic layer was concentrated under reduced pressure to give a toluene solution of the title compound (yield 340 g, apparent yield 100%).

Reference example 2

Synthesis of (E) -3- (2,3-dihydrobenzofuran-5-yl) propenoic acid ethyl ester Under cooling, 205.3 g (915.7 mmol) of triethylphosphonoacetate was added dropwise. Subsequently, a solution obtained by suspending 88.0 g (1187.3 mmol) of t-butoxy sodium in 530 g of toluene was added dropwise and stirred for 1 hour, and then 20 g of acetic acid and 500 g of water were further added dropwise. After the temperature was raised to room temperature, liquid separation was performed. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and water in this order, and the organic layer was concentrated to 300 mL or less under reduced pressure, and 396 g of methanol was added and dissolved by heating. 500 g of water was added dropwise at room temperature and stirred to precipitate crystals, which were collected by filtration and dried under reduced pressure to give the title compound (yield 161.3 g, yield 88.1%).

Reference example 3

Synthesis of ethyl 3- (2,3-dihydrobenzofuran-5-yl) propionate
Dissolve ethyl (E) -3- (2,3-dihydrobenzofuran-5-yl) propionate (50.0 g 227.3 mmol) in 312.0 g of acetic acid, purge the system with nitrogen, and then add 4.96 g of 5% Pd / C (as Dry) and pressurize with hydrogen to 196-294kPa. The mixture was reacted at 50 ° C. and a pressure of 196 to 294 kPa for 1 hour, and the catalyst was filtered and washed with 208 g of acetic acid to obtain an acetic acid solution of the title compound (yield 569.3 g, apparent yield 100%).

Reference example 4

Synthesis of 3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid To the PPE / acetic acid solution (569.3 g, 227.3 mmol) from the step of Reference Example 3 was added 18.6 g of anhydrous sodium acetate. While stirring and cooling, 221.6 g of bromine was added dropwise over 2 hours, followed by reaction at room temperature for 4 hours. The resultant was added dropwise to 670 ml of a cooled 15% anhydrous sodium sulfite aqueous solution and stirred for 30 minutes. After adding 118 g of acetonitrile and reacting with heating under reflux for 2 hours, cooling slowly, stirring for 1 hour, crystallizing, filtering, washing with water and drying under reduced pressure gave the title compound (yield 63.3 g, yield 73.2%). It was.

Reference Example 5

Synthesis of 4,5-dibromo-1,2,6,7-tetrahydro-8Hindeno [5,4-b] furan-8-one
3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid 40.0 g 114.3 mmol), ο-dichlorobenzene 182 g, N, N-dimethylformamide 0.1 g were mixed, and the internal temperature was 42 ° C. Then, 17.7 g (148.8 mmol) of thionyl chloride was added dropwise thereto and stirred for 30 to 40 minutes to obtain an acid chloride solution.
Next, 17.5 g (131.5 mmol) of anhydrous aluminum chloride was added in several portions under ice cooling, and the mixture was stirred for 30 minutes. Separately, 475 g of methanol was prepared, and the reaction solution was dropped into this methanol to cause crystallization. 76 g of water was added dropwise to the crystallization solution under cooling and stirred for 30 minutes, followed by filtration.The wet crystals were washed with methanol, water, saturated aqueous sodium bicarbonate, water and methanol and dried under reduced pressure to give 31.6 g of the title compound (92.2% yield) )

