WO2002078673A1 - Procede de production d'un medicament sous forme de granules fins - Google Patents

Procede de production d'un medicament sous forme de granules fins Download PDF

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Publication number
WO2002078673A1
WO2002078673A1 PCT/JP2002/003049 JP0203049W WO02078673A1 WO 2002078673 A1 WO2002078673 A1 WO 2002078673A1 JP 0203049 W JP0203049 W JP 0203049W WO 02078673 A1 WO02078673 A1 WO 02078673A1
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group
compound
water
acid
reaction
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PCT/JP2002/003049
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English (en)
Japanese (ja)
Inventor
Shigeo Yanai
Kazuhiro Saito
Tetsuo Hoshino
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Takeda Chemical Industries, Ltd.
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Publication of WO2002078673A1 publication Critical patent/WO2002078673A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present invention relates to a method for producing a fine water-insoluble or poorly water-soluble drug and the like.
  • Methods for formulating a water-insoluble or poorly water-soluble drug as an injection include a method of solubilizing a solution, for example, a method of ionizing using non-physiological pH, a method of using a non-aqueous solvent, and a surfactant. And a method of forming a complex with a water-soluble inclusion compound such as cyclodextrin. Other methods include emulsions, ribosomes, nanocapsules, microcapsules, nanocrystals, and microcrystals.
  • Emulsion formulations are obtained by dispersing oil droplets in which the drug is dissolved in water, and are effective for lipophilic drugs.
  • the oil used is one that is liquid at normal temperature, is metabolized in the body, and does not stimulate living tissues.
  • a surfactant is further used.
  • the surfactant those having an HLB value of about 8 to 18 are generally used.
  • Liposomes are vesicles composed of phospholipid bilayer membranes, and can incorporate poorly soluble drugs into hydrophobic lipid bilayer membranes.
  • Microcapsule preparations and nanocapsule preparations are prepared by encapsulating a drug in a base material, forming fine particles that can be passed through, and can be made into an aqueous suspension.
  • the base herein refers to a biocompatible and biodegradable polymer. Specific examples include polylactic acid (PLA) or lactic acid-glycolic acid copolymer (PLGA). Nanocrystals and microcrystals are microparticles of a drug, which can increase the melting velocity of the drug.
  • the present inventors have conducted intensive studies focusing on crystallization as a method for atomizing a water-insoluble or poorly water-soluble drug. It dissolves in an organic solvent that is miscible with an aqueous solvent together with the improver, and is mixed with an aqueous solvent containing a wettability improver to precipitate fine particles of the drug, resulting in a water-insoluble or poorly water-soluble drug. It has been found that fine particles of the above can be prepared. Furthermore, it has been found that the fine water-insoluble or poorly water-soluble drug thus produced has excellent stability and excellent dispersibility in a dispersion medium. As a result of further research based on these findings, the present invention has been completed.
  • wetting improver is one or more selected from sugars or sugar derivatives, phospholipids, surfactants, amphiphilic polymers, proteins and inorganic salts.
  • FIG. 1 is a graph showing the measurement results of changes in the concentration of the compound obtained in Reference Example 4 in rat plasma obtained in Test Examples 1 to 3.
  • Ichikokuichi shows the plasma concentration change after administration of the suspension obtained in the same manner as in Example 1
  • — ⁇ — shows the plasma concentration after administration of the suspension obtained in the same manner as in Example 31.
  • the transition of the mean concentration is shown, and one bite shows the transition of the concentration of the compound in plasma after administration of the suspension obtained in the same manner as in Example 38.
  • FIG. 2 is a graph showing the results of an in vitro dissolution test of the compound obtained in Reference Example 4 obtained in Test Examples 4 to 6.
  • ⁇ indicates the elution curve of the suspension obtained in the same manner as in Example 67
  • ⁇ indicates the suspension obtained in the same manner as in Example 71.
  • the elution curve of the solution is shown
  • ___________ is the drug elution curve of the suspension obtained by the same method as in Example 72.
  • the water-insoluble or poorly water-soluble drug used in the present invention means that the solubility in water at 20 ° C. is preferably about 0 to about 1 mg / mL, more preferably about 0 to about 0.1 mg / mL. , But the type is not limited.
  • the production method of the present invention is applied by converting into a water-insoluble or poorly water-soluble drug using a method known per se such as a method of chemically modifying a hydrophobic group at a site that does not contribute to pharmacological activity in the structure of the drug. can do.
  • a method known per se such as a method of chemically modifying a hydrophobic group at a site that does not contribute to pharmacological activity in the structure of the drug. can do.
  • the water-insoluble or poorly water-soluble drug used in the present invention is water-insoluble or poorly water-soluble, but is preferably soluble in a body fluid (eg, synovial fluid, subcutaneous or intramuscular fluid between tissues, etc.).
  • a body fluid eg, synovial fluid, subcutaneous or intramuscular fluid between tissues, etc.
  • the solubility in the body fluid at the administration site is preferably about 1.5 times or more, more preferably about 10 to about 10 times, the solubility in water at 20 ° C.
  • a 100-fold, more preferably 100,000 to about 100,000-fold drug is preferred.
  • drugs used in the present invention include, for example, antitumor agents, antibiotics, antiinflammatory agents, analgesics, bone / cartilage / joint disease prevention / treatment agents, antihyperlipidemic agents, antibacterial agents, sedation Agents, tranquilizers, antiepileptics, antidepressants, digestive disorders, allergic disorders, hypertension, arteriosclerosis, diabetes, hormonal drugs, moon soluble vitamins and And anti-androgens.
  • antitumor agent examples include HER2 inhibitors (heterocyclic compounds described in WO01 / 7717, etc.), anthracycline-based antineoplastic agents such as taxol and doxorubicin hydrochloride, methotrexe-1 , Etoposide, 5-fluorouracil, mitoxantrone, mesna, dimesna, aminoglutethimide, tamoxifen, acroline, cisplatin, carboplatin, cyclophosphamide, romusti (CC NU), carmustine (BC NU) and the like or derivatives thereof.
  • HER2 inhibitors heterocyclic compounds described in WO01 / 7717, etc.
  • anthracycline-based antineoplastic agents such as taxol and doxorubicin hydrochloride, methotrexe-1 , Etoposide, 5-fluorouracil, mitoxantrone, mesna, dimesna, amino
  • antibiotics examples include aminodaricoside antibiotics such as amikacin, debekacin, gentamicin, and derivatives thereof.
  • anti-inflammatory substance examples include salicylic acid-based anti-inflammatory drugs such as aspirin, pyrazolone-based anti-inflammatory drugs such as aminopyrine, aniline-based anti-inflammatory drugs such as phenacetin, acetoaminophenone, phenylbutazone, ketophenylbutazone and the like.
  • salicylic acid-based anti-inflammatory drugs such as aspirin
  • pyrazolone-based anti-inflammatory drugs such as aminopyrine
  • aniline-based anti-inflammatory drugs such as phenacetin, acetoaminophenone, phenylbutazone, ketophenylbutazone and the like.
  • Etc . virazolidinedione anti-inflammatory drugs such as mefenamic acid
  • anthranilate anti-inflammatory drugs such as mefenamic acid
  • acetic acid anti-inflammatory drugs such as indomitacin
  • trioxopyrimidine anti-inflammatory drugs such as bucolome
  • Analgesics include xylocaine, pentazocine, aspirin and the like.
  • Bone 'Prevention of cartilage diseases' include, for example, prostaglandin A 1 derivatives, vitamin D derivatives, vitamin K 2 derivatives, eicosapentaenoic acid derivatives, benzylphosphonic acid, bisphosphonic acid derivatives, sex hormone derivatives, phenolsulfophthalein Derivatives, benzothiopyran or benzozopine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthin derivatives, etc., non-peptide bone formation promoting substances, hardly soluble peptide bone formation promoting substances, and the like.
  • ⁇ 38 ⁇ kinase inhibitor thiazole compounds described in WO 00/64898, etc.
  • matrix meta-oral protease inhibitor ⁇ ⁇ ⁇
  • anti-inflammatory steroids such as prednisolone, hydrocortisone, methylprednisolone, dexamethasone, and betamethasone
  • nonsteroidal anti-inflammatory analgesics such as indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam, and sulindac.
  • Antihyperlipidemic agents include, for example, clinofibrate, clofibrate, cholestyramine, soysterone, tocopheronol nicotinate, nicomornole, niceritrol, probucol, elastase and the like.
  • tranquilizer examples include benzodiazepines such as diazepam, lorazepam and oxazolam.
  • Antiepileptic agents include, for example, phenytoin, phenobarbital, carbamazepine, primidone and the like.
  • antidepressant examples include imibranine, noxiptiline, phenelzine and the like.
  • Examples of the therapeutic agent for gastrointestinal diseases include methokapramide, famotidine, omeprazole, sulpiride, and trepivtone.
  • Examples of the therapeutic agent for allergic diseases include clemastine fumarate, sip mouth hydroheptadine, diphenhydramine, methdilamine, clemizole, methoxyphenamine and the like.
  • antihypertensive agent examples include calcium antagonists such as dicardipine hydrochloride, angiotensin converting enzyme inhibitors such as delapril hydrochloride and captopril, alpha 1-receptor blockers such as prazosin hydrochloride, and reserpines.
  • Examples of the therapeutic agent for arteriosclerosis include a defoamer, a cholesterol ester transfer protein inhibitor and the like.
  • Examples of the antidiabetic agent include glymidine, glipzide, dalibenclamide, buforenamine, metformin and the like.
  • Hormonal agents mainly include steroid hormones, for example, dexamethasone, betamethasone, prednisolone, hydroxy / retisone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, hexestrol, methimazole, estriol, etc.
  • steroid hormones for example, dexamethasone, betamethasone, prednisolone, hydroxy / retisone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, hexestrol, methimazole, estriol, etc.
  • fat-soluble vitamin preparations examples include vitamin A, vitamin D, vitamin E, vitamin K, folic acid (vitamin M), and various derivatives.
  • antiandrogens examples include oxendrone, arylestrenol, chlormadinone acetate, gestanolone caproate, osapron acetate, flutamide, and bicalutamide.
  • the water-insoluble or poorly water-soluble drug used in the present invention preferably includes a thiophene derivative (eg, a thienoindazole derivative), a benzothiopyran or a benzozopine derivative.
  • a thiophene derivative eg, a thienoindazole derivative
  • a benzothiopyran e.g., a benzothiopyran
  • benzozopine derivative e.g., a compound having a condensed benzothiophene derivative as a basic skeleton is described in the following literature and the like.
  • JP-A-8-245386 discloses 4,5-dihydro-8- (methylthio) isoxazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5-dihydro-8-
  • a cell differentiation inducing factor action enhancer comprising a compound represented by (methylthio) isoxazolo [5,4-d] benzo [c] thienophene-6-carboxaraide) is described.
  • Japanese Patent Application Laid-Open No. 10-130271 discloses that osteoporosis, fracture, osteoarthritis, and four joints have an effect of enhancing cell differentiation-inducing factor action and an anti-matrix metaoral protease action.
  • Fused thiophene compounds useful for the prevention and treatment of bone diseases such as rheumatism, arteriosclerosis, cancer metastasis and diseases based on neurodegeneration are described.
  • the thiophene derivative used in the present invention is preferably, for example, a compound described in JP-A-2000-309591, JP-A-2000-239280 or a salt thereof, and a compound represented by the formula (la): [Formula 1]
  • R la represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group
  • R 2a represents a cyano group, a formyl group.
  • a ring C a represents an optionally substituted 5- to 7-membered ring
  • R a is a hydrogen atom, halogen atom, Shiano group or each an optionally substituted amino group, an Ashiru group, a hydrocarbon residue or heterocyclic group
  • R a may be substituted with the ring-constituting atoms of Chiofen rings and ring C a It may form a hydrocarbon ring or a heterocyclic ring. Or a salt thereof.
  • R la represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group.
  • R 1 a Yo Le be substituted, examples of the hydrocarbon residue in the hydrocarbon residue, an aliphatic hydrocarbon residue which may be substituted respectively, alicyclic hydrocarbon Motozanmoto, An alicyclic monoaliphatic hydrocarbon residue, an aromatic hydrocarbon residue or an aromatic monoaliphatic hydrocarbon residue (an aralkyl group) is exemplified.
  • Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butynole, pentyl, isopentyl, neopentinole, tert-pentyl, hexinole, and isohexyl.
  • What C1-8 saturated aliphatic hydrocarbon residues such as butyl and octyl (eg, alkyl group), for example, butyl, arylin (allyl), 1-propinyl, 2-methyl-1-propininole, 1- Butenyl, 2-buteninole, 3-buteninole, 3-methyl-1-buteninole, 1-penteninole, 2-penteninole, 3-pentennole, 4-penteninole, 4-methylthin-3-pentenyl , 1-hexenyl, 2-hexenyl, 3-hexenyl,
  • alicyclic hydrocarbon residue examples include a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl (eg, cycloalkyl group). Etc.), 1-cyclopentenyl, 2-cyclopenteninole, 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexeninole, 3-cyclohexenyl, 1-cyclohepteninole, 2-cyclo Hepteninore,
  • C3-C7 unsaturated alicyclic hydrocarbon residue such as 3-cycloheptur, 2,4-cycloheptagenyl (eg, cycloalkenyl group, cycloalkadienyl group, etc.), 1-indur, 2- Indenyl, 1-danil, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2-dihydro_1-naphthyl, 1 1,2-dihydro-1-naphthyl, 1,4-dihydro-1-naphthinole, 1,4-dihydro-2-naphthyl, 3,4-dihydro 1-naphthyl, 3,4-dihydro-2- Partially saturated condensed bicyclic hydrocarbon residue such as naphthyl [preferably C 9 _ 1 () partially saturated condensed bicyclic hydrocarbon
  • alicyclic monoaliphatic hydrocarbon residue examples include those in which the alicyclic hydrocarbon residue is bonded to an aliphatic hydrocarbon residue, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, Cyclic butyl ethyl, Cyclic pentynolemethyl, 2-cyclopenteninolemethinole, 3-cyclopenteninolemethinole, cyclopentinolethy / re, cyclohexylmethyl, 2-cyclohexeninolemethinole, 3- Cyclohexeninolemethinole, Cyclohexinoleethyl, Cycloheptinolemethinole, Cycloheptinoletinole, 2- (3,4-dihydro-1-naphthyl) ethy
  • C W alkyl groups C 3 _ 7 cycloalkyl _C 2 _ 4 alkenyl group, C 3 _ 7 consequent opening Arukeniru C 2 _ 4 alkenyl group, partially saturated fused bicyclic hydrocarbon - .
  • CH alkyl group C ⁇ partially saturated fused bicyclic hydrocarbon - such as C 2 _ 4 alkenyl group).
  • aromatic hydrocarbon residue examples include phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 4-indininole, 5-indininole, 4-indaninole, 5-indanil, 5,6,7,8-tetrahydro-11 —Naphthyl, 5,6,7,8—tetrahydro-2-naphthyl, 5,6-dihydro1_naphthyl, 5,6-dihydro1-2-naphthyl, 5,6-dihydro-1-3-naphthyl
  • aryl groups having 6 to 10 carbon atoms including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is condensed with a phenyl group), such as 5,6-dihydro-4-naphthyl and the like.
  • aromatic-aliphatic hydrocarbon residue examples include phenyl-C 1 alkyl groups such as benzyl, phenethyl, 1-phenylethyl, 1-phenylenopropyl, 2-phenylinopropynole, 3-phenylpropyl, and the like.
  • C7-C14 aralkyl groups such as naphthyl-CH alkyl groups such as naphthylmethyl, ⁇ -naphthylethyl, 3-naphthylmethyl, / 3_naphthylethyl, etc., for example, styryl, C 6, such as 4 alkenyl group - - phenyl one C 2 such as cinnamyl, etc.
