WO2002040053A1 - Pharmaceutical preparation containing talc/barium sulfate - Google Patents

Abstract

A stabilized pharmaceutical preparation which comprises: a drug unstable in titanium oxide-containing preparations; and a coating agent which contains talc or/and barium sulfate serving as a light-shielding agent and with which the drug is coated.

Description

 Description talc / barium sulfate-containing preparation Technical field

 The present invention relates to a preparation excellent in storage stability, particularly a pharmaceutical preparation, which is coated with a coating agent containing talc and / or barium sulfate. Background art

 Tablets that are commonly used as oral preparations are formed using various additives such as diluents, binders, lubricants, and disintegrants. Depending on the active compound, there may be concerns about the stability to light in normal distribution and storage conditions, and these are often coated with a film to provide a light-shielding effect by film coating. Coating is also a useful measure to prevent the bitter taste of drugs. This coating is made of hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC) as a water-soluble coating agent, polyethylene dalicol (PEG) as a plasticizer, titanium oxide as a light-shielding agent, and, if necessary, iron sesquioxide. Is generally contained. Purpose of the invention

 In the process of development as a pharmaceutical product, it is common practice to apply a light-shielding film to a compound that is unstable to light, thereby stabilizing the compound. Often it is. However, depending on the compound, the chemical structure is changed by titanium oxide, and there is a pharmaceutical problem that the activity cannot be maintained for a sufficient period even in a normal storage state in the medical field. Summary of the Invention

The present inventors have intensively searched for a light-blocking agent that can replace titanium oxide in order to improve the above-mentioned problem. In addition, it has been found that a pharmaceutical preparation having sufficient light resistance can be obtained by coating the preparation. It is known to use talc as a component of a tablet coating agent (eg, JP-A-56-87518, JP-A-9-12976, JP-A-2000-44464), but it is used as a light-shielding agent. There is no example that suggests. In addition, there is no example of the use of barium sulfate not only as a light-blocking agent but also as a component of a coating agent, not only in pharmaceutical preparations but also in the field of preparations for cosmetics and foods.

 Thus, the present invention has been completed based on the above findings of the present inventors. That is, the present invention

 (1) A preparation comprising a drug coated with a coating agent (not containing titanium oxide) containing talc and / or barium sulfate as a sunscreen,

 (2) The preparation according to the above (1), wherein the drug is a drug which becomes unstable in a titanium oxide-containing preparation,

 (3) The preparation according to the above (1), wherein the coating agent contains a water-soluble polymer,

 (4) Drug is formula

[Wherein, R ¹ is 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,

R ² is a hydrogen atom or a hydrocarbon group which may have a substituent,

R ³ is a hydrogen atom, a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted 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 (however, when X represents CH ₂ , Y is C or CH ),

 ™ is a single or double bond,

 Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent, Ring B is a benzene ring which may have a substituent, and

m represents an integer of 1 to 4. The formulation according to the above (1), which is

 (I) a coating agent containing talc or Z and barium sulfate as a light-shielding agent, (6) a light-shielding method characterized by coating with a coating agent containing talc or / and / or barium sulfate.

 (7) Use of talc or Z and barium sulfate as a sunscreen,

 (8) Use according to (7) above for producing a coating agent,

 (9) a method for stabilizing a pharmaceutical preparation, which comprises coating the drug with a coating agent containing talc or Z and barium sulfate as a light-shielding agent;

 (10) Use of a coating material containing talc or barium sulfate as a sunscreen agent for shading,

 (II) the use of talc or barium sulfate in the stabilization of drugs that become unstable in formulations containing titanium oxide, and

 (12) It is intended to provide a preparation obtained by coating a drug with a coating agent containing barium sulfate. Detailed description of the invention

 The content of "talc and / or barium sulfate" in the coating is, for example, about 1 to about 50% by weight, preferably about 5 to about 30% by weight, more preferably about 10 to about 20% by weight.

 “Coating agent” includes a coating base in addition to “talc or Z and barium sulfate”. The content of the coating base in the coating is the amount used for the production of general preparations. The “coating agent” may further contain an additive which does not adversely affect the coating agent and the pharmaceutical preparation, if desired.

Furthermore, the “coating agent” is obtained by dissolving or dispersing the above components in water or an organic solvent. It may be a liquid. The type of the organic solvent is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropyl alcohol; and ketones such as acetone. Also, a mixture of water and an organic solvent can be used.

 Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base.

 Examples of the zK-soluble film coating base include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyxethyl cellulose, and methylhydroxyxethyl cellulose; Aminoacetate, aminoanolequinolemethacrylate copolymer Ε

Synthetic polymers such as [Eudragit (trade name), ROHMFA ^ / MA], polybulpyrrolidone; and polysaccharides such as pullulan.

 Examples of the enteric film coating base include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropinolemethinolecellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer LD [Eudragit L-30 D55 (trade name), Rohm Farma Co., Ltd.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Farma Acrylic acid polymers; natural products such as shellac.

 Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co., Ltd.); ethyl acrylate methacrylic acid Acrylic acid polymers such as methyl copolymer suspension [Eudragit (trade name), Rohm Pharma Co., Ltd.] and the like.

 The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio.

Examples of coating agents include hydroxypropylcellulose, hydroxypropylmethyl cenorellose, hydroxyxetinoresenorelose, and methinolehydroxechinoresenorelose. And the like.

 Examples of the above-mentioned additives include a colorant and a fragrance, and the amount of the additive is an amount used for manufacturing a general preparation.

 Examples of the coloring agent include water-soluble edible tar dyes (eg, edible red No. 2 and 3, edible yellow No. 4, edible blue No. 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (the above water-soluble dyes). Aluminum salts of edible tar pigments, etc.), natural pigments (eg,] 3-carotene, chlorophyll, etc.), iron tridiacid and the like.

 Flavors include, for example, lemon oil, orange, d1- or 1-menthol.

 The “coating agent” in the present invention is produced, for example, by mixing the above-mentioned “talc or Z and barium sulfate” with a coating base, if necessary, adding the above-mentioned additives, and then mixing.

 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.

 From the viewpoint of the working environment and the like, the coating agent is preferably water-soluble.

 The “pharmaceutical preparation” of the present invention is not limited to a drug, but is preferably obtained by coating a “drug unstable with a titanium-containing preparation” with the above coating agent. The “drug unstable in a titanium oxide-containing preparation” may be the “drug” alone or a mixture of the “drug” and a conventional “drug component” used in the production of a pharmaceutical preparation.

 Drug dosage forms include, for example, tablets, powders, granules, fine granules, and pills.

 “Drugs that become unstable with titanium oxide-containing preparations” mean that it is necessary to apply a film that imparts a light-blocking effect because it is unstable to light. However, when titanium oxide is added as a light-blocking agent, the chemical structure changes. A drug that changes and becomes less stable.

For example, among the drugs listed below, when stored at 40 ° C at a relative humidity of 75% for 4 weeks or at 60 ° C for 2 weeks in the B-sound place, the drug content becomes triple immediately after production. A drug that degrades by more than 5% by weight, especially a drug that degrades by more than 5% by weight. Or, According to the compatibility test with titanium oxide as shown in Test Example 1 below, it contains a compound that decomposes by 5% by weight or more, that is, a residual rate of 95 ° / ₀ or less.

 Examples of such drugs include nourishing tonics, antipyretics and analgesics, antipsychotics, anxiolytics, antidepressants, hypnotics, antispasmodics, central nervous system drugs, brain metabolism improvers, antiepileptics , Sympathetic stimulants, Gastrointestinal drugs, Antacids, Antiulcer agents, Antitussive expectorants, Antiemetic agents, Respiratory stimulants, Bronchodilators, Antiallergic agents, Oral dentistry, Antihistamines, Cardiotonic, Arrhythmic agents , Diuretics, Antihypertensives, Vasoconstrictors, Coronary vasodilators, Peripheral vasodilators, Hyperlipidemia, Digestives, Antibiotics, Chemotherapeutics, Diabetes, Osteoporosis One or more components selected from skeletal muscle relaxants, anti-sedatives, hormonal drugs, alkaloid drugs, sulfa drugs, gout drugs, anticoagulants, antineoplastic drugs, Alzheimer's drugs, etc. Is mentioned .

 The content of these “drugs” in the “pharmaceutical preparation” may be an effective amount of the “drug”. Hereinafter, specific examples of the above-mentioned drugs will be described.