Reference Example 6

Synthesis of 1,2,6,7-tetrahydro-8H-indeno [5,4-b] furan-8-one
2,5-dibromo-1,2,6,7-tetrahydro-8Hindeno [5,4-b] furan-8-one 23.3 g (70.3 mmol), anhydrous sodium acetate 14.4 g (175.5 mmol), and methanol 373 g The mixture was purged with nitrogen, and 1.28 g (as Dry) of 10% Pd / C was added. The mixture was pressurized to 490 kPa with hydrogen and stirred, and contact-reduced at 40 ° C. and a pressure of 294 to 490 kPa for 2 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure. Further, water was added and the mixture was concentrated under reduced pressure to replace the solvent, cooled, stirred for 1 hour and aged. The crystallized solution was filtered to obtain wet crystals of the title compound (yield 14.4 g, yield 86.5%).
[Purification process]
Wet crystals 13.2 g (55.7 mmol), activated carbon Shirasagi A-1 0.5 g, and methanol 320 g were mixed, stirred for 1 hour under reflux, and then filtered. The filtrate was concentrated under reduced pressure, then refluxed for 1 hour and cooled. Under cooling, 24 g of water was added dropwise, and after aging for 1 hour, the precipitate was filtered and dried under reduced pressure to obtain the title compound (yield 9.4 g, yield 96.0%).

Reference Example 7

Synthesis of (E)-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) acetonitrile 184 g of toluene, 1,2,6,7-tetrahydro-8H-indeno 11.3 g of 28% sodium methoxide methanol solution was added dropwise over 1 hour to 8.5 g (48.9 mmol) of [5,4-b] furan-8-one and 10.4 g (58.7 mmol) of diethyl cyanomethylphosphonate under ice-cooling. And reacted for 4 hours. After dropping 85 g of water into the reaction solution and heating and separating, the organic layer was washed with water, and the organic layer was subjected to dust filtration under pressure. The organic layer was concentrated under reduced pressure, methanol was added, and the mixture was concentrated under reduced pressure to replace the solvent. The mixture was stirred for 1 hour with heating under reflux, then cooled and aged for 1 hour. The crystallized solution was filtered and dried under reduced pressure to obtain the title compound (yield 8.1 g, yield 84.4%).

Reference Example 8

Synthesis of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine hydrochloride
(E)-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) acetonitrile (10.0 g, 50.7 mmol) in toluene (37.5 ml) and methanol (12.5 ml ) Expanded cobalt (7.22 g) and 14.4% aqueous potassium hydroxide solution (1.4 g) were added to the mixed suspension, and the mixture was stirred at 34-50 ° C. for 6.5 hours in a hydrogen atmosphere (0.2 MPa). After the reaction solution was filtered, toluene (170 ml) and methanol (35 ml) were added to the filtrate for liquid separation. 0.5 N Hydrochloric acid (101 ml) was added to the organic layer, and the mixture was stirred at 25-30 ° C. for 30 minutes and then separated. Activated carbon (1 g) was added to the aqueous layer and stirred. The activated carbon was filtered to obtain an aqueous solution of the title compound (246 g, Net 12.0 g, yield 99.6%).

Reference Example 9

Synthesis of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride
(E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine hydrochloride in 246 g (Net 12.0 g, 50.5 mmol) in toluene (44.4 ml) and 5% aqueous sodium hydroxide solution (40.2 g) were added, and the mixture was stirred at 22-26 ° C. for 1 hour. Separated, methanol (7 ml) and [RuCl (benzene) (R) -BINAP] Cl (0.0922 g) were added to the organic layer under a nitrogen atmosphere, and under a hydrogen atmosphere (4.9 MPa) at 70 ° C. for 15 hours. Stir. The reaction solution was cooled, water (17.6 and 1N hydrochloric acid 38.7 ml) was added at 0-10 ° C., and the mixture was stirred for 30 minutes and then separated. Pd-C (50% wet, 1.9 was added to the aqueous layer, and the mixture was stirred under a hydrogen atmosphere (4.9 MPa) for 3 hours at 50 ° C. After filtration, the organic layer was concentrated under reduced pressure to give a residue (10.2 g) Was recrystallized from a mixture of normal butanol and water to give the title compound (8.44 g, 69.7% yield), which was measured for its optical purity by high performance liquid chromatography at 100% ee. there were.

