JP2004175795A - Medicinal composition excellent in releasability of medicament - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a solid medicinal composition improved in releasability of a particulate medicinal compound. <P>SOLUTION: A method for modifying surfaces of medicinal compound fine particles comprises treating the particulate medicinal compound with a surface modifying agent comprising a polymeric compound, a surfactant, saccharides, or the like, in a water-soluble solvent. The solid medicinal composition improved in the releasability of the particulate medicinal compound is obtained by this method. <P>COPYRIGHT: (C)2004,JPO

Description

  TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a fine particle drug compound having improved drug release properties, and a method for producing the same (surface modification method).

  In general, a pharmaceutical composition containing a particulate pharmaceutical compound decreases the solubility (rate, amount) of the pharmaceutical compound from the pharmaceutical composition due to aggregation, adhesion, fusion, and the like in the formulation step, and as a result, It is well known that the availability is reduced. In order to overcome such problems, development of a technique for producing a preparation containing a fine particle drug compound, which is excellent in drug release from a pharmaceutical composition, has been desired.

  The present invention provides a pharmaceutical composition in which fine particles of a pharmaceutical compound are present without aggregation, adhesion, fusion, etc., and easily release the fine particle pharmaceutical compound in the gastrointestinal tract, thereby improving the inherent solubility of the fine particle pharmaceutical compound. It is an object to provide a pharmaceutical composition having excellent bioavailability as a result, without impairing it.

  The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that a fine particle drug compound can be converted into a water-soluble solvent containing a water-compatible substance composed of a polymer compound and / or a surfactant and / or a saccharide. It has been found that, by dispersing the drug compound in the water-soluble solvent or finely pulverizing the drug compound using a wet mill after dispersing the drug compound in the above-mentioned water-soluble solvent, the release of the drug compound can be remarkably improved unexpectedly. The present inventors have further studied based on this finding, and as a result, have completed the present invention.

〔式中、Ｒは置換されていてもよい芳香族複素環基を、Ｘは酸素原子、酸化されていてもよい硫黄原子、−Ｃ（＝Ｏ）−または−ＣＨ（ＯＨ）−を、ＹはＣＨまたはＮを、ｐは０〜１０の整数を、ｑは１〜５の整数を、式

で表される基が置換されていてもよい芳香族アゾール基を、環Ａはさらに置換されていてもよい。〕で表される化合物もしくはその塩またはそのプロドラッグである上記（２３）記載の医薬組成物；
（２５）ＨＥＲ２阻害薬が、式

〔式中、ｍは１または２、Ｒ^１はハロゲン原子またはハロゲン化されていてもよいＣ_１−２アルキル、Ｒ^２およびＲ^３の一方は水素原子、他方は式

（式中、ｎは３または４、Ｒ^４は１〜２個のヒドロキシ基で置換されたＣ_１−４アルキル基を示す）で表される基を示す。〕で表される化合物もしくはその塩またはそのプロドラッグである上記（２３）記載の医薬組成物；
（２６）ＨＥＲ２阻害薬が、（ｉ）１−（４−｛４−［（２−｛（Ｅ）−２−［４−（トリフルオロメチル）フェニル］エテニル｝−１，３−オキサゾール−４−イル）メトキシ］フェニル｝ブチル）−１Ｈ−１，２，３−トリアゾール、（ii）１−（３−｛３−［（２−｛（Ｅ）−２−［４−（トリフルオロメチル）フェニル］エテニル｝−１，３−オキサゾール−４−イル）メトキシ］フェニル｝プロピル）−１Ｈ−１，２，３−トリアゾール、（iii）３−（１−｛４−［４−（｛２−［（Ｅ）−２−（２，４−ジフルオロフェニル）エテニル］−１，３−オキサゾール−４−イル｝メトキシ）フェニル］ブチル｝−１Ｈ−イミダゾール−２−イル）−１，２−プロパンジオールもしくはその塩またはそのプロドラッグである上記（２３）記載の医薬組成物；
（２７）微粒子医薬化合物の平均粒子径が５μｍ以下である上記（１）記載の医薬組成物；
（２８）微粒子医薬化合物の平均粒子径が１．５μｍ以下である上記（１）記載の医薬組成物；
（２９）微粒子医薬化合物の平均粒子径が０．６μｍ以下である上記（１）記載の医薬組成物；
（３０）微粒子医薬化合物を水溶性溶媒中にて表面改質剤で処理することを特徴とする上記（１）記載の医薬組成物の製造法；
（３１）処理に使用する装置が湿式粉砕機である上記（３０）記載の表面製造法；
（３２）湿式粉砕機が摩砕式である上記（３１）記載の製造法；
（３３）湿式粉砕機が圧密剪断式である上記（３１）記載の製造法；
（３４）医薬化合物の微粉砕と表面改質とを同時に行うことを特徴とする上記（３０）記載の製造法、および
（３５）微粒子医薬化合物を水溶性溶媒中にて表面改質剤で処理して得られる医薬組成物などを提供する。 That is, the present invention
(1) a pharmaceutical composition comprising a fine particle pharmaceutical compound and a surface modifier;
(2) The pharmaceutical composition according to the above (1), wherein the surface modifier is a water-affinitive substance;
(3) The pharmaceutical composition according to the above (2), wherein the water-affinity substance is a polymer compound;
(4) the pharmaceutical composition according to (3), wherein the polymer compound is a cellulose derivative;
(5) The pharmaceutical composition according to the above (4), wherein the cellulose derivative is hydroxypropyl cellulose;
(6) The pharmaceutical composition according to the above (3), wherein the amount of the polymer compound to be added is 0.01 part to 100 parts relative to 100 parts of the fine particle pharmaceutical compound;
(7) The pharmaceutical composition according to the above (3), wherein the amount of the polymer compound added is 0.1 part to 10 parts with respect to 100 parts of the fine particle pharmaceutical compound;
(8) The pharmaceutical composition according to the above (3), wherein the addition amount of the polymer compound is 1 part to 10 parts with respect to 100 parts of the fine particle pharmaceutical compound;
(9) The pharmaceutical composition according to the above (2), wherein the water-affinity substance is a surfactant;
(10) The pharmaceutical composition according to the above (9), wherein the surfactant is an anionic surfactant;
(11) The pharmaceutical composition according to the above (10), wherein the anionic surfactant is sodium lauryl sulfate;
(12) The pharmaceutical composition according to the above (9), wherein the amount of the surfactant added is 0.01 part to 100 parts relative to 100 parts of the fine particle pharmaceutical compound;
(13) The pharmaceutical composition according to the above (9), wherein the amount of the surfactant added is 0.1 part to 10 parts based on 100 parts of the fine particle pharmaceutical compound;
(14) The pharmaceutical composition according to (9), wherein the amount of the surfactant is 1 part to 10 parts per 100 parts of the fine particle pharmaceutical compound;
(15) The pharmaceutical composition according to (2), wherein the water-affinity substance is a saccharide;
(16) the pharmaceutical composition according to the above (15), wherein the saccharide is a sugar alcohol;
(17) The pharmaceutical composition according to the above (16), wherein the sugar alcohol is mannitol;
(18) The pharmaceutical composition according to the above (15), wherein the amount of the saccharide added is 0.01 part to 100 parts relative to 1 part of the fine particle pharmaceutical compound;
(19) The pharmaceutical composition according to (15), wherein the amount of the saccharide added is 0.1 part to 10 parts with respect to 1 part of the fine particle pharmaceutical compound;
(20) The pharmaceutical composition according to the above (15), wherein the amount of the saccharide added is 0.1 part to 1 part per 1 part of the fine particle pharmaceutical compound;
(21) The pharmaceutical composition according to (2), wherein the water-affinity substance is a combination of two or more selected from the group consisting of a polymer compound, a surfactant, and a saccharide;
(22) The pharmaceutical composition according to the above (1), wherein the fine particle pharmaceutical compound is a poorly water-soluble compound;
(23) The pharmaceutical composition according to the above (22), wherein the poorly water-soluble compound is a HER2 inhibitor;
(24) a HER2 inhibitor having the formula

[Wherein, R represents an aromatic heterocyclic group which may be substituted, X represents an oxygen atom, a sulfur atom which may be oxidized, -C (= O)-or -CH (OH)-, Is CH or N; p is an integer of 0 to 10; q is an integer of 1 to 5;

The ring A may be further substituted with an aromatic azole group in which the group represented by may be substituted. Or a salt thereof or a prodrug thereof; the pharmaceutical composition according to the above (23),
(25) a HER2 inhibitor having the formula

[In the formula, m is 1 or 2, R ¹ is a halogen atom or an optionally halogenated C _1-2 alkyl, one of R ² and R ³ is a hydrogen atom, and the other is a formula

(Wherein, n represents 3 or 4, and R ⁴ represents a C _1-4 alkyl group substituted with one or two hydroxy groups). Or a salt thereof or a prodrug thereof; the pharmaceutical composition according to the above (23),
(26) The HER2 inhibitor is (i) 1- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4 -Yl) methoxy] phenyl} butyl) -1H-1,2,3-triazole, (ii) 1- (3- {3-[(2-{(E) -2- [4- (trifluoromethyl) Phenyl] ethenyl {-1,3-oxazol-4-yl) methoxy] phenyl} propyl) -1H-1,2,3-triazole, (iii) 3- (1- {4- [4-({2- [(E) -2- (2,4-difluorophenyl) ethenyl] -1,3-oxazol-4-yl {methoxy) phenyl] butyl} -1H-imidazol-2-yl) -1,2-propanediol Or a salt thereof or a prodrug thereof (23) The pharmaceutical composition according;
(27) The pharmaceutical composition according to the above (1), wherein the average particle size of the fine particle pharmaceutical compound is 5 µm or less;
(28) The pharmaceutical composition according to the above (1), wherein the average particle diameter of the fine particle pharmaceutical compound is 1.5 µm or less;
(29) The pharmaceutical composition according to the above (1), wherein the average particle diameter of the fine particle pharmaceutical compound is 0.6 μm or less;
(30) The method for producing a pharmaceutical composition according to the above (1), wherein the fine particle pharmaceutical compound is treated with a surface modifier in a water-soluble solvent;
(31) The surface production method according to the above (30), wherein the apparatus used for the treatment is a wet pulverizer;
(32) The production method according to the above (31), wherein the wet mill is a grinding mill;
(33) The production method according to the above (31), wherein the wet-type pulverizer is a consolidation shearing type;
(34) The production method according to the above (30), wherein the pulverization and the surface modification of the pharmaceutical compound are simultaneously performed, and (35) the fine particle pharmaceutical compound is treated with a surface modifier in a water-soluble solvent. And the like.

The pharmaceutical composition of the present invention is characterized by containing a fine particle pharmaceutical compound and a surface modifier.
As used herein, the term “particulate pharmaceutical compound” refers to a compound having an average particle size of a size equal to or less than that obtainable by a conventional pulverization technique such as jet mill pulverization and having biological activity. Specifically, the average particle diameter is about 5 μm or less, and more specifically, the average particle diameter when dispersed in at least an aqueous solvent (eg, water, aqueous methylcellulose solution) is about 5 μm or less. The average particle size can be measured using a method and a measuring device known per se. The average particle size is, for example, a laser diffraction / scattering type particle size distribution analyzer (eg, LA-920 (Horiba, Ltd.)) Volume average particle size as measured by The measurement of the particle size is usually performed by uniformly dispersing a drug compound suspension having a concentration of about 1 to 100 μg / ml at room temperature by short-time sonication within 1 minute or stirring using a vortex mixer. As the aqueous solvent used for the measurement, water is usually used, but depending on the purpose, buffers having various pH, a simulated body fluid, a 0.5% methylcellulose solution and the like are used.

Preferably, the average particle size of the particulate pharmaceutical compound of the present invention is about 5 μm or less, more preferably about 1.5 μm or less, and particularly preferably about 0.6 μm or less. Although the lower limit of the average particle size is not particularly limited, it is usually about 0.05 μm or more, preferably 0.1 μm or more, more preferably about 0.2 μm or more, and particularly preferably 0.4 μm or more. The average particle size is particularly preferably about 0.2 to 1.0 μm, more preferably 0.4 to 0.6 μm.
By setting the average particle size to about 5 μm or less, for example, the water solubility, absorbability (eg, oral absorbability, absorbability in blood), etc. of the pharmaceutical compound are further improved.

The pharmaceutical compound of the present invention may be water-soluble or hardly water-soluble (used in the sense of including water-insoluble herein), but the present invention is particularly suitable for a poorly water-soluble pharmaceutical compound.
"Poorly water-soluble" refers to, for example, having a solubility of less than 10000 ppm, preferably less than 100 ppm in water at 25 ° C, or having a solubility in water of less than 10 mg / mL at 25 ° C, preferably 0.1 mg / mL. It is less than. The solubility can be measured according to a conventional method.

Examples of poorly water-soluble or water-insoluble pharmaceutical compounds include the following.
(1) Antipyretic, analgesic, anti-inflammatory drugs salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, atropine, scopolamine, morphine, pethidine, levorfinol, ketoprofen, naproxen, ibuprofen, oxymorphone, aspirin, aminopyrine, phenacetin, acetaminoine Phenone, phenylbutazone, ketophenylbutazone, mefenamic acid, bucolome, benzidamine, mepyrizole, tiaramid, tinolidine, xylocaine, pentazocine, dexamethasone, hydrocortisone, prednisolone, azulene, isopropylantipyrine, sazapirin, clofezone, etodrug or salt thereof, etc. ;
(2) tranquilizer diazepam, lorazepam, oxazepam, oxazolam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazeboxoxide, and the like;
(3) antipsychotics chlorpromazine, prochlorperazine, trifloperazine, sulpiride, clocapramine hydrochloride, zotepin, haloperidol and the like;
(4) Antibacterial drugs griseofulvin, lancasidines (J. Antibiotics, 38, 877-885 (1985)), azole compounds [2-[(1R, 2R) -2- (2) , 4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetra Fluoropropoxy) phenyl-3- (2H, 4H) -1,2,4-triazolone, fluconazole, itraconazole, etc.], nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciploxacin hydrochloride , Sulfamethoxazole / trimethoprim and the like;
(5) Antibiotics gentamicin, dipekacin, canendomycin, lividomycin, topramycin, amikacin, dibekacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, cephaloridine, , Cefotiamhexetil, cefsulodin, cefmenoxime, cefmetazol, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam, amoxicillin, cephalexin, erythromycin, bacampicin, salt of minacycline, or minacycline;
(6) Antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine aladinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, HER2 inhibitor (such as a heterocyclic compound described in WO 98 / 03505A and WO 01 / 77107A, etc.), taxol, doxorubicin hydrochloride, etoposide, mitoxantrone, mesna , Dimesna, aminoglutethimide, tamoxifen, acroline, cisplatin, carboplatin, cyclophosphamide, lomustine (CCNU), mosquito Such as Musuchin (BCNU);
(7) Antihyperlipidemic agent Clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm Bull), 38, 2792-2796 (1990)], clinofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol, niceritrol, probucol, elastase and the like;