  • iN 7 Li one Roux C 2 _ 4 alkenyl group.
  • the heterocyclic group of the heterocyclic group which may be substituted in R la includes, for example, (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom.
  • a group, (ii) a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) a 5- to 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom (Iv) these heterocyclic groups may be condensed with a 5- to 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom .
  • the heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be any of aromatic and non-aromatic. There may be.
  • heterocyclic group in the optionally substituted heterocyclic group for R la examples include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group.
  • heterocyclic group in the heterocyclic group which may be substituted in R la include (i) an aromatic monocyclic heterocyclic group (eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl) , Imidazolyl, birazolinol, 1,2,3_oxaziazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxoxazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4—thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, virazinyl, triazinyl, etc., (ii) aromatic fused heterocyclic group (eg , Benzofuranyl, is
  • 1,3,4-oxadiazolyl flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazur, triazinyl, etc.) and sulfinyl group; aromatic condensation Heterocyclic groups (eg, benzofurayl, isobenzofuranyl, benzo [b] thenyl, indolyl, isoindolyl, 1H dazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, Quinolinole, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphth
  • Ci such as methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec-butynole, tert-butynole, pentynole, isopentynole, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.
  • _ 8 alkyl and a sulfinyl group is bonded to C _ 8 alkyl sulfide nil can be mentioned up.
  • R 1 a is a sulfonyl group in the optionally sulfonyl group which may be substituted, "hydrocarbon residue”, respectively optionally substituted hydrocarbon residue or heterocyclic group "as R la described above Or “heterocyclic group” and one SO 2 — bonded to each other.
  • Arylsulfonyl aromatic monocyclic heterocyclic group (eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4 —Oxadiazolyl, 1, 3, 4 —Oxadiazolyl, Frazanil, 1,2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,3,4-Thiadiazolyl, 1,2,3-Triazolyl, 1,2 4--triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.) and a sulfonyl group; aromatic condensed
  • C i _ such as methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec butynole, tert-butynole, pentynole, isopentizole, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.
  • R la as the hydroxy group which may be substituted, a hydroxyl group and the water group suitable substituents, for example, be "substituted respectively represented by R 1 a have good hydrocarbon residue or heterocyclic And a hydroxyl group substituted with a “group”.
  • Aryloxy; aromatic monocyclic heterocyclic group eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl, 1 , 3,4-oxadizazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, A hydroxyl group substituted with tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc .; fused aromatic heterocyclic group (eg, benzofuranyl, isobenzofurany
  • C 6 _ 10 Ariruokishi (particularly preferably phenyl), or substituted with an aromatic monocyclic Hajime Tamaki (particularly preferably pyridyl) or an aromatic fused Hajime Tamaki (particularly preferably quinolyl) hydroxyl Is mentioned.
  • hydrocarbon residue or “heterocyclic group” as a substituent of the substituted hydroxyl group exemplified here is the “hydrocarbon residue or heterocyclic group which may be substituted respectively” as R la described above. And may have the same substituents as the “hydrocarbon residue” or “heterocyclic group” in the above.
  • R 1 a as the thiol group that may be substituted, an appropriate substituent thiol group and the thiol group, e.g., Yo be "substituted respectively represented by R la les, hydrocarbon residue And a thiol group substituted with a “group or heterocyclic group”.
  • methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- Buchinore, tert- Buchinore, Penchinore, Isopenchinore, Neopenchinore, tert- pentyl, Kishinore, hexyl iso, to Puchinore, one 8 alkyl such Okuchiru substituted CI_ 8 alkylthio; phenyl, alpha-naphthyl, beta-naphthyl, 4 _ indenyl, 5-indenyl, 4-indanyl, 5-Indaninore, 5, 6, 7, 8-tetrahydro-one 1-naphthyl, 5, 6 , 7,8-tetrahydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-1-nap
  • Arylthio aromatic monocyclic heterocyclic group (eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, frazanil, 1, 2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.)
  • aromatic fused heterocyclic group eg, benzofuranyl, isobenzofuranyl, be
  • hydrocarbon residue or “heterocyclic group” as a substituent of the substituted thiol group exemplified here is the same as the above-mentioned “optionally substituted hydrocarbon residue or heterocyclic group” as R la. It may have the same substituent as the “hydrocarbon residue” or the “heterocyclic group” in the “ring group”.
  • Examples of the amino group which may be substituted in R la include an amino group, an N-mono-substituted amino group and an N, N-di-substituted amino group.
  • the substituted amino group is, for example, be optionally substituted hydrocarbon group substituted (e.g., represented by R 1 a That those similar to the substituted hydrocarbon may be residues, more specifically, C ⁇ al Kill group, C 3 - 7 cycloalkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl group, C 3 _ 7 shea Kuroarukeniru group may have a CH group.
  • Aryl group an optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R la ), or a formula: _ COR a '(wherein, R a ′ represents a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, and “a substituted or unsubstituted hydrocarbon residue or a heterocyclic group as R a ” '' Is the same substituent as the above-mentioned ⁇ hydrocarbon residue '' or ⁇ heterocyclic group '' in the above-mentioned ⁇ hydrocarbon residue or heterocyclic group optionally substituted '' as Ra ′ ), Preferably C w .
  • Ashiru group e.g., C 2 _ 7 Anorekanoi Le, Benzoiru, Nikochinoiru etc.
  • amino group e.g. having a one or two substituents, Mechiruamino, Jimechiruamino, Echiruamino, Jechiruamino, di Puropiruamino, Jibuchiruamino, Jiariruamino, cyclo Hexylamino, phenylamino, N-methyl-1-N-phenylamino, acetylamino, propionanolamino, benzoylamino, nicotinylamino, etc.).
  • two groups in the substituted amino group may combine to form a nitrogen-containing 5- to 7-membered ring (eg, piperidino, morpholino, thiomorpholino, etc.).
  • a nitrogen-containing 5- to 7-membered ring eg, piperidino, morpholino, thiomorpholino, etc.
  • Hydrocarbon residue "heterocyclic group”, “heterocyclic group” in “hydrocarbon residue optionally substituted, heterocyclic group, sulfinyl group, sulfonyl group” shown by R la
  • “Sulfiel group” and “sulfonyl group” may each be substituted with 1 to 3 substituents, such as lower (C ⁇ ) alkyl group (eg, methyl, ethyl, propyl , isopropyl, butyl, Isopuchiru, sec- butyl Honoré, tert- Buchinore, Penchinore, isopentyl, Neopenchinore, hexyl, etc.
  • substituents such as lower (C ⁇ ) alkyl group (eg, methyl, ethyl, propyl , isopropyl, butyl, Isopuchiru, sec- butyl Honoré, tert- Buchinore, Penchinore, isopentyl, Neopenchinore, hexyl, etc.
  • a lower (C 2 - 6) alkenyl e.g., Bulle, Ariru (allyl), 1-pro Peninole, 2-methyl-1-propeninole, 1-butenyl, 2-butul, 3-butul, 3-methinole1-2-buteninole, 1-penteninole, 2-penteninole, 3-pentenin Nore, 4-pentenole, 4-methinole, 3_pentenore, 1_hexeninole, 2-hexeninole, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.], lower (C 2 _ 6 ) Lucinyl groups (eg, ethur, 1-propyl, 2-propynyl, 1-butul, 2-butur, 3-butul, 1-pentul, 2-pentinyl, 3-pentinole, 4-pentinole, 1- Kishunore, to 2 _ Kishininore, Kishininore to 3, Kisheru
  • C 3 _ 7 cycloalkyl group e.g., Shikuropuropi Honoré, cyclobutyl, cyclopentyl, cyclohexylene cyclohexyl, cyclohexylene, etc. heptyl
  • C 6 — 1Q 7 reel group eg, phenyl, ⁇ -naphthyl,] 3-naphthyl, etc.
  • aromatic complex group eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isotizazolyl, imidazolyl, pyrazolyl , 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl, 1,3,4_oxadiazolyl, brazzanole, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiaziazolyl, 1,2,3-triazolinole, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazur, triazinyl, benzofuranyl, isobenzofuranyl,
  • H-benzotriazolyl quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazur, naphthyridinyl, purinyl, pteridinyl, carbazolinole, ⁇ -carbolininole, —carbolininole, ⁇ -forcenorebinil, phenylinyl Thiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyro [1, 2, b] pyridazyl, pyrazo [1, 5-a] pyridyl, imidazo [1, 2, a] pyridyl , Imidazo [1,5—a] pyridyl, imidazo [1,2—b] pyridazinyl, imidazo [1,
  • C 7 _ 14 Ararukiru group (example 7 membered, benzyl, phenethyl, 1-phenyl Echiru, C 6 _, aryl-CH alkyl groups such as 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, ⁇ -naphthinolemethyl / ⁇ , ⁇ -naphthylechinole, ⁇ -naphthylmethyl, ⁇ -naphthylethyl, etc.
  • N-monosubstituted amino group eg, N-alkyl such as methylamino, ethylamino, aryl (allyl) amino, cyclohexylamino, phenylamino
  • N-disubstituted Amino group e.g., Jimechiruamino, GETS Chiruamino, Jibuchiruamino, Jiariru (allyl) Amino, such as N- methyl-N- off Eniruamino, C w alkyl group, C 2 _ 6 Arukeeru group, C 3 _ 7 cycloalkyl and.
  • a carbonyl group a nitrogen atom, an oxygen atom, 5 to chromatic three 1 hetero atom selected from sulfur atom Or six-member aromatic or A heterocyclic monocarbonyl group formed by the combination of a non-aromatic heterocycle and a carbonyl group
  • a rubamoyl group an N-monosubstituted rubamoyl group [eg, methylcarbamoyl, ethyl Carbamoyl, carboxy carbamoyl cyclohexane, full carbamoylmethyl such like N- (C ⁇ 6 alkyl) force Rubamoiru group, N _ (C 2 - 6 alkenyl) force Rubamoiru group, N- (C 3 - 7 cycloalkyl) Power Rubamoyl group, N_.
  • N, N-disubstituted rubamoyl group eg, dimethylcarbamoyl, getylcarbamoyl, dibutylcarbamoyl, diallyl (allyl) rubamoyl, N-methyl-N-phenylcarbamoyl, etc. alkyl group, C 2 - 6 an alkenyl group, C 3 _ 7 cycloalkyl and.
  • an alkyl group C 2 _ 6 alkenyl Le group, C 3 Nkuroarukiru based on your Yopi C ⁇ .
  • carboxyl group lower (CM) alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , Isobutoxy carbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc., hydroxyl group, lower (C ⁇ 6 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy) , Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc., lower (C 2 _ 6 )
  • alkylsulfinyl group eg, methylsnolebuynyl, ethylsulfinolinole, propinoresnolefinyl, isopropinolesulfinyl, butinoresulfinyl, isobutylsulfininole, sec-butinoresnorefiel, tert- Buchirusunore Finiru, pliers Luz sulfide El, isopentyl Luz Honoré Fi El, Neopenchirusu Norefiniru, hexyl-sulfinyl, etc.), C 7 _ 14 ⁇ Lal kill sulfide El group (e.g., phenyl -CH alkylsulfide El, Nafuchiru CH alkylsulfide El of which Cw.
  • Lal kill sulfide El group e.g., phenyl -CH alkylsulfide El, Nafu
  • Arylsulfinyl group eg, phenylsulfinyl, naphthylsulfiel, etc.
  • lower (C 6 ) alkylsulfonyl group eg, methylsulfonyl, ethylsulfonyl, propinolesnorehoni / le, isopropinolesnorehonynor, butynoreth Nolehoninore, Isobutinoresnorenobinore, sec-butinoresnorelehoninore, tert-Butinoreszolehoninore, Pentinoreshoninore, Isopentinoresonelehoninore, Neopentinoresnoreleho Ninore, to such key Shinoresu Honoré Honi Le), C 7 _ 14 7 Lal kill sulfonyl group (
  • Ariru -CM alkylsulfenyl Honiru group such as naphthyl -CH alkylsulfonyl) ,.
  • Arylsulfonyl group eg, phenylsulfonyl, naphthylsulfonyl, etc.
  • sulfo group cyano group, azide group, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro group, nitroso group, ester Phosphono group which may be esterified [eg, phosphono group, anoreoxy such as ethoxyphosphoryl) phosphoryl group, di (C ⁇ 6 alkoxy) phosphoryl group such as diethoxyphosphoryl, etc., phosphono group which may be esterified (C ⁇ 6 ) alkyl group substituted with a group (eg, phosphono-C alkyl group, alkoxyphosphoryl-alky
  • a hydroxyl group and a lower (C, _ 6) alkoxy group when the adjacent the substituents may form a C alkylene O carboxymethyl such Mechirenjiokishi Oyobi Echirenjiokishi. Cw above.
  • C 6 — i as a substituent of an aryl group, N, N-disubstituted rubamoyl group.
  • Aryl, C 6 _ as a substituent of an N, N-disubstituted sulfamoyl group.
  • the aryl group is the same. Cw in arylthio group.
  • the aryl group may be further substituted with 1 to 3 substituents, and examples of the substituent include a lower (C w) alkyl group, an amino group, an N- (C w alkyl) amino group, N, N-di (C w alkyl) amino group, amidino group, a force Luba moil group, N- (!
  • N, N-di-alkyl) sulfamoyl group a carboxyl group, a lower (C 2 - 7) alkoxycarbonyl group, a hydroxyl group, a lower (C) alkoxy group, a mercapto group, a lower (C w) alkylthio group, a sulfo group, Shiano group, azido group, a halogen atom, a nitro group, a nitroso group, Esuterui spoon which may phosphono group optionally [example, a phosphono group, C w alkoxy phosphoryl group, di (C, - 6 alkoxy) a phosphoryl radical, is esterified Lower (C w) alkyl groups substituted by an optionally substituted phosphono group
  • phosphono-Cw alkyl group alkoxyphosphoryl-Cw alkyl group, dialkoxy such as diethoxyphosphorylmethyl
  • phosphoryl-Cw alkyl group and the like.
  • R la is preferably a sulfier group, a sulfonyl group, a hydroxyl group or a thiol group, each of which may be substituted.
  • R la is the formula: A SR 1 4a, - shows the S0 2 R 14a or a OR 14a (wherein, R 14a are each replacement which may be optionally hydrocarbon residue or heterocyclic group - SOR 14a, A group represented by) is preferred.
  • the “optionally substituted and optionally substituted hydrocarbon residue” represented by R 14a includes the “optionally substituted hydrocarbon residue or heterocyclic group” represented by R la
  • R 14a is preferably a group having 2 or more carbon atoms, more preferably an optionally substituted or cyclic group, and particularly preferably an optionally substituted group.
  • Aromatic groups are preferable.
  • R la ' is an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfur group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and is represented by the formula: — X a ' — '(wherein X a 'represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally sulfur atom, and W a ' represents a substituted Represents a carbon atom or a nitrogen atom having two or more substituents.)
  • R la ' optionally substituted hydrocarbon group which may be substituted respectively, heterocyclic group, scan Rufiniru group, a sulfonyl group, a hydroxyl group, a thiol group or amino group are each optionally substituted hydrocarbon as a R la It has the same meaning as residue, heterocyclic group, sulfinyl group, sulfonyl group, hydroxyl group, thiol group or amino group.
  • a X a' R la -W a ' (wherein, X a' is a bond, a carbon atom but it may also be substituted, a nitrogen atom which may be substituted, is an oxygen atom or oxide Represents a sulfur atom, and W a ′ represents a substituted or unsubstituted, cyclic group or a carbon or nitrogen atom having two or more substituents.)
