WO2002040053A1 - Preparation pharmaceutique contenant du talc/ du sulfate de baryum - Google Patents

Preparation pharmaceutique contenant du talc/ du sulfate de baryum Download PDF

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Publication number
WO2002040053A1
WO2002040053A1 PCT/JP2001/010017 JP0110017W WO0240053A1 WO 2002040053 A1 WO2002040053 A1 WO 2002040053A1 JP 0110017 W JP0110017 W JP 0110017W WO 0240053 A1 WO0240053 A1 WO 0240053A1
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WIPO (PCT)
Prior art keywords
group
substituent
coating
drug
talc
Prior art date
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PCT/JP2001/010017
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English (en)
Japanese (ja)
Inventor
Makoto Fukuta
Hajime Ishida
Original Assignee
Takeda Chemical Industries, Ltd.
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Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU2002214306A priority Critical patent/AU2002214306A1/en
Publication of WO2002040053A1 publication Critical patent/WO2002040053A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds

Definitions

  • 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.
  • Tablets that are commonly used as oral preparations are formed using various additives such as diluents, binders, lubricants, and disintegrants.
  • diluents such as diluents, binders, lubricants, and disintegrants.
  • 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
  • the present inventors have intensively searched for a light-blocking agent that can replace titanium oxide in order to improve the above-mentioned problem.
  • a pharmaceutical preparation having sufficient light resistance can be obtained by coating the preparation.
  • talc 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.
  • talc a component of a tablet coating agent
  • 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.
  • a preparation comprising a drug coated with a coating agent (not containing titanium oxide) containing talc and / or barium sulfate as a sunscreen,
  • 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 ),
  • TM 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
  • n an integer of 1 to 4.
  • (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;
  • 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.
  • 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.
  • the coating base examples 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 ⁇
  • Synthetic polymers such as [Eudragit (trade name), ROHMFA ⁇ / MA], polybulpyrrolidone; and polysaccharides such as pullulan.
  • enteric film coating base examples 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.
  • 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.]
  • sustained-release film coating base examples 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.
  • 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.
  • 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.
  • coloring agent examples 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).
  • 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.
  • 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.
  • 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.
  • it contains a compound that decomposes by 5% by weight or more, that is, a residual rate of 95 ° / 0 or less.
  • 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, antineo
  • the content of these “drugs” in the “pharmaceutical preparation” may be an effective amount of the “drug”.
  • specific examples of the above-mentioned drugs will be described.
  • Nourishing tonics include, for example, Vitamin A, Vitamin D, Vitamin E (d- ⁇ -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.
  • 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.
  • anti-ulcer agent examples include benzimidazole compounds (eg, lansoprazole, omebrazole, rabebrazole, pantoprazonole), famotidine, cimetidine, ranitidine hydrochloride and the like.
  • antiemetic examples include difedole hydrochloride, metoclopramide and the like.
  • respiratory enhancer examples include levallorphan tartrate.
  • bronchodilators examples include theophylline, salbutanol sulfate, and the like.
  • antiallergic drugs examples include amlexanox and seratrodast.
  • oral medicine examples include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.
  • antihistamine examples include diphenhydramine hydrochloride, promethazine, isotipendyl hydrochloride, chlorpheniramine d1-maleate, and the like.
  • cardiotonic agents examples include caffeine and digoxin.
  • agent for arrhythmia examples include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like.
  • diuretics examples 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.
  • vasoconstrictor for example, fenirephrine hydrochloride and the like can be mentioned.
  • coronary vasodilators examples 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.
  • 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.
  • chemotherapeutic agent examples include sulfamethizole hydrochloride, thiazosulfone and the like.
  • antidiabetic agents include tolbutamide, voglibos, and thiazolidinedione derivatives (eg, pioglitazone hydrochloride, troglitazone, 5-([4-1- [2-]
  • Examples of the therapeutic agent for osteoporosis include ibriflavon.
  • Examples of the skeletal muscle relaxant include metcarpamol.
  • antidepressant examples include meclizine hydrochloride, cymenhydrinate and the like.
  • Hormonal agents include, for example, riochunadium, dexamethasone sodium phosphate, prednisolone, oxendrone, leuprorelin acetate, and the like.
  • alkyloid-type narcotic drugs include, for example, aphen, morphine hydrochloride, tocon, oxycodone hydrochloride, aphenal hydroloid hydrochloride, cocaine hydrochloride and the like.
  • sulfa drug examples include sulfamine, sulfamethizole and the like.
  • Gout remedies include, for example, aloprinol, colchicine and the like.
  • examples of the anticoagulant include dicoumarol.
  • anti-malignant tumors examples 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
  • 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 ⁇ , when X represents CH 2, Y is Ru C or CH Der),
  • 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
  • n an integer of 1 to 4. Or a salt thereof.
  • 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.
  • alkyl group is preferably, for example, a lower alkyl group.
  • 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
  • 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.
  • phenyl 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, hex
  • 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.
  • G-lower alkylamino group for example, dialkylamino group such as dimethylamino, acetylamino, etc.
  • aryloxy group for example, phenyloxy group and the like such as phenyloxy and naphthyloxy
  • 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.
  • 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.
  • 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
  • Kishinore like to the consequent opening.
  • 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, ⁇ -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
  • Shi group) a lower Arukanoiru group (e.g., formyl;..
  • 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.
  • lower alkoxycarbonyl group e.g., main-butoxycarbonyl, ethoxycarbonyl Kano repo two Nore, Propoxy force Boni ⁇ ⁇ Isopropoxyka ⁇ / Boni ⁇ ⁇ , Butoh Butoxycarbonyl, isobutoxycarbonyl, tert- butoxy C 6 alkoxy such as carbonyl -.
  • 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, ⁇ 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
  • Di-C 6 alkylsulfamoyl groups such as N, N-getylsulfamoyl, N, N-dipropylsulfamoyl, ⁇ , ⁇ -dibutylsulfamoyl, etc., alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropyl) Alkylthio groups such as thio, butylthio, sec-butylthio, tert-butylthio, etc.) arylthio groups (eg, Cs ⁇ .
  • 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.
  • 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
  • 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.
  • 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
  • the substituent for example, the above “hydrocarbon group” may have 1 to 3 substituents and the like.
  • 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.
  • 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.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • 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, ⁇ 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.
  • an amide group for example, C 3 acylamino group such as honolemamide and acetoamide
  • a lower alkoxy group which may have a substituent
  • a lower alkylenedioxy group groups e.g., main Chirenjiokishi, ⁇ 3 alkylenedioxy O alkoxy group such as a Echirenjiokishi
  • optionally substituted hydrocarbon group examples 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.
  • 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.
  • 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
  • Ariru groups e.g., full E -. C 6 such as Le 1 4 7 aryl group, etc.