(8) Antitussive and expectorant drugs Ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, aroclamide, chlorphedianol, picoperidamine, cloperastine, protochlorol, isoproterenol, salptamol, tereptalin, bromhexine, carbocysteine, ethyl cysteine, methyl cysteine Or a salt thereof;
(9) Muscle relaxant Pridinol, tubocurarine, pancuronium, chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, dantrolene Sodium and the like;
(10) antiepileptic drugs phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, phenobarbital, carbamazepine, primidone and the like;
(11) anti-ulcer drug lansoprazole, metoclopramide, famotidine, omeprazole, sulpiride, trepibutone, cetraxate hydrochloride, gefernate, irsogladine maleate, cimetidine, ranitidine hydrochloride, nizatidine, roxatidine acetate hydrochloride and the like;
(12) antidepressants imipramine, clomipramine, noxiptiline, phenelzine and the like;
(13) antiallergic agents diphenhydramine, chlorpheniramine, tripelenamine, methdilamine, clemizole, diphenylpyrazine, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, mequitazine, alimemazine tartrate and the like;
(14) cardiotonic drugs trans-bioxo camphor, terephyllol, aminophylline, etilephrine and the like;
(15) antiarrhythmic agent propranolol, alprenolol, pfetrol, oxprenolol, procainamide hydrochloride, disopyramide, azimaline, quinidine sulfate, aprindine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, and the like;
(16) Vasodilator Oxyfedrine, diltiazem, tolazoline, hexobendine, bamethane, nifedipine, isosorbit dinitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep hydrochloride, verapamil, nicardipine hydrochloride, ifenprodil tartrate, cinepaside maleate, cyclandelate , Cinnarizine, pentoxifylline and the like;
(17) Antihypertensive diuretics hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine, furosemide, trichlormethiazide, methyclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopentiazide, florothiazide, ethacrynic acid, etc. ;
(18) antidiabetic agents glymidine, glipizide, phenformin, pformin, metformin, glibenclamide, tolbutamide and the like;
(19) antituberculous drugs isoniazid, ethambutol, para-aminosalicylic acid and the like;
(20) narcotic antagonists levallorphan, nalorphine, naloxone or a salt thereof;
(21) Hormonal drugs Steroid hormones such as dexamethasone, hexestrol, methimazole, petamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, estriol and the like;
(22) bone and cartilage disease preventive and therapeutic agent prostaglandin A1 derivative, vitamin D derivative, vitamin K ₂ derivative, eicosapentaenoic acid derivative, benzylphosphonic acid, bisphosphonic acid derivative, sex hormone derivative, phenol sulfonium phthalein derivative, Non-peptidic bone formation promoting substances such as benzothiopyran or benzothiepine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthin derivatives, peptide-based bone formation promoting substances, etc .;
(23) Agents for treating joint diseases Anti-inflammatory agents such as p38 MAP kinase inhibitors (such as thiazole compounds described in WO 00/64894), matrix metalloprotease inhibitors (MMPI), prednisolone, hydrocortisone, methylprednisolone, dexbetamethasone, and betamethasone Nonsteroidal anti-inflammatory analgesics such as steroids, indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam, sulindac;
(24) therapeutic agent for pollakiuria flavoxate hydrochloride, oxybutynin hydrochloride, terolidine hydrochloride and the like;
(25) antiandrogen agents oxendrone, allylestrenol, chlormadinone acetate, gestanolone caproate, osapron acetate, flutamide, bicalutamide and the like;

(26) Fat-soluble vitamin drugs Vitamin Ks (vitamin K ₁ , K ₂ , K ₃ and K ₄ ), folic acid (vitamin M) and the like;
(27) Various derivatives of vitamin derivatives vitamins, for example, 5,6-trans - cholecalciferol, 2,5-hydroxycholecalciferol, vitamin _{D 3} derivatives such as 1-alpha-hydroxycholecalciferol, 5,6 trans - vitamin D ₂ derivatives such as ergocalciferol;
(28) Others hydroxycam, diaserine, megestrol acetate, nicerogolin, prostaglandins and the like;
Furthermore, drugs for ischemic diseases, drugs for immunological diseases, drugs for Alzheimer's disease, drugs for osteoporosis, drugs for angiogenesis, drugs for retinopathy, drugs for retinal vein occlusion, senile discoid macular degeneration, cerebrovascular disease Drugs for spasm, drugs for cerebral thrombosis, drugs for cerebral infarction, drugs for cerebral obstruction, drugs for intracerebral hemorrhage, drugs for subarachnoid hemorrhage, drugs for hypertensive encephalopathy, drugs for transient ischemic attack, multiple infarcts Drugs for senile dementia, drugs for arteriosclerosis, drugs for Huntington's disease, drugs for brain tissue disorders, drugs for optic neuropathy, drugs for glaucoma, drugs for ocular hypertension, drugs for retinal detachment, drugs for arthritis, drugs for antirheumatic drugs, Sepsis drugs, anti-septic shock drugs, anti-asthmatic drugs, drugs for treating atopic dermatitis, drugs for treating allergic rhinitis and the like are also used.

  The poorly water-soluble pharmaceutical compound prescribed in the present invention is not particularly limited, and examples thereof include a HER2 inhibitor. "HER2" refers to growth factor receptor tyrosine kinase. In the present specification, the “HER2 inhibitor” is not particularly limited as long as it is a substance that inhibits the function of HER2. For example, a substance that inhibits the binding between HER2 and a ligand, a substance that inhibits HER2 production (eg, , DNA synthesis inhibitors, RNA synthesis inhibitors, mRNA transcription inhibitors).

〔式中、Ｒは置換されていてもよい芳香族複素環基を、Ｘは酸素原子、酸化されていてもよい硫黄原子、−Ｃ（＝Ｏ）−または−ＣＨ（ＯＨ）−を、ＹはＣＨまたはＮを、ｐは０〜１０の整数を、ｑは１〜５の整数を、式

で表される基が置換されていてもよい芳香族アゾール基を、環Ａはさらに置換されていてもよい。〕で表される化合物（Ｉ）もしくはその塩またはそのプロドラッグなどが用いられる。 The HER2 inhibitor used in the present invention specifically includes a poorly water-soluble HER2 inhibitor

[Wherein, R represents an aromatic heterocyclic group which may be substituted, X represents an oxygen atom, a sulfur atom which may be oxidized, -C (= O)-or -CH (OH)-, Is CH or N; p is an integer of 0 to 10; q is an integer of 1 to 5;

The ring A may be further substituted with an aromatic azole group in which the group represented by may be substituted. Or a salt thereof, a prodrug thereof, or the like.

In the above compound (I), the aromatic heterocyclic group in the optionally substituted aromatic heterocyclic group represented by R includes (1) a nitrogen atom, an oxygen atom, a sulfur atom other than a carbon atom as a ring-constituting atom. A 5- or 6-membered aromatic monocyclic heterocyclic group containing 1 to 4 atoms selected from atoms, and (2) (i) a nitrogen atom, an oxygen atom, a sulfur atom other than a carbon atom as a ring-constituting atom A 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 atoms selected from: and (ii) a 5- or 6-membered ring containing 1 or 2 ring atoms other than carbon atoms and a nitrogen atom. Aromatic or non-aromatic heterocyclic ring, benzene ring or aromatic condensed heterocyclic ring formed by condensing with a 5-membered aromatic or non-aromatic heterocyclic ring containing one sulfur atom other than a carbon atom as a ring-constituting atom And a ring group.
Specific examples of such an aromatic heterocyclic group include, for example, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (Eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl, thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg, 2-oxazolyl) , 4-oxazolyl, 5-oxazolyl), oxadiazolyl (examples) 1,2,4-oxadiazolyl such as 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (eg, 1,2,3- Thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-5-yl and like 1,2) 1,2,3-triazolyl such as 2,4-triazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl and 1,2,3-triazol-4-yl ), Tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl), indolyl Indole-1-yl, indol-3-yl), indazolyl (eg, 1H-indazol-1-yl, 1H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazinyl) , Pyrrolopyridyl (eg, 1H-pyrrolo [2,3-b] pyridyl), imidazopyridyl (eg, 1H-imidazo [4,5-b] pyridyl, 1H-imidazo [4,5-c] pyridyl), imidazopi Radinyl (eg, 1H-imidazo [4,5-b] pyrazinyl), pyrrolopyridazinyl (eg, pyrrolo [1,2-b] pyridazinyl), pyrazolopyridyl (eg, pyrazolo [1,5-a] ] Pyridyl), imidazopyridyl (eg, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl), imidazopyridazinyl (eg, imidazo [1,2-b] pi Ridazinyl), imidazopyrimidinyl (eg, imidazo [1,2-a] pyrimidinyl), furyl, thienyl, benzofuranyl, benzothienyl (eg, benzo [b] thienyl), benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, etc. Preferable examples thereof include, for example, 5-membered monocyclic aromatic azole groups such as oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, and benzene such as benzoxazolyl and benzothiazolyl. Examples include an aromatic condensed azole group condensed with a ring and a 6-membered monocyclic aromatic heterocycle such as pyridyl and pyrimidyl. More preferable examples of the aromatic heterocycle include a 5-membered monocyclic aromatic azole group such as an oxazolyl group and a thiazolyl group.

で示される芳香族アゾール基としては、（１）環構成原子として炭素原子以外に１〜４個の窒素原子を含み、１個の酸素原子あるいは１個の硫黄原子を含んでいてもよい５員の芳香族単環式複素環基、および（２）（ｉ）環構成原子として炭素原子以外に１〜４個の窒素原子を含み、１個の酸素原子あるいは１個の硫黄原子を含んでいてもよい５員の芳香族単環式複素環と、（ｉｉ）環構成原子として炭素原子以外に１もしくは２個と窒素原子を含む５員または６員の芳香族あるいは非芳香族複素環、ベンゼン環または環構成原子として炭素原子以外に１個硫黄原子を含む５員の芳香族あるいは非芳香族複素環とが縮合して形成する芳香族縮合複素環基等が挙げられる。
このような芳香族アゾール基としては、例えばピロリル（例、１−ピロリル）、イミダゾリル（例、１−イミダゾリル）、ピラゾリル（例、１−ピラゾリル）、トリアゾリル（例、１，２，４−トリアゾール−１−イル、１，２，３−トリアゾール−１−イル）、テトラゾリル（例、テトラゾール−１−イル）、ベンズイミダゾリル（ベンズイミダゾール−１−イル）、インドリル（例、インドール−１−イル）、インダゾリル（例、１Ｈ−インダゾール−１−イル）、ピロロピラジニル（例、１Ｈ−ピロロ〔２，３−ｂ〕ピラジン−１−イル）、ピロロピリジル（例、１Ｈ−ピロロ〔２，３−ｂ〕ピリジン−１−イル、イミダゾピリジル（例、１Ｈ−イミダゾ〔４，５−ｂ〕ピリジン−１−イル）、イミダゾピラジニル（例、１Ｈ−イミダゾ〔４，５−ｂ〕ピラジン−１−イル）等の芳香族複素環基等が挙げられ、それらの基は環構成原子の一つとして含まれる窒素原子を介して−（ＣＨ_２）_ｍ−と結合する。芳香族アゾール基の好適な例としてはイミダゾリル基およびトリアゾリル基が挙げられる。 An aromatic heterocyclic group represented by R and a formula

The aromatic azole group represented by (1) is a 5-membered member which may contain 1 to 4 nitrogen atoms other than carbon atoms as ring constituent atoms, and may contain one oxygen atom or one sulfur atom. And (2) (i) containing 1 to 4 nitrogen atoms other than carbon atoms as a ring-constituting atom, containing 1 oxygen atom or 1 sulfur atom. A 5-membered aromatic monocyclic heterocyclic ring, and (ii) a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing one or two nitrogen atoms other than carbon atoms as ring-constituting atoms, benzene As a ring or a ring-constituting atom, an aromatic condensed heterocyclic group formed by condensing a 5-membered aromatic or non-aromatic heterocyclic ring containing one sulfur atom in addition to a carbon atom, and the like can be mentioned.
Examples of such an aromatic azole group include pyrrolyl (eg, 1-pyrrolyl), imidazolyl (eg, 1-imidazolyl), pyrazolyl (eg, 1-pyrazolyl), triazolyl (eg, 1,2,4-triazole-). 1-yl, 1,2,3-triazol-1-yl), tetrazolyl (eg, tetrazol-1-yl), benzimidazolyl (benzimidazol-1-yl), indolyl (eg, indol-1-yl), Indazolyl (eg, 1H-indazol-1-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-1-yl), pyrrolopyridyl (eg, 1H-pyrrolo [2,3-b] pyridine- 1-yl, imidazopyridyl (eg, 1H-imidazo [4,5-b] pyridin-1-yl), imidazopyrazinyl (eg, 1H-imida [4,5-b] pyrazine-1-yl) and the like aromatic heterocyclic group and the like, and their group through a nitrogen atom contained as one of the ring members - (CH _{2) m} - Suitable examples of the aromatic azole group include an imidazolyl group and a triazolyl group.

で示される芳香族アゾール基は、置換可能な位置に置換基を１〜３個（好ましくは１または２個）有していてもよい。該置換基としては、例えば脂肪族炭化水素基、脂環式炭化水素基、芳香族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基、脂環式炭化水素基で置換された脂肪族炭化水素、芳香族複素環基、非芳香族複素環基、芳香族複素環基で置換された脂肪族炭化水素基、ハロゲン原子、ニトロ基、シアノ基、置換されていてもよいアミノ基、置換されていてもよいアシル基、置換されていてもよいヒドロキシル基、置換されていてもよいチオール基、エステル化もしくはアミド化されていてもよいカルボキシル基が挙げられる。置換基としての脂肪族炭化水素基、脂環式炭化水素基、芳香族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基、脂環式炭化水素基で置換された脂肪族炭化水素、芳香族複素環基、非芳香族複素環基、および芳香族複素環基で置換された脂肪族炭化水素基はそれぞれさらに置換されていてもよい。 An aromatic heterocyclic group represented by R and a formula

The aromatic azole group represented by may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions. Examples of the substituent include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group, and an aliphatic hydrocarbon group substituted with an alicyclic hydrocarbon group. Aliphatic hydrocarbon, aromatic heterocyclic group, non-aromatic heterocyclic group, aliphatic hydrocarbon group substituted with aromatic heterocyclic group, halogen atom, nitro group, cyano group, amino which may be substituted Groups, an optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, and an optionally esterified or amidated carboxyl group. Aliphatic hydrocarbon group as substituent, alicyclic hydrocarbon group, aromatic hydrocarbon group, aliphatic hydrocarbon group substituted with aromatic hydrocarbon group, aliphatic substituted with alicyclic hydrocarbon group The hydrocarbon, the aromatic heterocyclic group, the non-aromatic heterocyclic group, and the aliphatic hydrocarbon group substituted with the aromatic heterocyclic group may be further substituted.