Reference Example 10

Synthesis of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide (Compound B)
(S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride (20.0 g, 83.4 mmol) in tetrahydrofuran (50 ml) solution 2N aqueous sodium hydroxide solution (96 ml) and acetic anhydride (4.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. Pure water (200 ml) and seed crystals (10 mg) were added to the reaction solution and cooled. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (9.71 g, yield 94.8%).
[Purification process]
9.00 g (36.7 mmol) of the above crystals were dissolved in 28 ml of ethanol, 90 mg of activated carbon was added, and the mixture was stirred for 5 minutes and filtered. The filtrate was cooled by adding 72 ml of water under heating, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (8.64 g, yield 96.0%).

Reference Example 11

Synthesis of (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride monohydrate (Compound C)
(+)-N, N-dimethyl- (6- (4-biphenylyl) methoxy-2-tetralin) acetamide (obtained according to the method described in JP-A-11-310561) 695 g was suspended in 3475 mL of toluene, and the nitrogen stream was Then, 562 g of sodium dihydro-bis (2-methoxyethoxy) aluminate (70% toluene solution) was added dropwise at an internal temperature of 20 ° C. or lower. After stirring at room temperature for 1.5 hours, 695 mL of 4N aqueous sodium hydroxide solution was added dropwise at 20 ° C. or lower, and the mixture was stirred at room temperature for 30 minutes and then separated. Further, the organic layer was washed twice with 695 mL of 1N aqueous sodium hydroxide solution and twice with 1390 mL of water. To the organic layer was added 348 mL of toluene and heated to 60 ° C., and 175 mL of concentrated hydrochloric acid (content: 36%) was added dropwise. After stirring for 1 hour under ice cooling, the precipitated crystals were collected by filtration and washed with 695 mL of toluene and 1390 mL of 50% aqueous methanol solution. When dried under reduced pressure at 40 ° C., 723 g (yield: 94.4%) of the title compound was obtained as pale yellow crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.32-1.40 (1H, m), 1.62-1.74 (3H, m), 1.82-1.90 (1H, m), 2.28-2.38 (1H, m), 2.74 (6H, s), 2.76-2.82 (3H, br), 3.08-3.16 (2H, m), 5.09 (2H, s), 6.72-6.80 (2H, m), 6.96 (1H, d, J = 8.0 Hz), 7.32-7.38 (1H, m), 7.44-7.54 (4H, m), 7.64-7.72 (4H, m), 10.4 (1H, br).

  In a fluidized bed granulator / dryer, Compound A (160 g), lactose (4064 g) and corn starch (640 g) were uniformly mixed, sprayed with an aqueous solution in which 160 g of hydroxypropylcellulose was dissolved, and then granulated. The obtained granulated product was pulverized with a 1.5 mmφ punching screen using a power mill to obtain a sized powder. Take 3894g of this sized powder, add 124g of corn starch and 12.4g of magnesium stearate and mix to make granules for tableting. This granule was tableted to a weight of 130 mg with a tableting machine using a 7.0 mmφ punch to give an uncoated tablet. The obtained uncoated tablet was sprayed with hydroxypropylmethylcellulose 2910 in which titanium oxide and yellow ferric oxide were dispersed in a film coating machine and a copolyvidone solution, and the film tablet having the formulation shown in Table 1 containing 4 mg of compound A per tablet, About 25000 tablets were obtained.

  Compound B2.5g, lactose 228.8g, and corn starch 65g were uniformly mixed in a fluidized bed granulator / dryer, sprayed with an aqueous solution in which 10g of hydroxypropylcellulose was dissolved in the machine, and then granulated. The obtained granulated product was pulverized with a 1.5 mmφ punching screen using a power mill to obtain a sized powder. Take 245g of this sized powder, add 13g of corn starch and 2.0g of magnesium stearate and mix to make granules for tableting. This granule was tableted to a weight of 130 mg with a tableting machine using a 7.0 mmφ punch to give an uncoated tablet. The obtained uncoated tablets were sprayed with titanium oxide, hydroxypropylmethylcellulose 2910 in which yellow ferric oxide was dispersed in a film coating machine, and a copolyvidone solution. Film tablets having the formulation shown in Table 2 containing 1 mg of compound B per tablet, About 1200 tablets were obtained.