  • Ariru groups e.g., full E -. C 6 such as Le 1 4 7 aryl group, etc.
  • 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.
  • alkyl group 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.
  • alkyl group alkenyl group
  • alkynyl group examples 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.
  • 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.
  • 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.
  • 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.
  • a phenylamino group substituted with one or three lower alkoxy groups eg, an alkoxy group such as methoxy, etc.
  • a lower alkyl group eg, Mechinore, Echiru, propyl, butyl, C i. 4 alkyl group such as tert- butyl
  • 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.
  • Examples thereof include 2-furyl or 3-furyl, pyrazur, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazyl, 3-isothiazolyl, and 3-isoxazolyl.
  • a 6-membered nitrogen-containing heterocyclic group eg, pyridyl 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.
  • 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 Araru
  • R 1 is, for example, (i) a lower alkyl group optionally having a substituent, ( ⁇ ) 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.
  • “Ariruamino group”, c 6 of Fueniruamino such as if example example. I.
  • 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.
  • substituents that these groups may have, for example, 1 to 5 substituents and the like that the above “hydrocarbon group” may have are used.
  • R 1 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 ⁇ 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.
  • an optionally halogenated C 6 alkyl group for example, methyl, chloromethyl, difluoromethyl, trichloromethinole, triflinoleolomethyl, ethyl, 2-bromoethynole, 2,2,2-trifluoroethyl, pentafluene
  • cycloalkyl Group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • mono_C 6 alkylamino group for example, methylamino, ethynoleamino, propylamino, isopropylamino, butylamino, tert-butylamino, etc.
  • 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.
  • R 2 represents a hydrogen atom or a hydrocarbon group which may have a substituent.
  • 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 ( ⁇ 6 ) alkyl group optionally having substituent (s)” may be, for example, the above “hydrocarbon group” Represents a substituent.
  • 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, ⁇ 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.
  • an alkyl group e.g., methyl, Echiru, propyl, ⁇ Les 6 alkyl isopropyl, etc. group
  • an alkenyl group e.g., C 2 such Biel. 6 Arukeninore group
  • an alkynyl group e.
  • cyclohexylene 6 cycloalkyl group and Ariru group (Hue -.. ⁇ 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.
  • alkyl group e.g., methyl, etc. . C i e alkyl group
  • Ariru groups e.g., Hue -. C 6 such as Le 1 4 ⁇ Li Lumpur group
  • 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.
  • a 6-membered nitrogen-containing heterocyclic group eg, pyridyl and the like
  • 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
  • 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 a
  • 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
  • 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.
  • R 3 is a hydrogen atom, a phenyl group, a 2_, 3- or 4-pyridyl group. Particularly preferred is a hydrogen atom.
  • 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.
  • 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).
  • Y represents C, CH or N. Preferably it is C or CH.
  • ring A represents a compound ring containing a 5- to 7-membered oxygen atom which may have a substituent.
  • 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.
  • 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.
  • 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.
  • n represents an integer of 0 to 2
  • 2 represents a single bond or a double bond.
  • It is a ring represented by.
  • 2,3-dihydrofuran, furan, 2H-3,4-dihydropyran and 2H-pyran are widely used.
  • substituent of the ring A examples 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 hal
  • 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 -.
  • 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 -.
  • 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 Formula example, dimethyl
  • 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).
  • 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., ⁇ , ⁇ -, ⁇ , ⁇ - GETS chill sulfamoyl, New, Nyu- Jipuropirusuru Famoiru, New, New Di-C alkylsulfamoyl groups such as -dibutylsulfamoyl, etc .; alkylthio groups (eg, C 6 anoalkylthio
  • 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 ⁇ 6.1 () ⁇ reel sulfide El group
  • a lower alkylsulfonyl group e.g., methylsulfonyl, Echirusuruho sulfonyl, propyl
  • 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 “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.
  • each substituent may be the same or different.
  • 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 ⁇ 6 alkyl group, especially those wherein R 5 is hydrogen atom (unsubstituted ring A) is generally used.
  • the ring B may have a substituent and represents a benzene ring.
  • substituent on ring B examples 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.
  • 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.
  • 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.
  • n represents an integer of 0 to 2. n is preferably an integer of 0 or 1, particularly preferably n is 0.
  • 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.
  • Preferred examples of the compound (I) include a compound represented by the formula
  • Ri is (i) a lower alkyl group optionally having a substituent, ( ⁇ ) 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.
  • 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 ⁇ , when X represents CH 2, Y is Ru C or CH Der),
  • a ring may have a substituent heterocyclic ring containing a 5- to 7-membered oxygen atom
  • Ri is i) halogen or ⁇ 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) ⁇ 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),
  • [R 6 a represents a hydrogen atom, a halogen atom or a lower ( ⁇ 6) alkyl group.
  • 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- (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,
  • R to indicate CL 6 alkyl group (methyl, Echiru, propyl, isopropyl, blanking chill, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl and the like to).
  • compound A 1,6,7,8-tetrahydro-2H—indeno [5,4-b] furanone 8_ (yl) ethyl] propionamide
  • compound B 1,2,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-1 8-yl) ethyl acetoamide
  • salts with inorganic bases 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.
  • salts 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.
  • a pharmaceutically acceptable salt is preferable.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid is used.
  • 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.
  • 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.
  • 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, tal
  • formulations include 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 ⁇ m. 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 ⁇ m or more, and about 5% by weight 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 ⁇ m or more, and about 7% by weight 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.
  • 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.
  • 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
  • Parkinson's disease high blood pressure, glaucoma, cancer, insomnia, diabetes, etc.
  • 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).
  • 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 ,.
  • 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).
  • 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.
  • a water-soluble coating agent for example, hydroxypropyl pill cellulose, hydroxypropynolemethinole.
  • 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.
  • the coating amount was 5 mg per tablet.
  • the granules were tableted with a tableting machine to a weight of 130 mg using a 7.0 mm ⁇ 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.
  • the coating amount was 5 mg per tablet.
  • 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.
  • RH relative humidity
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation pharmaceutique stabilisée, comprenant un médicament non stable dans des préparations contenant de l'oxyde de titane et un agent d'enrobage qui enveloppe le médicament, cet agent contenant du talc et/ou du sulfate de baryum qui sert d'écran contre la lumière
PCT/JP2001/010017 2000-11-17 2001-11-16 Preparation pharmaceutique contenant du talc/ du sulfate de baryum WO2002040053A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002214306A AU2002214306A1 (en) 2000-11-17 2001-11-16 Pharmaceutical preparation containing talc/barium sulfate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000351226 2000-11-17
JP2000-351226 2000-11-17