Ring A may have, in addition to X and (CH ₂ ) _p , 1 to 4 (preferably 1 or 2) substituents at substitutable positions. Examples of the substituent include those exemplified as the substituent which the substituent on the aromatic heterocyclic group represented by R may have, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aromatic hydrocarbon group. Hydrocarbon group, aliphatic hydrocarbon group substituted with aromatic hydrocarbon group, aliphatic hydrocarbon substituted with alicyclic hydrocarbon group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group Aliphatic group substituted with a ring group, a halogen atom, a nitro group, a cyano group, an amino group which may be substituted, an acyl group which may be substituted, a hydroxyl group which may be substituted, And a carboxyl group which may be esterified or amidated. Aliphatic hydrocarbon group as substituent, alicyclic hydrocarbon group, aromatic hydrocarbon group, aliphatic hydrocarbon group substituted with aromatic hydrocarbon group, aliphatic substituted with alicyclic hydrocarbon group The hydrocarbon, the aromatic heterocyclic group, the non-aromatic heterocyclic group, and the aliphatic hydrocarbon group substituted with the aromatic heterocyclic group may be further substituted.

Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group.
Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl. , Isohexyl, heptyl, octyl, nonyl, decyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. And 6 alkyl groups.
Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, for example, vinyl (ethenyl), allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, -Butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl , 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, and more preferable examples are alkenyl groups having 2 to 6 carbon atoms.
Preferable examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, -Pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like, and more preferable examples include an alkynyl group having 2 to 6 carbon atoms.

Examples of the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group, and a partially unsaturated condensed bicyclic group. And a hydrocarbon group.
Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, for example, a cycloalkyl group having 6 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [ 4.2.1] nonyl, bicyclo [4.3.1] decyl and the like.
Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 5 to 10 carbon atoms, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1 -Yl and the like.
Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 5 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5 -Cyclohexadien-1-yl and the like.
Preferred examples of the partially unsaturated condensed bicyclic hydrocarbon group include an indanyl group, a partially saturated naphthyl group (eg, a dihydronaphthyl group such as 3,4-dihydro-2-naphthyl, 1,2,3,4- And a C9-12 group formed by condensing a benzene ring such as tetrahydronaphthyl such as tetrahydronaphthyl) with an alicyclic hydrocarbon.

Examples of the aromatic hydrocarbon group include a monocyclic or condensed polycyclic aromatic hydrocarbon group, and preferred examples thereof include an aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, Examples thereof include 9-fluorenon-2-yl and the like, and among them, monocyclic or condensed bicyclic aromatic hydrocarbon groups such as phenyl, 1-naphthyl and 2-naphthyl are preferable.
Examples of the aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group include aliphatic hydrocarbons substituted with 1 to 3 (preferably 1 or 2) aromatic hydrocarbon groups having 7 to 20 carbon atoms. Groups. Preferable examples of such an aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group include, for example, a C _1-6 alkyl group substituted with 1 to 3 C _6-14 aryl groups (for example, benzyl , A C _1-6 alkyl group substituted with 1 to 3 phenyl groups such as 2-phenylethyl, 1,2-diphenylethyl, 2,2-diphenylethyl, and a substituted with 1 to 3 naphthyl groups A C _1-6 alkyl group, 9-fluorenyl-C _1-6 alkyl, etc., a C _2-6 alkenyl group substituted with 1 to 3 C _6-14 aryl groups (for example, (E) -2-phenyl Substitute with 1 to 3 phenyl groups such as ethenyl, (Z) -2-phenylethenyl, 2,2-diphenylethenyl, 2- (2-naphthyl) ethenyl, 4-phenyl-1,3-butadienyl C _2-6 alkenyl group, C _2- substituted by 1-3 naphthyl groups ₆ alkenyl, 9-fluorenylidenealkyl group) and the like.
Examples of the aliphatic hydrocarbon group substituted with an alicyclic hydrocarbon group include the above aliphatic hydrocarbon group substituted with 1 to 3 (preferably 1 or 2) of the above alicyclic hydrocarbon groups. It is. Preferred examples of such an aliphatic hydrocarbon group substituted with an alicyclic hydrocarbon include, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenyl C ₁ substituted by 1 to 3 C _3-10 cycloalkyl groups such as methyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc. _-6 alkyl group, 1-3 C _3-10 C _2-6 alkenyl group substituted with a cycloalkyl group, 1-3 C _5-10 C _1-6 alkyl group substituted by a cycloalkenyl group , etc. 1-3 C _5-10 C _2-6 alkenyl group substituted with a cycloalkenyl group.

  Preferred examples of the aromatic heterocyclic group include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 1,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl , Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., a 5- or 6-membered aromatic monocyclic heterocyclic group containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur other than carbon as ring-constituting atoms Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, in Ryl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, Quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiadinil, phenazinyl, phenoxathynyl, thianthro nyl, phenatronidinyl, phenatronidinyl, phenatropinyl 1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imida [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl (I) a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to carbon as the ring-constituting atoms; and (ii) a ring-constituting atom. 5- or 6-membered aromatic or non-aromatic heterocycle containing one or two and a nitrogen atom other than a carbon atom, a benzene ring or a 5-membered aromatic containing one sulfur atom other than a carbon atom as a ring-constituting atom Alternatively, an aromatic condensed heterocyclic group formed by condensing with a non-aromatic heterocyclic ring and the like can be mentioned.

  Preferable examples of the non-aromatic heterocyclic group include, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc. Examples thereof include a 3- to 7-membered non-aromatic heterocyclic group containing one or two atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.

Examples of the aliphatic hydrocarbon group substituted with an aromatic heterocyclic group include aliphatic hydrocarbon groups having 1 to 6 carbon atoms and substituted with 1 to 3 (preferably 1 or 2) aromatic heterocyclic groups. Groups (for example, C _1-6 alkyl group, C _2-6 alkenyl group, etc.). Preferred examples of the aliphatic hydrocarbon group substituted with an aromatic heterocyclic group include, for example, 1 to 3 C _1-6 alkyl groups substituted with a furyl group, a thienyl group, an imidazolyl group or a pyridyl group ( examples, (2-furyl) methyl, thienylmethyl, 2- (1-imidazolyl) ethyl, etc.), 1-3 furyl group, a thienyl group, C _2-6 alkenyl group substituted with an imidazolyl group or a pyridyl group ( Examples include 2- (2-furyl) ethenyl, 2-thienylethenyl and the like.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferable.

Examples of the optionally substituted amino group include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 5 to 10 carbon atoms, An amino group which may be mono- or di-substituted by an acyl group having 1 to 10 carbon atoms or an aromatic hydrocarbon group having 6 to 12 carbon atoms (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino , Diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like; 4- to 6-membered cyclic amino group (for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, Morpholino, 1-piperazinyl and the like).
Here, the 4- to 6-membered cyclic amino group may be (1) a C _1-6 alkyl group, (2) a halogen atom, a C _1-6 alkoxy group or a C _6-14 aryl optionally substituted with trifluoromethyl. (Eg, phenyl, naphthyl, etc.), (3) 5- or 6-membered heterocyclic group containing 1-2 nitrogen atoms other than carbon as a ring-constituting atom (eg, 2-pyridyl, pyrimidinyl) or (4) 6 It may be further substituted by a membered cyclic amino group (eg, piperidino, 1-piperazinyl, etc.).

As the acyl group in the optionally substituted acyl group, an acyl group having 1 to 13 carbon atoms, specifically, formyl, for example, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, An alkenyl group having 2 to 6 carbon atoms, a cycloalkenyl group having 5 to 10 carbon atoms, an aromatic hydrocarbon group having 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.) or an aromatic heterocyclic ring (eg, pyridyl) and carbonyl A bonded group such as a C _2-7 alkanoyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, etc.), a C _3-10 cycloalkyl-carbonyl group (eg, Cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), C _3-7 Examples include an alkenoyl group (eg, crotonoyl and the like), a C _5-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl and the like), a benzoyl group, a nicotinoyl group and the like.
Examples of the substituent in the optionally substituted acyl group include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom (eg, chlorine, fluorine, bromine and the like), a nitro group, a hydroxyl group Groups, amino groups and the like. The number of substituents is, for example, 1 to 3.
Examples of the optionally substituted hydroxyl group include a hydroxyl group, an alkoxy group, a cycloalkyloxy group, an alkenyloxy group, a cycloalkenyloxy group, an aralkyloxy group, an aryloxy group, and an acyloxy group.

Preferable examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy. , Hexyloxy, heptyloxy, nonyloxy and the like.
Preferable examples of the cycloalkyloxy group include a cycloalkyloxy group having 3 to 10 carbon atoms, for example, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
Preferable examples of the alkenyloxy group include an alkenyloxy group having 2 to 10 carbon atoms, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like.
Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 5 to 10 carbon atoms, for example, 2-cyclopentenyloxy, 2-cyclohexenyloxy and the like.
Preferred examples of the aralkyloxy group include an aralkyloxy group having 7 to 20 carbon atoms, for example, a C _6-14 aryl-C _1-6 alkoxy group, specifically a phenyl-C _1-6 alkoxy group (eg, benzyl Oxy, phenethyloxy, etc.), and a naphthyl-C _1-6 alkoxy group.
Preferred examples of the aryloxy group include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a nitro group, a 6 to 6 carbon atoms which may be substituted with a hydroxyl group or an amino group. 14 aryloxy groups such as phenoxy, 4-chlorophenoxy and the like.
Preferable examples of the acyloxy group include an acyloxy group having 2 to 15 carbon atoms, for example, an alkanoyloxy group having 2 to 7 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), C _6-14 Aryl-carbonyloxy (eg, benzoyloxy, naphthoyloxy, etc.) and the like.
Examples of the thiol group which may be substituted include a mercapto group, an alkylthio group, a cycloalkylthio group, an alkenylthio group, an aralkylthio group, an arylthio group, a heteroarylthio group, a heteroarylalkylthio group, an acylthio group, and the like.
Preferred examples of the alkylthio group include alkylthio groups having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, and neopentylthio. , Hexylthio, heptylthio, nonylthio and the like.

Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
Preferable examples of the alkenylthio group include an alkenylthio group having 2 to 10 carbon atoms, such as allylthio, crotylthio, 2-pentenylthio, and 3-hexenylthio.
Preferred examples of the aralkylthio group include an aralkylthio group having 7 to 20 carbon atoms, for example, a C _6-14 arylthio group, specifically, phenyl-C _1-6 alkylthio (eg, benzylthio, phenethylthio, etc.), naphthyl —C _1-6 alkylthio group and the like.
Preferred examples of the arylthio group include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a carbon atom having 6 to 14 carbon atoms which may be substituted with a halogen atom, a nitro group, a hydroxyl group or an amino group. Arylthio group, for example, phenylthio, naphthylthio, 4-chlorophenylthio and the like.
Examples of the heteroarylthio group include a mercapto group substituted by the above-described aromatic heterocyclic group, among which pyridylthio (eg, 2-pyridylthio, 3-pyridylthio, etc.), imidazolylthio (2-imidazolylthio, etc.) And triazoylthio (1,2,4-triazol-5-ylthio and the like) are preferred.
Examples of the heteroarylalkylthio group include the above-mentioned alkylthio groups substituted with the above-described aromatic heterocyclic groups. Preferable examples of the heteroarylthio group include a pyridyl-C _1-6 alkylthio group (eg, 2-pyridylmethylthio, 3-pyridylmethylthio, etc.).
Preferable examples of the acylthio group include an acylthio group having 2 to 15 carbon atoms, for example, an alkanoylthio group having 2 to 7 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.), C _6-14 aryl-carbonylthio (Eg, benzoylthio, naphthoylthio, etc.).
The carboxyl group which may be esterified or amidated includes a carboxyl group, an esterified carboxyl group and an amidated carboxyl group.
Examples of the esterified carboxyl group include an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, and a heteroarylalkyloxycarbonyl group.
Preferable examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 2 to 7 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.
Preferable examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 21 carbon atoms, such as phenyl-C _2-7 alkoxycarbonyl (eg, benzyloxycarbonyl and the like), naphthyl-C _2-7 alkoxycarbonyl and the like. No.
Preferable examples of the aryloxycarbonyl group include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a carbon atom having 7 carbon atoms which may be substituted with a halogen atom, nitro group, hydroxyl group or amino group. To 15 aryloxycarbonyl groups such as phenoxycarbonyl and p-tolyloxycarbonyl.

Examples of the heteroarylalkyloxycarbonyl include the above-mentioned alkoxycarbonyl group substituted by the above-described aromatic heterocyclic group. Preferable examples of the heteroarylalkyloxycarbonyl group include a pyridyl-C _2-7 alkoxycarbonyl group (eg, 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, etc.).
The amidated carboxyl group includes a compound represented by the formula: -CON (R ¹ ) (R ² )
[Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group]. Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ or R ² include an aliphatic hydrocarbon group exemplified as a substituent on the aromatic heterocyclic group represented by R and an alicyclic group Examples include a hydrocarbon group and an aromatic hydrocarbon group. Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ or R ² include the aromatic heterocyclic groups exemplified as the substituents on the aromatic heterocyclic ring represented by R. . Examples of the substituent for the hydrocarbon group or heterocyclic group in R ¹ or R ² include a halogen atom (eg, chlorine, fluorine, bromine, iodine, etc.), an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. 1 to 3 substituents selected from an alkoxy group and the like.

で示される芳香族アゾール基または環Ａへの置換基が脂環式炭化水素基、芳香族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基、芳香族複素環基、非芳香族複素環基、または芳香族複素環基で置換された脂肪族炭化水素基であるときは、該脂環式炭化水素基、芳香族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基中の芳香族炭化水素基、芳香族複素環基、非芳香族炭化水素基、または芳香族複素環基で置換された脂肪族炭化水素基中の芳香族複素環基はさらにそれぞれ置換可能な位置に置換基を１〜３個（好ましくは１または２個）有していてもよく、このような置換基としては、例えば置換されていてもよい炭素数１〜６のアルキル基、炭素数２〜６のアルケニル基、炭素数２〜６のアルキニル基、炭素数３〜１０のシクロアルキル基、炭素数５〜１０のシクロアルケニル基、炭素数６〜１４のアリール基（例、フェニル、ナフチル等）、芳香族複素環基（例、チエニル、フリル、ピリジル、オキサゾリル、チアゾリル、テトラゾリル等）、非芳香族複素環基（例、テトラヒドロフリル、モルホリニル、ピペリジル、ピロリジル、ピペラジニル等）、炭素数７〜２０のアラルキル基（例、フェニル−Ｃ_1-6アルキル基、ナフチル−Ｃ_1-6アルキル基等）、アミノ基、Ｎ−モノ（Ｃ_1-6）アルキルアミノ基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルアミノ基、炭素数２〜７のアシルアミノ基（例、アセチルアミノ、プロピオニルアミノなどのＣ_2-7アルカノイルアミノ基、ベンゾイルアミノ基等）、アミジノ基、炭素数２〜７のアシル基（例、炭素数２〜７のアルカノイル基、ベンゾイル基等）、カルバモイル基、Ｎ−モノ（Ｃ_1-6）アルキルカルバモイル基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルカルバモイル基、スルファモイル基、Ｎ−モノ（Ｃ_1-6）アルキルスルファモイル基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルスルファモイル基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数８〜２１のアラルキルオキシカルボニル基（例、フェニル−Ｃ_2-7アルコキシカルボニル、ナフチル−Ｃ_2-7アルコキシカルボニル等）、ヒドロシキル基、置換されていてもよい炭素数１〜６のアルコキシ基、炭素数２〜６のアルケニルオキシ基、炭素数３〜１０のシクロアルキルオキシ基、炭素数５〜１０のシクロアルケニルオキシ基、炭素数７〜２０のアラルキルオキシ基（例、フェニル−Ｃ_1-6アルコキシ基、ナフチル−Ｃ_1-6アルコキシ基等）、炭素数６〜１４のアリールオキシ基（例、フェノキシ、ナフチルオキシ等）、メルカプト基、炭素数１〜６のアルキルチオ基、炭素数３〜１０のシクロアルキルチオ基、炭素数７〜２０のアラルキルチオ基（例、フェニル−Ｃ_1-6アルキル基、ナフチル−Ｃ_1-6アルキルチオ基等）、炭素数６〜１４のアリールチオ基（例、フェニルチオ、ナフチルチオ基等）、スルホ基、シアノ基、アジド基、ニトロ基、ニトロソ基、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）等が挙げられる。 In the general formula (I), an aromatic heterocyclic group represented by R;

And the substituent on the aromatic azole group or the ring A represented by alicyclic hydrocarbon group, aromatic hydrocarbon group, aliphatic hydrocarbon group substituted with aromatic hydrocarbon group, aromatic heterocyclic group, When the compound is an aromatic heterocyclic group or an aliphatic hydrocarbon group substituted with an aromatic heterocyclic group, the alicyclic hydrocarbon group, the aromatic hydrocarbon group, or the aliphatic substituted with the aromatic hydrocarbon group. The aromatic hydrocarbon group in the aromatic hydrocarbon group, the aromatic heterocyclic group, the non-aromatic hydrocarbon group, or the aromatic heterocyclic group in the aliphatic hydrocarbon group substituted with the aromatic heterocyclic group is further respectively It may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions, and examples of such a substituent include an optionally substituted alkyl group having 1 to 6 carbon atoms. Alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, 3 carbon atoms 10 cycloalkyl groups, C 5-10 cycloalkenyl groups, C 6-14 aryl groups (eg, phenyl, naphthyl, etc.), aromatic heterocyclic groups (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl) , Tetrazolyl, etc.), non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholinyl, piperidyl, pyrrolidyl, piperazinyl, etc.), aralkyl groups having 7 to 20 carbon atoms (eg, phenyl-C _1-6 alkyl group, naphthyl-C _1-6 alkyl group), amino group, N-mono (C _1-6 ) alkylamino group, N, N-di (C _1-6 ) alkylamino group, acylamino group having 2 to 7 carbon atoms (eg, acetylamino, C _2-7 alkanoylamino groups such as propionylamino, benzoylamino group, etc.), amidino group, an acyl group (examples of 2-7 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms Yl group, a benzoyl group, etc.), a carbamoyl group, N- mono (C _1-6) alkylcarbamoyl group, N, N- di (C _1-6) alkylcarbamoyl group, sulfamoyl group, N- mono (C _1-6 ) Alkylsulfamoyl group, N, N-di (C _1-6 ) alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, aralkyloxycarbonyl group having 8 to 21 carbon atoms (eg, Phenyl-C _2-7 alkoxycarbonyl, naphthyl-C _2-7 alkoxycarbonyl, etc.), a hydroxy group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, carbon number A cycloalkyloxy group having 3 to 10 carbon atoms, a cycloalkenyloxy group having 5 to 10 carbon atoms, an aralkyloxy group having 7 to 20 carbon atoms (eg, a phenyl-C _1-6 alkoxy group, Fuchiru -C _1-6 alkoxy group), an aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy, naphthyloxy, etc.), a mercapto group, an alkylthio group having 1 to 6 carbon atoms, cycloalkylthio having 3 to 10 carbon atoms Group, aralkylthio group having 7 to 20 carbon atoms (eg, phenyl-C _1-6 alkyl group, naphthyl-C _1-6 alkylthio group, etc.), arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio group, etc.) ), A sulfo group, a cyano group, an azido group, a nitro group, a nitroso group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.).

Examples of the substituent in the optionally substituted alkoxy group having 1 to 6 carbon atoms and the optionally substituted alkyl group having 1 to 6 carbon atoms include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine and the like) ), A hydroxyl group, and 1 to 3 substituents selected from alkoxy groups having 1 to 6 carbon atoms.
Examples of the substituted alkoxy group having 1 to 6 carbon atoms include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy and the like.
Examples of the substituted alkyl group having 1 to 6 carbon atoms include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, , 2-dimethoxyethyl and the like.

で示される芳香族アゾール基または環Ａへの置換基が脂肪族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基、または芳香族複素環基で置換された脂肪族炭化水素基であるときは、該脂肪族炭化水素基、芳香族炭化水素基で置換された脂肪族炭化水素基中の脂肪族炭化水素基、または芳香族複素環基で置換された脂肪族炭化水素基中の脂肪族炭化水素基はさらにそれぞれ置換可能な位置に置換基を１〜３個（好ましくは１または２個）有していてもよく、このような置換基としては、例えば非芳香族複素環基（例、テトラヒドロフリル、モルホリニル、ピペリジル、ピロリジル、ピペラジニル等）、アミノ基、Ｎ−モノ（Ｃ_1-6）アルキルアミノ基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルアミノ基、炭素数２〜７のアシルアミノ基（例、アセチルアミノ、プロピオニルアミノなどのＣ_２−７アルカノイルアミノ基、ベンゾイルアミノ基等）、アミジノ基、炭素数２〜７のアシル基（例、炭素数２〜７のアルカノイル基、ベンゾイル基等）、カルバモイル基、Ｎ−モノ（Ｃ_1-6）アルキルカルバモイル基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルカルバモイル基、スルファモイル基、Ｎ−モノ（Ｃ_1-6）アルキルスルファモイル基、Ｎ，Ｎ−ジ（Ｃ_1-6）アルキルスルファモイル基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数８〜２１のアラルキルオキシカルボニル基（例、フェニル−Ｃ_2-7アルコキシカルボニル基、ナフチル−Ｃ_2-7アルコキシカルボニル基等）、ヒドロシキル基、置換されていてもよい炭素数１〜６のアルコキシ基、炭素数２〜６のアルケニルオキシ基、炭素数３〜１０のシクロアルキルオキシ基、炭素数５〜１０のシクロアルケニルオキシ基、炭素数７〜２０のアラルキルオキシ基（例、フェニル−Ｃ_1-6アルコキシ基、ナフチル−Ｃ_1-6アルコキシ基等）、炭素数６〜１４のアリールオキシ基（例、フェノキシ、ナフチルオキシ等）、メルカプト基、炭素数１〜６のアルキルチオ基、炭素数３〜１０のシクロアルキルチオ基、炭素数７〜２０のアラルキルチオ基（例、フェニル−Ｃ_1-6アルキル基、ナフチル−Ｃ_1-6アルキルチオ基等）、炭素数６〜１４のアリールチオ基（例、フェニルチオ、ナフチルチオ基等）、スルホ基、シアノ基、アジド基、ニトロ基、ニトロソ基、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）等が挙げられる。 In the general formula (I), an aromatic heterocyclic group represented by R;

And the substituent on the aromatic azole group or the ring A is an aliphatic hydrocarbon group, an aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group, or an aliphatic hydrocarbon substituted with an aromatic heterocyclic group. When it is a group, the aliphatic hydrocarbon group, the aliphatic hydrocarbon group in the aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group, or the aliphatic hydrocarbon group substituted with an aromatic heterocyclic group The aliphatic hydrocarbon group therein may further have 1 to 3 (preferably 1 or 2) substituents at substitutable positions, and examples of such substituents include non-aromatic heterocyclic groups. Ring group (eg, tetrahydrofuryl, morpholinyl, piperidyl, pyrrolidyl, piperazinyl, etc.), amino group, N-mono (C _1-6 ) alkylamino group, N, N-di (C _1-6 ) alkylamino group, carbon Acylamino groups of the formulas 2 to 7 (eg, C _2-7 alkanoylamino groups such as acetylamino and propionylamino, benzoylamino groups, etc.), amidino groups, acyl groups having 2 to 7 carbon atoms (eg, alkanoyl groups having 2 to 7 carbon atoms, benzoyl groups, etc.), carbamoyl Group, N-mono (C _1-6 ) alkylcarbamoyl group, N, N-di (C _1-6 ) alkylcarbamoyl group, sulfamoyl group, N-mono (C _1-6 ) alkylsulfamoyl group, N, N-di (C _1-6 ) alkylsulfamoyl group, carboxyl group, C _2-7 alkoxycarbonyl group, C 8-21 aralkyloxycarbonyl group (eg phenyl-C _2-7 alkoxycarbonyl group , naphthyl -C _2-7 alkoxycarbonyl group), Hidoroshikiru group, optionally substituted alkoxy group having 1 to 6 carbon atoms, Arukeniruo of 2 to 6 carbon atoms Shi group, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 5 to 10 carbon atoms, an aralkyl group (e.g. having 7 to 20 carbon atoms, a phenyl -C _1-6 alkoxy group, naphthyl -C _{1 -6} alkoxy group), aryloxy group having 6 to 14 carbon atoms (eg, phenoxy, naphthyloxy, etc.), mercapto group, alkylthio group having 1 to 6 carbon atoms, cycloalkylthio group having 3 to 10 carbon atoms, carbon number 7-20 aralkylthio groups (eg, phenyl-C _1-6 alkyl group, naphthyl-C _1-6 alkylthio group, etc.), C 6-14 arylthio groups (eg, phenylthio, naphthylthio group, etc.), sulfo group , A cyano group, an azide group, a nitro group, a nitroso group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.).

  Examples of the substituent in the optionally substituted alkoxy group having 1 to 6 carbon atoms include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, and an alkoxy group having 1 to 6 carbon atoms. There may be mentioned 1 to 3 substituents selected. Examples of the substituted alkoxy group having 1 to 6 carbon atoms include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy and the like.

R represents (i) a hydroxyl group, an alkoxy group (eg, a C _1-6 alkoxy group), an arylalkoxy group (eg, a phenyl-C _1-6 alkoxy group), an alkyl group (eg, a C _1-6 alkyl group) , A cyano group, an aryl group (eg, a phenyl group, a naphthyl group) which may be substituted with one or two substituents selected from a halogen atom and a tetrazolyl group, (ii) an alkyl group (eg, a C _1- ( ₁₀ alkyl groups), (iii) hydroxyalkyl groups (eg, hydroxy-C _1-10 alkyl groups), (iv) alkoxycarbonylalkyl groups (eg, C _2-7 alkoxycarbonyl-C _1-10 alkyl groups), ( v) an alkyl group substituted with one or two aryl groups (eg, a C _1-6 alkyl group substituted with one or two phenyl groups), (vi) one or two aryl groups Replaced by Alkenyl group (e.g., one or two C _2-6 alkenyl group substituted with phenyl group), (vii) a cycloalkyl group (e.g., C _3-10 cycloalkyl group), (viii) a partially saturated naphthyl group (E.g., dihydronaphthyl group), (ix) may be substituted with one or two substituents selected from a hydroxy group, an alkoxy group, an arylalkoxy group, an alkyl group, a cyano group, an allyl group and a halogen atom. An oxazolyl group, a benzooxazolyl group or a thiazolyl group, each of which may be substituted with one or two substituents selected from a thienyl group or a furyl group, (x) a benzofuranyl group and (xi) a benzothienyl group, is preferred. , arylalkenyl group (e.g., phenyl -C _2-6 alkenyl group) oxazolyl group substituted with and arylalkoxy Sheet - aryl group (e.g., phenyl -C _1-6 alkoxy - phenyl) oxazolyl group substituted with more preferable.

で示される芳香族アゾール基としては、（ｉ）アルキル基（例、Ｃ_1-10アルキル基）、（ｉｉ）アリール基（例、フェニル基）、（ｉｉｉ）ヒドロキシアルキル基（例、ヒドロキシ−Ｃ_1-10アルキル基）、（ｉｖ）カルボキシル基、（ｖ）アルコキシカルボニル基（例、Ｃ_2-7アルコキシカルボニル基）および（ｖｉ）カルバモイル基から選ばれる１個もしくは２個の置換基でそれぞれ置換されていてもよいピロリル基、イミダゾリル基、ピラゾリル基、トリアゾリル基、テトラゾリル基またはベンズイミダゾリル基が好ましく、イミダゾリル基およびトリアゾリル基がさらに好ましい。
環ＡはＹの種類（ＣＨまたはＮ）により、置換されていてもよいベンゼン環または置換されていてもよいピリジン環を形成し、好適な例としては置換されていてもよいベンゼン環が挙げられ、さらに好適な例としては１もしくは２個のＣ_1-6アルコキシ基で置換されていてもよいベンゼン環またはピリジン環が挙げられる。 formula

The aromatic azole group represented by (i) includes (i) an alkyl group (eg, a C _1-10 alkyl group), (ii) an aryl group (eg, a phenyl group), and (iii) a hydroxyalkyl group (eg, hydroxy-C _1-10 alkyl groups), (iv) a carboxyl group, (v) an alkoxycarbonyl group (eg, a C _2-7 alkoxycarbonyl group) and (vi) a carbamoyl group. A pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group or a benzimidazolyl group, which may be used, is more preferable, and an imidazolyl group and a triazolyl group are more preferable.
The ring A forms an optionally substituted benzene ring or an optionally substituted pyridine ring depending on the type of Y (CH or N), and preferred examples include an optionally substituted benzene ring. More preferred examples include a benzene ring or a pyridine ring which may be substituted with one or two C _1-6 alkoxy groups.

で表される基の好適な例としては、式

で表される基が挙げられ、最も好適な例としては、１，３−フェニレン基または１，４−フェニレン基が挙げられる。
Ｘは酸素原子（Ｏ）、酸化されていてもよい硫黄原子〔Ｓ（Ｏ）ｋ（ｋは０〜２の整数を示す〕、−Ｃ（＝Ｏ）−または−ＣＨ（ＯＨ）−を示し、好適な例としては酸素原子等が挙げられる。
ｐは０〜１０の整数を示し、好適な例としては０〜６の整数が挙げられ、より好適な例としては３〜５の整数が挙げられる。
ｑは１〜５の整数を示し、好適な例としては１が挙げられる。 formula

Preferred examples of the group represented by the formula:

The most preferable example is a 1,3-phenylene group or a 1,4-phenylene group.
X represents an oxygen atom (O), a sulfur atom which may be oxidized [S (O) k (k represents an integer of 0 to 2)], -C (= O)-or -CH (OH)- Preferred examples include an oxygen atom.
p represents an integer of 0 to 10, and a preferable example is an integer of 0 to 6, and a more preferable example is an integer of 3 to 5.
q shows the integer of 1-5, and 1 is mentioned as a suitable example.