 Nourishing tonics include, for example, Vitamin A, Vitamin D, Vitamin E (d-α-tocopherol acetate), Vitamin B1 (dibenzoylthiamine, fursuultiamine hydrochloride, etc.), Vitamin B2 (riboflavin butyrate, etc.) , Vitamin B6 (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), vitamin B12 (hydroxocobalamin acetate, etc.) vitamins; minerals such as calcium, magnesium, iron, etc .; proteins, Examples include amino acids, oligosaccharides, and crude drugs.

 Antipyretic analgesics and anti-inflammatory drugs include, for example, aspirin, acetoaminophen, etenzamide, ibuprofen, diphenhydramine hydrochloride, d1-chloropheniramine maleate, dihydrocodine phosphate, noseptin, methylephedrine hydrochloride, chlorate hydrochloride Enylpropanolamine, caffeine, anhydrous caffeine, serapeptase, salted lysozyme, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminobiline, ketoprofen, indomethacin, bucolol, pentazocine, etc. .

Psychotropic drugs include, for example, chlorpromazine, reserpine and the like. Examples of anxiolytics include alprazolam, chlordazepoxide, and diazepa And the like.

 Antidepressants include, for example, imibramine, maprotiline, amphetamine and the like.

 Hypnotic sedatives include, for example, estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like.

 Antispasmodics include, for example, scoboramine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride and the like.

 Examples of central nervous system drugs include citicoline, oral thyrenine and the like. Brain metabolism improving agents include, for example, idebenone, vinpocetine, meclofenix hydrochloride, 8- [11-year-old xo 3- (1- (fueninolemethyl) piperidine-14-yl] propyl] -2,3,4,4 5-tetrahydro-1H-1-benzazepine or a salt thereof.

 Antiepileptic agents include, for example, phenytoin, canolebamazepine and the like.

 Sympathomimetics include, for example, isoproterenol hydrochloride. Gastrointestinal drugs include, for example, stomach-inhibiting agents such as diastase, sugar-containing pepsin, fungal extract, cellulase AP3, lipase AP, and keich oil; intestinal agents such as perperin hydrochloride, lactobacillus lactobacillus, and bifidobacteria. And the like.

 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, omebrazole, rabebrazole, pantoprazonole), famotidine, cimetidine, ranitidine hydrochloride and the like.

 Antitussive expectorants include, for example, caudal perastine hydrochloride, dextromertophan hydrobromide, theophylline, potassium guaiacole sulfonate, guaifenesin, codin phosphate and the like.

Examples of the antiemetic include difedole hydrochloride, metoclopramide and the like. Examples of the respiratory enhancer include levallorphan tartrate.

 Examples of bronchodilators include theophylline, salbutanol sulfate, and the like.

 Examples of antiallergic drugs include amlexanox and seratrodast.

 Examples of the oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.

 Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isotipendyl hydrochloride, chlorpheniramine d1-maleate, and the like.

 Examples of cardiotonic agents include caffeine and digoxin.

 Examples of the agent for arrhythmia include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like.

 Examples of diuretics include isosorbide, furosemide and the like.

 Antihypertensive agents include, for example, delapril hydrochloride, captopril, hexamethoxide bromide, hydralazine hydrochloride, raditalol hydrochloride, manidipine hydrochloride, candesartan cilexetinole, methinoredopa, rosanoletane, nonoresanoretan, eprosanorethan, thaprosanoletane, thaprosanoletane , Pomisanoletan, lipisartan, forasartan and the like.

 As the vasoconstrictor, for example, fenirephrine hydrochloride and the like can be mentioned.

 Examples of coronary vasodilators include carbochromene hydrochloride, molsidomine, perapamil hydrochloride and the like.

 Peripheral vasodilators include, for example, cinnarizine and the like.

 Examples of the therapeutic agent for hyperlipidemia include cerivastatin sodium, simvastatin, pravastatin and the like.

Bile agents include, for example, dehydrocholic acid, trepiptone and the like. Examples of the antibiotics include cephalexin, amoxicillin, pipmecillinam hydrochloride, cefotiam hydrochloride, cefozopran hydrochloride, cefmenoxime hydrochloride, cefus mouth sodium, and other cefem antibiotics; Antibacterial agent; Carmona Monopactam antibiotics such as munatridium; penem antibiotics and carpanem antibiotics.

 Examples of the chemotherapeutic agent include sulfamethizole hydrochloride, thiazosulfone and the like.

 Examples of antidiabetic agents include tolbutamide, voglibos, and thiazolidinedione derivatives (eg, pioglitazone hydrochloride, troglitazone, 5-([4-1- [2-]

(Methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -12,4-thiazoline), acarbose, miglitol, emidalitate and the like.

 Examples of the therapeutic agent for osteoporosis include ibriflavon. Examples of the skeletal muscle relaxant include metcarpamol.

 Examples of the antidepressant include meclizine hydrochloride, cymenhydrinate and the like.

 Hormonal agents include, for example, riochunadium, dexamethasone sodium phosphate, prednisolone, oxendrone, leuprorelin acetate, and the like.

 Examples of alkyloid-type narcotic drugs include, for example, aphen, morphine hydrochloride, tocon, oxycodone hydrochloride, aphenal hydroloid hydrochloride, cocaine hydrochloride and the like.

 Examples of the sulfa drug include sulfamine, sulfamethizole and the like.

 Gout remedies include, for example, aloprinol, colchicine and the like. Examples of the anticoagulant include dicoumarol.

 Examples of anti-malignant tumors include 5-fluorouracil, peracyl, and mitomicin.

 Drugs for treating Alzheimer's disease include, for example, idebenone, vinpocetine, 8- [1-oxo_3_ [1-1 (phenylmethyl) piperidine-14-yl] propynole] -12,3,4 , 5-tetrahydro-1H-1-benzazepine or a salt thereof.

The “drug that becomes unstable in the formulation containing titanium oxide” is more preferably a formula

[Wherein, R ¹ is 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,

R ² may have a hydrogen atom or a substituent, a hydrocarbon group,

R ³ is a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,

X represents C HR 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 (and伹, when X represents CH _2, Y is Ru C or CH Der),

 = Is a single or double bond,

 Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent,

Ring B is a benzene ring which may have a substituent, and

m represents an integer of 1 to 4. Or a salt thereof.

 Examples of the “hydrocarbon group” in the term “hydrocarbon group which may have a substituent” as used herein include, for example, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group and an aromatic hydrocarbon group. Hydrocarbon groups and the like are preferred, and those having 1 to 16 carbon atoms are preferable. Specifically, for example, an alkyl group, an alkyl group, an alkynyl group, a cycloalkyl group and an aryl group are used.

The “alkyl group” is preferably, for example, a lower alkyl group. For example, a C ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl and the like are generally used. Is done.

"The alkenyl group I is preferably, for example, a lower alkenyl group or the like. 1-C such as probenyl, aryl, isopropenyl, butenyl and isobutenyl

_2.6 alkenyl groups and the like are generally used.

"Alkynyl group", for example, a lower alkynyl group and the like are preferable, for example Echuru, etc. c _{2. 6} alkynyl group such as propargyl Contact Yopi 1 Purobyuru is generic.

"Cycloalkyl group", for example, lower cycloalkyl group and the like are preferable, for example, cyclopropyl, Shikuropuchinore, C _{3. 6} cycloalkyl group such hexyl etc. cyclopentyl and cyclohexane are commonly used.

"Ariru group", for example phenyl, 1 _ Nafuchinore, 2 _ naphthyl, Bifue two drill Contact Yopi 2 Ansurinore C _6. I ₄ Ariru group such are preferable, for example, phenylene Honoré group and the like are widely used.

Examples of the substituent which the "hydrocarbon group" of the "optionally substituted hydrocarbon group" may have include, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), nitro Group, cyano group, hydroxy group, lower halogenated alkyl group which may be halogenated (for example, methinole, chloromethinole, diphnoleolomethinole, trichloromethyl, trifluoromethyl, ethyl, 2-promoethyl, 2,2 , 2-Trifluoromethyl, Pentafluoroethylen, Propinole, 3,3,3-Trifluoropropyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, 4,4,4 , Pentinoles, isopentyl, neopentinoles, 5,5,5— trif noreolopentinoles, hexinoles, 6,6,6-trifluo To it may be halogenated, such as Kishinore. ₆ alkyl group, etc.), lower alkoxy groups (e.g., main butoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, C ₆ alkoxy group such as Penchiruo carboxymethyl to, Kishiruokishi ), Amino group, mono-lower alkylamino group (for example, mono-C ^ ealkylamino group such as methylamino, ethylamino, etc.), and G-lower alkylamino group (for example, dialkylamino group such as dimethylamino, acetylamino, etc.) ), A carboxyl group, a lower alkyl group, such as an alkenyl group such as acetyl or propionyl, and a lower alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. Alkoxy-carbonyl, etc.), rubamoyl, thiocarbamoyl, mono-lower alkyl Norelbamoyl groups (for example, mono-Ol- _6- alkyl-rubbamoyl groups such as methylcarbamoyl and ethylcarbamoyl), di-lower-alkyl-rubamoyl groups (for example, dicarbamoyl and dimethylcarbamoyl, etc.) Alkyl-based rubamoyl group, etc., aryl-based rubamoyl group (for example, phenylcarbamoyl, naphthylcarbamoyl, etc., aryl-based rubamoyl group, etc.), aryl-based

(For example, Ce.i such as phenyl and naphthyl; aryl group and the like), aryloxy group (for example, phenyloxy group and the like such as phenyloxy and naphthyloxy), and optionally halogenated lower alkylcarbolamino group (for example, acetyl An optionally halogenated group such as lumino or trifluoroacetylamino (eg, a _6- alkyl-carbonylamino group), or an oxo group may be used. The "hydrocarbon group" of the "hydrocarbon group which may have a substituent (s)" has 1 to 5, preferably 1 to 3 of the above substituents at a substitutable position of the hydrocarbon group. When the number of substituents is 2 or more, each substituent may be the same or different.

As the “heterocyclic group” in the term “heterocyclic group optionally having substituent (s)” used in the present specification, for example, one kind selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom Or a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic to tricyclic, preferably a single-membered) containing two to four (preferably one to three) heteroatoms. (Cyclic or bicyclic) heterocyclic groups and the like. For example, 2— or 3 mono-phenyl, 2— or 3-furyl, 1—, 2— or 3-pyrrolyl, 1 _, 2— or 3 _ pyrrolidinyl, 2—, 4 mono or 5-oxazolyl, 3—, 4— Or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3_, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2- ヽ 3- or 4-birazolidinyl, 2- , 4 mono- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, other than carbon, oxygen, sulfur or nitrogen 5-membered ring groups containing 1 to 4 heteroatoms selected from, for example, 2-, 3- or 4-pyridyl, N-oxide 2-, 3- or 4-pyridyl, 2_, 4-mono or 5-pyrimidi -R, N-Oxidone 2-, 4- or 5-pyrimidinyl, Omonoleforyl, morpholininole, piperidino, 2-, 3_ or 4-piperidyl, choviral, 1,4-oxazinyl, Oxygen and sulfur atoms other than carbon atoms such as 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazyl, N-oxide-13_ or 4-pyridazinyl And a 6-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atoms, such as indolyl, benzofuryl, benzothiazolinole, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolinole, phthalazinyl, quinazolinyl, quinoxalinyl , Indolizinyl, quinolizinyl, 1,8-naphthyridinyl, dibenzofuranyl, kyrvazolyl, ataridinyl, phenanthridinyl, chromanil, phenothiazinyl, phenoxazinyl, etc., and heteroatoms selected from oxygen, sulfur and nitrogen 1 to 4 Bicyclic or tricyclic fused ring group (preferably, even if the 5- or 6-membered ring contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms) And a group formed by condensing with one or two 5- or 6-membered ring groups). Among them, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms is preferred.

Examples of the substituent which the “heterocyclic group” of the “heterocyclic group optionally having” may have include, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), and a lower group. Alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butylinole, pentyl, hexinole, etc.), cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclobutyl) mouth pentyl, c ₃ of Kishinore like to the consequent opening. ₆ consequent opening alkyl group), a lower alkyl group (e.g., Echuru, 1 Puropieru, C _{2. 6} alkynyl group), lower alkenyl groups propargyl ( for example, vinyl, Ariru, isoproterenol base El, butene -. le, C _{2 6} alkenyl group such Isobuteyuru etc.), Ararukiru group (e.g. base Benzyl, α-methylbenzyl, Cm aralkyl groups such as phenyl, etc.), aryl groups (eg, phenyl group, naphthyl, etc., aryl groups, preferably phenyl group), lower alkoxy groups (eg, methoxy group). Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Ci.6 alkoxy groups, etc., and arylenooxy groups (for example, phenyloxy and other aryloxy groups). Shi group), a lower Arukanoiru group (e.g., formyl;.. Asechiru, propionyl, Puchiriru, C i e alkyl Ichiriki Ruponiru group), Arirukaru Boniru (e.g., Benzoiru groups isobutyryl etc., such as naphthoyl group C _{6 1 Q} 7 reel-carboxy group, etc.), lower alkanoyloxy group (for example, formyloxy; C- ₆ alkyl-carbonyloxy group such as acetyloxy, propionyloxy, ptyryloxy, isobutyryloxy, etc.) , § reel carbonyl O alkoxy group (e.g., benzo Iruokishi, C ₆ such Nafutoiruokishi. i. § Li one Roux carbonyl O alkoxy group), a carboxyl group, lower alkoxycarbonyl group (e.g., main-butoxycarbonyl, ethoxycarbonyl Kano repo two Nore, Propoxy force Boni Λ \ Isopropoxyka ^ / Boni Λ ^, Butoh Butoxycarbonyl, isobutoxycarbonyl, tert- butoxy C ₆ alkoxy such as carbonyl -. Carboxymethyl sulfonyl group, etc.), § Lal Kill O butoxycarbonyl (e.g., C ₇ such as benzylidene Ruo alkoxycarbonyl _{1 1} § Lal kill O butoxycarbonyl Group, etc.), canoleva's modyl group, mono-, di- or tri-halogeno-lower alkynole group (for example, methyl methyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) Mono-, di- or tri-halogeno-CA alkyl group, etc.), oxo group, thiomidino group, imino group, amino group, mono-lower alkylamino group (for example, methylamino, ethylamino, propinoleamino, isopropylamino, butynoleamino) mono one C ₄ alkylamino group, etc.) etc., di - lower alkylamino group (e.g., di Dialkylamino groups such as thilamino, getinoleamino, dipropylamino, diisopropylamino, dibutylamino, methylethylamino, etc.), carbon atoms and one nitrogen atom, as well as oxygen, sulfur and nitrogen atoms. A 3- to 6-membered cyclic amino group which may contain 1 to 3 heteroatoms (e.g. aziridinole, azetidur, pyrrolidinyl, pyrrolinole, pyrrolyl, imidazolyl, bilazolinole, imidazolidyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, N- Mechirubiperaji - le, N- E Ji ruby Bae Rajini 3 to 6-membered cyclic amino groups such as Le etc.), alkylenedioxy O carboxymethyl group (e.g., Mechirenjiokishi, 〇 ₃ alkylenedioxy O alkoxy group such Echirenjiokishi Etc.), hydroxy group, nitro , Shiano group, a mercapto group, a sulfo group, sulfino group, phosphono group, sulfa sulfamoyl group, mono alkylsulfamoyl group (e.g., N- methylsulfamoyl, N-ethylsulfamoyl, N-propinolesulfamoyl, N-isopropylsulfamoy

etc) ,

Di-C ₆ alkylsulfamoyl groups such as N, N-getylsulfamoyl, N, N-dipropylsulfamoyl, Ν, Ν-dibutylsulfamoyl, etc., alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropyl) Alkylthio groups such as thio, butylthio, sec-butylthio, tert-butylthio, etc.) arylthio groups (eg, Cs ^. Arylthio groups such as phenylthio, naphthylthio, etc.), lower alkylsulfinyl groups (eg, methylsulfiel) , Echirusuru Finiru, pro Pinot less zone les Fi -. Honoré, C j e Anorekirusunore Fier group such as Petit Luz Honoré alkylsulfonyl, etc.), § reel sulfide el groups (e.g., Hue Nils sulfide El, Na Fuchirusurufi - c _6, such as Le. i. arylsulfinyl group, etc.), lower alkyl Honizore group (e.g., methylsulfonyl, Echirusuruhoniru, Puropinoresu / Rehoni Le, like C ₆ alkylsulfonyl El group such Puchirusuruhoniru), Arirusuruhoni Le group (e.g., phenylalanine sulfonyl, such as naphthylsulfonyl. Ariru sulfonyl group, etc.) Are used.

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. The term "optionally substituted amino group" as used herein has, for example, one or two substituents such as the "optionally substituted hydrocarbon group" and the like. And an optionally substituted amino group. The preferable examples of substituents but it may also be "Amino group" have, for example may have a substituent group Al kill group which may have a substituent C _{6. 1 0} Ariru And the like. As the substituents that the “(^ .6 alkyl group” and the aryl group ”may have, the same as those described above for the“ hydrocarbon group ”and the substituents may be used. Can be

As used herein, the term "lower alkyl group" in the term "optionally substituted lower alkyl group" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl and tert-butyl. a C doctor ₆ alkyl group such as butyl, As the substituent, for example, the above “hydrocarbon group” may have 1 to 3 substituents and the like.

As used herein, the term "lower alkoxy group" in the term "optionally substituted lower alkoxy group" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and It represents a C ₁₆ alkoxy group such as tert-butoxy and the like, and may have, as a substituent, for example, 1 to 3 substituents and the like which the above “hydrocarbon group” may have.

As used herein, the term “optionally substituted benzene ring” includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and a carbon atom which may have a substituent. Hydrogen group, an amino group which may have a substituent, an amide group (for example, C ₃ acylamino group such as honolemamide and acetoamide), a lower alkoxy group which may have a substituent, and a lower alkylenedioxy group groups (e.g., main Chirenjiokishi, 〇 ₃ alkylenedioxy O alkoxy group such as a Echirenjiokishi) shows a 1 to a benzene ring which may have two substituents at substitutable positions selected from the like.

 Examples of the “optionally substituted hydrocarbon group”, “optionally substituted amino group” and “optionally substituted lower alkoxy group” include, for example, those described above. The same ones as described in detail above are used. When these “hydrocarbon group”, “amino group” and “lower alkoxy group” have two or more substituents, each substituent may be the same or different.

The “benzene ring optionally having substituent (s)” includes, for example, a nitrogen atom (eg, fluorine, chlorine, etc.), a C ₆ alkyl group (eg, methyl, ethyl, etc.), and mono C i. A benzene ring which may be substituted with one or two substituents selected from a _6- alkylamino group is preferred.

In the above formula, R ¹ represents a hydrocarbon group which may have a substituent, a diamino 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 which may have a substituent” represented by R ¹ include, for example, an alkyl group (eg, an alkyl group such as methyl, ethyl, propyl, isopropyl, etc.) , C _{2. 6} § alkenyl group (e.g., Bulle etc. Alkenyl group), an alkyl group (e.g., such as C _{2. 6} alkynyl group such Echuru), cycloalkyl group (e.g., cyclopropyl, Shikuropuchinore, cyclopentyl, c ₃ of cyclohexyl etc. cyclohexylene. ₆ cycloalkyl group ) and Ariru groups (e.g., full E -. C ₆ such as Le _{1 4} 7 aryl group, etc.) or the like, particularly alkyl groups (e.g., C ₆ alkyl group) Oyopi cycloalkyl group such as methyl (e.g., cyclo C ₃ of propyl. ₆ cyclopropyl, etc.) and the like are generally used. The “alkyl group”, “alkenyl group”,

The “alkynyl group”, “cycloalkyl group”, and “aryl group” include, for example, 1 to 5 substituents (preferably halogen atoms such as fluorine) which the above-mentioned “hydrocarbon group” may have. , Preferably one to three.

Preferred examples of the substituent of the "amino group optionally having substituent (s)" represented by R ¹ include, for example, a lower alkyl group optionally having a substituent and a substituent. One or two aryl groups or the like may be used, and in particular, one lower alkyl group or the like which may have a substituent is used. The "lower alkyl group", for example methylation, Echinore, Puropinore, isopropylidene Honoré, Buchinore, Isobuchinore, such as sec- butyl Contact Yopi tert- heptyl. ₆ alkyl group or the like is used. The “lower alkyl group” may have, for example, 1 to 3 substituents and the like which the “hydrocarbon group” may have. The "Ariru group" is, for example, 0 such as phenyl group, _6. For example, an aryl group is used. The “aryl group” is, for example, a substituent (preferably, a halogen atom such as fluorine or chlorine, or a C ₆ alkoxy group such as methoxy or ethoxy) which the above “hydrocarbon group” may have. Or five, preferably one to three. The “amino group optionally having substituent (s)” includes, for example, a phenylamino group substituted with one or three lower alkoxy groups (eg, an alkoxy group such as methoxy, etc.), or a lower alkyl group (eg, Mechinore, Echiru, propyl, butyl, C i. ₄ alkyl group such as tert- butyl) monoalkyl § amino group substituted by is generic.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ¹ include, for example, a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom. A 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms is used. Specifically, for example, 1_, 2- or 3-pyrrolidininole, 2- or 4- Midazolinyl, 2-, 3- or 4-birazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperadiel, morpholinyl, 2- or 3- phenyl, 2-, 3- or 3-pyridyl, Examples thereof include 2-furyl or 3-furyl, pyrazur, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazyl, 3-isothiazolyl, and 3-isoxazolyl. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) and the like are used.

Preferred examples of the substituent of the “heterocyclic group optionally having substituent (s)” represented by R ¹ include, for example, a halogen atom (eg, chlorine, fluorine, etc.), an alkyl group (eg, methyl, ethyl, etc.), . ₆ alkoxy group (e.g. main butoxy, ethoxy, etc.), (c _7, such as, for example, base Nji Ruo alkoxycarbonyl. _{1 2} Ararukiruokishi one carbonyl, etc.) § Lal Kill O butoxycarbonyl group and the like are used.

R ¹ is, for example, (i) a lower alkyl group optionally having a substituent, (ϋ) a lower cycloalkyl group optionally having a substituent, (iii) an optionally substituted substituent a lower alkenyl group, (i _v) may have a substituent group Ariru group, (V) an optionally substituted mono- or di-lower also. alkyl amino group, has a (vi) a substituent And an optionally substituted arylamino group or (vii) a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent.

The “lower alkyl group” is preferably, for example, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl. "Lower consequent opening alkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, C ₃ of cyclohexyl, etc., to a consequent opening. ₆ cycloalkyl group and the like. "Lower alkenyl group", for example Bininore, 1 one propenyl, C ₂ etc. Buteyuru. ₆ alkenyl group, and the like are preferable.

"Ariru group", for example phenyl, 1 _ naphthyl, etc. C _{6. 1 0} Ariru groups 2-naphthyl, etc. are preferable. "Lower alkylamino group", for example Mechiruamino, Echinoreamino, Puropiruamino, isopropylidene Honoré amino, Buchinoreamino, tert- Bed Chinoreamino, Jimechiruamino, Jechiruamino, mono- one or di- one C. ₆ alkyl amino group such as methyl E chill § Mino is preferable. "Ariruamino group", c ₆ of Fueniruamino such as if example example. I. An arylamino group or the like is preferred. "5- or 6-membered nitrogen-containing heterocyclic group" refers to 5- or 6-membered A nitrogen-containing heterocyclic group is preferred. As the substituents that these groups may have, for example, 1 to 5 substituents and the like that the above “hydrocarbon group” may have are used.

More preferred examples of R ¹ are, i) 1 not each a halogen or an alkoxy group to four optionally substituted C ₆ alkyl group, ii) C _{3. 6} cycloalkyl group, iii) C _{2. 6} Arukeyuru group, iv). _{6 It} may be substituted with 1 to 4 alkoxy, nitro, halogenoalkylcarbonylamino or halogen atoms, respectively. Ariru group, V) mono- or di-primary alkyl amino group, vi) 1 to may be substituted with 1-3 〇 ₆ alkoxy group. Aryl amino group or vii). And a 6-membered nitrogen-containing heterocyclic group which may be substituted with one or two aralkyloxycarbonyl groups. Particularly, an optionally halogenated C ₆ alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethinole, triflinoleolomethyl, ethyl, 2-bromoethynole, 2,2,2-trifluoroethyl, pentafluene) Oroethyl, propyl, 3,3,3-trifluoropropinole, isopropinole, petitnole, isobuchinole, sec-butinole, tert-butinole,

4, 4, 4 one triflumizole Ruo Russia butyl, pentyl, Isopenchinore, Neopenchinore, 5,5, 5-triflate Ruo b pentyl, hexyl, cyclohexyl and the like to 6,6,6 Torifuruo port), C _{3. 6} cycloalkyl Group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or mono_C ₆ alkylamino group (for example, methylamino, ethynoleamino, propylamino, isopropylamino, butylamino, tert-butylamino, etc.), and the like, Among them, a _6- alkyl group which may be halogenated or a mono-C i. _6- alkylamino group, particularly an alkyl group which may be halogenated, especially a ₃ alkyl group (for example, methyl, ethyl, propyl) Etc.) are preferred.

In the above formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent.

As R ² which may have a hydrogen atom or optionally substituted lower (C ₆₎ alkyl Le group is preferably used, more preferably a hydrogen atom or a lower (C. ₆₎ Al kill group, especially a hydrogen atom Commonly used. The “substituent” of the “lower (〇 ₆ ) alkyl group optionally having substituent (s)” may be, for example, the above “hydrocarbon group” Represents a substituent.

In the above formula, R ³ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent.

Represented by R ³ in the "optionally substituted hydrocarbon group" as preferred "hydrocarbon group" include an alkyl group (e.g., methyl, Echiru, propyl, 〇 Les ₆ alkyl isopropyl, etc. group), an alkenyl group (e.g., C ₂ such Biel. ₆ Arukeninore group), an alkynyl group (e.g., C ₂ etc. Echiniru. ₆ alkyl group), a cycloalkyl group (e.g., cyclopropyl, cyclobutyl , Shikuropen chill, for example c ₃ of cyclohexyl etc. cyclohexylene ₆ cycloalkyl group) and Ariru group (Hue -.. 〇 ₆ such as Le _{1 4} Ariru group) or the like, particularly alkyl groups (e.g., methyl, etc. . C i e alkyl group) and Ariru groups (e.g., Hue -. C ₆ such as Le _{1 4} § Li Lumpur group) and the like are generally used. The “alkyl group”, “alkenyl group”, “alkyl group”, “cycloalkyl group” and “aryl group” are, for example, substituents (preferably fluorine) which the above “hydrocarbon group” may have And the like may have 1 to 5, preferably 1 to 3, and the like.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ³ include, for example, a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom. A 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms is used. Specifically, for example, 1,2- or 3-pyrrolidinyl, 2- or 4-midazolyl, 2_, 3- or 4-birazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1_ or 2-piperajur, morpholiel, 2- or 3-chenyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, birazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3- Examples include isothiazolyl and 3-isoxazolyl. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) and the like are used.

Preferred examples of the substituent of the “heterocyclic group optionally having substituent (s)” for R ³ include, for example, a halogen atom (eg, chlorine, fluorine, etc.), an alkyl group (eg, methyl, ethyl, etc.), An alkoxy group (for example, methoxy, ethoxy, etc.), an aralkyloxycarbonyl group (for example, C 7.12 aralkyloxy-carbonyl, etc.), amino group, mono-alkylamino group (eg, methylamino, ethylamino, etc.), di-C ₆ alkylamino group

(For example, dimethylamino, getylamino, etc.) and the like.

R ³ includes, for example, (i) a hydrogen atom, (ii) a lower alkyl group optionally having a substituent, (iii) an aryl group optionally having a substituent, and (iv) a group having a substituent. May be

It is preferably a 5- or 6-membered heterocyclic group, and may further have (i) a hydrogen atom, (ii) a lower alkyl group, and (iii) a substituent. And aryl groups, and (iv) a 6-membered nitrogen-containing heterocyclic group which may have a substituent. Examples of the substituent include a halogen atom, a ₆ alkyl group, a ₆ alkoxy group, an amino group, a mono ₆ alkyl amino group, and a di-C 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.

In the above formula, X 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 a hydrogen atom or a lower group which may have a substituent.

₆ ) An alkyl group is preferred, and a hydrogen atom is commonly 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). In the above formula, Y represents C, CH or N. Preferably it is C or CH. In the above formula, ring A represents a compound 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 one or two or more selected from nitrogen, oxygen and sulfur atoms in addition to carbon and oxygen atoms (preferably 5 or 7-membered (preferably 5- or 6-membered) heterocyclic ring which may be included. As the ring, a compound represented by the formula

[Where E is (i) CH. CH ₂ , (ii) CH = CH, (iii) CH ₉ 〇, (iv) OC H ₂ , (v) CH ₂ S (0) q ′ ′ is an integer of 0 to 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 'is 0 to

Indicates an integer of 2. ] Is preferable.

E is (i) CH ₂ CH ₂ , (ii) CH = CH, (iii) CH ₂ 〇, (iv) OCH ₂ , (v) CH ₂ NH, (vi) NHCH ₂ , (vii) N = N, (viii) CH = N or (ix) N 2 CH is preferred, and (i) CH ₂ CH ₂ or (ii) CH = CH is particularly preferred.

 Specifically, for example, a 5-membered heterocyclic ring containing an oxygen atom such as 2,3-dihydrofuran, furan, 1,3-dioxole, thioxazolin, isoxazole, 1,2,3-oxadiazole, oxazole, etc., for example, 2H— Six-membered heterocycles containing an oxygen atom, such as 3,4-dihydropyran, 2H-pyran, 2,3-dehydro_1,4-dioxane, and 2,3-dehydromorpholine, are preferred.

 More preferably, the formula

 [In the formula, n represents an integer of 0 to 2, and 2 represents a single bond or a double bond. ] It is a ring represented by.

 Specifically, for example, 2,3-dihydrofuran, furan, 2H-3,4-dihydropyran and 2H-pyran are widely used.

Examples of the substituent of the ring A 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, Alkoxy groups such as propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., aryloxy groups (for example, phenyloxy and aryloxy groups, etc.), lower alkanol groups (for example, formyl; acetyl, propionyl) , Petit A C ₆ alkyl-carbonyl group such as ril, isobutyryl, etc .; an arylcarbonyl group (eg, Cs ^ such as a benzoynole group, a naphthoyl group; an aryl monocarbonyl group, etc.); a lower alkenyl group (eg, formyloxy; acetyloxy) propionyl Ruo alkoxy, Puchiriruokishi, etc. C i. ₆ alkyl Ichiriki Ruboniruokishi group such as isobutyryl O carboxymethyl), § reel carbonyl O carboxymethyl group (e.g., Benzoiru old alkoxy, C _{6. 1 Q} 7 reel one Karuboeruokishi group such Nafutoiruokishi Etc.), carbonyl group, lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycanoleponinole, propoxycanoleponinole, isopropoxycanoleboninole, butoxycarbonole, isobutoxycanoleponyl, tert-butoxycanole Leponil A C ₆ § alkoxy - carbonyl group, etc.), § Lal Kill O alkoxycarbonyl (e.g., C ₇ and benzyl O alkoxycarbonyl Ararukiruokishi -. Power carbonyl group), Karubamo I group, Chiokarupamoiru group, mono-, di- or tri one halogeno one lower alkylene Honoré group (e.g., chloromethyl, dichloromethyl, triflumizole Ruo Russia methyl, 2, 2, 2 - triflate Ruo Roe mono one chill etc., di -. or Toriharogeno one d ₄ alkyl group), Okiso group, amidino group, an imino group, an amino group, a mono one lower alkylamino amino group (e.g., Mechinoreamino, Echiruamino, Puropiruamino, isopropyl § amino, such as mono- _ C ₄ alkylamino group such Puchiruamino), di one lower alkylamino group (For example, dimethylamino, getylamino, dipropylamino, I Sopuropiruamino, Jibuchiruamino, di and methyl E chill § amino -. D ₄ alkyl Ruamino group), carbon and oxygen atoms in addition to one nitrogen atom, a hetero atom selected from sulfur atom Contact Yopi nitrogen atom A 3- to 6-membered cyclic amino group which may contain 1 to 3 (e.g., aziridyl, azetidur, pyrrolidinyl, pyrrolininorre, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl, monorephorinyl, dihydropyridyl, pyridyl, A 3- to 6-membered cyclic amino group such as N-methylpiperazinyl and N-ethylpiperazinyl), an alkylenedioxy group '(for example, methylenedioxy, ethylenedioxy and the like). 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-methylsulfamoyl, N-ethylsulfamoine, N-propylsulfamoy , N- butyl Roh less Alpha Moi Honoré mono- 0 ₆ group such as and the like), dialkyl sulfamoyl group (e.g., Ν, Ν-, Ν, Ν- GETS chill sulfamoyl, New, Nyu- Jipuropirusuru Famoiru, New, New Di-C alkylsulfamoyl groups such as -dibutylsulfamoyl, etc .; alkylthio groups (eg, C ₆ anoalkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) ), Arylthio group (for example, phenylthio, naphthylthio, etc.)

^C 6. 1 0 Ariruchio group), a lower alkylsulfinyl group (e.g., methylstyrene Norefi two Honoré, E Chino less Honoré Fi two Honoré, pro Pinot less Honoré Fi two Honoré, butyl Roh less Honoré Fi C ₆ alkyl, such as two Honoré sulfinyl group, etc.), § reel sulfide el groups (e.g., full E Nils sulfide El, such naphthylsulfinyl 〇 _{6.1 ()} § reel sulfide El group), a lower alkylsulfonyl group (e.g., methylsulfonyl, Echirusuruho sulfonyl, propyl For example, sulfonyl, butylsnolephonyl, etc., ₆ alkynolesulfonyl group, etc., and arylsulfonyl group (for example, phenylsulfonyl, naphthylsulfonyl, etc., 6 ^. Arylsulfonyl group, etc.), etc.

 The “lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “lower cycloalkyl group”, and “aryl group” are, for example, those which the above “hydrocarbon group” may have, It may have 1 to 5, preferably 1 to 3, substituents and the like.

The preferred substituents for ring A, halogen atom, which may have a substituent C i. ₆ alkyl group, which may have a substituent. ₆ alkoxy group, a hydroxyl group, a nitro group, Shiano group, Examples include an amino group and an oxo group which may have a substituent. The expression "may have a substituent. ₆ alkyl group", "substituted" but it may also have a substituent. ₆ alkoxy group "," amino group which may have a substituent " The “group” represents, for example, a substituent which the “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, depending on the size of the ring. In the formula, each substituent may be the same or different.

As ring A, for example,

[N has the same meaning as described above, and R ⁵ represents a hydrogen atom or 1 or 2 substituents represented by the above-mentioned “preferable substituents for ring A”. And the like. Among them, R ⁵ is a hydrogen atom, those have a substituent is also may 〇 ₆ alkyl group, especially those wherein R ⁵ is hydrogen atom (unsubstituted ring A) is generally used.

 In the above formula, the ring B may have a substituent and represents a benzene ring.

Examples of the substituent on ring B include the “substituent” of the above-mentioned “optionally substituted benzene ring”. Among them, a halogen atom or a lower (C ₆ ) alkyl group which may have a substituent is preferable, and a halogen atom or a lower (C ^ ₆ ) alkyl group (preferably methyl) is widely used. The "lower which may have a substituent (. ₆₎ alkyl group", "substituent" of, for example, shows the above-mentioned "hydrocarbon group" mosquitoes may have substituent.

 Ring B may have one or two, preferably one, substituents at the substitutable position. When the number of substituents is two, each substituent may be the same or different.

 As B ring, for example,

[R ⁶ is a hydrogen atom, a halogen atom, shows the optionally substituted lower (C ^) which may lower have a § alkyl group or a substituent (d. ₆₎ alkoxy group. Are preferred. R ⁶ is preferably, for example, a hydrogen atom, a halogen atom or a lower (C ^ ₆ ) alkyl group (preferably methyl). More preferably, a hydrogen atom is used.

In the above formula, m represents an integer of 1 to 4. m is preferably an integer of 1 to 3. Further, m is preferably 2 or 3, and particularly preferably m is 2. In the above formula, n represents an integer of 0 to 2. n is preferably an integer of 0 or 1, particularly preferably n is 0.

[In the formula, R ⁴ ′ represents a hydrocarbon group which may have a substituent, and other symbols are as defined above. And the like.

R ⁴ ′ is preferably a lower group which may have a substituent

Alkyl.

Wherein each symbol is as defined above. ] Etc. are shown. Among them, Ma

Wherein each symbol is as defined above. Are preferred.

Or

Wherein each symbol is as defined above. ] And the like _t Among the preferably used,

Wherein each symbol is as defined above. Are preferred. Particularly preferably

Wherein each symbol is as defined above. ].

_C As the compound (I), for example, such as those having the following structural formula is particularly generic

Wherein each symbol is as defined above. ]

Preferred examples of the compound (I) include a compound represented by the formula

Wherein each symbol is as defined above. And the like. Preferred examples of the compound (I) include:

Ri is (i) a lower alkyl group optionally having a substituent, (ϋ) a lower cycloalkyl group optionally having a substituent, (iii) a lower alkyl group optionally having a substituent. (Iv) an aryl group optionally having a substituent, (V) a mono- or di-lower alkylamino group optionally having a substituent, (vi) an aryl group optionally having a substituent. good Ari Ruamino group or (vii) a substituent having optionally may 5 or 6-membered nitrogen-containing heterocyclic group, R ² is optionally a hydrogen atom or optionally substituted lower (. ₆₎ alkyl group,

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 hydrogen atom or a lower (C _e ) alkyl group optionally substituted with an oxo group),

Y is C, CH or N (and伹, when X represents CH _2, Y is Ru C or CH Der),

 ™ indicates a single or double bond,

 A ring may have a substituent heterocyclic ring containing a 5- to 7-membered oxygen atom,

A benzene ring in which ring B may have a substituent, and

Compounds in which m is 1 or 2 are exemplified.

 More preferably,

Ri is i) halogen or 〇 1 respectively ₆ alkoxy to four optionally substituted alkyl group, ii) C _{3 6} Shikuroarukinore group, iii) C _{2 6} 7 Luque -.. Le group, iv) 〇 ₆ Alkoxy, nitro, nologeno. ₆ alkyl one carbonyl amino or C port plasminogen to 1 respectively atoms which may be four substituted C _{6. 1Q} § aryl group, V) mono- one or di- ten ₆ alkylamino group, vi) 1 to 3 C ₁ may be substituted with ₆ alkoxy group _{<6 10} Ariruamino group or _V ii) C 7. ii Ararukiruokishi -. carbonyl 1 to 2 optionally substituted 6-membered nitrogen-containing heterocyclic group in group, R ² is a hydrogen atom or a lower (C ^ e) alkyl group,

R ³ is, (i) a hydrogen atom, (ii) a lower (Cj.e) alkyl or (iii) C _{6. 14} 7 Lee Honoré group,

X is CHR ⁴ or NR ⁴ (R ⁴ represents a hydrogen atom or a lower (C ^ e) alkyl group optionally substituted with an oxo group),

Y is C, CH or N (where X is CH ₂ , Y is C or CH),

™ indicates a single or double bond,

A ring

 [Each symbol is as defined above. ]

B ring

[R ⁶ a represents a hydrogen atom, a halogen atom or a lower (〇 ₆₎ alkyl group. 〕 and

Compounds in which m is 1 or 2 are exemplified.

 Of these, the expression

Examples of compound (I) include N— [2- (1,6,7,8-tetrahydro-12H-indeno [5,4-b] furan-18-yl) ethyl] acetamide and N— [2- (1,6,7,8-tetrahydro 2H-indeno [5,4-b] furan-1-yl) ethyl] butyramide N- [2- (1,6,7,8-tetrahydro- 1H-indeno [5,4-b] furan-8-inole) ethyl] propionamide,

 N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indole-1-yl) ethyl] propionamide,

N- [2- (5-fluoro-3,7,8,9-tetrahydrocyclopenta [f]

[1] Benzopyran (91-yl) ethyl] propionamide,

N— [2- (3,7,8,9-tetrahydropyrano [3,2-e] indole) ethyl] butylamide,

 N- [2 -— (1,2,3,7,8,9—hexahydridopyrano [3,2-e] indole-1-yl) ethyl] propionamide,

 N- [2— (1,2,3,7,8,9-hexahydridopyrano [3,2-e] indole_1_yl) ethyl] butylamide,

 N— [2- (4-monofluoro-1,6,7,8-tetrahydro-1 2H—indeno

[5,4-b] franc-8-inole) ethyl] butylamide,

N— [2— (4-Fluoro-1,6,7,8-tetrahydro-1 H-indeno

[5,4-b] franc 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-1H-indeno [5,4-b] furan-1-yl) ethyl] propionamide,

 N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide,

 N— [2- (1,6-dihydro-2H—indeno [5,4-b] furan-1-yl) ethyl] acetamide,

N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-18fle) ethyl] propionamide,

 N— [2- (1,6-dihydro-1 2H—indeno [5,4-b] furan-1-yl) ethyl] butylamino,

N— [2— (7,8—dihydro-6 H—indeno [4, 5—d] —1, 3-dithio Kizol—8—ethyl) propionamide,

 N— [2— (7,8—dihidro 6H—indeno [4,5—d] —1,3-dioxol-8-yl) ethyl] butyramide

 N- [2- (2,3,8,9-tetrahydro-1H-indeno [4,5-b] —1,4-dioxin-1-9-yl) ethyl] propionamide,

 N- [2- (2,3,8,9-tetrahydro-7H-indeno [4,5_b]-1,4-dioxin-1 9-yl) ethinole] butynoleamide,

 N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] india 1 f 8 f) ethyl] propionamide,

N— [2- (1,6,7,8-tetrahydro-1H-furo [3,2_e] indole-1-8-yl) ethyl] butylamide,

 N— [2- (7-Feninole-1,6-dihydro-1 2H—indeno [5,4_b] furan-8-inole) ethyl] propionamide,

 N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-1b] furan-18-yl) ethyl] butylamide and the like are preferred. More preferably, N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-1b] furan-18-inole) ethyl] acetoamide,

N- [2- (1,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-1-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-1-yl) ethyl] propionamide,

 (S) — N— [2- (1,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-1-yl) ethyl] propionamide,

 (R) -N- [2- (1,6,7,8-tetrahydro-1H-indeno [5,4—b] .furan-8-yl) ethyl] propionamide,

N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-1b] furan-1-yl) ethyl] butylamino, N— [2- (1,6-dihydro-2H—indeno [5,4-b] furan-18-yl) ethyl] acetamide,

 N— [2 -— (1,6-dihydro-1H-indeno [5,4-b] furan-1-yl) ethyl] propionamide,

N— [2 -— (1,6-dihydro-2H—indeno [5,4-b] furan-1-yl) ethyl] butylamide,

 N- [2-(1,6,7,8-tetrahydro-1H-furo [3,2-e] India 1-8-yl) ethyl] propionamide

 N— [2— (1,6,7,8-tetrahydro-2H—furo [3,2—e] India 1-one 8-inole) etinole]

 N- [2- (7-pheninole-1,6-dihydro-2H-indeno [5,4-b] furan-1-81 f) ethyl] propionamide,

 N- [2- (7-Feru-1,6-dihydro_2H-indeno [5,4-b] furan-1-yl) ethyl] butylamide.

 Particularly preferred are (S) -N- [2- (1,6,7,8-tetrahydro-12H-indeno [5,4-b] furan-18-inole) ethyl] propionamide, N- [2 -(1,6,7,8-tetrahydro-2H-furo [3,2-e] India 1 8th-yl) ethyl] propionamide,

 N— [2- (1,6,7,8-tetrahydro-2H—furo [3,2-e] indole-1-yl) ethyl] butylamide,

 N— [2- (7-Feru-1,6-dihydro-1H-indeno [5,4-b] furan-1-yl) ethyl] propionamide,

 N— [2- (7-Feru-1,6-dihydro-2H—indeno [5,4-b] furan-1-yl) ethyl] butylamide,

N— [2 -— (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-1-yl) ethyl] acetamide.

As the compound (I), a compound represented by the formula

[Wherein, R to indicate CL ₆ alkyl group (methyl, Echiru, propyl, isopropyl, blanking chill, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl and the like to). Particularly preferred is a compound represented by the formula: (S) —N— [2— (1,6,7,8-tetrahydro-2H—indeno [5,4-b] furanone 8_ (yl) ethyl] propionamide (hereinafter referred to as compound A) or (S) -N- [2- (1,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-1 8-yl) ethyl acetoamide (hereinafter referred to as compound B) is preferred.

As the salt of compound (I), for example, pharmacologically acceptable salts and the like are used. Examples 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, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-noretidine, ethanolanolamine, diethanolamine, triethanolamine, cyclohexylamine / diamine, and dicycloamine. Salts with hexylamine, N, N, dibenzylethylenediamine and the like can be mentioned. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, forenoic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acids and salts with p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, or-tin and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, etc. Are listed. 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, and phosphoric acid is used. And salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, taenoic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. Examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salt.

 Compound (I) may be a hydrate or a non-hydrate.

 Compound (I) can be obtained, for example, by the method described in Japanese Patent No. 2884153 or a method analogous thereto.

 Examples of the above-mentioned “formulation components” include, for example, excipients (eg, lactose, sucrose, D-mannitol, D-sorbitol, starch (such as corn starch, potato starch), starch starch, dextrin, crystalline cellulose, Degree of substitution hydroxypropylcellulose, canoleboxy methinoresenorelose sodium, 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 carboxymethinoresenorelose, hydroxypropinoresenorelose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, knot Cellulose, dextrin, pullulan, etc.), lubricants (e.g., magnesium stearate, calcium stearate, talc, colloidal silica, etc.), collapse 壌剤 [eg,? L-sugar, sucrose, carboxymethylcellulose, low-substituted hydroxypropylcellulose, starch

(Such as corn starch and potato starch), light caffeic anhydride, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose calcium, crospolyvinylpyrrolidone, etc.), coloring agents, flavors, flavoring agents, adsorbents, Examples include a preservative, a wetting agent, an antistatic agent, and a disintegration extender. The amounts of the above-mentioned formulation components may be the same as those used for the production of general formulations. The “formulation” of the present invention includes pharmaceutical preparations, cosmetic preparations, food preparations, and the like. The following describes pharmaceutical preparations, but the description below applies to other preparations. Can be applied in any way.

The dosage form of the “pharmaceutical preparation” of the present invention includes, for example, tablets, capsules, powders, granules, fine granules, pills and the like. The granules weigh, for example, about 90% by weight of particles having a particle size of about 500 to about 140 μm. Approximately 5 weight of particles having a particle size of not less than / _{0 and not} more than about 1 77 ^ m. / Contains _{0 or} less. The fine granules are, for example, about 75% by weight or more of particles having a particle size of about 10 to about 500 m, about 5% by weight or less of particles having a particle size of about 500 μm or more, and about 5% by weight or less. Contains up to about 10% by weight of particles of 10 m or less. Preferred fine granules are about 75% by weight or more of particles having a particle size of about 150 to about 500 m, about 5% by weight or less of particles having a particle size of about 500 μm or more, and about 7% by weight or less. Contains about 10% by weight or less of particles of 4 μm or less.

 The “pharmaceutical preparation” of the present invention is produced by coating a “drug-containing composition” obtained by mixing the above “drug” and “pharmaceutical components” by a conventional method with a “coating agent”.

 The amount of the coating agent used may be selected according to the dosage form of the pharmaceutical preparation. The amount of the coating agent (dry weight) used for the pharmaceutical preparation is, for example, about 0.1 to about 30% by weight, preferably about 0.5 to about 10% by weight for tablets; For pills, about 0.1 to about 50% by weight, preferably about 1 to about 20% by weight; for fine granules, about 0.1 to about 100% by weight, preferably about It is about 1 to about 50% by weight.

 As the coating method, a method known per se, for example, a pan coating method, a fluid coating method, a tumbling coating method, and a method combining them can be used. When the coating agent is a solution or a dispersion containing water or an organic solvent, a spray coating method can be employed as the coating method.

 The temperature during coating is usually from about 25 to about 60 ° C, preferably from about 25 to about 40 ° C.

 The time required for coating can be appropriately selected in consideration of the coating method, characteristics and amount of coating agent used, characteristics of pharmaceutical preparations, and the like.

 The above-mentioned compound (I) has an excellent melatonin agonist action, has low toxicity and is safe without side effects, and thus can be suitably used for the preparation of the present invention.

The “pharmaceutical preparation” of the present invention uses, for example, compound (I) or a salt thereof as a drug. Disorders that may be affected by melatonin, such as dysregulation of biological rhythms, such as sleep-wake rhythm disorders, jet lag, physical shifts due to three shifts, seasonal depression, reproductive and Neuroendocrine disease, senile dementia, Alzheimer's disease, various disorders associated with aging (eg, aging prevention), cerebral circulation disorder (stroke, etc.), head trauma, bone marrow injury, stress, epilepsy, convulsions, anxiety, depression Can be used for the prevention and treatment of Parkinson's disease, high blood pressure, glaucoma, cancer, insomnia, diabetes, etc., and is also effective against immune regulation, cognitive intelligence, mental stability or ovulation adjustment (eg, contraception) It is. Therefore, when the compound (I) or a salt thereof is used in the pharmaceutical preparation of the present invention, for example, a biological rhythm regulator, preferably a therapeutic agent for sleep disorders (eg, a sleep inducer, etc.), a sleep-wake rhythm regulator (sleep-wake rhythm) It is used as a preventive and therapeutic agent for time zone change syndrome, so-called jet lag (lag). '

 The dosage of the “pharmaceutical preparation” of the present invention may be selected in consideration of the type of the drug, the type of the target disease, the symptoms, the dosage form, and the like so that the dosage as the drug is an effective amount of the drug. Les ,. For example, when the compound (I) or a salt thereof is used as a drug, the “pharmaceutical preparation” may be prepared such that the dose of the compound (I) or a salt thereof is about 0.01 mg / day for an adult (body weight of 6 O kg). About 10 Omg, preferably about 0.1 to about 3 Omg, more preferably about 0.3 to about 1 Omg, in a single dose or in two to three doses . Further, in the present invention, in order to block contact between a drug reacting with titanium oxide and titanium oxide, an uncoated tablet is coated with a water-soluble coating agent (for example, hydroxypropyl pill cellulose, hydroxypropynolemethinole). Senorelose, hydroxyxetinoresenorelose, methinolexyloxethyl cellulose, etc.), and then coating the film component thereon to obtain a stabilized pharmaceutical preparation. The amount of the water-soluble coating agent coated on the uncoated tablet is preferably about 1 to about 10% by weight. Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples. Example 1

In a fluidized bed granulation drying process, 160 g of ligation product A, 4064 g of lactose, and 640 g of corn starch were uniformly mixed, and then an aqueous solution in which 160 g of hydroxypropylcellulose was dissolved in the machine was granulated by atomization. Then it was dried on the same machine. The obtained granulated product is power milled And crushed with a 1.5 mm φ punching screen to obtain sized powder. Take 3894 g of the sized powder, add 124 g of corn starch and 12.4 g of magnesium stearate and mix to obtain granules for tableting. The granules were tableted with a tableting machine using a 7.0 mm 130 punch to a weight of 130 mg to give uncoated tablets. The obtained uncoated tablets are sprayed with a solution of hydroxypropylmethylcellulose 2.910 and polyethylene glycol 600 in which talc and yellow iron sesquioxide are dispersed in a film coating machine. About 25,000 film tablets having the formulation shown in 1 were obtained.

table 1

Composition Blended amount (mg)

Compound A 4.0

Lactose 101.6

 Tumor starch 20.0

Hydroxypropinoresenolerose 4.0

Magnesium stearate 0.4

Uncoated tablets 130.0

Hydroxypropinolemethinoresenolerose 2 9 1 0 3.74

Polyethylene glycol 600 0 0.75

Talc 0.5

Yellow ferric oxide 0.01

 A coming + 135.0

The coating amount was 5 mg per tablet.

 Example 2

 After 160 g of compound B, 4064 g of lactose, and 640 g of corn starch were uniformly mixed in a fluidized bed granulator, the mixture was sprayed with an aqueous solution in which 160 g of hydroxypropyl cellulose was dissolved in the machine, and the mixture was granulated, and then dried with the same machine. The obtained granules were pulverized using a power mill with a 1.5 mm φ punching screen to obtain sized powder. Take 3894 g of the sized powder, add 124 g of corn starch and 12.4 g of magnesium stearate and mix to obtain granules for tableting. The granules were tableted with a tableting machine to a weight of 130 mg using a 7.0 mmφ punch to give uncoated tablets. The obtained uncoated tablets were sprayed with a solution of barium sulfate and yellow iron sesquioxide dispersed in hydroxypropylmethyl cellulose 2910 and polyethylene glycol 600 in a film coating machine to give compound B per tablet. About 25,000 film tablets containing 4 mg ^ and having the formulation shown in Table 2 were obtained.

Table 2 Oral mg

 1 rem mouth ifel R

 丄 u 丄 · υ

p ¹ノ r I- ¹ ? — r,, no ^ no, no, no ^ no f ヽ no no on Π

 Λ Π

Ma Thanoano Uso ^, No Nishi R¾, ヾ? No ^ ^, no, no r r ^ ^ 0 4

 130.0

Hydroxypropinolemethinoresenolerose 2 9 1 0 3.74

Polyethylene glycol 600 0 0.75

Sulfuric acid barrier 0.5

Yellow ferric oxide 0.01

 135.0

The coating amount was 5 mg per tablet.

 Test example 1

 Compound A and barium sulfate are mixed at a ratio of 1:50, and the mixture is stored at 40 ° C and a relative humidity (RH) of 75% for 2 weeks and at 60 ° C for 2 weeks. The stability of A was confirmed by HPLC measurement of its residual ratio. A mixture of compound A and titanium oxide was measured in the same manner. Table 3 shows the results.

Table 3

Additive Storage condition Residual rate (%)

At the start of preservation 100

 40 ° C 75% RH 2 weeks 99.5

 while

 60 ° C 2 weeks 81.6

Sulfuric acid barium at the start of storage 100

 40 ° C 75% RH 2 weeks 104.7

 while

 60 ° C 2 weeks 105.6

 The results in Table 3 show that barium sulfate is a stable additive for Compound A.

 Test example 2

Light resistance test compound A tablet coated with sulfuric Bariumu or talc-containing film (xenon Nranpu, 1. 2 X 1 0 ⁶ lux 'time) was performed. The results are shown in Tables 4 and 5. Table 6 shows the formulations. Table 4

 Coating amount Survival rate

 (With U) (%)

 | ¾] Taro candy 1 no

 0 97.2

 3.7 mg 98.4

 4.9 mg 97.3

After irradiation 7.6 mg 98.5

(1 · 2 10 ⁶ 1χh) 9.6 mg 99.3

 14.1 mg 99.1

 20.1 mg 100.0

Coating amount Survival rate

 (Per tablet) (%)

Starting uncoated tablets 100

 0 97.1

 3.4 mg 100.0

After irradiation 0.6 mg 100.2

(1 · 2 10 ⁶ 1χh) 8.7 mg 100.9

 10.9 mg 101.3

 13.3 mg 99.1 Table 6

Itogane Sulfuric acid "!) Pharma-containing formulation Talc-containing formulation Compound A plain tablet 130.0 130.0

A p-xif in the chick. p-Pirmethi Lulose 2910-3.99

Hydroxif. ρ pill cellulose 3.74

E. Lithylene ^ alcohol 6000 0.75

Sulfuric acid, Li 0.5

Talc-1.0

Yellow ferric oxide 0.01 0.01

Total 135.0 135.0

The case of 5 mg per tablet was shown. From the results shown in Tables 4 and 5, it can be seen that compound A tablets can be coated with barium sulfate or talc-containing films to obtain light-stable tablets. Industrial applicability The formulation of the present invention is stable to light, especially ultraviolet light and heat, and has excellent storage stability. In addition, according to the present invention, light-shielding coating can be performed without instability of the drug. Such a coated preparation has a uniform surface, so that, for example, processing such as engraving can be easily performed. Is also beautiful. In addition, the formulation also helps prevent bitterness when the drug is bitter, and does not show adhesion to the esophageal mucosa upon administration.

 The coating agent of the present invention has excellent light-shielding properties and does not destabilize the drug, and thus is useful as a raw material for producing a preparation having excellent storage stability as described above. Further, the coating agent is excellent in operability and uniform coating because of excellent strength and spreadability.

Claims

The scope of the claims

1. A preparation comprising a drug coated with a coating containing talc and / or barium sulfate as a sunscreen.

 2. The drug product according to claim 1, wherein the drug is a drug which is unstable in a preparation containing titanium dioxide.

 3. The preparation according to claim 1, wherein the coating agent contains a water-soluble polymer.

 4 The drug is the formula

[Wherein, R ¹ is 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,

R ² may have a hydrogen atom or a substituent, a hydrocarbon group,

R ³ is a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,

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 (and伹, when X represents CH _2, Y is Ru C or CH Der),

 = Is a single or double bond,

Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent,

Ring B is a benzene ring which may have a substituent, and

m represents an integer of 1 to 4. The preparation according to claim 1, which is a compound represented by the formula or a salt thereof.

5. Coating agent containing talc or phenol and barium sulfate as a sunscreen.

6. A light-shielding method characterized by coating with a coating agent containing talc or / and parium sulfate.

 7. Use of talc or Z and sulfate sulfate as sunscreen.

 8. Use according to claim 7, for the manufacture of a coating.

 9. A method for stabilizing a pharmaceutical preparation, which comprises coating a drug with a coating agent containing talc or / and barium sulfate as a light-shielding agent.

 10. Use of talc or coatings containing Z and barium sulphate for shading, as shading agents.

 11. Talc or talc in drug-stabilizing drugs that become unstable with titanium oxide-containing preparations

/ And use of parium sulfate.

 12. A preparation obtained by coating a drug with a coating agent containing barium sulfate.