Publications (1)

Publication Number Publication Date
WO2002040053A1 true WO2002040053A1 (fr) 2002-05-23

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ID=18824319

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/010017 WO2002040053A1 (fr) 2000-11-17 2001-11-16 Preparation pharmaceutique contenant du talc/ du sulfate de baryum

Country Status (2)

Country Link
AU (1) AU2002214306A1 (fr)
WO (1) WO2002040053A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11801205B2 (en) 2018-07-04 2023-10-31 Capsugel Belgium Nv Film-forming composition containing surfactant or surfactant and salt as whitening agent

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4497847A (en) * 1982-10-12 1985-02-05 Sankyo Company, Limited Process for coating solid pharmaceutical preparations and coated preparations thus obtained
WO1997032871A1 (fr) * 1996-03-08 1997-09-12 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et leur utilisation
US6124358A (en) * 1996-12-23 2000-09-26 Mazal Pharmaceutique (Sarl) Pharmaceutical composition containing rhein or diacerhein with improved bioavailability

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4497847A (en) * 1982-10-12 1985-02-05 Sankyo Company, Limited Process for coating solid pharmaceutical preparations and coated preparations thus obtained
WO1997032871A1 (fr) * 1996-03-08 1997-09-12 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et leur utilisation
US6124358A (en) * 1996-12-23 2000-09-26 Mazal Pharmaceutique (Sarl) Pharmaceutical composition containing rhein or diacerhein with improved bioavailability

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11801205B2 (en) 2018-07-04 2023-10-31 Capsugel Belgium Nv Film-forming composition containing surfactant or surfactant and salt as whitening agent
US12303575B2 (en) 2018-07-04 2025-05-20 Capsugel Belgium Nv Film-forming composition containing surfactant or surfactant and salt as whitening agent

Also Published As

Publication number Publication date
AU2002214306A1 (en) 2002-05-27

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