  As a specific example of the compound (I), the compounds produced in Examples of JP-A-11-60571 are used, and among them, (i) 1- [4- [4- [2-[(E ) -2-Phenylethenyl] -4-oxazolylmethoxy] phenyl] butyl] -1,2,4-triazole, (ii) 4- [4- [4- (1-imidazolyl) butyl] phenoxymethyl] -2-[(E) -2-phenylethenyl] oxazole, (iii) 4- [4- [3- (1-imidazolyl) propyl] phenoxymethyl] -2-[(E) -2-phenylethenyl Oxazole, (iv) 4- [3- [3- (1-imidazolyl) propyl] phenoxymethyl] -2-[(E) -2-phenylethenyl] oxazole, (v) 2- (4-benzyloxy Phenyl) -4- [4- [4- [3- (1-Imidazolyl) propyl] phenoxymethyl] oxazole, (vi) 4- [4- [3- (1-Imidazolyl) propyl] phenoxymethyl] -2- (2-thienyl) oxazole, (vii) 4 -[4- [3- (1-Imidazolyl) propyl] phenoxymethyl] -2- (5-methyl-2-thienyl) oxazole, (viii) 2- (5-chloro-2-thienyl) -4- [4 -[3- (1-Imidazolyl) -propyl] phenoxymethyl] oxazole, (ix) 4- [4- [3- (1-Imidazolyl) propyl] phenoxymethyl] -2- (2-thienyl) thiazole, (x ) 5- [4- [3- (1-Imidazolyl) propyl] phenoxymethyl] -2- (2-thienyl) benzoxazole and the like are preferred.

〔式中、ｍは１または２、Ｒ¹はハロゲン原子またはハロゲン化されていてもよいＣ_1-2アルキル、Ｒ²およびＲ³の一方は水素原子、他方は式

（式中、ｎは３または４、Ｒ⁴は１〜２個のヒドロキシ基で置換されたＣ_1-4アルキル基を示す）で表される基を示す。〕で表される化合物（I'）またはその塩などが好ましい。 Further, as the compound (I), for example,

[In the formula, m is 1 or 2, R ¹ is a halogen atom or optionally halogenated C _1-2 alkyl, one of R ² and R ³ is a hydrogen atom, and the other is a formula

(Wherein, n represents 3 or 4, and R ⁴ represents a C _1-4 alkyl group substituted with one or two hydroxy groups). Or a salt thereof.

In the above formula (I ′), examples of the “halogen atom” represented by R ¹ include fluorine, chlorine, bromine, iodine and the like. Of these, fluorine is preferred.
Examples of the halogen atom used for halogenation of “optionally halogenated C _1-2 alkyl” represented by R ¹ include fluorine, chlorine, bromine, iodine and the like. Of these, fluorine is preferred.
Examples of the “C _1-2 alkyl” of the “optionally halogenated C _1-2 alkyl” for R ¹ include methyl and ethyl, with methyl being preferred.
The “C _1-2 alkyl” may have 1 to 3, preferably 2 to 3 of the halogen atoms at substitutable positions, and when the number of the halogen atoms is 2 or more, Each halogen atom may be the same or different.
Specific examples of the “optionally halogenated C _1-2 alkyl” include methyl, ethyl, trifluoromethyl and the like.
As R ¹ , a halogen atom or halogenated C _1-2 alkyl is preferable, and fluorine and trifluoromethyl are more preferable.
When m is 2, each R ¹ may be different.

〔式中、Ｒ⁴は上記と同意義を示す〕で表される基は、好ましくは式

〔式中、Ｒ⁴は上記と同意義を示す〕で表される基である。 Formula represented by R ² or R ³

Wherein R ⁴ is as defined above, is preferably a group represented by the formula

[Wherein, R ⁴ has the same meaning as described above].

As "C _1-4 alkyl group" of the "one or two C _1-4 alkyl group substituted by a hydroxy group" represented by R ^4, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Among them, ethyl, propyl and the like are preferable.
Specific examples of the “C _1-4 alkyl group substituted with one or two hydroxy groups” include 2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl and the like. Among them, 2,3-dihydroxypropyl is preferable.

で表される基およびＲ³が水素原子である場合が好ましい。
Ｒ²が水素原子およびＲ³が式

で表される基である場合も好ましい。
Ｒ²が式

〔式中、ｎは上記と同意義を示す〕で表される基およびＲ³が水素原子である場合も好ましく、さらに好ましくはｎが４である。 In the above formula, R ² is a formula

It is preferred that the group represented by and R ³ be a hydrogen atom.
R ² is a hydrogen atom and R ³ is a formula

It is also preferred that the group is represented by
R ² is the formula

In the formula, n is as defined above, and R ³ is preferably a hydrogen atom, and more preferably n is 4.

〔式中、各記号は上記と同意義を示す〕で表される化合物またはその塩が挙げられる。
化合物（Ｉ’）中、ｍが１、Ｒ¹が４−トリフルオロメチル、Ｒ²が式

で表される基、およびＲ³が水素原子である化合物またはその塩が特に好ましい。 Preferred examples of the compound (I ′) include compounds represented by formulas disclosed in JP-A-2001-348385.

Wherein each symbol is as defined above, or a salt thereof.
In the compound (I ′), m is 1, R ¹ is 4-trifluoromethyl, and R ² is a compound of the formula

And a compound or a salt thereof, wherein R ³ is a hydrogen atom, or a salt thereof.

As specific examples of the compound (I ′), the example compounds disclosed in JP-A-2001-348385 are used, and more preferably (1) 1- (4- {4-[(2-｛( E) -2- [4- (Trifluoromethyl) phenyl] ethenyl {-1,3-oxazol-4-yl) methoxy] phenyl} butyl) -1H-1,2,3-triazole, (2) 1- (3- {3-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} propyl) -1H-1 , 2,3-triazole, (3) 3- (1- {4- [4-({2-[(E) -2- (2,4-difluorophenyl) ethenyl] -1,3-oxazole-4] -Yl {methoxy) phenyl] butyl} -1H-imidazole -2-yl) -1,2-propanediol and the like.

The salt of the compound (I) of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or And salts with acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like. Suitable examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. 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, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be
The compound (I) includes two types, a (Z) -ethenyl form and a (E) -ethenyl form, and the present invention includes both isomers alone and mixtures thereof.
When the compound (I) has an asymmetric carbon, an optical isomer is generated, and the present invention includes a case where the isomer is used alone and a case where a mixture thereof is used.

Compound (I) or a salt thereof can be obtained by a method known per se, for example, a method according to the method described in JP-A-11-60571.
In particular, the compound (I ′) or a salt thereof is obtained, for example, by a method represented by the following reaction formulas A to H or the like.
Each symbol of the compounds in the schematic diagrams of the following reaction formulas has the same meaning as described above. The compounds in the reaction formulas also include cases where salts are formed.

As the “leaving group” for X ¹ , for example, a halogen atom (eg, chlorine, bromine, etc.) or a formula: —OSO ₂ R ^{5 wherein} R ⁵ may have an alkyl or a substituent Represents an aryl].
The “alkyl” represented by R ⁵ includes, for example, C _1-6 alkyl such as methyl, ethyl and propyl.
The “aryl” of the “aryl which may have a substituent” for R ⁵ includes, for example, C _6-14 aryl such as phenyl.
Examples of the “substituent” of the “aryl which may have a substituent” represented by R ⁵ include C _1-6 alkyl such as methyl, ethyl and propyl.
Specific examples of the “aryl which may have a substituent” include phenyl which may have a C _1-6 alkyl (eg, p-tolyl).

The compound (II) is reacted with the compound (III) to obtain a compound (I ′).
In this reaction, compound (II) and compound (III) are generally condensed in the presence of a base.
Examples of the "base" include hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, etc.), carbonates of alkali metals or alkaline earth metals (eg, sodium hydrogen carbonate, carbonate Sodium, potassium carbonate, etc., amines (eg, pyridine, triethylamine, N, N-dimethylaniline, etc.), hydrides of alkali metals or alkaline earth metals (eg, sodium hydride, potassium hydride, calcium hydride, etc.) ), Lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.).
The preferred amount of the "base" to be used is about 1 to 5 molar equivalents relative to compound (II).
The preferred use amount of "compound (III)" is about 0.5 to 5 molar equivalents relative to compound (II).
This reaction is advantageously performed in the presence of a solvent that does not affect the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, amides, sulfoxides, or a mixture of two or more thereof are used.
The reaction temperature is usually -50 to + 150C, preferably about -10 to + 100C. The reaction time is usually 0.5 to 48 hours.

Compound (II) can be produced according to a method known per se or a method analogous thereto. For example, compound (IIa) wherein X is chlorine can be produced by a method represented by the following reaction formula B or the like.

Compound (IV) and 1,3-dichloroacetone are subjected to a condensation / dehydration reaction to obtain compound (IIa).
When the compound (IV) is commercially available, a commercially available product may be used as it is, or may be produced according to a method known per se or a method analogous thereto.
The amount of “1,3-dichloroacetone” to be used is about 1 equivalent to a large excess (solvent amount) with respect to compound (IV).
This reaction is advantageously performed without a solvent or in the presence of a solvent that does not affect the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, or a mixture of two or more thereof are used.
The reaction temperature is usually 50 to 150 ° C, preferably about 60 to 120 ° C. The reaction time is usually 0.5 to 48 hours.
The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

Among the compounds (III), the compound (IIIa) wherein R ³ is a hydrogen atom can be produced according to a method known per se or a method analogous thereto, for example, a method represented by the following reaction formula C.

In the above formula, Pa represents ^a hydrogen atom or a protecting group, and Xa represents ^a leaving group.
The "protecting group" represented by P ^a, for example, alkyl (e.g., methyl, a C _1-6 alkyl such as ethyl), phenyl -C _1-6 alkyl (e.g., benzyl etc.), C _1-6 alkyl - Examples include carbonyl, alkyl-substituted silyl (eg, trimethylsilyl, tert-butyldimethylsilyl, and the like).
The "leaving group" represented by X ^a, for example, those similar to the "leaving group" represented by X ¹ are exemplified.

The compound (V) is condensed with the compound (VI) or the compound (VII) to obtain a compound (VIII), and if necessary, then subjected to a deprotection reaction to obtain a compound (IIIa).
When the compound (V), the compound (VI) and the compound (VII) are commercially available, a commercially available product may be used as it is, or may be produced according to a method known per se or a method analogous thereto, or the like. Is also good.
The "condensation reaction" is usually performed in the presence of a base in a solvent that does not affect the reaction.
As the “base”, the base described in detail in the above Reaction Formula A is used.
The preferred amount of the "base" to be used is about 1 to 5 molar equivalents relative to compound (V).
The preferred use amount of “compound (VI) or compound (VII)” is about 0.5 to 5 molar equivalents relative to compound (V).
The solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, amides, sulfoxides, or a mixture of two or more thereof are used.
The reaction temperature is usually -50 to + 150C, preferably about -10 to + 100C. The reaction time is about 0.5 to 48 hours.
The obtained compound (VIII) can be used in the next reaction as it is as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

The “deprotection reaction” can be appropriately selected from conventional methods.
For example, when ^Pa is alkyl, compound (VIII) is subjected to an acid treatment (eg, a mineral acid such as hydrobromic acid, a Lewis acid such as titanium tetrachloride).
For example, when P ^a is a phenyl -C _1-6 alkyl, subjecting a compound (VIII) to hydrogenation reaction.
For example, when P ^a is an alkyl-substituted silyl, fluoride (e.g., tetrabutylammonium fluoride) and the compound (VIII) is reacted with.
The obtained compound (IIIa) can be used in the next reaction as it is as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

Among the compounds (III), the compound (IIIb) wherein R ² is a hydrogen atom can be produced according to a method known per se or a method analogous thereto, for example, a method represented by the following reaction formula D.

In the above formula, P ^b is a hydrogen atom or a protecting group, X ^b is as "protecting group" represented by P ^b of a leaving group include the same "protecting group" for the P ^a .
As the “leaving group” for X ^b , for example, those similar to the “leaving group” for X ¹ above can be mentioned.
The compound (IX) and the compound (VI) or the compound (VII) are condensed to obtain a compound (X) by a method similar to the method described in the above reaction formula C, and then subjected to a deprotection reaction if necessary. Thereby, compound (IIIb) is obtained.
When the compound (IX) is commercially available, a commercially available product may be used as it is, or may be produced according to a method known per se or a method analogous thereto.

上記式中、Ｘ^cは脱離基を示す。
Ｘ^Cで示される「脱離基」としては、例えば上記Ｘ¹で示される「脱離基」と同様のものが挙げられる。 Among the compounds (I ′), the compound (I′a) in which R ³ is a hydrogen atom can also be produced according to the method described in the following reaction formula E.

In the above formula, ^Xc represents a leaving group.
As the “leaving group” for X ^C , for example, those similar to the “leaving group” for X ¹ above can be mentioned.

The compound (XI) is reacted with the compound (VI) or the compound (VII) to obtain a compound (I'a).
In this reaction, compound (XI) is condensed with compound (VI) or compound (VII) in the presence of a base.
As the “base”, the base described in detail in the above Reaction Formula A is used.
The preferred amount of the "base" to be used is about 1 to 5 molar equivalents relative to compound (XI).
The preferred amounts of “Compound (VI)” and “Compound (VII)” are each about 0.5 to 5 molar equivalents relative to Compound (XI).
This reaction is advantageously performed in the presence of a solvent that does not affect the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, amides, sulfoxides, or a mixture of two or more thereof are used.
The reaction temperature is usually -20 to + 150C, preferably about -10 to + 100C. The reaction time is usually 0.5 to 48 hours.

Compound (XI) can be produced according to a method known per se or a method analogous thereto, for example, a method represented by the following reaction formula F.

In the above formula, X ^d represents a leaving group.
The “leaving group” represented by X ^d includes, for example, those similar to the “leaving group” represented by X ¹ above, and is preferably a leaving group having lower reactivity than X ¹ .
The compound (II) is reacted with the compound (XII) by a method similar to the method described in the above Reaction Formula A to obtain a compound (XI).
When the compound (XII) is commercially available, a commercially available product may be used as it is, or it may be produced according to a method known per se or a method analogous thereto.

Among the compounds (I ′), the compound (I′b) in which R ² is a hydrogen atom can also be produced according to the method described in the following reaction formula G.

In the above formula, X ^e represents a leaving group.
The "leaving group" represented by X ^e, for example, those similar to the "leaving group" represented by X ¹ are exemplified.
The compound (XIII) is reacted with the compound (VI) or the compound (VII) by a method similar to the method described in the above Reaction Formula E to obtain a compound (I'b).

Compound (XIII) can be produced according to a method known per se or a method analogous thereto, for example, a method represented by the following reaction formula H.

In the above formula, ^Xf represents a leaving group.
The "leaving group" represented by X ^f, for example, include those similar to the "leaving group" represented by X ^1, and preferably, less reactive than X ¹ leaving group.
Compound (XIII) is obtained by reacting compound (II) with compound (XIV) by a method similar to the method described in the above Reaction Formula A.
When the compound (XIV) is commercially available, a commercially available product may be used as it is, or it may be produced according to a method known per se or a method analogous thereto.

As the above "aromatic hydrocarbons", for example, benzene, toluene, xylene and the like are used.
As the above “ethers”, for example, tetrahydrofuran, dioxane and the like are used.
As the above “ketones”, for example, acetone, 2-butanone and the like are used.
As the “halogenated hydrocarbons”, for example, chloroform, dichloromethane and the like are used.
As the "amides", for example, N, N-dimethylformamide and the like are used.
As the “sulfoxides”, for example, dimethyl sulfoxide and the like are used.

In each of the above reactions, when the product is obtained as a free form, it can be converted into a salt thereof, and when the product is obtained as a salt, it can be converted into the free form according to a conventional method.
In the above reaction, when amino (NH ₂ ), hydroxy (OH), carboxyl (COOH) and the like are contained in the substituents, those in which these groups are protected are used as a raw material, and after the reaction, a method known per se is used. The target compound may be produced by removing the protecting group by a method. Examples of the amino-protecting group include acyl (eg, C _1-6 alkyl-carbonyl such as acetyl; benzyloxycarbonyl; C _1-6 alkoxy-carbonyl such as tert-butoxycarbonyl; phthaloyl; formyl, etc.). . Examples of the hydroxy-protecting group include C _1-6 alkyl (eg, methyl, ethyl, etc.), phenyl-C _1-6 alkyl (eg, benzyl, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, etc.), Examples include benzoyl, alkyl-substituted silyl (eg, trimethylsilyl, tert-butyldimethylsilyl, and the like). Examples of the carboxyl protecting group include C _1-6 alkyl (eg, methyl, ethyl, etc.), phenyl-C _1-6 alkyl (eg, benzyl, etc.).

Compound (I ′) (including (I′a) and (I′b)) thus obtained can be obtained by a separation method known per se, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, It can be isolated and purified by chromatography and the like.
When the compound (I ′) is obtained in a free form, it can be converted to a target salt by a method known per se or a method analogous thereto. It can be converted to a free form or another desired salt by a method or a method analogous thereto.
Compound (I) may be a hydrate or a non-hydrate.
When the compound (I) is obtained as a mixture of optically active substances, it can be separated into the desired (R) -form or (S) -form by a known optical resolution means.
Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, etc.).

A prodrug of compound (I) or a salt thereof (abbreviated as compound (I)) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, enzymatically oxidizes or reduces. And a compound which undergoes hydrolysis or the like to change to the compound (I) or a compound which undergoes hydrolysis or the like due to stomach acid or the like to change to the compound (I).
As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Compound, dimethylaminomethylcarbonylated compound, etc.); Amidated compounds (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified) Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) changes to compound (I) under physiological conditions, as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pages 163 to 198, Molecular Design. It may be something.

  As used herein, the term "surface modifier" refers to, for example, aggregation of fine particles of a pharmaceutical compound, adhesion, fusion, etc., so that the release property of the fine pharmaceutical compound from the pharmaceutical composition is improved. Means a substance capable of modifying the surface of the fine particles so that the fine particles can exist without being present. The surface modifier is not particularly limited as long as it has the above properties, but preferably includes a water-affinity substance.

The “water-affinity substance” used in the present invention is defined as a substance having a contact angle of water on the substance surface of about 50 ° or less. In the present specification, a combination of a plurality of substances having the property is used. Shall be used in a sense that also includes
As the water-affinity substance used in the present invention, preferably, a polymer compound, a surfactant, a saccharide, or a combination of two or more thereof are exemplified.

As the polymer compound, for example, a hydrophilic polymer, preferably a water-soluble polymer or the like is used. As the water-soluble polymer, for example, hydroxypropylcellulose, hydroxyalkylcellulose such as hydroxypropylmethylcellulose, cellulose derivatives such as alkylcellulose such as methylcellulose, polyalkenylpyrrolidone such as polyvinylpyrrolidone, polyalkylene glycol such as polyethyleneglycol, polyvinyl alcohol Are used.
Among the above polymers, hydroxyalkyl cellulose such as hydroxypropylcellulose, polyalkenylpyrrolidone such as polyvinylpyrrolidone and the like are more preferable, and hydroxypropylcellulose and polyvinylpyrrolidone are more preferable, and among them, hydroxypropylcellulose is preferable.

  The amount of the polymer compound to be added can be appropriately selected in the range of 0.01 part to 100 parts based on 100 parts of the fine particle drug compound. Preferably, the amount is 0.1 part to 10 parts, and more preferably, 1 part to 10 parts per 100 parts of the fine particle drug compound.

As the surfactant used in the present invention, a nonionic surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant, a surfactant derived from a natural product, and the like are used.
Nonionic surfactants include higher alcohol ethylene oxide adducts, alkylphenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alkylamine ethylene oxide adducts, fatty acid amide ethylene oxide adducts Products, ethylenoxide adducts of fats and oils, glycerin fatty acid esters, fatty acid esters of pentaerythritol, alkyl ethers of polyhydric alcohols, fatty acid amides of alkanolamines, and the like.
Among the nonionic surfactants, for example, fatty acid esters of sorbitol and sorbitan, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hardened Castor oil (polyethoxylated hydrogenated castor oil), polyoxyethylene polypropylene glycol copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester and the like are preferably used. Examples of the sorbitan fatty acid ester include sorbitan monostearate (trade name: SS-10, Nikko Chemicals Co., Ltd.), sorbitan sesquioleate (trade name: SO-15, Nikko Chemicals Co., Ltd.), sorbitan trioleate (Trade name: SO-30, Nikko Chemicals Co., Ltd.) and the like are suitable. As polyoxyethylene sorbitan fatty acid esters, particularly, polysorbate 20 (trade name: TL-10, Nikko Chemicals Co., Ltd.), polysorbate 40 (trade name: TP-10, Nikko Chemicals Co., Ltd.), polysorbate 60 (trade name) : TS-10, Nikko Chemicals Co., Ltd.), Polysorbate 80 (trade name: TO-10, Nikko Chemicals Co., Ltd.) and the like are preferable. As the polyethylene glycol fatty acid ester, polyethylene glycol monolaurate (10E.O.) (trade name: MYL-10, Nikko Chemicals Co., Ltd.) is particularly suitable. Examples of the sucrose fatty acid ester include sucrose palmitate esters (for example, trade name: P-1670, Mitsubishi Chemical Foods Co., Ltd.) and sucrose stearic esters (for example, trade name: S-1670, Mitsubishi Chemical Foods) And the like are preferred. As polyoxyethylene castor oil, polyoxyethylene glycerol triricinoleate 35 (Polyoxy 35 Castor Oil, trade name Cremophor EL or EL-P, BSF Japan Ltd.) is particularly suitable. . As polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (Polyoxyethylene Hydrogenated Castor Oil 60) and the like are particularly preferable. is there. As the polyoxyethylene polyoxypropylene glycol copolymer, in particular, polyoxyethylene (160) polyoxypropylene (30) glycol (trade name: Adecapluronic F-68, Asahi Denka Kogyo KK) and the like are suitable. . As the glycerin fatty acid ester, glyceryl monostearate (MGS series, Nikko Chemicals Co., Ltd.) and the like are suitable. As the polyglycerin fatty acid ester, tetraglycerin monostearic acid (MS-310, Sakamoto Pharmaceutical Co., Ltd.) and decaglycerin monolauric acid (Decaglyn 1-L, Nikko Chemicals Co., Ltd.) are particularly suitable.

Examples of the anionic surfactant include, for example, sulfates (eg, higher alcohol sulfates, higher alkyl ether sulfates, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, sulfated olefins), sulfonates ( For example, sodium alkylbenzene sulfonate, oil-soluble alkylbenzene sulfonate, α-olefin sulfonate, Igepon T type, aerosol OT type), phosphates (eg, phosphate ester salt of higher alcohol ethylene oxide adduct), A dithiophosphate ester salt or the like is used.
Among the anionic surfactants, for example, bile salts such as sodium glycocholate and sodium deoxycholate, fatty acids and salts thereof such as stearic acid and sodium caprate, and alkyl sulfates such as sodium lauryl sulfate are preferred. .
Examples of the cationic surfactant include amine salt-type cationic surfactants (eg, amine salt-type cationic surfactants made from higher alkylamines, amine salt-type cationic surfactants made from lower alkylamines), A quaternary ammonium salt type cationic surfactant (eg, a quaternary ammonium salt type cationic surfactant made from a higher alkylamine, a quaternary ammonium salt type surfactant made from a lower alkylamine) and the like are used. .
As the amphoteric surfactant, for example, an amino acid type amphoteric surfactant, a betaine type amphoteric surfactant and the like are used.
Examples of natural surfactants include lecithin phospholipids such as egg yolk lecithin (trade name: PL-100H, Kewpie Co., Ltd.) and soybean lecithin (trade name: Resinol S-10, Nikko Chemicals Co., Ltd.) Used.
Among the above surfactants, anionic surfactants are more preferred, and sodium lauryl sulfate is particularly preferred.
Or sodium deoxycholate, alkyl sulfates, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30), polyoxyethylene glycerol triricinoleate 35, lecithins, polyoxyethylene hydrogenated castor oil, sucrose fatty acid Esters and polyglycerin fatty acid esters are preferred, and alkyl sulfates and sucrose fatty acid esters are more preferred. Further, among the above alkyl sulfates, sodium lauryl sulfate is more preferable, and among sucrose fatty acid esters, for example, sucrose stearic acid is more preferable.

  The addition amount of the surfactant can be appropriately selected in the range of 0.01 to 100 parts based on 100 parts of the fine particle drug compound. Preferably, the amount is 0.1 part to 10 parts, and more preferably, 1 part to 10 parts per 100 parts of the fine particle drug compound.

Examples of the saccharide used in the present invention include monosaccharides or oligosaccharides such as mannose, xylose, sorbose, fructose, glucose, galactose, sucrose, maltose, lactose, raffinose, trehalose, and the like, for example, mannitol, sorbitol, xylitol, maltitol. , Erythritol, ribitol, lactitol, arabitol, sugar alcohols such as inositol, and other sugar derivatives.
Preferably, it is a sugar alcohol, and more preferably, mannitol.

  The addition amount of the saccharide can be appropriately selected in the range of 0.01 part to 100 parts per part of the fine particle pharmaceutical compound. Preferably, the amount is 0.1 part to 10 parts per part of the fine particle drug compound, and more preferably 0.1 part to 1 part per part of the fine particle drug compound.

  The above-mentioned water-affinity substances can be used alone or in combination of two or more. For example, two or more polymer compounds, two or more surfactants, two or more saccharides may be used in combination, or a polymer compound and a surfactant; a polymer compound and a saccharide; An agent and a saccharide, or a polymer compound, a surfactant and a saccharide may be used in combination. Among them, it is preferable to use a combination of a polymer compound, a surfactant and a saccharide, for example, a cellulose derivative such as hydroxypropyl cellulose, an anionic surfactant such as sodium lauryl sulfate, and a sugar alcohol such as mannitol. It is suitable.

The pharmaceutical composition of the present invention is characterized in that the release property of the fine particle pharmaceutical compound is improved by adding a surface modifier such as the above-mentioned water-affinity substance. “Improved release” means that water solubility and absorbency are improved.
"Improved in water solubility" specifically means that "the dissolution rate is promoted", and for example, the dissolution rate at 37 ° C is 2 times, preferably 5 times, more preferably 10 times. , More preferably 100 times or more. The dissolution rate can be measured by a method known per se, but can also be conveniently measured, for example, by a dissolution test method.
The term “improved absorbability” specifically refers to, for example, an “increase in absorption rate” or “absorption rate, bioavailability” of a particulate pharmaceutical compound, as compared to a pharmaceutical composition containing no surface modifier. Improvement "is achieved. Indices of "enhancement of drug absorption rate" include _Tmax (time to reach maximum blood concentration), MRT (average residence time) and the like. Indicates AUC (area under the blood concentration-time curve), C _max (maximum blood concentration) and the like. Specifically, for example, the absorbability is about 2 times, preferably about 5 times, more preferably 10 times, still more preferably 100 times, 1000 times, 1 time, as compared with a pharmaceutical composition containing no surface modifier. It means that it is improved by 10,000 times, 100,000 times, 1,000,000 times or more.

The pharmaceutical composition of the present invention may contain an excipient, a lubricant, a binder, a disintegrant, a coating agent and the like in addition to the fine particle pharmaceutical compound and the surface modifier. If necessary, the composition can also contain pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like.
The pharmaceutical composition of the present invention may be solid, semi-solid, or suspended, and is not particularly limited, but a solid pharmaceutical composition is preferred.

The content of the fine particle pharmaceutical compound in the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier and the like, but is usually 0.02 to 90% (w / w) based on the total amount of the preparation.
The pharmaceutical composition of the present invention has excellent physical and chemical stability under high-temperature, high-humidity storage conditions. For example, even when stored at 40 ° C. and 75% RH for about 3 months, the drug composition has a high Characteristics such as particle diameter and crystal state are maintained. Therefore, an additive for stabilizing the preparation is not required, so that a high content of the drug can be achieved together with the improved release. Specifically, the drug content in the preparation can be 0.2 to 90% (w / w), more preferably 2 to 50% (w / w), based on the total amount of the preparation. Preferably, it can be 10 to 50% (w / w).
The content of the surface modifier in the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, etc., but is generally 0.01 to 50% (w / w) based on the total amount of the preparation as a whole. However, in order to achieve a high content of the drug, it can be 0.1 to 50% (w / w) based on the total amount of the preparation, and more preferably 1 to 25% (w / w). ), More preferably 5 to 25% (w / w).
The content of other additives in the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, and the like, but can be usually 0 to 99.5% (w / w) based on the total amount of the preparation. is there.

  The pharmaceutical composition of the present invention is preferably prepared, for example, by treating the fine particle pharmaceutical compound of the present invention with the surface modifier of the present invention in a water-soluble solvent, preferably by treating the pharmaceutical compound of the present invention with a surface modifier. Can be produced by pulverization in a water-soluble solvent containing Furthermore, in the production of the pharmaceutical composition of the present invention, excipients and lubricants are used in the surface modifier treatment step (for example, the above-mentioned pulverization step) and other steps (for example, the granulation and mixing steps). , A binder, a disintegrant, a coating agent and the like may be added. If necessary, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be coexisted in any of the above steps. Specific examples of these additives will be described later.

The pulverization operation can be performed in a state in which the pharmaceutical compound is dispersed in a water-soluble solvent, for example, “in water” (used in the present specification also including an aqueous solution containing a salt). Chemical Pharmaceutical Bulletin, vol. 41, pp. 737-740, 1993, a method using a grind container and a crushed ball, and the International Journal of Pharmaceutics, vol. 196. , Pp. 161-164, 2000, using a high-pressure homogenizer.
The water-soluble solvent for performing the pulverizing operation is selected from water, alcohols, and ketones, preferably water, ethanol, acetone, and more preferably water. Also, a mixed solvent of two or more solvents arbitrarily selected from water, alcohols and ketones can be used.
For the pulverization, for example, a medium stirring mill using a grind container and a pulverizing medium, a container driving medium mill, a high-pressure homogenizer such as Micron Lab 40 (APV Homogenaizer) or the like is used alone or in combination. The grinding temperature is usually in the range of 4 ° C. to 80 ° C., and is strictly controlled as necessary.
The pulverization time depends on the pulverization conditions, the type and presence or absence of additives, and the properties of the drug crystals. For example, when using a grinding container and a grinding medium (the material of the grinding medium is usually selected from stainless steel, zirconium oxide, agate, polystyrene, etc., and the average particle size of the medium is usually 3 mm or less), The pulverization time is usually about several hours to about 10 days, preferably about 15 hours to about 5 days, and more preferably about 24 hours to about 3 days. On the other hand, in the method using a high-pressure homogenizer, usually about 1 to 30 times at a pressure of about 200 to 2000 bar, preferably about 5 to 20 times at a pressure of about 500 to 1500 bar, more preferably at a pressure of about 1000 to 1500 bar. By performing the treatment about 5 to 10 times, the suspension composition of the HER2 inhibitor of the present invention can be obtained.
The drug addition concentration at the time of pulverization in a solution varies depending on the properties of the drug, additives, and the like. (W / w), more preferably in the range of about 0.5-60% (w / w).

More specifically, for example, it can be prepared by the following production method.
(1) A mixture of a pharmaceutical compound and a surface modifier is pulverized by a container driving medium mill at room temperature for about 10 minutes to 10 hours, preferably for about 10 minutes to 5 hours. Thereafter, the suspension is suspended in a solution such as water and subjected to ultrasonic treatment in ice-cold water to obtain a dispersion of the pharmaceutical compound. Further, the dispersion is treated with a high-pressure homogenizer usually for about 100 to 3000 bar (preferably about 1000 to 2000 bar) for about 1 to 20 times (preferably about 5 to 10 times), so that the fine particles whose surface is modified are obtained. A suspension composition of the pharmaceutical compound is obtained.
(2) After water is added to the mixture of the pharmaceutical compound and the surface modifier, ultrasonic treatment is performed in ice-cold water to obtain a dispersion of the pharmaceutical compound. Further, the dispersion is treated with a high-pressure homogenizer usually for about 100 to 3000 bar (preferably about 1000 to 2000 bar) for about 1 to 20 times (preferably about 5 to 10 times), so that the fine particles whose surface is modified are obtained. A suspension composition of the pharmaceutical compound is obtained.
(3) Water is added to the mixture of the pharmaceutical compound and the surface modifier, and then ultrasonication is performed in ice-cold water to obtain a dispersion of the pharmaceutical composition. A pulverizing medium made of stainless steel is added to the obtained dispersion, and the mixture is shaken at room temperature for usually about 1 hour to 10 days to obtain a suspension composition of the fine particle drug compound whose surface is modified.
(4) After water is added to the mixture of the pharmaceutical compound and the surface modifier, ultrasonic treatment is performed in ice-cold water to obtain a dispersion of the pharmaceutical compound. A stainless steel grinding medium is added to the obtained dispersion, and the mixture is shaken at room temperature for usually about 1 hour to 10 days. After the shaking treatment, the fine particles whose surface has been modified by further treating with a high-pressure homogenizer usually about 100 to 3000 bar (preferably about 1000 to 2000 bar), about 1 to 20 times (preferably about 5 to 10 times) A suspension composition of the pharmaceutical compound is obtained.
The suspension composition of the fine particle drug compound having the surface modified obtained by the above method can be powdered by a method generally used for formulation. For powderization, for example, means such as a spray dryer (for example, Okawara Kakoki Co., Ltd. L-8), freeze-drying, spray granulation, and spray coating to non-pareil particles can be used. The obtained powder can be further dried under vacuum if necessary. When the suspension composition is powdered, if necessary, various additives that can be pharmaceutically used for the purpose of improving stability and the like can be added. Examples of pharmaceutical additives added for the purpose of improving stability include sugars and sugar alcohols such as mannitol and trehalose, and coating agents such as hydroxypropylcellulose. Surfactants such as sugar ester and sodium lauryl sulfate may be further added as an anti-agglomeration agent.

The composition in the present invention can also be prepared by a reprecipitation method (nano-precipitation), and after a known method, for example, dissolving the pharmaceutical compound of the present invention in a solvent capable of volatilization removal such as methylene chloride, It can also be obtained by a method of recrystallization in a solution (for example, in an aqueous solution) while controlling the crystal deposition rate. Further, a base such as a polymer is mixed with a pharmaceutical compound (which may be in any of a crystalline state and an amorphous state, or may be in a mixed state of crystal and amorphous). By treating, it can be obtained as a dispersion of fine crystal fine particles in the base.
Further, the pharmaceutical composition of the present invention may contain an excipient, a lubricant, a binder, a disintegrant, a coating agent and the like in the crystallization step. If necessary, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be contained in the crystallization step. Specific examples of these additives will be described later.
In the reprecipitation method, the pharmaceutical composition of the present invention can be obtained by dispersing a solvent in which a drug compound is dissolved in water (or an aqueous solution) and then removing the solvent in the presence of a surface modifier. The solvent that can be removed by volatilization used in the preparation is not particularly limited as long as it can dissolve the pharmaceutical compound.Examples thereof include water-immiscible solvents such as methylene chloride and ethyl acetate, and water such as acetone, methanol, ethanol, and tetrahydrofuran. Miscible solvents are preferred. A solvent in which a pharmaceutical compound is dissolved is dropped into water or an aqueous solution containing salt in the presence of a surface modifier, and then a stirrer such as a magnetic stirrer or Ultra-Turrax T-25 (Ika), VP-25 (TITEC) And a high-pressure homogenizer such as Micron Lab 40 (APV Homogenaizer). The solvent used as the solvent for the drug can be removed by reducing the pressure or heating, for example, using a rotary evaporator. Further, it is also possible to remove the solvent with a spray drier or a freeze dryer to obtain fine crystal particles as a dry powder. Furthermore, it is also possible to carry out desolvation using carbon dioxide gas in a supercritical state.

The pharmaceutical composition of the present invention can also be obtained as a dispersion of fine crystalline fine particles by preliminarily mixing a pharmaceutical additive such as a polymer serving as a base and a pharmaceutical compound, and then treating with a solvent vapor, for example. . The pharmaceutical compound in a state of being mixed with the pharmaceutical additive may exist in any of a crystalline state and an amorphous state, or may be in a mixed state of both.
Additives serving as bases include polymer compounds, surfactants, surface modifiers composed of water-affinitive substances such as sugars, excipients, lubricants, binders, disintegrants, coating agents, Preservatives, antioxidants, coloring agents, sweeteners and the like can be mentioned.

  The pharmaceutical composition of the present invention can be prepared by a pulverizing operation using a general medium mill or a high-pressure homogenizer or a reprecipitation operation of recrystallizing while controlling the deposition rate. (Registered trademark; manufactured by Nara Machinery Co., Ltd.) using a compacting shearing mill. This type of crusher is a grinding-type wet crusher that sandwiches sample material particles between a number of high-speed rotating rollers (or crushing rings) and the inner wall of the mill and performs crushing by compression and shearing action. Yes, the contact area between the roller (or crushing ring) and the inner wall of the mill is increased to increase the crushing efficiency.

In the preparation of crystal fine particles by a reprecipitation operation, a solvent harmful to the human body is generally used, and these harmful solvents may remain in the prepared fine particles. In addition, since there is a problem that it is difficult to control the precipitation of crystals and it is difficult to store the fine particles for a long period of time, a preparation method by pulverization using a medium mill or a high-pressure homogenizer is more simply performed.
In a general medium mill, particles are broken by an impact force and a shear force when the medium collides with the crushed particles. Therefore, in order to increase the grinding efficiency, it is required to move a higher density, a smaller medium at a higher speed.However, by using the smaller medium, the separation of the sample from the medium and the washing operation of the medium become more difficult. It is expected to be complicated. Also, the milling period can often be long (USP 5145684, 1992), and attention must be paid to problems such as microbial development. On the other hand, the microparticle method using a high-pressure homogenizer has the advantage that contamination of foreign substances into the sample can be kept low.On the other hand, when the control compound is a hard crystal particle, sufficiently fine particles can be obtained when used alone. In some cases, it may not be practical or it may be necessary to perform the pulverization process (number of passes) many times (USP 6177103, 2001).
In a consolidation shearing mill, a large compressive force and a large shear force are applied to the pulverized particles by centrifugal force generated by a large number of pulverizing rollers (or pulverizing rings or the like) which revolve and rotate at high speed. By "grinding" the pulverized particles by such a large compression force or the like, the compaction shearing mill can achieve finer particles in the submicron region in a processing time of 1/6 to 1/30 as compared with a conventional pulverizer.
In addition, the wet grinding method using a consolidation shear mill has a higher concentration of suspension (slurry) than the grinding method using a medium mill or a high-pressure homogenizer that mechanically fluidizes grinding media such as balls and beads. Grinding can be performed in a relatively short time, and crystal fine particles having an average particle size of 1 μm or less can be obtained more efficiently. Furthermore, operations such as decomposing and washing are easy due to the structure of the crusher, and the possibility of generating microorganisms is low.

When the pharmaceutical compound of the present invention is administered to mammals such as humans, it is mixed with a pharmaceutically acceptable carrier, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules, and suppositories. Or as a pharmaceutical composition such as a pellet, orally or parenterally.
As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and are blended as excipients, lubricants, binders, disintegrants, coating agents and the like. In addition, if necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used.
Suitable examples of the excipient include lactose, sucrose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like.
Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.
Preferred examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinylpyrrolidone, and the like.
As preferred examples of the coating agent, hydrophilic polymers and the like are generally used, and among them, water-soluble polymers such as the above-mentioned cellulose derivatives such as hydroxyalkylcellulose and alkylcellulose and polyalkyl alcohols such as polyvinyl alcohol , Enteric polymers, gastric polymers and the like are preferably used. These hydrophilic polymers may be used as a mixture of two or more kinds.
Examples of the enteric polymer include hydroxyalkylcellulose phthalate such as hydroxypropylmethylcellulose phthalate; hydroxyalkylcellulose acetate succinate such as hydroxypropylmethylcellulose acetate succinate; carboxyalkylcellulose such as carboxymethylethylcellulose; cellulose acetate phthalate; Copolymers of ethyl acrylate and methacrylic acid such as acrylic acid copolymer L-100-55; and copolymers of methyl methacrylate and methacrylic acid such as methacrylic acid copolymer L and methacrylic acid copolymer S are used. Can be
As the gastric-soluble polymer, for example, aminoalkyl methacrylate copolymer E; polyvinyl acetal diethylaminoacetate and the like are used.
In addition, copolymers containing a small amount of quaternary ammonium group of ethyl acrylate and methyl methacrylate such as methacrylic acid copolymer RL and methacrylic acid copolymer RS, carboxymethylcellulose, carboxyvinyl polymer, gum arabic, sodium alginate, alginic acid A hydrophilic polymer such as propylene glycol ester, agar, gelatin, and chitosan is used.
Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.
Suitable examples of the sweetener include, for example, xylitol, sodium saccharin, glycyrrhizic acid, stevia extract and the like.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
Maize starch, hydroxypropyl cellulose, magnesium stearate, crystalline cellulose, polyvinylpyrrolidone, lactose, croscarmellose sodium (Ac-Di-Sol), polyethylene glycol, red iron sesquioxide, titanium oxide, lauryl used in the following examples As sodium sulfate, mannitol, polysorbate 80, and nifedipine, products conforming to the 14th Revised Japanese Pharmacopoeia were used.

Example 1
1- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] pulverized by a jet mill ] Phenyl @ butyl) -1H-1,2,3-triazole (hereinafter abbreviated as "compound A") (average particle size: 3 [mu] m) An aqueous solution in which 100 g of hydroxypropylcellulose, 10 g of sodium lauryl sulfate, and 50 g of mannitol are dissolved. Surface treatment was carried out by dispersing 561 g using a disperser. The treated suspension was dried by a spray dryer to obtain a powder.

Example 2
Example 1 300 g of coarse-grained compound A was dispersed in 1533 g of an aqueous solution in which 30 g of hydroxypropylcellulose and 3 g of polysorbate 80 were dissolved using a dispersing machine, and subsequently the compound A was dispersed with a high-pressure homogenizer (LAB60-10TBS type, APV GAULIN). It was pulverized simultaneously with the surface treatment until the average particle size became 1.5 μm. 60 g of mannitol was added to this pulverized liquid, and 1262 g of this liquid was sprayed onto a mixed powder of 1238 g of lactose and 300 g of corn starch flowing in a fluidized-bed granulator and granulated, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. 180 g of the obtained sized powder was filled in a No. 2 capsule to obtain a capsule preparation. Approximately 9,000 capsules containing 20 mg of Compound A per capsule and having the theoretical formulation shown in Table 1 were obtained.

Example 3
500 g of coarse-grained nifedipine was dispersed in 1706.5 g of an aqueous solution in which 25 g of hydroxypropylcellulose and 15 g of sodium lauryl sulfate were dissolved using a dispersing machine, followed by a grinding-type wet grinder (Micros type 2, Nara Machine Works). The powder was pulverized simultaneously with the surface treatment until the average particle size of nifedipine became 1.5 μm. 125 g of mannitol was added to the pulverized liquid, and 1865.2 g of this liquid was sprayed and granulated on a mixed powder of 900 g of mannitol and 260 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. . The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. With respect to 1607.4 g of the sized powder, 85.5 g of croscarmellose sodium (Ac-Di-Sol) and 17.1 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted to a weight of 450 mg with a tableting machine using a 13 × 8 mm oval punch, to obtain about 3800 uncoated tablets having the theoretical formulation shown in Table 2 and containing 100 mg of nifedipine per tablet.

Example 4
500 g of the coarse-grained compound A was dispersed in 1706.5 g of an aqueous solution obtained by dissolving 25 g of hydroxypropylcellulose and 15 g of sodium lauryl sulfate using a dispersing machine, followed by a grinding-type wet grinding machine (Micros type 2, Nara Machine Works) And pulverized simultaneously with the surface treatment until the average particle size of compound A became 0.7 μm. 125 g of mannitol was added to the pulverized liquid, and 1865.2 g of this liquid was sprayed and granulated on a mixed powder of 900 g of mannitol and 260 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. . The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. With respect to 1607.4 g of the sized powder, 85.5 g of croscarmellose sodium (Ac-Di-Sol) and 17.1 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine to a weight of 450 mg using a 13 × 8 mm oval punch to obtain about 3800 uncoated tablets having the theoretical formulation shown in Table 3 and containing 100 mg of Compound A per tablet. .

Example 5
1500 g of the coarse-grained compound A was dispersed in 5119.5 g of an aqueous solution in which 75 g of hydroxypropylcellulose and 45 g of sodium lauryl sulfate were dissolved using a dispersing machine, and then a grinding-type wet grinding machine (Micros 5 type, Nara Machine Works) And pulverized simultaneously with the surface treatment until the average particle size of compound A became 1.5 μm. 750 g of mannitol was added to the pulverized liquid, and 5895.6 g of the liquid was sprayed and granulated on a mixed powder of 2400 g of mannitol and 780 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. . The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 4822.2 g of the sized powder, 256.5 g of croscarmellose sodium (Ac-Di-Sol) and 51.3 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were compressed to a weight of 450 mg using a 13 × 8 mm oval punch with a tableting machine to obtain uncoated tablets. The obtained uncoated tablet was sprayed with a 2910 solution of hydroxypropylmethylcellulose in which titanium oxide, polyethylene glycol and red iron sesquioxide were dispersed in a film coating machine, and contained 100 mg of compound A per tablet, a film having the theoretical formulation shown in Table 4. About 11400 tablets were obtained.

Example 6
3000 g of the coarse-grained compound A was dispersed in 7800 g of an aqueous solution prepared by dissolving 150 g of hydroxypropylcellulose and 150 g of sodium lauryl sulfate using a dispersing machine, and then using a grinding-type wet grinding machine (Micros 5 type, Nara Machine Works). Compound A was pulverized simultaneously with the surface treatment until the average particle size became 0.5 μm. 1500 g of mannitol was added to this pulverized liquid, and 4060 g of this liquid was sprayed and granulated on a mixed powder of 2080 g of mannitol and 652 g of crystalline cellulose in a fluidized bed granulator and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.0 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate were added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 7 mmφ punch to obtain about 36,000 uncoated tablets having the theoretical formulation shown in Table 5 and containing 25 mg of Compound A per tablet.

Example 7
3000 g of the coarse-grained compound A is dispersed in 7740 g of an aqueous solution obtained by dissolving 150 g of hydroxypropylcellulose and 150 g of sodium lauryl sulfate using a dispersing machine, and then using a grinding wet grinder (Micros 5 type, Nara Machine Works). Compound A was pulverized simultaneously with the surface treatment until the average particle size became 0.5 μm. 548 g of mannitol and 1000 g of purified water were added to 1432 g of the pulverized liquid, and this liquid was sprayed into a mixed powder of 2692 g of mannitol and 652 g of crystalline cellulose in a fluidized-bed granulator and granulated. Dried. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. 201.6 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate are added to 389.7 g of the sized powder, and mixed to give granules for tableting. The granules were tableted with a tableting machine using a 7 mmφ punch to obtain about 36,000 uncoated tablets having the theoretical formulation shown in Table 6 and containing 10 mg of Compound A per tablet.

Example 8
3000 g of the coarse-grained compound A was dispersed in 150 g of hydroxypropylcellulose and 7740 g of an aqueous solution in which 90 g of sodium lauryl sulfate was dissolved using a dispersing machine, and subsequently, using a grinding-type wet grinding machine (Micros 5 type, Nara Machine Works). Compound A was pulverized simultaneously with the surface treatment until the average particle size became 0.5 μm. 1500 g of mannitol was added to this pulverized liquid, and 4160 g of this liquid was sprayed and granulated on a mixed powder of 2100 g of mannitol and 650 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.5 g of croscarmellose sodium (Ac-Di-Sol) and 40.5 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine to a weight of 460 mg using a 13 × 8 mm oval punch to obtain about 9,000 uncoated tablets having the theoretical formulation shown in Table 7 and containing 100 mg of Compound A per tablet.

Example 9
3000 g of the coarse-grained compound A was dispersed in 150 g of hydroxypropylcellulose and 7740 g of an aqueous solution in which 90 g of sodium lauryl sulfate was dissolved using a dispersing machine, and subsequently, using a grinding-type wet grinding machine (Micros 5 type, Nara Machine Works). Compound A was pulverized simultaneously with the surface treatment until the average particle size became 0.5 μm. 1500 g of mannitol was added to this pulverized liquid, and 4160 g of this liquid was sprayed and granulated on a mixed powder of 2100 g of mannitol and 650 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.5 g of croscarmellose sodium (Ac-Di-Sol) and 40.5 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine to a weight of 460 mg using a 13 × 8 mm oval punch to obtain uncoated tablets. The obtained uncoated tablets were sprayed with an aqueous dispersion of Operdry-2 (high performance) in a film coating machine to obtain about 9000 tablets of the theoretical formulation shown in Table 8 containing 100 mg of Compound A per tablet. .

Example 10
3000 g of the coarse-grained compound A was dispersed in 150 g of hydroxypropylcellulose and 7740 g of an aqueous solution in which 90 g of sodium lauryl sulfate was dissolved using a dispersing machine, and subsequently, using a grinding-type wet grinding machine (Micros 5 type, Nara Machine Works). Compound A was pulverized simultaneously with the surface treatment until the average particle size became 0.5 μm. 1500 g of mannitol was added to this pulverized liquid, and 4160 g of this liquid was sprayed and granulated on a mixed powder of 2100 g of mannitol and 650 g of crystalline cellulose in a fluidized bed granulating dryer, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.5 g of croscarmellose sodium (Ac-Di-Sol) and 40.5 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine to a weight of 460 mg using a 13 × 8 mm oval punch to obtain uncoated tablets. The obtained uncoated tablets were sprayed with an aqueous dispersion of overdry-AMB (high performance) in a film coating machine to obtain about 9000 film tablets having the theoretical formulation shown in Table 9 and containing 100 mg of compound A per tablet. .

Example 11
3000 g of the coarse-grained compound A is dispersed in 4400 g of an aqueous solution in which 30 g of sodium lauryl sulfate is dissolved by using a high-speed shearing disperser, and then finely pulverized by a grinding-type wet pulverizer (Micros 5 type, Nara Machine Works). Processing was performed. During the pulverization step, about 60 g was added so that the total amount of sodium lauryl sulfate was 90 g, and the point in time when the average particle size became 0.5 μm was defined as the end point of the pulverization. A solution obtained by dissolving 150 g of hydroxypropylcellulose in 500 g of purified water was added to this pulverized solution, stirred for about 1 hour, and 1500 g of mannitol was added to complete the surface treatment. 3200 g of this liquid was sprayed and granulated on a mixed powder of 2105 g of mannitol and 652 g of crystalline cellulose in a fluidized bed granulator and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.0 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate were added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 6.5 mmφ punch to obtain about 40,000 uncoated tablets having the theoretical formulation shown in Table 10 and containing 25 mg of Compound A per tablet.

Example 12
3000 g of the coarse-grained compound A is dispersed in 4400 g of an aqueous solution in which 30 g of sodium lauryl sulfate is dissolved by using a high-speed shearing disperser, and then finely pulverized by a grinding-type wet pulverizer (Micros 5 type, Nara Machine Works). Processing was performed. During the pulverization step, about 60 g was added so that the total amount of sodium lauryl sulfate was 90 g, and the point in time when the average particle size became 0.5 μm was defined as the end point of the pulverization. A solution obtained by dissolving 150 g of polyvinylpyrrolidone in 500 g of purified water was added to the pulverized liquid, stirred for about 1 hour, and 1500 g of mannitol was added to complete the surface treatment. 3203 g of this liquid was sprayed on a mixed powder of 2080 g of mannitol and 652 g of crystalline cellulose in a fluidized-bed granulator and granulated, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.0 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate were added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 6.5 mmφ punch to obtain about 40,000 uncoated tablets having the theoretical formulation shown in Table 11 and containing 25 mg of Compound A per tablet.

Example 13
4000 g of the coarse-grained compound A is dispersed in 4000 g of an aqueous solution in which 40 g of sodium lauryl sulfate is dissolved by using a high-speed shearing disperser, and then finely pulverized by a grinding type wet pulverizer (Micros 5 type, Nara Machinery Works). Processing was performed. During the pulverization step, about 80 g was added so that the total amount of sodium lauryl sulfate became 120 g, and the point when the average particle diameter became 0.5 μm was defined as the end point of the pulverization. A solution obtained by dissolving 200 g of hydroxypropylcellulose in 700 g of purified water was added to this pulverized solution, and the mixture was stirred for about 1 hour, and 2,000 g of mannitol was further added to complete the surface treatment. 2745 g of this liquid was sprayed on a mixed powder of 2100 g of mannitol and 652 g of crystalline cellulose in a fluidized bed granulator and granulated, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.0 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate were added and mixed to obtain granules for tableting. The granules were tableted with a tablet machine using a 6.5 mmφ punch to obtain about 40,000 uncoated tablets having the theoretical formulation shown in Table 12 and containing 25 mg of Compound A per tablet.

Example 14
2000 g of the coarse-grained compound A was dispersed in 6100 g of an aqueous solution in which 900 g of mannitol and 200 g of polyvinylpyrrolidone were dissolved by using a high-speed shearing disperser, and then, using a grinding-type wet pulverizer (Micros 5 type, Nara Machine Works). A fine grinding treatment was performed. During the pulverization process, sodium lauryl sulfate was gradually added so that the total amount added became 60 g, and the point in time when the average particle size became 0.8 μm was defined as the end point of the pulverization and surface treatment. 4100 g of this liquid was sprayed on a mixed powder of 2080 g of mannitol and 652 g of crystalline cellulose in a fluidized-bed granulator and granulated, and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 389.7 g of the sized powder, 202.0 g of croscarmellose sodium (Ac-Di-Sol) and 40.3 g of magnesium stearate were added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 6.5 mmφ punch to obtain about 40,000 uncoated tablets having the theoretical formulation shown in Table 13 and containing 25 mg of Compound A per tablet.

Example 15
3000 g of the coarse-grained compound A is dispersed in 7110 g of an aqueous solution in which 150 g of hydroxypropylcellulose is dissolved using a high-speed shearing disperser, and then finely pulverized by a wet-type pulverizer (Micros 5 type, Nara Machinery Works). Processing was performed. During the pulverization step, 630 g of a solution in which 90 g of sodium lauryl sulfate was dissolved was gradually added within 30 minutes after the start of the pulverization. The point in time when the average particle diameter became 0.5 μm was regarded as the end point of the pulverization. To 465 g of the pulverized solution, 572 g of a dispersion liquid containing 624 g of mannitol, 26 g of bengara and 26 g of sodium lauryl sulfate was added, and the mixture was stirred to complete the treatment. 5850 g of this liquid was sprayed and granulated on a mixed powder of 2704 g of mannitol and 847.6 g of crystalline cellulose in a fluidized bed granulator and then dried by the same machine. The obtained granules were pulverized with a power mill with a 1.5 mmφ punching screen to give sized powder. To 4765 g of the sized powder, 246.4 g of croscarmellose sodium (Ac-Di-Sol) and 48.4 g of magnesium stearate are added and mixed to obtain granules for tableting. The granules were tableted with a tableting machine using a 6.5 mmφ punch to obtain about 40,000 uncoated tablets having the theoretical formulation shown in Table 14 and containing 25 mg of Compound A per tablet.

  According to the surface modification method of the present invention, the fine particle pharmaceutical compounds exist without aggregation, adhesion, fusion, etc., and easily release the fine particle pharmaceutical compounds in the gastrointestinal tract. , And as a result, a pharmaceutical composition having excellent bioavailability is provided.

Claims (35)

A pharmaceutical composition comprising a fine particle pharmaceutical compound and a surface modifier. The pharmaceutical composition according to claim 1, wherein the surface modifier is a water-affinity substance. 3. The pharmaceutical composition according to claim 2, wherein the water-affinity substance is a polymer compound. The pharmaceutical composition according to claim 3, wherein the polymer compound is a cellulose derivative. The pharmaceutical composition according to claim 4, wherein the cellulose derivative is hydroxypropyl cellulose. The pharmaceutical composition according to claim 3, wherein the amount of the polymer compound is 0.01 to 100 parts based on 100 parts of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 3, wherein the amount of the polymer compound is 0.1 part to 10 parts based on 100 parts of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 3, wherein the amount of the polymer compound is 1 to 10 parts based on 100 parts of the fine particle pharmaceutical compound. 3. The pharmaceutical composition according to claim 2, wherein the water-affinity substance is a surfactant. The pharmaceutical composition according to claim 9, wherein the surfactant is an anionic surfactant. The pharmaceutical composition according to claim 10, wherein the anionic surfactant is sodium lauryl sulfate. The pharmaceutical composition according to claim 9, wherein the surfactant is added in an amount of 0.01 to 100 parts based on 100 parts of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 9, wherein the surfactant is added in an amount of 0.1 part to 10 parts based on 100 parts of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 9, wherein the amount of the surfactant is 1 part to 10 parts based on 100 parts of the fine particle pharmaceutical compound. 3. The pharmaceutical composition according to claim 2, wherein the water-affinity substance is a saccharide. The pharmaceutical composition according to claim 15, wherein the saccharide is a sugar alcohol. 17. The pharmaceutical composition according to claim 16, wherein the sugar alcohol is mannitol. The pharmaceutical composition according to claim 15, wherein the amount of the saccharide added is 0.01 part to 100 parts based on 1 part of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 15, wherein the amount of the saccharide added is 0.1 part to 10 parts based on 1 part of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 15, wherein the added amount of the saccharide is 0.1 part to 1 part based on 1 part of the fine particle pharmaceutical compound. The pharmaceutical composition according to claim 2, wherein the water-affinity substance comprises a combination of two or more selected from the group consisting of a polymer compound, a surfactant, and a saccharide. The pharmaceutical composition according to claim 1, wherein the fine particle pharmaceutical compound is a poorly water-soluble compound. 23. The pharmaceutical composition according to claim 22, wherein the poorly water-soluble compound is a HER2 inhibitor. HER2 inhibitor has the formula

[Wherein, R represents an aromatic heterocyclic group which may be substituted, X represents an oxygen atom, a sulfur atom which may be oxidized, -C (= O)-or -CH (OH)-, Is CH or N; p is an integer of 0 to 10; q is an integer of 1 to 5;

The ring A may be further substituted with an aromatic azole group in which the group represented by may be substituted. 24. The pharmaceutical composition according to claim 23, which is a compound represented by the formula: or a salt thereof or a prodrug thereof. HER2 inhibitor has the formula

[In the formula, m is 1 or 2, R ¹ is a halogen atom or an optionally halogenated C _1-2 alkyl, one of R ² and R ³ is a hydrogen atom, and the other is a formula

(Wherein, n represents 3 or 4, and R ⁴ represents a C _1-4 alkyl group substituted with one or two hydroxy groups). 24. The pharmaceutical composition according to claim 23, which is a compound represented by the formula: or a salt thereof or a prodrug thereof. The HER2 inhibitor is (i) 1- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) Methoxy] phenyl} butyl) -1H-1,2,3-triazole, (ii) 1- (3- {3-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl) {-1,3-oxazol-4-yl) methoxy] phenyl} propyl) -1H-1,2,3-triazole, (iii) 3- (1- {4- [4-({2-[(E ) -2- (2,4-Difluorophenyl) ethenyl] -1,3-oxazol-4-yl {methoxy) phenyl] butyl} -1H-imidazol-2-yl) -1,2-propanediol or a salt thereof Or a prodrug thereof. Composition. The pharmaceutical composition according to claim 1, wherein the average particle diameter of the fine particle pharmaceutical compound is 5 µm or less. The pharmaceutical composition according to claim 1, wherein the average particle diameter of the fine particle pharmaceutical compound is 1.5 µm or less. The pharmaceutical composition according to claim 1, wherein the average particle size of the fine particle pharmaceutical compound is 0.6 µm or less. The method for producing a pharmaceutical composition according to claim 1, wherein the fine particle pharmaceutical compound is treated with a surface modifier in a water-soluble solvent. 31. The method according to claim 30, wherein the apparatus used for the treatment is a wet pulverizer. The method according to claim 31, wherein the wet mill is of a grinding type. 32. The method according to claim 31, wherein the wet mill is of a consolidation shearing type. 31. The method according to claim 30, wherein the pulverization of the pharmaceutical compound and the surface modification are performed simultaneously. A pharmaceutical composition obtained by treating a fine particle pharmaceutical compound with a surface modifier in a water-soluble solvent.