Comparative Example 1

  Film tablets were produced in the same manner as in Example 1, except that 0.75 mg of polyethylene glycol 6000 was used instead of 0.75 mg of copolyvidone.

Comparative Example 2

  A film tablet was produced in the same manner as in Example 1 except that polyethylene glycol 6000 of Comparative Example 1 was not used.

Test example 1

  The film tablets of Example 1, Comparative Example 1 and Comparative Example 2 were stored at 60 ° C. for 4 weeks, and the stability of Compound A in the tablets, the content of Compound A (residual rate) and the total amount of unknown degradation substances were measured by HPLC. It was confirmed by doing. The results are shown in Table 3.

表中の単位は対表示量（％）を示す。 −は定量限界未満（＜０．０２％）を示す。

The unit in the table indicates the display amount (%). -Indicates less than the limit of quantification (<0.02%).

  From the results in Table 3, the formulation that is unstable when polyethylene glycol is contained in the coating is equivalent to the case where polyethylene glycol is not contained in the coating when the coating contains copolyvidone instead of polyethylene glycol. It can be seen that it is stable.

Table 4 shows the practice of the present invention.
Compound C 2.3g, lactose 222.2g, and corn starch 50g were uniformly mixed in a fluidized bed granulator / dryer, sprayed with an aqueous solution in which 9g of hydroxypropyl cellulose was dissolved, and then dried in the same machine. . The obtained granulated product was pulverized with a 1.5 mmφ punching screen using a power mill to obtain a sized powder. Take 226.8g of this sized powder, add 12g of croscarmellose sodium and 1.2g of magnesium stearate, and mix to make granules for tableting. This granule was tableted to a weight of 150 mg with a tableting machine using a 7.5 mmφ punch to give an uncoated tablet. The obtained uncoated tablet was sprayed with hydroxypropylmethylcellulose 2910 in which titanium oxide and iron sesquioxide were dispersed in a film coating machine and a copolyvidone solution, and a film tablet containing 1.15 mg of Compound C per tablet shown in Table 4, about 1500 I got a tablet.

Comparative Example 3

  Film tablets were produced in the same manner as in Example 3, except that 0.9 mg of polyethylene glycol 6000 was used instead of 0.9 mg of copolyvidone.

Comparative Example 4

  A film tablet was produced in the same manner as in Example 3 except that polyethylene glycol 6000 of Comparative Example 3 was not used.

Test example 2

表５の結果から、化合物Ｃについても被膜中にポリエチレングリコールを含む場合には不安定である製剤が、被膜中にポリエチレングリコールの代わりにコポリビドンを含んだ場合には、被膜中にポリエチレングリコールを含まない場合と同等に安定であることが分かる。
The results of the storage test are shown in Table 5 in the same manner as in Test Example 1.

From the results shown in Table 5, the compound C which is unstable when polyethylene glycol is contained in the coating also contains polyethylene glycol in the coating when copolyvidone is contained in the coating instead of polyethylene glycol. It turns out that it is as stable as the case without it.

Claims (11)

  A stable preparation obtained by coating 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, an optically active substance thereof or a salt thereof with a copolyvidone-containing coating agent. A stable preparation in which (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin or a salt thereof is coated with a copolyvidone-containing coating agent.   A stable preparation obtained by coating (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin with a copolyvidone-containing coating agent. A stable preparation in which (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride is coated with a copolyvidone-containing coating agent. (R)-(+)-6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin / hydrochloride / monohydrate coated with a copolyvidone-containing coating Formulation.   The preparation according to claim 1, wherein the coating agent contains a water-soluble polymer.   The preparation according to claim 1, wherein the coating further contains a light-shielding agent. A preparation characterized by coating 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, an optically active substance or a salt thereof with a coating containing copolyvidone. Stabilization method. Use of a copolyvidone-containing coating for stabilizing 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, its optically active form or a salt thereof. Use of copolyvidone for stabilizing 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, an optically active form thereof or a salt thereof. Use of copolyvidone according to claim 10 in a coating for stabilizing 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, optically active forms thereof or salts thereof. .