  • the “optionally substituted carbon atom” means a divalent group having two hydrogen atoms, one hydrogen atom and one substituent or two substituents at the carbon atom, and X
  • the “optionally substituted nitrogen atom” represented by a ′ represents a divalent group having one hydrogen atom or a substituent at the nitrogen atom.
  • R 1a hydrocarbon residue or “heterocyclic group” in the above-mentioned “optionally substituted hydrocarbon residue or heterocyclic group” as R 1a. And the same groups as the “substituted, hydrocarbon residue or heterocyclic group, respectively” as R la .
  • the “optionally oxidized sulfur atom” represented by X a ′ represents a divalent sulfur atom represented by one of S—, SO—, or —SO 2 —.
  • cyclic group in W a is indicated as '' carbon atom or a nitrogen atom having an optionally substituted cyclic group or 2 or more substituents ", and" substituted respectively as R la described above
  • a cyclic group in the ⁇ optionally substituted hydrocarbon residue or heterocyclic group '' for example, an optionally substituted alicyclic hydrocarbon residue, an optionally substituted aromatic hydrocarbon residue, Heterocyclic groups (aromatic monocyclic heterocyclic groups, aromatic condensed heterocyclic groups, and non-aromatic heterocyclic groups).
  • Examples of the substituent which the “cyclic group” may have include: As R la , the same substituents as the “hydrocarbon residue” or “heterocyclic group” in “hydrocarbon residue or heterocyclic group optionally substituted” may be mentioned. Can be
  • the “carbon atom having two or more substituents” in the “optionally substituted cyclic group or carbon atom or nitrogen atom having two or more substituents” shown as W a ′ is, for example, tert-butynole , Isopropyl, etc., in which the same or different 2 to 3 substituents are bonded to the carbon atom (in other words, those having 0 to 1 hydrogen atom on the atom are mentioned. substitutions may be possessed by the "hydrocarbon residue” or "heterocyclic group” in "each optionally substituted hydrocarbon residue or heterocyclic group” as the group as a R 1 a described above Examples of the group and R la include groups similar to the “optionally substituted hydrocarbon residue or heterocyclic group”.
  • the nitrogen atom having two or more substituents is an N, N-disubstituted amino group.
  • the substituent in the “N, N-disubstituted amino group” is R la described above. And the same substituents as in the “amino group” in the “optionally substituted amino group”.
  • R la ' may hydrocarbon residue which may be substituted respectively, heterocyclic group, Surufi group, a sulfonyl group, a hydroxyl group, among the thiol or Amino group of the formula: - X a' -, (wherein, X a 'represents an oxygen atom or a sulfur atom which may be oxidized, and W' represents a cyclic group which may be substituted.
  • R 2a represents a cyano group, a formyl group, a thioformyl group or a formula: — Z la — Z 2a (where Z la represents one CO—, —CS—, — so— or _so 2 _, and z 2a represents Represents an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group.
  • Z la in R 2a is preferably one CO— or one CS—, more preferably one CO—.
  • R 2a is represented by —CO—Z 2a ′ (wherein, Z 2a ′ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group). Groups are preferred.
  • the optionally substituted hydrocarbon residue for Z 2a examples include, for example, the same as the optionally substituted hydrocarbon residue for R la .
  • the optionally substituted hydrocarbon residue in Z 2a is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl) such as tert-butynole, pentynole, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl.
  • Examples of the optionally substituted heterocyclic group for Z 2a include the same as the optionally substituted heterocyclic group for R la .
  • Examples of the optionally substituted amino group for Z 2a include, for example, the same as the optionally substituted amino group for R la .
  • the optionally substituted amino group in Z 2a is preferably an amino group or an amino group having one or two Cw alkyl groups as a substituent (e.g., methyl / reamino, dimethylamino, ethylamino, ethylamino, , Dibutylamino, etc.).
  • the optionally substituted hydroxyl group for Z 2a examples include, for example, the same as the optionally substituted hydroxyl group for R la .
  • the optionally substituted hydroxyl group in Z 2a is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butinole, pentyl, isopentyl, neopentyl, tert-pentyl pentyl, hexyl, cyclohexyl isobutyl, heptyl, CI_ 8 ⁇ Rukiruokishi substituted with alkyl such Okuchiru.
  • Z 2a is good also be a substituted amino group or substituted or optionally substituted in R 2a les is preferably a hydroxyl group.
  • Z 2 a is amino group which may be substituted in R 2 a is more preferable.
  • Z 2a is Amino group in R 2a or amino group with a C ⁇ alkyl group as one or two substituents, (e.g., Mechiruamino, dimethyl Amino, Echiruamino, Jechiruamino, Jibuchiruamino etc.) are preferable.
  • R 3a represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.
  • the optionally substituted hydrocarbon residue for R 3a include the same as the optionally substituted hydrocarbon residue for R la .
  • the R 3 definitive to a optionally substituted hydrocarbon residue, preferably an aliphatic hydrocarbon residue, more preferably methyl, Echiru, propyl, isopropyl, Petit Honoré, Isobuchinore, sec- Buchinore, tert —Buchinore, Pentinole, Isopentyl, Examples thereof include a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group) such as neopentinole, tert-pentinole, hexinole, isohexinole, heptinole, and octyl.
  • an alkyl group such as neopentinole, tert-pentinole, hexinole, isohexinole, heptinole, and octyl.
  • Examples of the optionally substituted heterocyclic group for R 3a include the same as the optionally substituted heterocyclic group for R la .
  • Examples of the optionally substituted hydroxyl group for R 3a include, for example, the same as the optionally substituted hydroxyl group for R la .
  • Examples of the optionally substituted amino group in R 3a include, for example, the same as the optionally substituted amino group in R la .
  • the optionally substituted sulfonyl group for R 3a includes, for example, the same as the optionally substituted sulfonyl group for R la .
  • Examples of the optionally substituted acyl group for R 3a include, for example, those in which a ⁇ carboyl group or a hydrocarbon residue or heterocyclic group, each of which may be substituted '' represented by R la is bonded. preferably a hydrocarbon residue represented by R la, heterocyclic group, sulfinyl group, those similar to the Ashiru group as a substituent of the sulfonyl group can be mentioned up.
  • R 3a ′ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group.
  • R 3a ′ an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group, or an acyl group
  • a hydrogen atom of R 3a an optionally substituted hydrocarbon residue
  • Examples include the same as the ring, sulfonyl or acyl group.
  • R 3a ′′ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group.
  • R 3a respectively optionally substituted hydrocarbon residue', heterocyclic group, the sulfonyl group or Ashiru group, R 3 each optionally substituted by hydrocarbon residues of a, a heterocyclic group , A sulfonyl group or an acyl group.
  • R 4a represents a substituted hydroxyl group.
  • the hydroxyl group substituted in R 4a, substituted hydroxyl groups in the hydroxyl group may be substituted may be substituted represented by R 1 a, for example, optional substituents on the hydroxyl group include, in R la And a hydroxyl group substituted by the "hydrocarbon residue or heterocyclic group which may be substituted".
  • 8- alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butynole, pentynole, isopentynole, neopentynole, tert-pentyl, hexinole, isohexyl / heptyl, octyl, etc.
  • C ⁇ such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexynole, heptyl, octyl and the like.
  • dialkyloxy substituted with s-alkyl more preferably dialkyloxy substituted with methyl, ethyl, propyl and isopropyl.
  • hydrocarbon residue or “heterocyclic group” as the substituent of the substituted hydroxyl group exemplified here is the “optionally substituted hydrocarbon residue or heterocyclic group” as R 1a described above. And the “hydrocarbon residue” or “heterocyclic group” in “” may have the same substituent as the substituent.
  • R 5 a represents a good Surufi alkenyl group or Sunorehoninore group be it that substitution at R 1 a.
  • R 6 a have the same meaning as thiol group that may be substituted in R la.
  • R 7a has the same meaning as the substituent of the optionally substituted amino group in R la .
  • R 8 a is of the same meaning as R 2 a.
  • R 9a has the same meaning as Z 2a above.
  • R 1Qa represents a protecting group for a carboxyl group.
  • Examples of the carboxyl protecting group represented by R 1Ga include the same groups as the optionally substituted hydrocarbon residue represented by R la .
  • R lla represents an amino group which may be substituted.
  • the amino group which may be substituted in R l la similar to an amino group which may be substituted represented by R la, for example, an amino group, N- mono-substituted amino group and N, N- disubstituted An amino group is mentioned.
  • the substituted amino group for example, optionally substituted hydrocarbon residue (e.g., those similar to the substituted hydrocarbon may be residues represented by R la, more specifically, C t _ 8 alkyl group, C 3 _ 7 consequent opening alkyl group, C 2 -.
  • Ashiru group e.g., C 2 - 7 Arukanoiru, Benzoiru, Nikochinoiru etc.
  • amino group e.g. having a one or two substituents, methyl Amino, Jimechinoreamino, Echinoreamino, Jechinoreamino, Puropiruamino, di Puropiruamino, Jibuchiruamino, Jiariruamino, Cyclohexylamino, phenylamino, N-methyl-1-N-phenylamino, acetylamino, propionanolamino, benzoylamino, nicotinylamino and the like.
  • N, N- disubstituted amino group e.g., Jimechiruamino, Jechiruamino, Jipu port Piruamino, Jibuchiruamino, Jiariruamino, N- methyl one N- Fuenirua amino, etc.
  • an alkylamino group eg, dimethylamino, getylamino, dipropylamino, etc.
  • R 13a represents an optionally substituted amino group or a substituted hydroxyl group.
  • the 13a include the same groups as the R 4 a or the R 11 a.
  • R 13a ′ represents an optionally substituted amino group or hydroxyl group.
  • Hal represents a halogen atom such as fluorine, chlorine, bromine and iodine
  • Z 5a indicates one CO—.
  • Z 6a has the same meaning as the optionally substituted amino group in Z 2a .
  • Z 7a indicates one CO—.
  • Z 8 a have respective Yo Le substituted, as defined hydrocarbon residue or multiple heterocyclic group in Z 2 a.
  • Ring Ca represents an optionally substituted 5- to 7-membered ring.
  • the optionally substituted 5- to 7-membered 5- to 7-membered ring in ring Ca may be any of a 5- to 7-membered hydrocarbon ring or a 5- to 7-membered heterocyclic ring.
  • the 5- to 7-membered hydrocarbon ring may be an alicyclic ring or an aromatic ring.
  • the alicyclic ring C 5 _ 7 saturated alicyclic hydrocarbon ring (e.g., cyclopentane, hexane cyclo, C 5 _ 7 cycloalkane such as cycloheptane) and C 5 - 7 unsaturated alicyclic Group hydrocarbon rings (eg, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene, 2 , C 5 _ 7 cycloalkene such as butadiene, and C 5 _ 7 cycloalkadiene), and the 4-Sik port.
  • the aromatic ring include a benzene ring.
  • Examples of the 5- to 7-membered heterocyclic ring include (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom, and (ii) two to four-membered heterocyclic ring.
  • a 5- to 7-membered heterocycle containing a nitrogen atom, or (iii) one or two nitrogen atoms and one sulfur or oxygen Examples include 5- to 7-membered heterocycles containing atoms.
  • the heterocyclic rings exemplified in (i) to (iii) may be saturated or unsaturated heterocyclic groups, respectively.
  • the unsaturated heterocyclic ring may be any of aromatic and non-aromatic. Is also good.
  • the ring C a is particularly preferably an aromatic 5-membered heterocyclic ring represented by the following ring C.
  • Ring C is
  • R 3 a is a hydrogen atom, an optionally substituted hydrocarbon residue which may be substituted respectively, the heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or Ashiru group.
  • R 3 a has. As defined above, an aromatic 5-membered heterocyclic ring represented by is preferable
  • Ra is a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), Shiano group or each an optionally substituted amino group, Ashiru group, a hydrocarbon residue or heterocyclic group, also R a is optionally substituted also with the ring constituent atoms of the thiophene ring and ring C a Yo And may form a hydrocarbon ring or a heterocyclic ring.
  • halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • the amino group which may be substituted in R a for example, those similar to the amino group which may be substituted in R la.
  • As good Ashiru group optionally substituted in R a, for example, those similar to the good Ashiru group be substituted in R 3 a.
  • the hydrocarbon residue may be substituted in R a, for example, it includes the same contact Keru hydrocarbon residue may be substituted in R la.
  • heterocyclic group which may be substituted in R a for example, those similar to the heterocyclic group which may be substituted in R la.
  • the optionally substituted hydrocarbon ring formed by Ra with a thiophene ring and a ring-constituting atom of ring C a is alicyclic or aromatic. Is also good.
  • the hydrocarbon ring is preferably a 5- to 14-membered ring, and more preferably a 5- to 7-membered ring.
  • the hydrocarbon ring is preferably a hydrocarbon ring represented by the following ring D. Ring D represents a 5- to 7-membered hydrocarbon ring which may have a substituent.
  • any of an alicyclic or aromatic 5- to 7-membered hydrocarbon ring may be used. Is also good.
  • C 5 _ 7 saturated alicyclic hydrocarbon ring e.g., cyclohexane cyclopen
  • aromatic hydrocarbon residue examples include a benzene ring.
  • C 5 _ 7 saturated alicyclic hydrocarbon ring or more preferably C 6 saturated alicyclic hydrocarbon ring (cyclohexane).
  • Ra is preferably a 5- to 14-membered heterocyclic ring which may be substituted with a thiophene ring and a ring-constituting atom (preferably a ring-constituting carbon atom) of ring Ca, and more preferably a 5- to 14-membered heterocyclic ring. It is a 5- to 7-membered heterocycle.
  • heterocyclic ring examples include (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom, (ii) two to four nitrogen atoms A 5- to 7-membered heterocyclic ring, or (iii) a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms and one sulfur or oxygen atom.
  • the heterocycles exemplified in (i) to (iii) may be either saturated or unsaturated, and the unsaturated heterocyclic group may be aromatic or non-aromatic.
  • preferred compounds include compounds represented by the following formula (Ia '). That is, the formula (la '):
  • the compound represented by is preferred.
  • R la and R 2a are each synonymous with R la and R 2a as defined in the above formula (la), ring C,
  • R 3 is a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group
  • R 14 is a hydrogen atom, a halogen atom or a substituted respectively.
  • An aromatic 5-membered heterocyclic ring represented by any of the following: a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group. And represents a 5- or 7-membered hydrocarbon ring which may be possessed.
  • a compound represented by the formula (provided that the formula:
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group
  • R 14 represents a hydrogen atom
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group.
  • the optionally substituted hydrocarbon residue in R 3 examples include, for example, the same as the aforementioned optionally substituted hydrocarbon residue in R la .
  • the optionally substituted hydrocarbon residue in R 3 is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butylene, isobutynole, sec-butyl, tert-butyl And saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl group) such as pentynole, isopentynole, neopentynole, tert-pentynole, hexynole, isohex ⁇ heptinole, and octyl. It is.
  • Examples of the optionally substituted heterocyclic group for R 3 include the same as the aforementioned optionally substituted heterocyclic group for R la .
  • Examples of the optionally substituted hydroxyl group for R 3 include the same as the optionally substituted hydroxyl group for R la described above.
  • Examples of the optionally substituted amino group for R 3 include, for example, the same as the aforementioned optionally substituted amino group for R la .
  • Examples of the optionally substituted sulfonyl group for R 3 include the same as the aforementioned optionally substituted sulfonyl group for R la .
  • R 14 represents a hydrogen atom, a halogen, a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.
  • the halogen for R 14 include fluorine, chlorine, bromine, and iodine.
  • Hydrocarbon residue which may each be substituted in R 14, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or Ashiru groups include those similar to those shown in R 3.
  • R 14 is preferably a hydrogen atom. Rings D, D-1, E, F, F-2, F-3, F-4, F ', F'-l, F'-2, F'-3 Shows a good 5- to 7-membered hydrocarbon ring.
  • the 5- to 7-membered hydrocarbon ring which may have a substituent may be an alicyclic or aromatic 5- or 7-membered hydrocarbon ring. ,.
  • the alicyclic 5- to 7-membered hydrocarbon ring, C 5 _ 7 saturated alicyclic hydrocarbon ring eg example, hexane cyclopentane, cyclohexane, C 5 _ 7 Shikuroa glucan such as cycloheptane
  • C 5 — 7 unsaturated alicyclic hydrocarbon rings eg 1-cyclopentene, 2 —C 5 such as cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene, 2,4-cycloheptadiene, etc.
  • — 7 cycloalkene, C 5 — 7 cycloalkadiene and the like.
  • aromatic hydrocarbon residue examples include a benzene ring.
  • C 5 - 7 saturated alicyclic hydrocarbon ring or more preferably C 6 saturated alicyclic hydrocarbon ring (cyclohexane). May have a substituent in ring D, D-1, E, F, F-2, F-3, F-4, F ', F, _l, F'-2, F'_3 5
  • substituent of the 7-membered hydrocarbon ring include the same substituents as those of the “optionally substituted hydrocarbon residue” in R la .
  • the number of substituents is preferably one to three.
  • the substituent of the 5- to 7-membered hydrocarbon ring which may have a substituent is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptinol, sec- Saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms such as butynole, tert-butyl, pentynole, isopentynole, neopentynole, tert-pentyl, hexynole, isohexyl, heptinole, octyl (eg, alkyl group) Are mentioned.
  • Rings D, Dl, E, F, F-2, F-3, F-4, F, F'-1 and F'_2, F'_3 may have 5 to 7 members
  • a hydrocarbon ring preferably a 5- to 7-membered hydrocarbon ring having no substituent. More preferably, a 5- to 7-membered saturated hydrocarbon ring having a substituent is mentioned. More preferably, a 6-membered saturated hydrocarbon ring having no substituent is used.
  • R 1 a are each optionally substituted scan even if ⁇ Finiru group, a sulfonyl group, a hydroxyl group or a thiol group; scale ⁇ is - 1 - 2 (wherein, Z 1 is —CO— or one CS—, and Z 2 represents an optionally substituted hydroxyl group or an amino group, respectively.
  • R 3 has the same meaning as described above.
  • a compound wherein Ring D is a 5- to 7-membered hydrocarbon ring which may have a substituent, or a salt thereof is preferred.
  • R la are each CI- 8 Surufi alkenyl group or a sulfonyl group bonded with alkyl, C, _ 8 alkyl Yo Le be substituted, a thiol group or a 1, respectively, C 6 — i which may be substituted with three substituents.
  • R 2a is —7 ⁇ — (wherein, Z 1 represents one CO—, and Z 2 represents an optionally substituted hydroxyl group or an amino group, respectively);
  • Ring C represents
  • R 3 has the same meaning as described above.
  • R 3 is a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group);
  • ring D is a C 5 _ 7 saturated alicyclic hydrocarbon ring, or a salt thereof, preferable.
  • R la may be a sulfinyl group, a sulfonyl group, a hydroxyl group or a thiol group each of which may be substituted;
  • R 2a is — Z la — Z 2a (where Z la is — Represents CO— or one CS—, and Z 2 a is an optionally substituted hydroxyl group Or an amino group.
  • R 4 A is alkyloxy; and ring E is a 5- to 5-membered hydrocarbon ring which may have a substituent, or a salt thereof.
  • R la represents a sulfinyl group or a sulfonyl group bonded to each other by 8 alkyl, a thiol group optionally substituted by 8 alkyl, or 1 to 3 substituents, respectively.
  • C 6 _i which may be substituted by A hydroxyl group which may be substituted by aryl (particularly preferably phenyl), an aromatic monocyclic heterocyclic group (particularly preferably pyridyl) or an aromatic fused heterocyclic group (particularly preferably quinolyl); , — Z LA — Z 2 A (wherein, Z LA represents one CO— and Z 2 A represents an optionally substituted hydroxyl group or an amino group, respectively); R 4 A represents a C alkyloxy group ; ring C is a compound which is a compound which is C 5 _ 7 saturated alicyclic hydrocarbon ring or a salt thereof is more preferable.
  • a salt of a raw material compound for producing the salt thereof 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, Examples thereof include salts with basic or acidic amino acids.
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Is mentioned.
  • Suitable 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.
  • 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
  • preferable examples of the salt with the acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.
  • Compound (la) or a salt thereof may be a prodrug thereof.
  • a prodrug of compound (la) or a salt thereof is a compound that is converted into compound (Ia) or a salt thereof by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, (1) enzymatic oxidation, reduction, A compound that undergoes hydrolysis or the like to convert to compound (la) or a salt thereof, and (2) A compound that undergoes hydrolysis or the like by stomach acid or the like to change to compound (la) or a salt thereof.
  • a compound or a salt thereof for example, a compound (la) in which a hydroxyl group of the compound (la) or a salt thereof is acylated, alkylated, phosphorylated, and borated Ia
  • a salt thereof in which the hydroxyl group is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, or a compound thereof, or a compound thereof (la )
  • a compound in which the carboxyl group of the salt is esterified or amidated (for example, the compound (la) or a salt thereof is converted into ethyl ester, phenyl ester, carboxoxymethyl ester, dimethyla Minomethyl esterification, bivaloyloxymethyl esterification, ethoxycarbonyloxy Chiruesuteru of
  • the prodrug of compound (Ia) or a salt thereof can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Vol. 7, Molecular Design, pp. 163 to 198, under physiological conditions. It may change to salt.
  • Compound (Ia) or a salt thereof is an isotope (eg, 2 H, 3 H, 14 C, 35 S, 125
  • R la is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group
  • R 2a is _Zi—Z 2 (wherein Z 1 is — CO— or —CS—, and Z 2 represents an optionally substituted hydroxyl group or amino group. )
  • R 13a is, CI_ 8 Arukiruokishi or N, N-disubstituted ⁇ amino group
  • ring F are of compounds are 7-membered hydrocarbon ring to 5 which may have a substituent or a salt thereof .
  • R la is, a sulfinyl group or a sulfonyl group bonded with each CI_ 8 alkyl, CI_ 8 alkyl optionally substituted thiol group, or is respectively 1-3 substituents C 6 — i which may be substituted.
  • Aryl (particularly preferably phenyl), an aromatic monocyclic heterocyclic group (particularly preferably pyridyl) or an aromatic condensed heterocyclic group (particularly preferably quinolyl), a hydroxyl group;
  • R 2a represents one Z 1 —Z 2 (wherein, Z 1 represents one CO— and Z 2 represents a hydroxyl group or an amino group which may be substituted, respectively);
  • R 13a represents ⁇ , ⁇ — di flicking 3 alkylamino group or Arukiruokishi;
  • ring F ', C 5 7 saturated alicyclic compound is a hydrocarbon ring or a salt thereof is more preferable.
  • a salt thereof represented by the present invention or a salt of a raw material compound for producing the salt thereof is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, Examples thereof include salts with acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salt with an inorganic base include, for example, alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt. No.
  • salts with organic bases examples thereof include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like.
  • salts with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, conoic acid, malic acid, methanesulfonic acid, benzenesulfonic acid And p-toluenesnolefonic acid.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid and glutamic acid And salts with
  • Compound (IX) or a salt thereof may be labeled with an isotope (eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.).
  • an isotope eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.
  • Compound (la) or a salt thereof can be prepared by a method known per se (for example, the method described in JP-A-2000-309959, the method described in JP-A-2000-239280, the method described in W9809958) Or the method described in JP-A-2000-169470, the method described in JP-A-2000-169471, the method described in JP-A-2000-169472, or a method analogous thereto. Can be.
  • R may be substituted with a thiophene ring and a ring-constituting carbon atom in ring C a to form a hydrocarbon ring or a heterocyclic ring.
  • compound (Ia) or a salt thereof can be produced, for example, by the following Method A to Method F or a method analogous thereto.
  • compound (III) represents a hydroxyl ⁇ Min or monosubstituted hydrazine (R 3 a 'NHNH 2) or their salts, other symbols that have a the same meaning as defined above.
  • compound (Ia,) is produced by reacting compound (IIa ') with compound (III).
  • This reaction is carried out according to a conventional method, in a neutral or in the presence of an acid or a base, in a solvent that does not adversely influence the reaction.
  • Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, acetic acid, and trifluoroacetic acid.
  • Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, hydrogen hydride, potassium t-butoxide, sodium acetate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] —7— Organic bases such as pendecene and sodium methoxide are exemplified.
  • the amount of the acid and compound (III) to be used is preferably about 1 to about 5 molar equivalents relative to compound (IIa ').
  • Solvents that do not adversely affect the reaction include, for example, water, alcohols such as methanol, ethanol, and propanol; ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated carbon such as chloroform and dichloromethane. Hydrides; aromatic hydrocarbons such as benzene, toluene, and xylene; amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethylsulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about 0 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • R 3a ′ on ring C generated by this reaction can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R 3a using a method known per se.
  • the compound (Ia ') thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • the compound (IIa ') used as the starting material compound in the above-mentioned Method A is a novel compound, and the compound (IV):
  • orthoformate That is, a known method, for example, the method described in Indian Journal J. Chem. Sec. B, Vol. 35, pp. 49-51 (1996), can be used for compound (IV). Alternatively, it is performed by a method according to it. That is, this reaction is usually performed in the presence of an acid and a base in a solvent that does not adversely influence the reaction.
  • the amount of the orthoformate to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).
  • Examples of the acid include boron trifluoride monoethenole complex.
  • the amount of the acid to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).
  • Examples of the base include triethylamine, diisobutylethylamine, 1,8-diazabicyclo [5.4.0] _7-indene.
  • the amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).
  • solvent which does not adversely affect the reaction examples include halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene and xylene. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is usually about -100 to about 150C, preferably about -70 to about 0C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (IIa ') thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • the compound (IV-2, 3) used as a starting compound for the compound represented by the ano group which may be substituted for R 1 a of the compound (la ′) is synthesized by the following synthesis method. Manufactured.
  • compound (V) is produced by reacting 1,3-cycloalkanedione with an alkyl isothiocyanate or an aryl isothiocyanate in the presence of a base.
  • alkali metal salts such as hydroxylated sodium, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N
  • Amines such as zinc hydride; metal hydrides such as lithium hydride and sodium hydride; sodium methoxide, sodium ethoxy Metal alkoxides such as potassium tert-butoxide.
  • the amount of the reaction reagent used is preferably about 1 to 1,3-cycloalkanedione.
  • the amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to 1,3-cycloalkanedione.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about 0 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • compound (VI) is produced by reacting compound (V) with compound (VII). This method is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction.
  • Examples of the compound (VII) include halo acid esters, specifically, ethyl ethyl acetate, ethyl bromoacetate, t-butyl bromoacetate, and the like.
  • the amount of compound (VII) to be used is preferably about 1 to about 10 molar equivalents relative to compound (V).
  • alkali metal salts such as hydroxylated sodium, sodium hydroxide, sodium bicarbonate, and potassium carbonate
  • pyridine triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0]
  • Amines such as 7-diene
  • metal hydrides such as lithium hydride and sodium hydride
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.
  • the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (V).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Examples include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and getyl ether
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • Examples include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (VI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • compound (IV-2) is produced from compound (VI).
  • This method is carried out according to a conventional method, in the presence of a base, in a solvent that does not adversely influence the reaction.
  • alkali metal salts such as hydroxylated sodium, sodium hydroxide, sodium bicarbonate, and potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] ]
  • Indekar 7 Amines such as sodium hydride; metal hydrides such as lithium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide.
  • the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (VI).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Examples include amides such as N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and getyl ether
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • Examples include amides such as N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is generally about -50 to about 150 ° C, preferably about -10 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (IV-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • compound (IV-2) is acylated to produce compound (IV-3).
  • This method employs a method of appropriately reacting compound (IV-2) with an acylating agent. Done.
  • acylating agent examples include acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides, or mixed acid anhydrides (eg, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, etc.). And the like.
  • the amount of the acylating agent to be used is preferably about 1 to about 5 molar equivalents relative to compound (VI-2).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; N And amides such as N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as tetrahydrofuran, dioxane and getyl ether
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • N And amides such as N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide.
  • the reaction temperature is generally about -50 to about 150 ° C, preferably about -10 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (IV-3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • compound (I-I) is produced by reacting compound (I-I) with a nucleophilic reagent.
  • This reaction is carried out by a method known per se, for example, the method described in WO98Z18792, or a method analogous thereto.
  • nucleophilic reagent examples include metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, and thioalcolate.
  • the amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-2).
  • Solvents which do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is usually about -50 to about 150 ° C, preferably about 110 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (1-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (I 2) used as the starting compound in the above-mentioned Method B can be produced by the following method.
  • compound (1-2) is produced using compound (1-3) and an oxidizing agent.
  • This reaction is carried out in a manner known per se, for example, as an oxidizing agent, manganese dioxide, permanganic acid, chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide, organic peroxide, organic peracid, peroxide
  • This is performed by a method, or anodization, or a method analogous thereto. That is, this reaction is usually performed in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
  • the oxidizing agent for example, m-chloroperbenzoic acid, peracetic acid
  • Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. And amides such as N, N-dimethylformamide and 1-methylpyrrolidone. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is generally about -50 to about 150 ° C, preferably about -10 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (1-2) thus obtained can be obtained by a known separation and purification means, for example, enrichment. It can be isolated and purified by condensation, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • compound (1-5) is produced by the elimination reaction of the carboxyl protecting group.
  • all conventional methods used for elimination reaction of carboxyl protecting group for example, hydrolysis, reduction, elimination using Lewis acid and the like can be applied.
  • the carboxyl protecting group is an ester, it can be removed by hydrolysis or elimination with a Lewis acid.
  • the hydrolysis can be eliminated by elimination using a base or a Lewis acid.
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • Oxides eg, sodium hydroxide, calcium hydroxide, etc.
  • alkaline earth metal hydroxides eg, magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonates eg, sodium carbonate, potassium carbonate, etc.
  • Alkaline earth metal carbonates eg, magnesium carbonate, calcium carbonate, etc.
  • alkali metal bicarbonates eg, sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal acetates eg, sodium acetate, potassium nitrate, etc.
  • alkali Earth metal phosphate eg magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate Salts e.g., hydrogen phosphate Ninatoriumu, hydrogen phosphate such as a secondary force Riumu
  • inorganic bases such as trialkylamines (e.g.
  • the hydrolysis using a base is often performed in water or a hydrophilic organic solvent or a mixed solvent.
  • Suitable acids include organic acids (eg, formic acid, hydrobromic acid, sulfuric acid, and the like).
  • This hydrolysis reaction is usually performed in an organic solvent, water or a mixed solvent composed of these.
  • the reaction temperature is not particularly limited and is appropriately selected according to the elimination method if the type of carboxyl protecting group is ⁇ .
  • the elimination using a Lewis acid is performed by converting the compound (1_4) or a salt thereof into a Lewis acid, for example, Boron trihalide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, titanium tetrabromide, etc.), aluminum halide (eg, aluminum chloride, aluminum bromide, etc.) And trihaloacetic acid (for example, trichloroacetic acid, trifluoroacetic acid, etc.).
  • a Lewis acid for example, Boron trihalide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrach
  • This elimination reaction is preferably carried out in the presence of a cation scavenger (eg, anisol, phenol, etc.), and usually, a nitroalkane (eg, nitromethane, nitroethane, etc.), an alkylene halide (eg, Shiraidani methylene,
  • a cation scavenger eg, anisol, phenol, etc.
  • a nitroalkane eg, nitromethane, nitroethane, etc.
  • an alkylene halide eg, Shiraidani methylene
  • Elimination by reduction can be accomplished with alkyl halides (eg, 2-iodoethyl, 2,2,
  • the reduction method used in this elimination reaction is, for example, a metal (eg, zinc) , Zinc amalgam, etc.) or salts of compounds (eg, chromic chloride, chromic acetate, etc.) with organic or inorganic salts (eg, acetic acid, propionic acid, hydrochloric acid, etc.); conventional metal catalysts (eg, Conventional catalytic reduction in the presence of palladium carbon, Raney nickel, etc.).
  • the reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating.
  • R 2a represents a compound represented by the formula: Z 5a — Z 6a (wherein, Z 5a represents —CO—, and Z 6a represents an amino group which may be substituted; 1-6) is manufactured, for example, by the following Method D.
  • the compound (I_5) or its reactive derivative at the carboxyl group or its salt is reacted with the compound (VIII) or its reactive derivative at its amino group or its salt to give the compound (1_6) To manufacture.
  • a suitable reactive derivative at the amino group of the compound (VIII) a Schiff base imino or its enamine type formed by the reaction of the compound (VIII) with a carbonyl dicarboxylic acid such as an aldehyde or a ketone can be used.
  • silyl derivatives produced by the reaction of compound (VIII) with silyl compounds such as bis (trimethylsilyl) acetamide, mono (trimethylsilinole) acetamide, bis (trimethylsilyl) urea; compound (VIII) And a derivative formed by the reaction of the compound with phosphorus trichloride or phosgene.
  • Suitable reactive derivatives at the carboxyl group of the compound (1-5) include, specifically, acid halides, acid anhydrides, activated amides, activated esters and the like.
  • Reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkylphosphoric acid, pheninoleic acid, diphenylphosphoric acid, dibenzinoleic acid, nodogenated phosphoric acid, and dialkyl phosphates.
  • substituted phosphoric acids such as dialkylphosphoric acid, pheninoleic acid, diphenylphosphoric acid, dibenzinoleic acid, nodogenated phosphoric acid, and dialkyl phosphates.
  • esters with N-hydroxy compounds such as (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimid, 1-hydroxy-1H-benzotriazole and the like.
  • These reactive derivatives can be arbitrarily selected depending on the type of the compound (1-5) to be used.
  • Suitable salts of the reactive derivative of the compound (I-15) include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; Base salts such as organic base salts and the like, such as luamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt and the like.
  • the reaction is usually carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, ⁇ , ⁇ -dimethylformamide, and pyridine.
  • water for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, ⁇ , ⁇ -dimethylformamide, and pyridine.
  • the reaction is carried out in such a conventional solvent, but the reaction can be carried out in any other organic solvent that does not adversely affect the reaction.
  • These conventional solvents may be used as a mixture with water.
  • the reaction can also be carried out with inorganic or organic bases such as alkali metal bicarbonate tri (lower) alkylamine, pyridine, ⁇ - (lower) alkylmorpholine, ⁇ , ⁇ -di (lower) alkylbenzylamine, etc. It may be performed in the presence.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating.
  • the amount of compound (VIII) to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (1_5).
  • the reaction temperature is usually between ⁇ 30 ° C. and 100 ° C.
  • the reaction time is usually 0.5 to 20 hours.
  • compound (1-5) and carbonic acid ester (Eg, methyl methyl carbonate, ethyl ethyl carbonate, isobutyl carbonate, etc.)
  • a base eg, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, carbon dioxide
  • compound (VIII) e.g, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, carbon dioxide
  • the amount of compound (VIII) to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (1-5).
  • the reaction temperature is usually from -30 ° C to 100 ° C.
  • the reaction time is usually 0.5 to 20 hours.
  • the compound (1-6) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • the compound (I-15) used as a starting compound in the above method D is produced by the above method C.
  • compound (I-18) is produced from compound (I-17) in the presence of a dehydrating agent.
  • This reaction is carried out using a method of appropriately reacting compound (I-17)) with a dehydrating agent.
  • the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, hydrin pentate, and ichthionyl chloride.
  • the amount of the dehydrating agent used is 0.1 to 100 molar equivalents relative to compound (1-7), Or 1 to 10 molar equivalents.
  • the reaction temperature is usually from 130 ° C to 100 ° C.
  • the reaction time is usually 0.5 to 20 hours.
  • the compound (1-8) thus obtained should be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Can be.
  • the compound (I-17) used as a starting material compound in the above-mentioned Method E is produced by the above-mentioned Method D or Method B.
  • the reaction is performed in the presence of a base in a solvent that does not adversely influence the reaction.
  • Solvents that do not adversely affect the reaction include, for example, ethers such as ethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Examples include amides such as N, N-dimethylformamide and 1-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the compound (I-10) is produced by reacting the nucleophilic reagent with the compound (1-9).
  • the nucleophilic reagent include metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcoholates, etc. are used.
  • the amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-9).
  • This reaction is usually performed in a solvent that does not adversely influence the reaction.
  • solvents that do not adversely affect the reaction include ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethylsulfoxide.
  • the reaction temperature is generally about -70 to about 150 ° C, preferably about -70 to about 0 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (1-10) thus obtained should be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Can be.
  • the compound (1-9) used as a starting compound in the above Method F can be produced by the Method D.
  • Compound (la ′) can also be obtained by the following production method in addition to the above production method. [G method]
  • (IX-1) is produced by reacting compound (IV) with an amide acetal.
  • Amidoacetals include, for example, an active acetal form of N, N-dialkylformamide, preferably N, N_dimethylformamide dimethylacetal, ⁇ , ⁇ -dimethylformamide dodecylacetal , T-butoxybisdimethylaminomethane, trisdimethylaminomethane, ⁇ , ⁇ -dimethylformamide dipropyl acetate, ⁇ , ⁇ -dimethylformamide bis (2-trimethylsilylethyl) acetal, ⁇ , ⁇ - Dimethylformamide benzyl acetal, ⁇ , ⁇ -dimethylformamide tert-butyl acetal, ⁇ , ⁇ -dimethylformamide dodineopentyl acetal,
  • Active acetal forms of dimethylformamide such as ⁇ , ⁇ -dimethylformamide dicyclohexyl acetal and ⁇ , ⁇ -dimethylformamide diisopropyl acetal are used, and more preferably ⁇ , ⁇ -dimethylformamide dimethyl acetamate.
  • Cetal, ⁇ , ⁇ -dimethylformamide dodecyl acetal, trisdimethylamino methane, etc. are used.
  • the amount of the amide acetal to be used is 1 mol to 50 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IV).
  • Any solvent may be used for this reaction as long as it does not inhibit the reaction.
  • examples thereof include hydrocarbons (eg, ⁇ -hexane, ⁇ -heptane, benzene, toluene, xylene, etc.), halogenated carbon Hydrogens (eg, dichloromethane, etc.), ethers (diethylenoate, diisopropinoleate, ethylene glycolone resin methinoleate, tetrahydrofuran, dioxane, etc.), amides (eg, ⁇ , ⁇ - Dimethylform New such Ami de, Nyu- di C i _ 3 alkyl formamidine de, New, Nyu- dimethyl ⁇ Seto Ami de, Nyu- Mechirupirori dong, etc.), esters (e.g., acetate Echiru, methyl acetate, etc.), two tri (Eg, acetonitrile, etc.), sulfoxides (eg
  • reaction is carried out at a reaction temperature of 0 to 150 ° C, preferably 50 to 120 ° C, for about 30 minutes to 24 hours, preferably 1 to 6 hours.
  • the amidoacetals described herein are all publicly known and can be easily obtained as commercial products.
  • Compound (IV) can be prepared by a known method, for example, a paper by D. Prira et al.
  • Compound (IX-2) is produced by a dealcoholization reaction of compound (IIa,).
  • This reaction is performed using an acid or a base.
  • the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and P-toluenesulfonic acid.
  • Alkali metal or alkaline earth metal hydrides such as sodium, lithium metal or alkaline earth metal amides such as lithium diisopropylamide, lithium hexamethyldisilazide, and sodium hexamethyldisilazide , Sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • alkali metals or alkaline earth metals hydroxides of alkali metals or alkaline earth metals such as lithium hydroxide and sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid
  • organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are preferable, and the compound (IIa ') It is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol.
  • any solvent can be used as long as it does not inhibit the reaction.
  • Anorekoru acids e.g., methanol, ethanol, d _ 3 alcohols, such as-propanol
  • the above-mentioned acid or base may be used also as a solvent.
  • Compound (IIa ') can be prepared by a method known from compound (IV), for example, the method described in the article of A. Nangia et al. (Indian J. Chem., 35B, 49, 1996) or a method analogous thereto. It is manufactured by a method.
  • the compound is produced by ring closure with a hydrazine represented by the formula or a salt thereof.
  • any solvent may be used as long as it does not inhibit the reaction.
  • alcohols eg, Ci-3 alcohols such as methanol, ethanol and propanol
  • a mixed system with other solvents or water is used.
  • an acid may be present in order to adjust the reaction rate, regioselectivity, solubility and the like.
  • the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. It is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol. Further, it may be used also as a solvent. This reaction is carried out at a reaction temperature of 0 to 120 ° C, preferably 50 to 100 ° C, for about 10 minutes to 6 hours, preferably for 1 hour to 3 hours.
  • R 3 a on ring C caused by the reaction ' is an amino group which is also a good hydroxyl group or substituted optionally be substituted as described as R 3 a, converts a method known per se be able to.
  • the hydrazine is used in an amount of 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol.
  • the solvent used in this reaction as long as it does not inhibit the reaction either good Iga, preferably alcohols (e.g., methanol, ethanol, C 3 alcohols propanol) is used.
  • alcohols e.g., methanol, ethanol, C 3 alcohols propanol
  • the anhydrous conditions in this reaction are substantially anhydrous conditions, specifically, do not actively add water to the solvent, for example, a solvent having a water content of about 5% or less, preferably a water content of about 3%.
  • a solvent having a water content of about 5% or less preferably a water content of about 3%.
  • the reaction is carried out using the following solvent, more preferably a solvent having a water content of 1% or less.
  • Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • methanesulfonic acid is preferred, and it is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IX-3). Further, it may be used also as a solvent.
  • This reaction is carried out at a reaction temperature of 0 to 120 ° C, preferably 40 to 70 ° C, for about 10 minutes to 6 hours, preferably 1 hour to 3 hours.
  • Compounds of the hydroxyl groups R 1 3 a ' is substituted with a cyclic group in the general formula (I X- 3), a known method from Compound (IV), for example!).
  • Prim et al (Synth. Commun., 25 Volume, 2449 pages, 1995) or a method analogous thereto.
  • Compound (IX) is subjected to a general acid hydrolysis reaction (for example, using a mixed system of alcohols or amides and water as a solvent). Using the same acid as described above in an amount of 0.1 mol to 10 mol per 1 mol of compound (IX) and reacting at 120 ° C for 10 minutes to 6 hours at a reaction temperature of 0). May be.
  • the target compound can be industrially advantageously produced without using a compound such as a boron fluoride ether complex.
  • compound (1-12) is subjected to an oxidation reaction to obtain compound (1-13).
  • the oxidizing agent include peroxy acids such as metabenzo-perbenzoic acid, peracetic acid, formic acid, and trifluoroperacetic acid, peroxides such as dioxysilane, hydrogen peroxide in the presence of a metal catalyst, and oxone (trade name).
  • the compound (1-12) is used in an amount of 2 to 10 mol per 1 mol.
  • an acid such as hydrochloric acid or sulfuric acid is added in an amount of 1 to 10 mol, preferably 2 to 5 mol, per 1 mol of compound (1-12) to promote the reaction. desirable.
  • Any solvent may be used for this reaction as long as it does not hinder the reaction, and examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, and Silene, etc.), halogenated hydrocarbons (eg, dichloromethane, etc.), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), alcohols (eg, methanol) , Ethanol, propanol, etc.), amides (eg, ⁇ , ⁇ -di-formyl 3- alkylformamide such as ⁇ , ⁇ -dimethylformamide, N, N-dimethylacetamide, N- Methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), nitriles (eg, ace
  • the temperature and time in this reaction vary depending on the oxidizing agent used.For example, when the reaction is performed with peracetic acid, the reaction temperature is 0 to 100 ° C, preferably 30 to 60 ° C, 1 to 24 hours, preferably 2 to 5 hours. It is performed by reacting for a time.
  • the compound (1-13) obtained as described above is subjected to a substitution reaction to produce a compound (1-14).
  • 1 to 2 mol, preferably 1 to 1.5 mol of R "-0H is used per 1 mol of compound (1-13).
  • R a "- OH of R a" - O moiety corresponds to an optionally substituted hydroxyl group of R la.
  • Examples of the base used in this reaction include the bases described in [Method H], among which sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, and carbonate Sodium hydrogen and the like are preferable, and 1 to 3 moles, preferably 1 to 2 moles are used per 1 mole of compound (1-13).
  • Any solvent may be used for this reaction as long as it does not inhibit the reaction.
  • examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated carbon Hydrogens (eg, dichloromethane, etc.), ethers (diethylenoate, diisopropinoleate, ethylene glycolone resin methinoleate, tetrahydrofuran, dioxane, etc.), amides (eg, ⁇ , ⁇ - Dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, etc.), esters (eg, Ethyl acetate, methyl acetate, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-
  • This reaction is carried out at a reaction temperature of 20 to 120 ° C, preferably 70 to 100 ° C, for 1 to 24 hours, preferably 2 to 6 hours.
  • the compound (1-4) in which R 1 Qa represents a carboxyl-protecting group can be converted to the compound (1-7) in one step by reacting with formamide in the presence of a base.
  • Formamide is usually used also as a solvent, and 1 to 30 milliliters, preferably 2 to 10 milliliters per gram of compound (1-4) is used.
  • Examples of the base used in this reaction include the bases described in [Method H], among which sodium methoxide, sodium methoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate , Sodium hydrogencarbonate and the like are preferable, and 1 to 10 mol, preferably 1 is not per 1 mol of compound (1-4) 5 moles are used.
  • any solvent may be used as long as it does not inhibit the reaction.
  • examples thereof include alcohols (eg, dg alcohol such as methanol, ethanol, and propanol), amides (eg, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, formamide, etc.) are preferred.
  • This reaction is carried out at a reaction temperature of 20 to 120 ° C, preferably 70 to 100 ° C, for 1 to 12 hours, preferably 1 to 3 hours.
  • Compound (la) where R a is Chiofen rings and ring C a ring structure substituted by a carbon atom together with not formed also may hydrocarbon ring or heterocyclic compound, Compound (I a) or The salt can be produced, for example, by the following methods A ′ to L ′ or a method analogous thereto.
  • R 16a represents a hydrocarbon residue which may optionally be substituted corresponding to the R a
  • R 1 "and R 18a are each respectively substitution similar to exemplified by hydrogen atom or
  • R 1 a Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group which may be
  • Hal is a halogen atom (e.g., fluorine, salt , Bromine, iodine, etc.), and Q represents a sulfur atom, an oxygen atom or an NH group.
  • R 1 5 a is a hydrogen atom or a hydrocarbon residue which may be substituted respectively, a heterocyclic group, a hydroxyl group, Ashiru group, a sulfonyl group or an amino group. Other symbols are as defined above. ]
  • compound (1) is halogenated by a method known per se to give compound (1).
  • compound (4) is produced by reacting compound (3) with amide, thioamide or amidine.
  • the reaction between compound (2) and compound (3) is performed in an appropriate solvent in the presence or absence of a base.
  • the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; and halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • Hydrocarbons such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethoxy ethanol, and ethylene glycol;
  • Examples include N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate or a mixed solvent thereof.
  • the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating lime; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; sodium methoxide; sodium methoxide; potassium tert.
  • Alkali metal alkoxides such as butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium acetate, sodium acetic acid and other potassium salts, disodium hydrogen phosphate, disodium hydrogen phosphate, etc.
  • Alkali metal hydrogen phosphates alkali metal hydrides such as sodium hydride and potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylbilysine, N-methylmorpholine, N, N-dimethyla Amines such as nilin
  • the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (2), and the amount of amide, thioamide or amidine (3) used depends on compound (2). About 1 to about 5 molar equivalents are preferred.
  • This reaction is generally carried out at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours.
  • the compound (4) thus obtained is a known separation and purification method. It can be isolated and purified by steps, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the corresponding carboxylic acid (5) can be produced by subjecting the compound (4) in which R 2a is —COOR 16a [ie, the compound (4,)] to an acid or hydrolysis reaction known per se. And compound (5) can be converted into an amidation reaction known per se.
  • Compound (7) can be produced by subjecting it to [Reaction with compound (6)].
  • the amidation reaction can be carried out, for example, by converting the compound (5) into an acid halide with a halogenating agent such as oxalyl chloride or thionyl chloride, and then reacting the compound with the compound (6).
  • the reaction between the compound (5) and the halogenating agent is usually performed in a solvent, and examples of the solvent include aromatic hydrocarbons such as benzene and toluene, and ethers such as getyl ether and tetrahydrofuran. .
  • pyridine, N, N-dimethylformamide and the like may be used as the reaction accelerator.
  • This reaction is generally carried out at about 0 ° C to about + 120 ° C for about 30 minutes to about 24 hours.
  • the amount of the halogenating agent to be used is preferably about 1 to 2 molar equivalents relative to compound (5).
  • the obtained acid halide may be separated by a conventional separation and purification means and then subjected to the reaction with the compound (6).
  • the reaction mixture containing the acid halide without separation is subjected to the reaction with the compound (6). It can also be attached.
  • the reaction between the acid halide and the compound (6) is usually performed in a solvent.
  • the solvent examples include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, ethers such as getyl ether, dioxane and tetrahydrofuran, acetone, and acetonitrile. , Ethyl acetate, N, N-dimethylformamide and the like.
  • the reaction can also be carried out using an excess amount of compound (6) as a solvent.
  • This reaction can be carried out in the presence or absence of a base.
  • the base include organic bases such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, and the like, for example, sodium hydrogen carbonate, carbon dioxide And the like.
  • the amount of the compound (6) to be used is preferably about 1 to 2 mol equivalent to the acid halide, but an excessive amount of the compound (6) can be used as a solvent.
  • This reaction is generally performed at about 0 ° C. to about + 120 ° C. for about 30 minutes to about 24 hours.
  • compounds in which Q is an NH group include compound (4-1) and compound Compounds (9_1) and (9-2) can be produced by subjecting compound (8) to a reaction with halogenated hydrocarbon, which can be isomerized as in (4-2). This reaction is carried out in an appropriate solvent in the presence or absence of a base.
  • solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane;
  • Examples include N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a mixed solvent thereof.
  • the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium.
  • tert-Alkali metal alkoxides such as butoxide, sodium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium carbonate, alkali metal salts such as sodium acetate, potassium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • Alkali metal hydrogen phosphates such as alkali metal hydrides such as sodium hydride and potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaniline, etc.
  • This reaction is carried out usually at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours.
  • the compound thus obtained (9-
  • a carboxylic anhydride (11) eg, acetic anhydride, propionic anhydride, butyric anhydride
  • Compound (12) is produced by reduction in the presence of isobutyric anhydride.
  • a transition metal catalyst eg, palladium, platinum, rhodium, etc.
  • hydrogen is preferable, and this reaction is performed in a solvent that does not adversely affect the reaction.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; ⁇ , ⁇ -dimethylformamide; and ethyl acetate;
  • the reaction temperature is usually about -20 ° C to about + 150 ° C, particularly about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (12) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (13) is produced by subjecting compound (12) to a reaction with phosphorus oxychloride in an appropriate solvent or without a solvent.
  • solvent examples include benzene, Aromatic hydrocarbons such as toluene, xylene, etc .; halogenated hydrocarbons such as dichloromethane, chlorophonolem, tetrasalt ⁇ (Danicarbon, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane), Jetil Examples include ethers such as ether, tetrahydrofuran, dioxane, and dimethoxetane, dimethyl sulfoxide, acetonitrile, or a mixed solvent thereof, etc.
  • the amount of phosphorus oxychloride to be used is about 1 to about 5 mol, based on compound (12).
  • the reaction temperature is usually about 0 ° C. to about + 150 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours.
  • the compound (13) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Rukoto can.
  • R 2a is - COOR 16a, Compound (13) R 2a by subjecting the known acid or alkali pressurized water decomposing is - COOH, Compound (13) can be produced, also, R 2a is one
  • R 2a is _CONR 17a R 18a
  • This reaction can be carried out under the same conditions as the reaction for deriving compound (5) from compound (4 ') and the reaction for deriving compound (7) from compound (5).
  • R 19a represents a methyl group or an ethyl group. Other symbols have the same meanings as described above.
  • compound (14) is produced by reducing compound (10).
  • reducing compound (10) catalytic reduction using a transition metal catalyst (eg, palladium, platinum, rhodium, etc.) and hydrogen is preferable, and this reaction is performed in a solvent that does not adversely influence the reaction.
  • a transition metal catalyst eg, palladium, platinum, rhodium, etc.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; methanol, ethanol, propanol, isopropanol, butanol, 2- Examples include alcohols such as methoxyethanol, ethylene glycol, and the like, N, N-dimethylformamide, ethyl acetate, and a mixed solvent thereof.
  • the reaction temperature is usually about ⁇ 20 ° C. to about + 150 ° C., preferably about 0 ° C. to about + 100 ° C., and the reaction time is about 1 hour to about 24 hours.
  • the compound (14) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (16) is produced by subjecting the compound (14) to a reaction with dithioestenole represented by the general formula (15) in an appropriate solvent or without a solvent.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • Examples include hydrocarbons, ethenols such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof.
  • the amount of dithioester (15) used is preferably about 1 to about 5 molar equivalents relative to compound (14).
  • the reaction temperature is usually about 0 ° C to about + 150 ° C, preferably about + 30 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (16) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (17) is produced by reacting compound (16) with oxysalt ichrylin in the same manner as in Method B '.
  • Compound R 2a is _COOR 16a (17) R 2a by the subjected to per se known acid or alkali pressurized water decomposition reaction - COOH, Compound (17) can be produced, also, R 2a gar COOH, compound (17) known per se ami de reaction [compound reaction with (6)] R 2a by subjecting the the - CONR 1 7a R 18a, compound (17) can be also produced.
  • This reaction can be carried out under the same conditions as the reaction for deriving compound (5) from compound (4 ') and the reaction for deriving compound (7) from compound (5).
  • compound (18) is produced by subjecting compound (1) to a reaction with phosphorus oxychloride in the presence of N, N-dimethylformamide.
  • solvents include dichloromethane, chloroform, carbon tetrachloride, halogenated carbons such as 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, getyl ether, tetrahydrofuran, dioxane, dimethyloxetane, etc. May be used, or a mixed solvent thereof.
  • the amounts of N, N-dimethylformamide and phosphorus oxychloride used are preferably about 1 to about 5 molar equivalents relative to compound (1).
  • the reaction temperature is usually about -20 ° C to about + 180 ° C, particularly about 0 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (18) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (20) is produced by reacting the compound (18) with a hydroxylamine derivative or a hydrazine derivative of the compound (19). This reaction is advantageously performed in a solvent that does not adversely influence the reaction, in the presence of a base.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloromethane.
  • Examples include halogenated hydrocarbons such as roethane, ethenols such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and a mixed solvent thereof.
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating lime, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide, potassium tert.
  • Alkali metal alkoxides such as butoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium bicarbonate, sodium acetate, sodium acetate, alkali metal salts such as sodium acetate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, etc.
  • the base is preferably used in an amount of about 1 to about 5 molar equivalents with respect to the compound (18).
  • the amount of hydroxylamine and hydrazine (19) is preferably selected from the compound (18). From about 1 to about 5 molar equivalents based on This reaction is carried out usually at about 0 ° C to about + 180 ° C, preferably at about + 30 ° C to about + 120 ° C, for about 30 minutes to about 50 hours.
  • the compound (20) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (20) in which R 2a is —COOH can be produced by subjecting the compound (20) in which R 2a is one COOR 16a to a known acid or alkali hydrolysis reaction, and wherein R 2a is it is also possible to produce CONR a 1 7a R 18a compound (20) - R 2a is by subjecting the compound of one COOH (20) known per se ami de reaction [compound reaction with (6) to . This reaction can be carried out under the same conditions as the reaction for deriving compound (5) from compound (4 ') and the reaction for deriving compound (7) from compound (5).
  • the compound (21) is produced by subjecting the above compound (18) to a reaction with sulfur and sodium sulfide in an appropriate solvent, and then treating with sulfuryl chloride.
  • the solvent include ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol / ethylene, and ethylene glycol; N, N — Dimethylformamide, dimethyl sulfoxide, acetonitrile, or a mixed solvent thereof.
  • the amount of sulfur and sodium sulfide to be used is preferably about 1 to about 3 mol equivalent to compound (18), respectively.
  • the reaction temperature is usually about 0 ° C to about + 180 ° C, particularly about + 30 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours. .
  • the sulfuryl chloride treatment of the intermediate thus obtained is performed in a solvent that does not adversely influence the reaction.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like.
  • Examples thereof include halogenated hydrocarbons, ethers such as methyl ether, tetrahydrofuran, dioxane, and dimethoxetane, and a mixed solvent thereof.
  • the amount of sulfuryl chloride to be used is preferably about 1 to about 3 molar equivalents relative to compound (18).
  • the reaction temperature is usually about 2 Preferred is 0 ° C to about + 150 ° C, especially about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (21) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (22) is produced by reacting compound (21) with a large excess of ammonia. This reaction is performed in a solvent that does not adversely influence the reaction.
  • the solvent include ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; and mixed solvents thereof. Is mentioned.
  • This reaction is generally carried out at about 120 ° C. to about + 180 ° C., preferably about 0 ° C. to about + 120 ° C., for about 1 hour to about 50 hours.
  • the compound (22) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (22) in which R 2a is —COOH can be produced by subjecting the compound (22) in which R 2a is one COOR 16a to a known acid or alkali hydrolysis reaction, and wherein R 2a is over COOH, compound (22) known per se ami de reaction [compound (6) reaction with] R 2a by subjecting the can - CONR may 1 7a R 18a, compound (22) to be produced .
  • This reaction can be carried out under the same conditions as the reaction for deriving compound (5) from compound (4 ') and the reaction for deriving compound (7) from compound (5).
  • R 2 () a represents an ethoxycarbonyl group or a p-toluenesulfonyl group. Other symbols are as defined above.
  • the compound (1) is subjected to the reaction of the compound (23) with ethyl carbazate or p_toluenesulfonylhydrazide in an appropriate solvent to give the compound
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, xylene, and halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • Alcohols such as acetylated hydrocarbons, ethynol ether, tetrahydrofuran, dioxane, dimethoxetane, etc., methanol, ethanolol, propanol, isopropanol, butanol, butanol, 2-methoxyethanol, ethylene glycol, N, N —Dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate or a mixed solvent thereof.
  • the use amount of ethyl canolevadate or p-toluenesulfonyl hydrazide (23) is preferably about 1 to about 2 molar equivalents with respect to compound (1).
  • the reaction temperature is usually about 0 ° C to about + 180 ° C, particularly about + 30 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (24) thus obtained can be purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Can be isolated and purified.
  • Compound (25) is produced by treating compound (24) with thionyl chloride. This reaction is performed in an appropriate solvent or without a solvent.
  • the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • hydrocarbons, ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane, and mixed solvents thereof.
  • This reaction is generally performed at about 120 ° C to about + 180 ° C, preferably about 0 ° C to about + 120 ° C, for about 1 hour to about 50 hours.
  • the compound (25) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (25) in which R 2a is —COOH can be produced by subjecting the compound (25) in which R 2a is one COOR 16a to a known acid or alkali hydrolysis reaction, and wherein R 2a is it is also possible to produce the compound R 2a is an CONR 1 7a R 18a (25) by subjecting the compound of one COOH (25) known per se ami de reaction [compound (6) reaction with] .
  • the reaction
  • reaction for deriving compound (5) from (4 ') and the reaction for deriving compound (7) from compound (5) can be carried out under the same conditions.
  • the compound (18) is subjected to the reaction of the compound (26) with a thiol in an appropriate solvent in the presence of a base to produce a compound (27).
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like.
  • Examples include hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate, and a mixed solvent thereof.
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, and sodium ethoxide.
  • Alkali metal alkoxides such as oxide and potassium tert-butoxide, sodium carbonate, carbon dioxide lime, sodium hydrogen carbonate, hydrogen carbonate lime, sodium acetate, alkali metal salts such as potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate Alkali metal hydrogen phosphates such as dipotassium, sodium hydride, alkali metal hydrides such as lithium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methinolepyrrolidine, N-methylmorpholine, N, Amines such as N-dimethylaniline Which base is used suitably selected, these bases
  • the amount of the thiol (26) is preferably about 1 to about 3 molar equivalents relative to the compound (18).
  • This reaction is generally carried out at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 1 hour to about 50 hours.
  • the compound (27) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (28) may be partially produced, but usually, the compound (27) is subjected to an aldol-type dehydration condensation reaction to produce the compound (28).
  • This reaction is performed in a solvent that does not adversely influence the reaction.
  • the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • Hydrocarbons such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; acetonitrile, ethyl acetate; And the like.
  • the dehydration reagent include lower carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, and isobutyric anhydride; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; and amines.
  • the amount of the dehydrating reagent used is a catalyst amount or a large excess with respect to compound (27), and the reaction temperature is usually about 0 ° C to about + 180 ° C, particularly about + 30 ° C to about + 120 ° C.
  • the reaction time is from about 1 hour to about 50 hours.
  • the compound (28) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • R 2a is - a COOR 16a is compound (28) R 2a by the subjected to per se known acid or alkali pressurized water decomposition reaction - COOH, Compound (28) can be produced, also, R 2a is -Compound 2 (COOH) is subjected to an amidation reaction [reaction with compound (6)] known per se, whereby R 2a becomes -CONR 1 Compound (28) which is 7a R 18a can also be produced.
  • reaction for deriving compound (5) from (4 ') and the reaction for deriving compound (7) from compound (5) can be carried out under the same conditions.
  • compound (30) is produced by reacting compound (2) with imine of compound (29) in an appropriate solvent in the presence of a base.
  • a solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethenoles such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; and mixed solvents thereof.
  • the base for example, a base such as lithium ethyl amide or lithium diisopropyl amide is appropriately selected and used.
  • the amount of the base to be used is preferably about 1 to about 2 molar equivalents relative to compound (2).
  • the amount of (29) to be used is preferably about 1 to about 2 molar equivalents relative to compound (2).
  • This reaction is advantageously performed by first treating imine (29) with a base and then adding compound (2).
  • the reaction temperature is usually about -80 ° C to about + 100 ° C, preferably about 180 ° C to about +30, and the reaction time is about 30 minutes to about 24 hours.
  • the compound (30) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • R 2a is - a COOR 16a is compound (30) can be prepared compound is R 2a gar COOH (30) by the subjected to per se known acid or alkali pressurized water decomposition reaction, also, R 2a is Compound (30), which is COOH, is Compound is R 2a Gar CONR 1 7a R 18a by subjecting to the reaction with the compound (6)] amino-de-reaction (30) can be also produced.
  • the reaction is
  • reaction for deriving compound (5) from (4 ') and the reaction for deriving compound (7) from compound (5) can be carried out under the same conditions.
  • compound (Ia) can also be produced according to the following method.
  • n 1 or 2, and the other symbols have the same meanings as described above.
  • 1,3-diketone is converted to a base, carbon disulfide, and hydrogenated hydrocarbon (
  • the dithioester of compound (32) is produced by treating in the order of 31).
  • This reaction is performed in a solvent that does not adversely influence the reaction.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethenoles such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane, ⁇ , ⁇ -dimethylformamide, dimethylsulfoxide, and acetonitrile.
  • a mixed solvent thereof may be used.
  • the base include alkali metal hydroxides such as sodium hydroxide sodium and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxy.
  • Alkali metal alkoxides such as potassium tert-butoxide, and sodium carbonate
  • Alkali metal salts such as lime, carbonated lime, sodium bicarbonate, hydrogen hydride, sodium acetate, potassium acetate, disodium hydrogen phosphate, hydrogen phosphate
  • Alkali metal hydrogen phosphate such as double lime
  • hydrogenation Bases such as alkali metal hydrides such as sodium and hydrogen hydride, amines such as trimethylamine, triethylamine, pyridin, picoline, N-methylpyrrolidine, N-methylinomorpholine, and N, N-dimethylaniline It is appropriately selected and used.
  • the amount of these bases used is preferably about 1 to about 2 molar equivalents with respect to 1,3-diketone, and the amount of carbon disulfide used is preferably about 1 to about 2 molar equivalents with respect to 1,3-diketone.
  • the amount of hydrogen hydride (31) to be used is about 1 to about 2 molar equivalents, preferably about 1 molar equivalent, based on 1,3-diketone. This reaction is carried out usually at about 180 ° C. to about + 150 ° C., preferably at about ⁇ 20 ° C. to about + 100 ° C., for about 1 hour to about 24 hours.
  • the compound (32) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (34) is produced by subjecting compound (32) to a reaction with a halogenated hydrocarbon represented by formula (33) in an appropriate solvent in the presence of a base.
  • a halogenated hydrocarbon represented by formula (33) examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; methanol, ethanol, propanol, isopropanol, butanol, and 2-methoxy.
  • Examples include alcohols such as ethanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate, and a mixed solvent thereof.
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating lime, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium hydroxide.
  • Alkali metal alkoxides such as tert-butoxide, sodium carbonate, sodium carbonate, sodium bicarbonate, alkali metal salts such as sodium hydrogen carbonate, sodium acetate, potassium acetate, disodium hydrogen phosphate, and sodium hydrogen phosphate
  • alkali metal hydrogen phosphate sodium hydride, potassium hydride, etc.
  • Bases such as alkali metal hydride, amines such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaniline are appropriately selected and used.
  • the amount used is preferably about 1 to about 10 molar equivalents, particularly preferably about 1 to about 5 molar equivalents, based on compound (32).
  • the amount of halogenated hydrocarbon (33) used depends on compound (32). About 1 to about 2 molar equivalents are preferred.
  • the reaction temperature is generally about 0 ° C to about + 180 ° C, preferably about + 30 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (35) is produced by subjecting compound (34) to an oxidation reaction.
  • the oxidizing agent used in this reaction examples include peracids such as peracetic acid, pertrifluoroacetic acid, and m-chlorobenzoic acid; metal oxides such as potassium permanganate and chromium oxide; and hydrogen peroxide.
  • the oxidizing agent is used at 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (34).
  • Any solvent may be used for this reaction as long as it does not hinder the reaction.
  • hydrocarbons such as n-hexane, N-heptane, benzene, toluene and xylene, dichloromethane chloroform, carbon tetrachloride
  • Halogenated hydrocarbons such as dimethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc., N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methylpyrrolidone; esters such as ethyl acetate and methyl acetate; ketones such as acetone, 2-butanone, 4-methyl-2-pentanone, and cyclohexone; , Halogenated hydrocarbons such as carbon tetrachloride, getyl ether, diisopropane Ethers such as ropiré tenor, ethylene glyco
  • This reaction is carried out at a reaction temperature of 0 ° C. to 120 ° C., preferably 20 ° to 80 ° C., for 1 to 24 hours, preferably 2 to 6 hours.
  • the compound (35) thus obtained can be obtained by a known separation and purification means, for example, concentration, It can be isolated and purified by vacuum concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.
  • compound (1) is produced by subjecting compound (35) to a reaction with various nucleophilic reagents.
  • nucleophilic reagent for example, metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, thioalcoholate, amine and the like are used. In this reaction, it is preferable to add a base in some cases.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogen carbonate
  • Alkali metal salts such as cesium fluoride, sodium acetate and potassium acetate
  • metal hydrogen phosphates such as disodium hydrogen phosphate and dihydrogen phosphate
  • metal hydroxides such as sodium hydroxide and potassium hydroxide
  • amines such as triethylamine, pyridine and N-methylmorpholine.
  • the amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (35).
  • the amount to be used is preferably about 1 to about 5 molar equivalents relative to compound (35).
  • Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. And amides such as N, N-dimethylformamide and 1-methylpyrrolidone, and sulfoxides such as dimethylsulfoxide. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is generally about -70 to about 150 ° C, preferably about -20 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 24 hours.
  • the compound (1) thus obtained can be isolated by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. You can elaborate.
  • R 2a is - COOR 16a, Compound (1) R 2a by subjecting the known acid or alkali hydrolysis reactions - COOH, Compound (1) can be produced, also, 1 23 one 00 ⁇ Dearu compound (1) to produce compound R 2a is an CONR ⁇ R 1 8a to (1) by the subjected to known per se ami de reaction [compound (6) reaction with] Can also.
  • Compound (20) can also be synthesized by the following method c
  • R 19a and R 2Qa each represent a hydrogen atom or a substituted or unsubstituted hydrocarbon residue or a heterocyclic group as exemplified for R la , and each other symbol represents It has the same meaning as above. ]
  • compound (31) is produced by subjecting compound (1) to a reaction with trialkyl orthoformate and boron trifluoride-ethyl ether complex in the presence of a base.
  • a base an organic base such as triethylamine or diisopropylethylamine is used.
  • the solvent for example, halogenated carbons such as dichloromethane, chloroform, and tetrachloromethane are preferred.
  • the amounts of trialkyl orthoformate, boron trifluoride-ethyl ether complex and base used are determined by compound (1). About 1 to about 10 molar equivalents are preferred.
  • the reaction temperature is usually about 170 ° C to about 60 ° C, preferably 150 ° C to 30 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (31) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (32) is produced by reacting compound (1) with N, N-dimethylformamide dialkyl acetal or trisdialkylaminomethane. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • amides such as N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and ⁇ ⁇ ⁇ -methylpyrrolidone are preferred.
  • the compound (20) is produced by reacting the compound (31) and the compound (32) thus obtained with the hydroxylamine derivative or the hydrazine derivative of the compound (19).
  • the reaction may be accelerated by adding an acid to the reaction system.
  • the acid to be used the above-mentioned inorganic acids and organic acids are used.
  • This reaction is performed in a solvent that does not adversely influence the reaction.
  • the solvent include alcohols such as methanol, ethanol and the like, aromatic hydrocarbons such as benzene, toluene and xylene, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methyl Amides such as rupyrrolidone are preferred.
  • the amount of the acid to be used is preferably about 0.1 to about 10 molar equivalents relative to compound (1).
  • the reaction temperature is usually about 0 ° C to about 120 ° C, particularly preferably 50 ° C to 100 ° C, and the reaction time is about 1 hour to about 24 hours.
  • the compound (20) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (la) can also be synthesized by the following method.
  • Y represents boronic acid, boronic ester, zinc halide, copper halide, trialkyltin or triflate.
  • a known compound [W02000047578, EP 676395, and Monassieufetfur Chemie (Monatshefte fur Chemie), volume 120, page 65 (1987)] may be used as it is or may be used as such. It can be produced by the method described or a method analogous thereto.
  • compound (36) By reacting compound (36) with compound (37) in which Y (boronic acid, boronic ester or triflate) is bonded to a 5- to 7-membered ring in the presence of a metal catalyst, compound (3 6) is reacted. 8) is manufactured.
  • compound (36) By reacting compound (36) with compound (37) in which Y (boronic acid, boronic ester or triflate) is bonded to a 5- to 7-membered ring in the presence of a metal catalyst, compound (3 6) is reacted. 8) is manufactured.
  • metal catalysts used in this reaction include metal catalysts generally used in aryl coupling.
  • metal catalysts generally used in aryl coupling.
  • tetrakis (triphenylphosphine) palladium (0), dichloropalladium (11), diacetoxypalladium (11), tetrakis (triphenylphosphine) nickel (0), dichloronickel (11), diacetoxynickel ( 11), copper (II) chloride, copper (II) chloride and the like are used.
  • phosphine for example, triphenyl phosphine, tributy phosphine, etc.
  • This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
  • the solvent include ethers such as getyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide.
  • amides such as ⁇ -methinolepyrrolidone are preferred.
  • the amount of compound (37) to be used is preferably about 1 to about 5 molar equivalents relative to compound (36).
  • the amount of the metal catalyst to be used is preferably about 0.1 to about 1 molar equivalent with respect to compound (36).
  • the reaction temperature is usually about 170 ° C. to about 150 ° C. (: particularly preferably 20 ° C. to 80 ° C., and the reaction time is about 1 hour to about 24 hours.
  • the compound (38) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the conversion of R 1 a in compound (la) can also be performed by the following method.
  • R 1 a is an optionally substituted hydrocarbon residue which may be substituted, the compounds of the heterocyclic group, a hydroxyl group or Amino groups, are prepared by the following method.
  • R la ′ ′′ represents an optionally substituted hydrocarbon residue, and other symbols have the same meanings as described above.
  • a sulfinyl compound or a sulfonyl compound (40) is produced by subjecting a sulfanyl group of a compound (39) which can be produced from the compound (34) by the A ′ method to the K ′ method to acid conditions.
  • the oxidizing agent used in the present oxidation reaction include hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, pertrifluoroacetic acid, potassium permanganate, and chromium oxychloride. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
  • the solvent include ethers such as getyl ether, tetrahydrofuran and dioxane, and halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride.
  • the amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound (39).
  • the reaction temperature is usually about 0 ° C. to about 100 ° C., preferably 0 ° C. to 50 ° C., and the reaction time is about 1 hour to about 24 hours.
  • the compound (40) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • compound (1) is produced by reacting compound (40) with a nucleophile in the presence of a base as necessary.
  • a nucleophile organic metal reagents such as Grignard reagents and organic lithium reagents, alcohols such as aromatic alcohols and aliphatic alcohols, and amines such as aromatic amines and aliphatic amines can be used.
  • the base the above-mentioned inorganic bases and organic bases can be used.
  • This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
  • the solvent include ethers such as dimethyl ether, tetrahydrofuran, and dioxane; halogenated carbons such as dichloromethane, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; Amides such as N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and ⁇ -methylpyrrolidone are preferred.
  • the nucleophile and the base are preferably used in an amount of about 1 to about 10 molar equivalents relative to compound (39).
  • the reaction temperature is usually about 170 ° C.
  • the compound (1) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. All compounds used or obtained in the above-mentioned production methods are intended to include the corresponding salts, even if not specified, and can be converted into each other by a method known per se or a method analogous thereto.
  • the compound used in the present invention or a salt thereof is an asymmetric molecule, it can be separated into a d-isomer and a single isomer by ordinary optical resolution means.
  • the compound used in the present invention or a salt thereof can be isolated and purified by, for example, solvent extraction, concentration under reduced pressure, crystallization, recrystallization, distillation, chromatography and the like.
  • the obtained compound or its salt can be used in the next step without any purification or as a reaction solution. Is also good.
  • benzothiopyran or benzocepin derivatives in water-insoluble or poorly water-soluble drugs include, for example, JP-A-3-23280 (European Patent Application Publication No. 3771697) and JP-A-4-3.
  • Japanese Patent Application Laid-Open No. 6-4179 Japanese Patent Application Publication No. 4640488
  • ring A a is a benzene ring which may be substituted
  • Ra is a hydrogen atom or a hydrocarbon group which may be substituted
  • Ba may be esterified or amidated.
  • X represents a carboxy group
  • Xa represents one CH (OH) — or one CO—
  • & represents 0 or 1
  • k ′ a represents 0, 1 or 2.
  • compound (X) or a salt thereof.
  • examples of the substituent on the optionally substituted benzene ring represented by ring Aa include a halogen atom, a nitro group, an optionally substituted alkyl group, and a substituted A hydroxyl group which may be substituted, a mercapto group which may be substituted, an amino group which may be substituted, an acyl group, a mono- or di-alkoxyphosphorinole group, a phosphono group, an aryl group which may be substituted, And a substituted or unsubstituted aromatic heterocyclic group is the same or different, and 1 to 4, preferably 1 or 2, substituents are substituted on the benzene ring.
  • substituents are substituted on the benzene ring.
  • the “halogen atom” for example, fluorine, chlorine, bromine, iodine and the like are used.
  • the alkyl group in the “optionally substituted alkyl group” is preferably an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butynole, isobutyl, sec-butynole, tert.
  • cycloalkyl groups having 3 to 7 carbon atoms include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, hexoxy, etc.), Mono- or di-Ci-6 alkoxyphosphoryl groups (for example, methoxypho One to three of them may be substituted with a phosphoryl, ethoxyphosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, etc.) or
  • substituted alkyl group examples include, for example, trifluoromethyl, trifluorophenol, trichloromethinole, hydroxymethyl, 2-hydroxyxetinole, methoxethyl, 1-methoxyl, 2-methoxethyl, 2,2-jetoxyl. Shetyl, 2-ethoxyphosphorylethyl, phosphonomethyl and the like.
  • substituted hydroxyl group in the “optionally substituted hydroxyl group for example, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like are used.
  • alkoxy group is preferably an alkoxy group having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentinoleoxy, hexyloxy, heptyloxy or nonyloxy, etc.), carbon number 4 to 6 cycloalkoxy groups (eg, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.) and the like are used.
  • alkenyloxy group is preferably an alkenyloxy group having 2 to 10 carbon atoms, for example, aryloxy, crotyloxy, 2-pentenyloxy, and 3-alkenyloxy. Hexenyloxy, 2-cyclopentenyl methoxy or 2-cyclohexenyl methoxy is used.
  • the “aralkyloxy group” is preferably an aralkyloxy group having 6 to 19 carbon atoms, more preferably an aralkyl having 7 to 14 carbon atoms—an alkyloxy group having 1 to 4 carbon atoms (eg, benzyloxy, phenethyloxy and the like). Is used.
  • an alkanoyloxy group preferably an alkanoyloxy group, for example, an alkanoyloxy group having 2 to 10 carbon atoms (eg, acetyloxy, propionoxy, n-butyryloxy, hexanoyloxy, etc.) is used. .
  • an aryloxy group having 6 to 14 carbon atoms (eg, phenoxy, biphenyloxy, etc.) is preferably used. These groups are further substituted with 1 to 3 halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, mono- or di-Ci-6 alkoxyphosphoryl groups, phosphono groups, etc., as described above. May be.
  • Specific examples of the substituted hydroxyl group include, for example, trifluoromethoxy, 2,2,2-trifluoromethoxy, difluoromethoxy, 2-methoxetoxy, 4-cyclobenzyloxy, 2- (3,4-dimethylethoxy) And ethoxy.
  • Examples of the substituted mercapto group in the “optionally substituted mercapto group” include an alkylthio group, an aralkylthio group and an acylthio group.
  • alkylthio group is preferably an alkylthio group having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, nonylthio, etc.), cycloalkyl having 4 to 6 carbon atoms Thio groups (eg, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are used.
  • the "aralkylthio group” is preferably an aralkylthio group having 7 to 19 carbon atoms, more preferably an aralkyl having 6 to 14 carbon atoms-an alkylthio group having 1 to 4 carbon atoms, such as benzylthio or phenethylthio. Used for
  • acylthio group is preferably an alkanoylthio group, for example, 2 to 10 alkanoylthio groups (eg, acetylthio, propionylthio, n-butyrylthio, hexanolthio, etc.) are used.
  • These groups may be further substituted with, for example, 1 to 3 halogen atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a mono- or dialkoxyphosphoryl group, a phosphono group, and the like as described above.
  • Specific examples of the substituted mercapto group include, for example, trifluoromethylthio, 2,2,2-trifluoroethylenorethio, 2-methoxethylthio, 4-methylbenzylthio, 4-dichlorobenzene benzylthio, 4-fluorobenzylthio, 2- (3,4-dimethoxyphenyl) ethylthio and the like.
  • Examples of the substituent of the substituted amino group in the “amino group which may be substituted” include an alkyl group having 1 to 10 carbon atoms and an alkenyl group having 2 to 10 carbon atoms as described above.
  • Examples of the substituent of the substituted amino group in the “amino group which may be substituted” include an alkyl group having 1 to 10 carbon atoms and an alkenyl group having 2 to 10 carbon atoms as described above.
  • Arinole, Bier 2-pentene 1-inole, 3-pentene 1-inole, 2-hexene 1-inole, 3-hexene 1-inole, 2-cyclohexeninole, 2-cyclopentene Tulle, 2-methyl_2-propene_1-inole, 3-methinole-2-butene-1-yl, etc.
  • aryl group having 6 to 14 carbon atoms eg, phenyl, naphthyl, etc.
  • substituted amino group examples include, for example, methylamino, dimethylamino, ethylamino, getylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N-methyl-1-N-phenylamino, N-methylN- (4-methylamino) Benzyl) amino, ⁇ , ⁇ -di (2-methoxyhexyl) amino and the like.
  • acyl group a sulfonic acid having an organic carboxylate group or a hydrocarbon group having 1 to 6 carbon atoms [eg, alkyl (eg, methyl, ethyl, n-propyl, hexyl, etc.), phenyl, etc.]
  • alkyl eg, methyl, ethyl, n-propyl, hexyl, etc.
  • phenyl etc.
  • An acyl group or the like is used.
  • acyl group examples include formyl, an alkyl-carbonyl group having 1 to 10 carbon atoms (eg, acetyl, propionyl, butyryl, valeryl, bivaloyl, hexanol, octanol, cyclobutanecarbonyl, cyclohexanecarbonyl, cyclohexane).
  • Heptanecarbonyl, etc. alkenyl-carbonyl group having 2 to 10 carbon atoms (eg, crotonyl, 2-cyclohexenecarbonyl, etc.), aryl-carbonyl group having 6 to 14 carbon atoms (eg, benzoyl, etc.), carbon number 7 to 19 aralkyl-carbonyl group (eg, benzylcarbonyl, benzhydrylcarbonyl, etc.), 5- or 6-membered aromatic heterocyclic carbonyl group (eg, nicotinoyl, 4-thiazolylcarbonyl, etc.), 5- or 6-membered Aromatic heterocyclic acetyl group (eg, 3-pyridylacetyl, 4-thiazolyl Cetyl, etc.) is used.
  • alkenyl-carbonyl group having 2 to 10 carbon atoms eg, crotonyl, 2-cyclohexenecarbonyl, etc.
  • a sulfonate group having a hydrocarbon group having 1 to 6 carbon atoms examples include methanesulfonyl, ethanesulfonyl and the like. These groups may be further substituted with 1 to 3 substituents, for example, the same halogen atom, hydroxyl group, alkoxy group having 1 to 6 carbon atoms, amino group and the like as described above.
  • Specific examples of the acyl group include, for example, trifluoroacetyl, trichloroacetyl, 4-methoxybutyryl, 3-cyclohexyloxypropionyl, 4-cyclobenzoyl, 3,4-dimethoxybenzoyl and the like.
  • Examples of the “mono- or di-alkoxyphosphoryl group” include, for example, mono-C such as methoxyphosphoryl, ethoxyphosphoryl, propoxyphosphoryl, isopropoxyphosphoryl, butoxyphosphorinole, pentyloxyphosphoryl, hexyloxyphosphoryl and the like.
  • ⁇ e An alkoxyphosphoryl group for example, dimethoxyphosphoryl, ethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, dibutoxyphosphoryl, dipentoxyloxyphosphoryl, di-alkoxyphosphoryl, etc.
  • di one C Bok 6 alkoxy group for example dimethyl Tokishihosuhoriru, diethoxyphosphoryl, Jipu port Pokishihosuhoriru, diisopropoxy phosphoryl, ethylene O carboxymethyl phosphoryl, dibutoxyethoxyethyl Shiho Suho drill or the like is used.
  • the aryl group in the "optionally substituted aryl group” is preferably an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl and the like. These may be substituted with one to three alkyl groups, halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, etc., as described above.
  • Specific examples of the substituted aryl group include, for example, 4-chlorophenyl, 3,4-dimethoxyphenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydrido-naphthyl and the like.
  • aralkyl group in the “optionally substituted aralkyl group” is preferably an aralkyl group having 7 to 19 carbon atoms, for example, benzyl, naphthylethyl, trityl and the like. 1 to 3 alkyl groups, halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, etc., which may be substituted with one to three.
  • Specific examples of the substituted aralkyl group include, for example, 4-chlorobenzyl, 3,4-dimethoxybenzyl, 4-cyclohexylbenzyl, 5,6,7,8-tetrahydro-1-naphthylethyl and the like. No.
  • the aromatic heterocyclic group in the “optionally substituted aromatic heterocyclic group” is preferably a 5- to 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and Z or sulfur atoms.
  • furyl, chenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl and the like are used, and these groups are the above-mentioned alkyl groups having 1 to 10 carbon atoms, halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms and the like. 1-3 may be substituted.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” for Ra examples include an alkyl group (preferably an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl / le, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), and the same alkenyl group as described above (preferably an alkenyl group having 2 to 10 carbon atoms) Further, an aryl group (preferably an aryl group having 6 to 14 carbon atoms) and an aralkyl group (preferably an aralkyl group having 7 to 19 carbon atoms) similar to those described above are used.
  • an alkyl group preferably an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, Butyl, isobuty
  • substituent on the hydrocarbon group examples include a 5- to 6-membered aromatic heterocyclic group (eg, furinole, chenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, etc.), the same hapogen as described above, similar di - C i _ 6 Arukokishihosuho Lil group, a phosphono group or the like is used.
  • Ba represents a carboxyl group which may be esterified or amidated.
  • the esterified carboxyl group in the “optionally esterified carboxyl group” for Ba is, for example, an alkoxycarbonyl group, preferably Ci.
  • Alkoxycarbonyl group e.g., main butoxycarbonyl, Etokishikaru Boninore, propoxy carbonylation Honoré, butoxide Shikano levo Nino Les etc.
  • Ariruokishi force Honoré Boniru group preferably Flip 6 _ 1 4 ⁇ reel O alkoxycarbonyl group (e.g., phenoxy force carbonyl etc.
  • the amidated carboxyl group in the “optionally amidated carboxyl group” represented by Ba is preferably a compound represented by the formula: —CON (Ra (R a 2 ) [wherein, R a R a 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted 5- to 7-membered heterocyclic group, respectively. No.
  • hydrocarbon groups are, for example, (i) halogen atoms (eg, (Iv) fluorine, chlorine, bromine, iodine, etc.), (ii) a hydroxyl group, (iii) an alkoxy group having 16 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), (iv l or two identical or different C16 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butynole, tert-butyl, pentinole, isopentyl, neopentinole, Amino group (eg, amino, methylamino, ethylamino, dimethyl) (A), acetylamino, dipropylamino, etc.), (V) Amino groups substituted
  • mono- or di-alkoxyphosphoryl group for example, dimethoxyphosphoryl, diethoxyphosphoryl, ethylenedioxyphosphoryl, etc.), etc.
  • mono- or di-alkoxyphosphorylalkyl group e.g. Jiju _ 6 alkoxyphosphoryl monoalkyl group (eg, methoxyphosphorylmethyl, ethoxyphosphorylmethinole, methoxyphosphorinolethi ⁇ ⁇ ethoxyphosphorinolethione, dimethoxyphosphorylmethyl, diethoxyphosphorinolemethyl, dimethoxyphosphorylmethyl , Diethoxyphosphorylethyl, etc.), and (X)
  • the 5- to 7-membered heterocyclic group in the “optionally substituted 5- to 7-membered heterocyclic group” represented by R a R a 2 includes, for example, one sulfur atom, nitrogen atom or oxygen atom 5- to 7-membered heterocyclic group, 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom These heterocyclic groups may be fused to a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom.
  • Preferred examples of the 5- to 7-membered heterocyclic group represented by R a R a 2 include, for example, 2-pyridyl, pyrimidyl, pyrazul, pyridazinyl, pyrazolyl, imidazolinol, thiazolyl, oxazolyl, tetrazolyl, thiadiazolyl, oxaziazolyl, triazinyl, Triazolyl, chenyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzocenyl, indolinole, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,2,3 Quinolyl, thieno [2,3-b] pyridyl and the like.
  • R a 1 and R a 2 is the formula linked to each other: one N (R a Li (R a 2) Ca ⁇ to 7-membered ring may optionally form a form, and as such rings, such as morpholine Thiomorpholine, piperidine, homopirazine, piperazine, pyrrolidine, pyrroline, pyrazoline, imidazoline, imidazolidine, thiazolidine, azepine and the like.
  • R a 1 and alkyl group substituted R a 2 in shown a preferred have examples of "substituted also substituted hydrocarbon group", for example triflates Ruo Russia methyl, triflumizole Ruo Roe Chino les , Difluoromethyl, Trichloromethyl, 2-Hydroxyethyl, 2-Methoxyxetil, 2-Ethoxethyl, 2,2-Dimethoxethyl, 2,2-Jetoxethyl, 2-Pyridylmethyl, 3-Pyridylmethyl, 4-Pyridylmethyl, 2 _ (2-Chenyl) ethyl, 3- (3-furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl, 2-piberidinoethyl, 2- (N, N-dimethylamino) ethyl, 2- (N-methyl-N —Ethylamino) ethyl, 2 _
  • the group include, for example, 5-methyl-2-pyridyl, 3-methoxy-12-pyridyl, 5-methyl-12-benzothiazolinole, Cyl 4-phenyl 2-thiazolyl, 3-phenylenol 5-isoxosazolyl, 4- (4-chlorophenyl) _5_methyl-12-oxazolyl, 3-phenyl-1,2,4-thiadiazoyl 5-yl, 5-methyl-1,3,4-thiazidazole-12-yl, 5-acetylamino-12-pyrimidyl, 3-methyl-12-phenyl, 4,5-dimethyl-12-flael, 4 Monomethyl-1-morpholinyl and the like.
  • the rings Aa are preferably the same or different and each is a halogen atom, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted mercapto group and / or And a benzene ring which may be substituted with one or more, more preferably one or two, amino groups which may be substituted.
  • More preferred rings Aa are the same or different and are each a halogen atom, an alkyl group having 1 to 10 carbon atoms (more preferably 1 to 5 carbon atoms), )), An alkylenedioxy group represented by the formula: —O— (CH 2 ) na—O— (wherein, na represents an integer of 1 to 3), and Z or C 1 to C 10 ( More preferably, it is a benzene ring which may be substituted by one or two alkylthio groups having 1 to 5 carbon atoms.
  • ring Aa include a carbon atom adjacent to an alkylenedioxy group represented by the formula: 1 O— (CH 2 ) na—O—, wherein na represents an integer of 1 to 3.
  • the atom is a substituted benzene ring.
  • Ra is preferably a hydrogen atom, a C ⁇ e alkyl group (eg, methyl, ethyl, etc.) or a phenyl group.
  • Ba is, for example, an alkoxy-carbonyl group and a formula: one CONiRa iRa 2 ) wherein Ra Ra 2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted 5- to 7-membered complex Which represents a cyclic group].
  • R a 1 and R a 2 represents an alkyl group of Ra 1 is hydrogen atom or a carbon number from 1-10 (e.g., methyl, Echiru, propyl, etc.), R a 2 is halogen (e.g., full Tsu element, Chlorine, bromine, etc.), alkoxy (eg, methoxy, ethoxy, etc.), mono- or di-alkoxyphosphoryl (eg, mono- or di-alkoxyphosphoryl, such as dimethoxyphosphoryl, diethoxyphosphoryl, etc.), mono- or mono- Is a di-alkoxyphosphorylalkyl (eg, mono- or di-alkoxyphosphorylalkyl such as dimethoxyphosphorylmethyl, ethoxyphosphorylmethyl, etc.) (dialkyl in di-e-alkoxy is taken together with ci- e may be an alkylene group) or C ⁇ e alkoxycarbonyl (eg, methoxy 1 and C
  • R a 1 and R a 2 is a R a 1 is a hydrogen atom, Ra 2 mono - or di C _ 6 alkoxy phosphoryl one C i _ 3 alkyl substituted off Eniru group (e.g., 4-diethoxyphosphorylmethylphenyl).
  • X a represents one CH (OH) — or one CO—, preferably one CO—.
  • 3 ⁇ 4 3 represents 0 or 1 and k ′ a3 ⁇ 40, 1 or 2; preferably, ka is 1 and k ′ a is 0. More preferred examples of the compound (X) include, for example, those represented by the formula (XI)
  • R a 3 represents an alkyl group
  • R a 4 and R a 5 is either indicating each Ji bets 6 alkyl group, or together a connexion CI_ 6 alkylene group showing a] optically active you express in Nzochepine derivatives.
  • Ra 3 as "Ji 6 Al kill group” represented by R a 4 and R a 5, for example methyl, Echiru, propyl, isopropyl, butyl, Isobuchinore, sec- butyl, tert- butyl And alkyl groups such as pentynole, isopentyl, neopentyl and hexyl, and preferably an alkyl group having 1 to 4 carbon atoms.
  • R 4 and R 5 may be taken together to form a — 6 alkylene group, in which case, for example,
  • R a 3 as the R a 4 and R a 5, for example methyl, respectively, an alkyl group having 4 to C 1 -C such as Echiru are preferred.
  • the compound (Ila) is an (2R, 4S) -coordinated optically active compound, which is substantially free of a (2S, 4R) -coordinated compound, and is preferred as having an optical purity closer to 100%. is there.
  • Particularly preferred examples of the compound (Ila) include, for example, (2R, 4S) — (—) — ⁇ ⁇ [4- (Jetoxyphosphorylmethyl) phenyl] 1,1,2,4,5-tetrahydro--4-methyl-17,8-methylenedioxy-5-oxo-1 3-benzobenzopine-12-canoleboxamide
  • salts of the benzothiopyran or benzochepine derivative used in the present invention a pharmacologically acceptable salt is preferably used.
  • a salt with an inorganic base a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like is used.
  • Salts that can form salts of benzothiopyran or benzochepine derivatives include inorganic bases such as alkali metal (eg, sodium and potassium) and alkaline earth metals (eg, calcium and magnesium).
  • the benzothiopyran or benzochepine derivative or a salt thereof used in the present invention is described in, for example, Japanese Patent Application Laid-Open No. