JP2002212104A - Preparation containing talc/barium sulfate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To stabilize a preparation containing titanium oxide and an unstable medicine. SOLUTION: The preparation in which the medicine is coated with a coating containing talc and/or barium sulfate as a shading agent is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation having excellent storage stability, particularly a pharmaceutical preparation, which is coated with a coating agent containing talc and / or barium sulfate.

[0002]

2. Description of the Related Art Tablets, which are generally 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 the normal distribution and storage conditions, and these are often coated with a film to provide a light-shielding effect. It is also a useful means to apply a coating to prevent the bitter taste of the drug. This film is made 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 coloring agent such as iron sesquioxide. Is generally used.

[0003]

In the process of developing a drug, a method of stabilizing a compound that is unstable to light by coating a light-shielding film is generally used. The light-shielding agent used is often titanium oxide. 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.

[0004]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have intensively searched for a light-shielding agent that can replace titanium oxide. By coating
It has been found that a pharmaceutical preparation having sufficient light fastness can be obtained. It is known to use talc as a component of a tablet coating agent (eg, JP-A-56-87518, JP-A-9-2976, JP-A-2000-44464). No suggested example is found. Also,
Examples of using barium sulfate not only as a light-shielding agent but also as a component of a coating agent are not found in the fields of pharmaceuticals, cosmetics, foods and other pharmaceuticals. Thus, the present invention has been completed based on the above findings of the present inventors. That is, the present invention provides (1) a preparation comprising a drug coated with a coating agent (not containing titanium oxide) containing talc or / and barium sulfate as a light-shielding agent;
(2) the preparation according to the above (1), wherein the drug is a drug which becomes unstable in a preparation containing titanium oxide; (3) the preparation according to the above (1), wherein the coating agent contains a water-soluble polymer; Drug formula

Embedded image [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 hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X is 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 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 a benzene ring which may have a substituent, and m is Shows an integer of 1 to 4. (13) a preparation containing talc or / and barium sulfate as a light-shielding agent, (6)
A light-shielding method characterized by coating with a coating agent containing talc and / or barium sulfate; (7) use of talc or / and barium sulfate as a light-shielding agent; (8)
Use according to the above 7 for producing a coating agent, (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) light shielding. Use of a coating agent containing talc or / and barium sulfate as an agent for shading (1)
1) Use of talc or / and barium sulfate in stabilizing a drug which becomes unstable with a titanium oxide-containing preparation, and (12) a preparation obtained by coating a drug with a coating agent containing barium sulfate. .

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The content of "talc or / and barium sulfate" in a coating agent is, for example, about 1 to about 50% by weight, preferably about 5 to about 30% by weight, and more preferably about 10 to about 20% by weight. % By weight.

The "coating agent" includes a coating base in addition to "talc and / or barium sulfate". The content of the coating base in the coating is the amount used for the production of general preparations. Further, the “coating agent” may be, if desired,
It may further contain additives that do not adversely affect the coating agent and the pharmaceutical preparation. Further, the “coating agent” may be a liquid in which each of the above components is dissolved or dispersed in water or an organic solvent. The type 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.
Also, a mixture of water and an organic solvent can be used.

[0007] Examples of the above-mentioned coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like. 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, and polysaccharides such as pullulan. Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose 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-30D5
5 (trade name), Rohm Pharma Co., Ltd.], acrylic acid polymers such as methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co.]; and natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethylcellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co., Ltd.), ethyl acrylate / methyl methacrylate copolymer suspension An acrylic acid-based polymer such as a suspension (Eudragit NE (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. As the coating agent, a water-soluble polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose is preferable.

The above-mentioned additives include, for example, colorants,
Flavoring agents and the like are included, and the amount of addition is an amount used for production of general preparations. Examples of the coloring agent include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow 4).
No. 5 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (such as aluminum salts of the above water-soluble edible tar dyes), natural dyes (eg, β-carotene, chlorophyll, etc.), iron sesquioxide and the like. No. Examples of the flavor include lemon oil, orange, dl- and 1-menthol, and the like.

The "coating agent" in the present invention is produced, for example, by mixing the above-mentioned "talc or / and barium sulfate" with a coating base, if necessary, after adding the above-mentioned additives. Further, the "coating agent" is also produced by dissolving or dispersing the above components in water or the above organic solvent, and by such a production method,
A uniform coating can be obtained. From the viewpoint of the working environment and the like, the coating agent is preferably water-soluble.

[0010] 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 oxide-containing preparation" with the above coating agent. The "drug which becomes unstable with a titanium oxide-containing preparation"
May be a “drug” alone or a mixture of a “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, pills, and the like.

[0011] The term "drug which becomes unstable in a preparation containing titanium oxide" means that it is necessary to apply a film which imparts a light-shielding effect because it is unstable to light. A drug whose chemical structure changes and its stability deteriorates. For example, of the following drugs, when stored at 40 ° C. and 75% relative humidity for 4 weeks or at 60 ° C. for 2 weeks in the dark, the drug content decomposes by 3% by weight or more of the content immediately after production. Drugs, especially 5
Refers to a drug that decomposes by weight percent or more. Alternatively, it contains a compound that decomposes in an amount of 5% by weight or more, that is, a residual rate of 95% or less in a compoundability test with titanium oxide as shown in Test Example 1 below. Such drugs include, for example, nourishing tonic health drugs, antipyretic analgesics and anti-inflammatory drugs, psychotropic drugs, anxiolytic drugs,
Antidepressants, hypnotics, sedatives, anticonvulsants, central nervous system drugs, cerebral metabolism improvers, antiepileptics, sympathomimetics, gastrointestinal drugs, antacids, antiulcers, antitussive expectorants, antiemetic, respiratory stimulants Agents, bronchodilators, antiallergic agents, oral agents, antihistamines, cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia treatments , Bile drugs, antibiotics, chemotherapeutics, diabetes treatments,
Osteoporosis treatment, skeletal muscle relaxant, antidiarrheal, hormonal, alkaloid drug, sulfa, gout,
One or more components selected from blood coagulation inhibitors, antineoplastic agents, Alzheimer's therapeutics, and the like. The content of the “drug” in the “pharmaceutical preparation” may be an effective amount of the “drug”.

The following are specific examples of the above-mentioned drugs. Nourishing tonic health drugs include, for example, vitamin A, vitamin D, vitamin E (d-α-tocopherol acetate, etc.),
Vitamin B1 (dibenzoylthiamine, fursultiamine hydrochloride, etc.), vitamin B2 (riboflavin butyrate, etc.), vitamin B6 (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), vitamin B12 (hydroxo acetate, etc.) Vitamins such as cobalamin); minerals such as calcium, magnesium and iron; proteins, amino acids, oligosaccharides, and crude drugs. Antipyretic analgesics and anti-inflammatory drugs include, for example, aspirin, acetaminophen, ethenzamide, 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. Psychotropic drugs include, for example, chlorpromazine, reserpine and the like. Examples of the anxiolytic include alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imipramine, maprotiline, amphetamine and the like.

The hypnotic sedatives include, for example, estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Examples of antispasmodics include scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride and the like. Examples of central nervous system drugs include citicoline, rothyrenine and the like. Examples of cerebral metabolism improving agents include idebenone,
Vinpocetine, meclofenixate hydrochloride, 8- [1-
Oxo-3- [1- (phenylmethyl) piperidine-4
-Yl] propyl] -2,3,4,5-tetrahydro-
1H-1-benzazepine or a salt thereof and the like. Antiepileptic agents include, for example, phenytoin, carbamazepine and the like. Sympathetic stimulants include, for example, isoproterenol hydrochloride and the like.
As gastrointestinal drugs, for example, diastase, sugar-containing pepsin,
Gastric digestive agents such as funnel extract, cellulase AP3, lipase AP, calyx oil; perperin hydrochloride, resistant lactic acid bacteria,
Intestinal preparations such as bifidobacteria and the like. Examples of the antacid include magnesium carbonate, sodium hydrogencarbonate, 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 antitussive expectorants include cloperastine hydrochloride, dextromeltophan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, codeine phosphate and the like. Examples of the antiemetic include difenidol hydrochloride, metoclopramide and the like. Examples of the respiratory enhancer include levallorphan tartrate. As a bronchodilator,
Examples include theophylline and salbutanol sulfate. Examples of antiallergic agents include amlexanox, seratrodast, and the like. 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, dl-chlorpheniramine maleate, and the like. Examples of cardiotonic agents include caffeine, digoxin and the like. Examples of the agent for arrhythmia include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of diuretics include isosorbide, furosemide and the like. Examples of antihypertensive agents include delapril hydrochloride, captopril, hexamethonium bromide, hydralazine hydrochloride, lapetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, losartan, valsartan, eprosartan,
Irbesartan, tasosartan, telmisartan, pomisartan, lipisartan, forasartan and the like.

Examples of the vasoconstrictor include phenylephrine hydrochloride. 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. As antibiotics, for example, cefem antibiotics such as cephalexin, amoxicillin, pipmecillinam hydrochloride, cefotiam hydrochloride, cefozopran hydrochloride, cefmenoxime hydrochloride, cefsulodin sodium; synthetic antibacterial agents such as ampicillin, cyclasin, sulbenicillin sodium, nalidixic acid, enoxacin Agents; monobactam antibiotics such as carmonam sodium; penem antibiotics and carpapenem antibiotics.
As chemotherapeutic agents, for example, sulfamethizole hydrochloride,
And thiazosulfone. Examples of the therapeutic agent for diabetes include tolbutamide, voglibose, and 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. As a treatment for osteoporosis,
For example, ipriflavone and the like can be mentioned. Examples of the skeletal muscle relaxant include metocarpamol.
Examples of the antitussive include meclizine hydrochloride, cimenhydrinate and the like.

Examples of the hormone agent include liotinin sodium, dexamethasone sodium phosphate, prednisolone, oxendrone, leuprorelin acetate and the like. Examples of the alkaloid narcotics include opium, morphine hydrochloride, tocon, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride and the like. Examples of the sulfa drug include sulfamine, sulfamethizole and the like. Examples of gout remedies include allopurinol, colchicine and the like. Examples of the anticoagulant include dicoumarol.
Examples of antineoplastic agents include 5-fluorouracil,
Uracil, mitomycin and the like. Examples of the drug for treating Alzheimer's disease include idebenone, vinpocetine, and 8- [1-oxo-3- [1- (phenylmethyl) piperidin-4-yl] propyl] -2,3,4,4.
5-tetrahydro-1H-1-benzazepine or a salt thereof, and the like. The “drug that becomes unstable in a titanium oxide-containing preparation” is more preferably a compound of the formula

Embedded image [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 hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X is 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 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 a benzene ring which may have a substituent, and m is Shows an integer of 1 to 4. Or a salt thereof.

As used herein, the term "substituted
As "hydrocarbon group"
Is, for example, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group
And aromatic hydrocarbon groups.
Sixteen are preferred. Specifically, for example, alkyl
Group, alkenyl group, alkynyl group, cycloalkyl group
And an aryl group. "Alkyl group" is an example
For example, a lower alkyl group and the like are preferable.
, Propyl, isopropyl, butyl, isobutyl, se
c-butyl and tert-butyl, pentyl, hexyl, etc.
C_1-6Alkyl groups and the like are widely used. "Alkenyl group"
Is preferably, for example, a lower alkenyl group.
, 1-propenyl, allyl, isopropenyl, butenyl
And isobutenyl _2-6Alkenyl groups are common
Is done. An “alkynyl group” is, for example, a lower alkynyl group
And the like, for example, ethynyl, propargyl and 1
-C such as propynyl_2-6Alkynyl groups and the like are commonly used.
“Cycloalkyl group” is, for example, a lower cycloalkyl group.
And the like, for example, cyclopropyl, cyclobutyl,
C such as cyclopentyl and cyclohexyl_{3- 6}Cyclo
Alkyl groups and the like are widely used. An “aryl group” is, for example,
Phenyl, 1-naphthyl, 2-naphthyl, biphenylyl
And C such as 2-anthryl_6-14Aryl groups etc. are preferred
For example, a phenyl group is widely used.

"Hydrocarbon group optionally having substituent (s)"
As the substituent which the “hydrocarbon group” may have,
For example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxy group, a lower alkyl group which may be halogenated (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trichloromethyl) Fluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Optionally halogenated C ₁ such as butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl _-6 alkyl group),
Lower alkoxy (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., methylamino, A mono-C _1-6 alkylamino group such as ethylamino, etc., a di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, etc.), a carboxyl group, a lower alkylcarbonyl group (For example, C such as acetyl, propionyl, etc.)
_1-6 alkyl-carbonyl group, etc.), lower alkoxycarbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl group, thiocarbamoyl group, mono- Lower alkylcarbamoyl groups (eg, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc.),
Di-lower alkylcarbamoyl groups (eg, di-C _1-6 alkyl-carbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl); arylcarbamoyl groups (eg, C _6-10 aryl-carbamoyl groups such as phenylcarbamoyl and naphthylcarbamoyl) etc.), an aryl group (e.g., phenyl, etc. C _6-10 aryl group naphthyl), an aryloxy group (e.g., phenyloxy, etc. C _6-10 aryloxy group naphthyloxy), optionally halogenated A lower alkylcarbonylamino group (eg, an optionally halogenated C _1-6 alkyl-carbonylamino group such as acetylamino and trifluoroacetylamino), an oxo group and the like are 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 substitutable positions of the hydrocarbon group. When the number of substituents is two or more, each substituent may be the same or different.

The "heterocyclic group" of the term "heterocyclic group optionally having substituent (s)" used herein is, for example, selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. And 5 to 14 (preferably 5 to 10 membered) (monocyclic to tricyclic, preferably monocyclic) containing one or two kinds of 1 to 4 (preferably 1 to 3) heteroatoms. Formula or bicyclic) heterocyclic group. 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 5-imidazolyl, 1,2,3-triazolyl, 1,2,4
5-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as -triazolyl, 1H- or 2H-tetrazolyl, for example, 2-, 3- or 4-pyridyl , N-oxide-2
-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino, 2-, 3- or 4-piperidyl, thiopyranyl ,
1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- or 4
A 6-membered ring group having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as -pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, for example, indolyl, benzofuryl ,
Benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiadinyl, phenothiadinyl A bicyclic or tricyclic fused ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to the carbon atom (preferably, the above 5- or 6-membered ring is other than carbon atom) And a group formed by condensing with one or two 5- or 6-membered ring groups which may contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. Among them, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than a carbon atom is preferable.

The "heterocyclic group optionally having substituent (s)"
Examples of the substituent which the “heterocyclic group” may have include, for example,
For example, a halogen atom (for example, fluorine, chlorine, bromine, iodine
A lower alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl
C such as tyl, tert-butyl, pentyl and hexyl_1-6A
Alkyl group), a cycloalkyl group (eg, cyclopro
Pill, cyclobutyl, cyclopentyl, cyclohexyl
Etc. C_3-6Cycloalkyl group), lower alkynyl group
(Eg, ethynyl, 1-propynyl, propargyl, etc.
C_2-6Alkynyl group, etc.), lower alkenyl group (for example,
Vinyl, allyl, isopropenyl, butenyl, isobute
C such as Nil_2-6Alkenyl group, etc.), aralkyl group (eg,
C such as benzyl, α-methylbenzyl, phenethyl, etc.
_7-11Aralkyl group, etc.), aryl group (for example, phenyl
C such as le and naphthyl_6-10Aryl group etc., preferably
A lower alkoxy group (e.g., methoxy, ethoxy, etc.)
Xy, propoxy, isopropoxy, butoxy, isobut
C such as toxic, sec-butoxy, tert-butoxy_1-6Arco
An aryloxy group (eg, phenoxy, etc.)
C_6-10Aryloxy group, etc.), lower alkanoyl group
(Eg, formyl; acetyl, propionyl, butyric)
C, such as toluene and isobutyryl_1-6Alkyl-carbonyl group
Etc.), arylcarbonyl (e.g., benzoyl group, na
C such as futoyl group_6-10Aryl-carbonyl group, etc.), low
Higher alkanoyloxy groups (for example, formyloxy;
Cetyloxy, propionyloxy, butyryloxy,
C such as isobutyryloxy_1-6Alkyl-carbonyl
Xy group), an arylcarbonyloxy group (for example,
C such as nzoyloxy and naphthoyloxy_6-10Aryl
-Carbonyloxy group, etc.), carboxyl group, lower alkyl
Oxycarbonyl group (for example, methoxycarbonyl,
Toxoxycarbonyl, propoxycarbonyl, isopropo
Xoxycarbonyl, butoxycarbonyl, isobutoxyca
C such as rubonyl and tert-butoxycarbonyl_1-6Alkoki
A-carbonyl group, etc.), aralkyloxycarbonyl
(For example, C such as benzyloxycarbonyl)_7-11Aral
Killoxycarbonyl group), carbamoyl group, mono
-, Di- or tri-halogeno-lower alkyl groups (e.g.
For example, chloromethyl, dichloromethyl, trifluoromethyl
Mono- and di-mers such as 2,2,2-trifluoroethyl
Or tri-halogeno-C_1-4Alkyl group), oxo
Group, amidino group, imino group, amino group, mono-lower alkyl
Killamino groups (eg, methylamino, ethylamino,
Propylamino, isopropylamino, butylamino, etc.
Mono-C _1-4Alkylamino group), di-lower alkyl
Amino group (for example, dimethylamino, diethylamino
No, dipropylamino, diisopropylamino, dibuti
Di-C such as ruamino, methylethylamino, etc._1-4Alkyl
Amino group, etc.), oxygen atom in addition to carbon atom and one nitrogen atom
A heteroatom selected from the group consisting of
A 3- to 6-membered cyclic amine optionally containing 1 to 3
Groups (eg, aziridinyl, azetidinyl, pyrrolidi)
Nil, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl
, Imidazolidinyl, piperidyl, morpholinyl, di
Hydropyridyl, pyridyl, N-methylpiperazinyl, N-
3- to 6-membered cyclic amino group such as ethylpiperazinyl
Etc.), an alkylenedioxy group (for example, methylenedioxy)
C, such as ethylenedioxy_1-3Alkylenedioxy group
Etc.), hydroxy, nitro, cyano, mercapto
Group, sulfo group, sulfino group, phosphono group, sulfamo
Group, monoalkylsulfamoyl group (for example, N-meth
Tilsulfamoyl, N-ethylsulfamoyl, N-pro
Pilsulfamoyl, N-isopropylsulfamoyl,
Mono-C such as N-butylsulfamoyl_1-6Alkylsul
Famoyl group, etc.), dialkylsulfamoyl group (eg,
For example, N, N-dimethylsulfamoyl, N, N-diethylsulfur
Amoyl, N, N-dipropylsulfamoyl, N, N-dibuty
Di-C such as rusulfamoyl_1-6Alkylsulfamoy
Alkylthio group (eg, methylthio, ethyl)
Luthio, propylthio, isopropylthio, butylthio
C such as e, sec-butylthio, tert-butylthio, etc._1-6Archi
Ruthio group, etc.), arylthio group (for example, phenylthio group)
C such as o, naphthylthio, etc._6-10Arylthio group, etc.), lower
Alkylsulfinyl groups (eg, methylsulfinyl
, Ethylsulfinyl, propylsulfinyl, butyral
C such as rusulfinyl_1-6Alkylsulfinyl group
Etc.), arylsulfinyl group (for example, phenylsulfinyl)
C such as finyl and naphthylsulfinyl_6-10Aryls
Rufinyl group), lower alkylsulfonyl group (eg,
For example, methylsulfonyl, ethylsulfonyl, propyls
C such as rufonyl and butylsulfonyl_1-6Alkylsulfo
An arylsulfonyl group (for example, phenyl
C such as sulfonyl, naphthylsulfonyl, etc._6-10Aryls
And the like are used. The "having a substituent
The "heterocyclic group" of the "optionally heterocyclic group" may be the above substituent
At 1 to 5 substitutable positions of the heterocyclic group, preferably
Or may have 1 to 3 substituents and 2 or more substituents.
In the above case, each substituent may be the same or different.

As used herein, the term "optionally substituted amino group" includes, for example, one or two of the above-mentioned "optionally substituted hydrocarbon group" and the like. And an amino group which may be present. Preferred examples of the substituent which the “amino group” may have include, for example, a C _1-6 alkyl group which may have a substituent and a C _6-10 which may have a substituent. And an aryl group. As the substituents that the “C _1-6 alkyl group” and “C _6-10 aryl group” may have, the same substituents as the above-mentioned “hydrocarbon group” may have Used.

As used herein, the term "lower alkyl group" of the term "lower alkyl group optionally having substituent (s)"
Is, for example, methyl, ethyl, propyl, isopropyl,
A C _1-6 alkyl group such as butyl, isobutyl, sec-butyl and tert-butyl; You may have.

As used herein, the term "lower alkoxy group" of the term "optionally substituted lower alkoxy group" means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert- indicates C _{1 -6} alkoxy group such butoxy, as a substituent, for example, the the "hydrocarbon group" substituent may have such may have three from 1.
As used herein, the term “optionally substituted benzene ring” includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally substituted carbon atom. A hydrogen group, an amino group which may have a substituent, an amide group (for example, a C _1-3 acylamino group such as formamide or acetamido), a lower alkoxy group which may have a substituent, An oxy group (for example, C _1-3 such as methylenedioxy and ethylenedioxy);
Benzene ring which may have one or two substituents selected from an alkylenedioxy group and the like at substitutable positions. 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, the respective substituents may be the same or different. The “optionally substituted benzene ring” includes, for example, a halogen atom (eg, fluorine, chlorine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, etc.), and mono-C _1-6 A benzene ring or the like which may be substituted with one or two substituents selected from an alkylamino group is preferred.

In the above formula, R¹May have a substituent
Hydrocarbon group, amino group which may have a substituent or
Represents a heterocyclic group which may have a substituent. R¹Indicated by
Of the "hydrocarbon group which may have a substituent"
Preferred examples of the “hydrogen group” include, for example, an alkyl group (eg,
For example, C such as methyl, ethyl, propyl, isopropyl, etc.
_1-6Alkyl group, etc.), alkenyl group (eg, vinyl, etc.)
C_2-6Alkenyl group), alkynyl group (for example,
C such as tinyl_2-6Alkynyl group, etc.), cycloalkyl group
(Eg, cyclopropyl, cyclobutyl, cyclopen
C such as tyl and cyclohexyl_3-6Cycloalkyl group, etc.)
And an aryl group (for example, C_6-14Ally
Especially alkyl groups (eg, C such as methyl)
_1-6Alkyl group) and cycloalkyl group (for example,
C such as cyclopropyl_3-6Such as cyclopropyl)
Is done. The “alkyl group”, “alkenyl group”, “alk
Quinyl group "," cycloalkyl group "," aryl group "
Is, for example, a substitution which the above “hydrocarbon group” may have
Group (preferably a halogen atom such as fluorine) and the like.
It may have five, preferably one to three.

Preferred examples of the substituent of the "amino group optionally having substituent (s)" for R ¹ include a lower alkyl group optionally having substituent (s) and a substituent (s) having substituent (s). 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. As the “lower alkyl group”, for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl is used. The “lower alkyl group” may have, for example, 1 to 3 substituents and the like which the “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 (preferably a halogen atom such as fluorine or chlorine, a C _1-6 alkoxy group such as methoxy or ethoxy, etc.) which the above “hydrocarbon group” may have. It may have from 5 to 5, preferably from 1 to 3. Examples of the “optionally substituted amino group” include, for example, 1 to 3 lower alkoxy groups (eg,
A phenylamino group substituted with a C _1-4 alkoxy group such as methoxy, or a lower alkyl group (eg, a C _1-4 alkyl group such as methyl, ethyl, propyl, butyl, tert-butyl, etc.) Monoalkylamino groups and the like are widely used.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” for R ¹ include:
For example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom 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 and the like. Particularly preferably,
A 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) and the like are used.

R¹Which may have a substituent
Preferred examples of the substituent of the `` heterocyclic group '' include, for example,
Halogen atom (for example, chlorine, fluorine, etc.), C_1-6Archi
Group (eg, methyl, ethyl, etc.), C_1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.), aralkyloxyca
Rubonyl group (for example, C such as benzyloxycarbonyl)
_7-12Aralkyloxy-carbonyl and the like are used.
You.

R ¹ is, for example, (i) a lower alkyl group optionally having a substituent, (ii) a lower cycloalkyl group optionally having a substituent, or (iii) a substituent. (Iv) optionally substituted lower alkenyl group, (iv) optionally substituted aryl group, (v) optionally substituted mono or di lower alkylamino group, (vi) optionally substituted And an optionally substituted arylamino group or (vii) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group.

The above "lower alkyl group" is, for example, methyl
, Ethyl, propyl, isopropyl, butyl, pliers
C, e.g._1-6Alkyl groups and the like are preferred. "Low
Lower cycloalkyl group '' is, for example, cyclopropyl, cycloalkyl,
C such as robutyl, cyclopentyl and cyclohexyl_3-6
Cycloalkyl groups and the like are preferred. "Lower alkenyl group"
Is a C such as vinyl, 1-propenyl, butenyl and the like.
_2-6Alkenyl groups and the like are preferred. "Aryl group" is an example
For example, C such as phenyl, 1-naphthyl and 2-naphthyl _6-10
Aryl groups and the like are preferred. "Lower alkylamino group"
Is, for example, methylamino, ethylamino, propylamido
, Isopropylamino, butylamino, tert-butyl
Amino, dimethylamino, diethylamino, methylethyl
Mono- or di-C such as ruamino_1-6Alkylamino group
Are preferred. An “arylamino group” is, for example, phenyl
C such as ruamino_6-10Arylamino groups and the like are preferred.
“5- or 6-membered nitrogen-containing heterocyclic group” is, for example, 2-, 3-
Or a 5- or 6-membered nitrogen-containing heterocyclic group such as 4-pyridyl and the like
Is preferred. As a substituent which these groups may have
May be, for example, a position that the above “hydrocarbon group” may have.
One to five substituents are used.

[0030] More preferred examples of R ¹ are, i) halogen or C _1-6 to 1 respectively with an alkoxy group four optionally substituted C _1-6 alkyl group, ii) C _3-6 cycloalkyl group, iii) C _2-6 alkenyl group, iv) C _1-6 alkoxy, nitro, halogeno C _1-6 alkyl - 1 respectively carbonylamino or halogen atom to four substituents which may be C _6-10 aryl group, 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 aralkyloxycarbonyl group. And an optionally substituted 6-membered nitrogen-containing heterocyclic group. Particularly, an optionally halogenated C _1-6 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentane 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
- trifluoro hexyl, etc.), C _3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or mono -C _1-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropyl Amino, butylamino, tert
-Butylamino and the like are widely used, and among these, an optionally halogenated C _1-6 alkyl group or a mono-C _1-6 alkylamino group, especially an optionally halogenated C
Preferred are _1-6 alkyl groups, especially C _1-3 alkyl groups (eg, methyl, ethyl, propyl, etc.).

In the above formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent. As R ² , a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent is preferably used, and more preferably, a hydrogen atom or a lower (C _1-6 ) alkyl group, particularly a hydrogen atom Is commonly used. The “substituent” of the “lower (C _1-6 ) alkyl group _optionally having substituent (s)” is, for example, a substituent which the above “hydrocarbon group” may have.

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. Preferred examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ³ include an alkyl group (for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, etc.). An alkenyl group (eg, a C _2-6 alkenyl group such as vinyl), an alkynyl group (eg, a C _2-6 group such as ethynyl).
_2-6 alkynyl group, etc.), cycloalkyl group (eg, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and aryl group (eg, C _6-14 aryl group such as phenyl, etc.) etc,
Particularly, an alkyl group (for example, a C _1-6 alkyl group such as methyl) and an aryl group (for example, a C _6-14 aryl group such as phenyl) are widely used. The “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” are, for example, substituents (preferably fluorine and the like) which the above “hydrocarbon group” may have. 1 to 5, preferably 1 to 3
You may have one.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” for R ³ include:
For example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom 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 and the like. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) and the like are used.

R^ThreeWhich may have a substituent
Preferred examples of the substituent of the `` heterocyclic group '' include, for example,
Halogen atom (for example, chlorine, fluorine, etc.), C_1-6Archi
Group (eg, methyl, ethyl, etc.), C_1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.), aralkyloxyca
Rubonyl group (for example, C such as benzyloxycarbonyl)
_7-12Aralkyloxy-carbonyl, etc.), amino group,
No-C_1-6Alkylamino groups (eg methylamino, d
Tylamino, etc.), di-C_1-6Alkylamino group (for example,
Dimethylamino, diethylamino, etc.)
You.

R ³ represents, for example, (i) a hydrogen atom, (ii) a lower alkyl group optionally having a substituent, (iii) an aryl group optionally having a substituent, (iv) a substituent And a 5- or 6-membered heterocyclic group which may have, for example, (i) a hydrogen atom, (ii) a lower alkyl group, and (iii) a C _6-10 aryl optionally having a substituent. And (iv) a 6-membered nitrogen-containing heterocyclic group which may have a substituent.
Examples of the substituent include a halogen atom, a C _1-6 alkyl group,
_Examples thereof include a _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, 2-,
It is a 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 preferably a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent, 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).

In the above formula, Y represents C, CH or N.
Preferably it is C or CH.

In the above formula, the ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent. The "5
The term "heterocycle containing a to 7-membered oxygen atom" refers to one or two (preferably one or two) selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and an oxygen atom. 5) to 7-membered (preferably 5- or 6-membered) heterocyclic rings which may be contained. The ring has the formula

Embedded image [Wherein E is (i) CH ₂ CH ₂ , (ii) CH = CH, (i
ii) CH ₂ O, (iv) OCH ₂ , (v) CH ₂ S (O) q ′
(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 2, wherein n ′ is 0 to 2
Indicates an integer. Are preferred. 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 preferred, especially (i) CH ₂ CH ₂ or (ii) C
H = CH is preferred. 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, etc., for example, 2H -3,4-dihydropyran, 2H-pyran, 2,3
6-membered heterocycles containing an oxygen atom, such as -dehydro-1,4-dioxane and 2,3-dehydromorpholine, are preferred. More preferably, the formula

Embedded image [In the formula, n represents an integer of 0 to 2, and ---- represents a single bond or a double bond. ]. Specifically, for example, 2,3-dihydrofuran, furan, 2
H-3,4-dihydropyran and 2H-pyran are widely used.

Examples of the substituent for the ring A include, for example, a halogen atom
Child (eg, fluorine, chlorine, bromine, iodine, etc.), substituent
May have a lower alkyl group or a substituent
Cycloalkyl group, which may have a substituent
Lower alkynyl group, lower alkynyl which may have a substituent
Kenyl group, aryl group which may have a substituent, lower
Alkoxy groups (eg methoxy, ethoxy, propoxy)
Si, isopropoxy, butoxy, isobutoxy, sec-butyl
C such as toxic and tert-butoxy_1-6Alkoxy group, etc.)
Reeloxy group (for example, C such as phenoxy)_6-10Ally
A lower alkanoyl group (for example,
Acetyl, propionyl, butyryl, isobutyryl
Etc. C_1-6Alkyl-carbonyl group, etc.), arylcal
Bonyl group (e.g., benzoyl group, naphthoyl group, etc.
_6-10Aryl-carbonyl group, etc.), lower alkanoyl
Xy groups (eg, formyloxy; acetyloxy,
Lopionyloxy, butyryloxy, isobutyryloxy
C such as shi_1-6Alkyl-carbonyloxy group, etc.)
Carbonyloxy group (for example, benzoyloxy,
C such as naphthoyloxy_6-10Aryl-carbonyloxy
Group), carboxyl group, lower alkoxycarbonyl
Groups (eg, methoxycarbonyl, ethoxycarboni
, Propoxycarbonyl, isopropoxy carbonyl
, Butoxycarbonyl, isobutoxycarbonyl, te
C such as rt-butoxycarbonyl_1-6Alkoxy-carboni
Aralkyloxycarbonyl (for example, benzene
C such as ziroxycarbonyl_7-11Aralkyloxy-ca
Rubonyl group, etc.), carbamoyl group, thiocarbamoyl
Group, mono-, di- or tri-halogeno-lower alkyl
Groups (eg, chloromethyl, dichloromethyl, trifur
Mono such as olomethyl, 2,2,2-trifluoroethyl
-, Di- or tri-halogeno-C_1-4Alkyl group
Oxo, amidino, imino, amino,
No-lower alkylamino groups (e.g., methylamino,
Tylamino, propylamino, isopropylamino,
Mono-C such as tilamino_1-4Alkylamino group), di
A lower alkylamino group (e.g., dimethylamino, di
Ethylamino, dipropylamino, diisopropylami
Di-C such as di-, dibutylamino, methylethylamino, etc.
_1-4Alkylamino group), carbon atom and one nitrogen atom
Other than oxygen, sulfur and nitrogen
3 to 6 which may contain 1 to 3 hetero atoms
Membered cyclic amino groups (eg, aziridinyl, azetidiny
, Pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazoly
, Pyrazolyl, imidazolidinyl, piperidyl, mol
Folinyl, dihydropyridyl, pyridyl, N-methylpipe
3- to 6-membered ring such as radinyl and N-ethylpiperazinyl
Amino groups), alkylenedioxy groups (eg, methyl
C such as rangeoxy and ethylenedioxy_1-3Alkylene
Dioxy group, etc.), hydroxy group, nitro group, cyano group,
Mercapto group, sulfo group, sulfino group, phosphono group,
Sulfamoyl group, monoalkylsulfamoyl group (eg
For example, N-methylsulfamoyl, N-ethylsulfamoy
, N-propylsulfamoyl, N-isopropylsulfur
Mono-C such as amoyl and N-butylsulfamoyl_1-6A
Rualkylsulfamoyl group), dialkylsulfamoy
(For example, N, N-dimethylsulfamoyl, N, N-die
Tylsulfamoyl, N, N-dipropylsulfamoyl,
Di-C such as N, N-dibutylsulfamoyl_1-6Alkyls
Rufamoyl group, etc.), alkylthio group (eg, methyl
Thio, ethylthio, propylthio, isopropylthio,
C such as butylthio, sec-butylthio, tert-butylthio, etc.
_1-6Alkylthio group, etc.), arylthio group (for example,
C such as enylthio, naphthylthio, etc._6-10Arylthio group
Etc.), lower alkylsulfinyl group (for example, methyls
Rufinil, ethylsulfinyl, propylsulfinyl
And butylsulfinyl_1-6Alkylsulfini
Group), an arylsulfinyl group (for example, phenyl
C such as sulfinyl and naphthylsulfinyl_6-10Ally
Rusulfinyl group), lower alkylsulfonyl group (eg
For example, methylsulfonyl, ethylsulfonyl, propyl
C such as sulfonyl and butylsulfonyl_1-6Alkylsul
A sulfonyl group), an arylsulfonyl group (for example, phenyl
C such as rusulfonyl and naphthylsulfonyl_6-10Aryl
And the like are used. The "lower alkyl
A "lower alkenyl group", a "lower alkynyl group",
"Lower cycloalkyl group" and "aryl group"
If the above "hydrocarbon group" may have a substituent or the like
1 to 5, preferably 1 to 3
No. As a substituent for the ring A, a halogen atom,
C optionally having a substituent _1-6Has alkyl group and substituent
C that may be_1-6Alkoxy group, hydroxyl group, nitro
Group, cyano group, amino group which may have a substituent,
And a xo group. The `` may have a substituent
C_1-6Alkyl group "," optionally substituted C "_1-6
Alkoxy group "," optionally substituted amino "
The “substituent” of the “group” has, for example, the above “hydrocarbon group”
Represents a substituent which may be substituted. The ring A has the above substituent
Is 1 to 4 at a substitutable position depending on the size of the ring.
, Preferably 1 to 2 substituents
When the number is two or more, each substituent is the same or different
You may. As the ring A, for example,

Embedded image [N represents the same meaning as described above, and R ⁵ represents a hydrogen atom or a substituent 1 or 2 represented by the above-mentioned “preferable substituent on ring A”.
Shows the individual. And the like. Among them, R ⁵ is a hydrogen atom and a C _1-6 alkyl group which may have a substituent, especially those wherein R ⁵ is hydrogen atom (unsubstituted ring A) is generally used. In the above formula, ring B represents a benzene ring which may have a substituent. Examples of the substituent on ring B include the “substituent” of the above-mentioned “benzene ring which may have a substituent”. 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 widely used. “Substituent” of the “lower (C _1-6 ) alkyl group _optionally having substituent (s)”
Represents, for example, a substituent which the “hydrocarbon group” may have. Ring B may have one or two, preferably one at the position where the substituent can be substituted, and the number of substituents is 2
In this case, each substituent may be the same or different.
As the ring B, for example,

Embedded image [R ⁶ represents a hydrogen atom, a halogen atom, a lower (C _1-6 ) alkyl group which may have a substituent or a lower (C _1-6 ) alkoxy group which may have a substituent. And the like. R ⁶ is preferably, for example, a hydrogen atom, a halogen atom or a lower (C _1-6 ) alkyl group (preferably methyl). More preferably, it is a hydrogen atom. 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,
m is preferably 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.

Embedded image [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 an optionally substituted lower (C _1-3 ) alkyl.

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

Embedded image Wherein each symbol is as defined above. And the like.

Embedded image Wherein each symbol is as defined above. ] Is preferably used. this house,

Embedded image Wherein each symbol is as defined above. And the like. Particularly preferred

Embedded image Wherein each symbol is as defined above. ]. As the compound (I), for example, those having the following structural formulas are particularly widely used.

Embedded image Wherein each symbol is as defined above. As a preferable example of the compound (I), a compound represented by the formula:

Embedded image Wherein each symbol is as defined above. And the like. Further, as preferable examples of the compound (I), R ¹ is (i) a lower alkyl group optionally having a substituent, (ii) a lower cycloalkyl group optionally having a substituent, (iii) A) a lower alkenyl group which may have a substituent, (iv) an aryl group which may have a substituent, (v) a mono- or di-lower alkylamino group which may have a substituent, vi) an optionally substituted arylamino group or (vii) an optionally substituted 5
Or a 6-membered nitrogen-containing heterocyclic group, R ² has a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent, R ³ has (i) a hydrogen atom, and (ii) a substituent. Or an optionally substituted lower alkyl group or (iii) an optionally substituted aryl group, wherein X is CHR ⁴ or NR ⁴ (R ⁴ is a lower alkyl (C ⁴⁾ optionally substituted with a hydrogen atom or an oxo group; _1-6 ) represents an alkyl group), Y is C, CH or N (where X is CH
₂ represents Y or C or CH), ---- represents a single bond or a double bond, and the ring A includes a 5- to 7-membered heteroatom containing an optionally substituted oxygen atom. A benzene ring in which the ring and the ring B may have a substituent, and a compound in which m is 1 or 2.

More preferably, R¹Is i) halogen
Or C_1-6Each substituted with 1 to 4 alkoxy groups
C that may be_1-6Alkyl group, ii) C_3-6Cycloal
Kill group, iii) C_2-6Alkenyl group, iv) C_1-6Alkoki
Si, nitro, halogeno C_1-6Alkyl-carbonylamido
Substituted with 1 to 4 each of
May be C_6-10Aryl groups, v) mono- or di-
C_1-6An alkylamino group, vi) one to three C _1-6Al
C optionally substituted with a oxy group_6-10Arylamino
Group or vii) C _7-11Aralkyloxy-carbonyl group
6-membered nitrogen-containing heterocycle optionally substituted by 1 or 2
Group, R^TwoIs a hydrogen atom or lower (C_1-6) Alkyl group, R
^ThreeIs (i) a hydrogen atom, (ii) a lower (C_1-6) Alkyl group
Or (iii) C_6-14Aryl group, X is CHR^FourOr NR^Four
(R^FourMay be substituted with a hydrogen atom or an oxo group.
Low (C_1-6) Represents an alkyl group), Y is C, CH or
Or N (where X is CH_Two, Y is C or C
H),---- Represents a single bond or a double bond;
Ring

Embedded image [Each symbol is as defined above. The ring B

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

Embedded image Also, the formula

Embedded image As the compound (I), for example, 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] butylamide, 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] butylamide, 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] butylamide, N- [2-
(4-fluoro-1,6,7,8-tetrahydro-2H
-Indeno [5,4-b] furan-8-yl) ethyl]
Butyramide, N- [2- (4-fluoro-1,6,6,
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] butylamide, 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] butylamide, 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] butylamide, 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] butylamide is preferred. 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] butylamide, 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] butylamide, N- [2- (1,6,7,8-tetrahydro-2)
H-Flo [3,2-e] indol-8-yl) ethyl] propionamide, N- [2- (1,6,7,8-
Tetrahydro-2H-furo [3,2-e] indole-
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] butylamide. 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] indole-
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] butylamide, N- [2- (1,6,7,8-tetrahydro -2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide. As the compound (I), a compound represented by the formula

Embedded image [In the formula, 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 is particularly preferable, 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 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. Suitable 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-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine,
Salts with N, N'-dibenzylethylenediamine and the like can be mentioned. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid,
Examples thereof include salts with acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. It is. Among them, pharmaceutically acceptable salts are preferable, and examples thereof include, when the compound (I) has a basic functional group, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Salts of, for example, acetic acid,
Phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid,
Salts with organic acids such as succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and when having an acidic functional group, for example, alkali metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt and the like Alkaline earth metal salts, ammonium salts and the like. Compound (I) may be a hydrate or a non-hydrate. Compound (I) is described, for example, in Japanese Patent No. 2884153.
The method can be obtained by the method described in (1) or a method analogous thereto.

Examples of the above "formulation components" include excipients (eg, lactose, sucrose, D-mannitol, D-sorbitol, starch (such as corn starch, potato starch), pregelatinized starch, dextrin, crystalline cellulose, Low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic,
Dextran, pullulan, light silicic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate, etc.), binders (eg, pregelatinized starch, sucrose, gelatin,
Gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, dextrin, pullulan, etc.), lubricants (eg,
Magnesium stearate, calcium stearate,
Talc, colloidal silica, etc.), disintegrants (eg, lactose, sucrose, carboxymethylcellulose, low-substituted hydroxypropylcellulose, starch (corn starch, potato starch, etc.), light anhydrous silicic acid, croscarmellose sodium, carboxymethyl starch sodium , Carboxymethylcellulose calcium,
Cross-polyvinylpyrrolidone], coloring agents, flavors, flavoring agents, adsorbents, preservatives, wetting agents, antistatic agents, disintegration extenders and the like. The amount of the above-mentioned formulation component may be the same as that used for the production of a general formulation.

The "formulation" of the present invention includes pharmaceutical preparations, cosmetic preparations, food preparations, and the like. Hereinafter, the pharmaceutical preparation will be described, but the following description can be similarly applied to other preparations. Examples of the dosage form of the “pharmaceutical preparation” of the present invention include tablets, capsules, powders, granules, fine granules, pills and the like. The granule has, for example, a particle size of about 5
About 90% by weight or more of particles having a particle size of 00 to about 1400 μm and about 5% by weight or less of particles having a particle size of about 177 μm 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 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. It contains below. Preferred fine granules include particles having a particle size of about 150 to about 500 μm of about 75% by weight or more, and a particle size of about 500 μm.
m and about 5 wt.

The "pharmaceutical preparation" of the present invention is produced by coating a "drug-containing composition" obtained by mixing the above "drug" and "formulation components" by a conventional method with a "coating agent". . The amount of the coating agent to be 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; 0.1 to about 50% by weight, preferably about 1 to about 20% by weight;
To about 100% by weight, preferably 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 adopted. When the coating agent is a solution or a dispersion containing water or an organic solvent, a spray coating method can be adopted as a coating method. The temperature during coating is usually about 25 to about 60C, preferably about 25 to about 40C.
Further, the time required for coating can be appropriately selected in consideration of the coating method, characteristics and amount of the coating agent, characteristics of the pharmaceutical preparation, and the like.

The above-mentioned compound (I) has excellent melatonin agonistic activity, has low toxicity and is safe without side effects, and therefore can be suitably used in the preparation of the present invention. The "pharmaceutical preparation" of the present invention includes, for example, when compound (I) or a salt thereof is used as a drug, diseases that may be affected by melatonin, such as biological rhythm regulation disorder, for example, sleep-wake rhythm disorder, jet lag (jet jet). la
g), physical shifts due to three shifts, seasonal depression,
Reproductive and neuroendocrine diseases, senile dementia, Alzheimer's disease, various disorders associated with aging (eg, aging prevention), cerebral circulation disorders (stroke, etc.), head trauma, bone marrow injury, stress, epilepsy, convulsions, anxiety, depression Disease, Parkinson's disease,
It can be used for the prevention and treatment of hypertension, glaucoma, cancer, insomnia, diabetes, etc., and is also effective for immune regulation, cognition, mental stability or ovulation adjustment (for example, 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 therapeutic agent for sleep disorders (eg, a sleep inducer, etc.), a sleep-wake rhythm regulator (sleep-wake rhythm) And a time-lag change syndrome, a so-called jet lag prevention / treatment agent. The dose 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 dose as the drug is an effective amount of the drug. . For example, when compound (I) or a salt thereof is used as a drug, the “pharmaceutical preparation” is a compound (I) or a salt thereof administered to an adult (body weight 60 kN).
g) per day from about 0.01 mg to about 100 mg, preferably from about 0.1 to about 30 mg, more preferably from about 0.3 to about 30 mg.
The dose is about 10 mg and is administered once or in two or three divided doses. In the present invention, in order to block the contact between the titanium oxide and a drug that reacts with the titanium oxide, the uncoated tablet is coated with a water-soluble coating agent (for example, hydroxypropyl cellulose,
(Hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, etc.), and then coating the film component thereon to obtain a stabilized pharmaceutical preparation. The coating amount of the water-soluble coating agent 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.

[0047]

Example 1 160 g of compound A, 4064 g of lactose, and 640 g of corn starch were uniformly mixed in a fluidized bed granulator and sprayed with an aqueous solution in which 160 g of hydroxypropylcellulose was dissolved in the machine, followed by granulation. Dried with the same machine. The obtained granules were pulverized with a power mill using a 1.5 mmφ punching screen to give sized powder. Take 3894 g of the sized powder, add 124 g of corn starch and magnesium stearate
12.4 g is added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 7.0 mmφ punch to a weight of 130 mg to give uncoated tablets. The obtained uncoated tablet was obtained by dispersing talc and yellow iron sesquioxide in hydroxypropylmethylcellulose 2910, polyethylene glycol 600 in a film coating machine.
Solution 0 was sprayed to obtain about 25,000 film tablets having the formulation shown in Table 1 and containing 4 mg of compound A per tablet.

[0048]

[Table 1] The case where the coating amount was 5 mg per tablet was shown.

Example 2 Compound B (160 g), lactose (4064 g) and corn starch (640 g) were uniformly mixed in a fluidized bed granulator and sprayed with an aqueous solution in which 160 g of hydroxypropylcellulose was dissolved in the machine, followed by granulation. And dried. The obtained granules were pulverized with a power mill using a 1.5 mmφ punching screen to give sized powder. Take 3894 g of the sized powder, add 124 g of corn starch and magnesium stearate
12.4 g is added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 7.0 mmφ punch to a weight of 130 mg to give uncoated tablets. The obtained uncoated tablets were sprayed with a solution of barium sulfate and yellow iron sesquioxide dispersed hydroxypropylmethylcellulose 2910 and polyethylene glycol 6000 in a film coating machine, and containing 4 mg of compound B per tablet, a film having the formulation shown in Table 2. About 25,000 tablets were obtained.

[0050]

[Table 2] The case where the coating amount was 5 mg per tablet was shown.

Test Example 1 Compound A and barium sulfate were mixed at a ratio of 1:50, and the mixture was stored at 40 ° C. and 75% relative humidity (RH) for 2 weeks and at 60 ° C. for 2 weeks. 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.

[0052]

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

Test Example 2 A compound A tablet coated with a barium sulfate or talc-containing film was subjected to a light resistance test (xenon lamp, 1.2 × 10 ⁶ lux · hour). The results are shown in Tables 4 and 5. Table 6 shows the respective formulations.

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6] The case where the coating amount was 5 mg per tablet was shown.

From the results shown in Tables 4 and 5, it can be seen that the compound A tablets can be obtained by coating with a barium sulfate or talc-containing film to obtain tablets stable to light.

[0058]

The preparation of the present invention is stable against light, especially ultraviolet rays and heat, and has excellent storage stability. Further, according to the present invention, it is possible to perform light-shielding coating without destabilizing the drug, and since such a coated preparation has a uniform surface, for example, processing such as engraving is easy, and the finish is beautiful. . Furthermore, the formulation also helps prevent bitterness when the drug is bitter, and shows no adhesion to the esophageal mucosa upon administration. Since the coating agent of the present invention has excellent light-shielding properties and does not destabilize the drug, it is useful as a raw material for producing a preparation having excellent storage stability as described above.
In addition, since the coating agent has excellent strength and spreadability, it is excellent in operability and enables uniform coating.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/407 A61K 31/407 A61P 1/00 A61P 1/00 1/02 1/02 1/04 1 / 04 1/06 1/06 1/08 1/08 1/14 1/14 1/16 101 1/16 101 3/02 3/02 3/06 3/06 3/10 3/10 5/00 5 / 00 7/02 7/02 9/00 9/00 9/04 9/04 9/06 9/06 9/10 9/10 9/12 9/12 11/00 11/00 11/08 11/08 11 / 10 11/10 11/14 11/14 13/02 13/02 19/06 19/06 19/10 19/10 21/02 21/02 25/00 25/00 25/02 104 25/02 104 25 / 08 25/08 25/18 25/18 25/22 25/22 25/24 25/24 25/28 25/28 29/00 29/00 31/04 31/04 35/00 35/00 37/08 37/08 43/00 113 43/00 113 // C07D 307/77 C07D 307/77 311/94 311/94 317/70 317/70 319/14 319/14 491/048 491/048 491/052 491 / 052 F term (reference) 4C037 XA01 4C050 AA01 BB04 CC16 CC18 DD10 EE01 FF02 GG01 HH01 4C062 HH55 4C076 AA44 BB01 CC01 CC03 CC11 CC14 CC15 CC16 CC17 CC21 CC27 CC29 CC30 CC32 DD24Q DD28Q DD29 EE01H FF21 FF51 FF63 4C086 AA01 AA02 AA03 BA05 BA08 BA13 CB22 MA03 MA05 MA52 NA03 ZA02 ZA08 ZA06 ZA08 ZA06 ZA05 ZA06 ZA06 ZA67 ZA68 ZA71 ZA83 ZA94 ZA96 ZA97 ZB13 ZB26 ZB35 ZC03 ZC13 ZC21 ZC33 ZC35

Claims (12)

[Claims] 1. A preparation comprising a drug coated with a coating containing talc and / or barium sulfate as a light-shielding agent. 2. The preparation according to claim 1, wherein the drug is a drug which becomes unstable in a preparation containing titanium oxide. 3. The preparation according to claim 1, wherein the coating agent contains a water-soluble polymer. 4. The method according to claim 1, wherein the drug is of 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 is a hydrogen atom or a hydrocarbon group which may have a substituent, R ³ is a hydrogen atom, A hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X is 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 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 a benzene ring which may have a substituent, and m is Shows 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. A coating agent containing talc and / or barium sulfate as a light-shielding agent. 6. A light-shielding method comprising coating with a coating agent containing talc and / or barium sulfate. 7. Use of talc and / or barium sulfate as a sunscreen. 8. Use according to claim 7, for the production of coatings. 9. A method for stabilizing a pharmaceutical preparation, comprising coating a drug with a coating agent containing talc and / or barium sulfate as a light-shielding agent. 10. Use of a coating agent containing talc and / or barium sulfate as a light shielding agent for light shielding. 11. Use of talc and / or barium sulfate in the stabilization of a drug which becomes unstable in a preparation containing titanium oxide. 12. A preparation obtained by coating a drug with a coating agent containing barium sulfate.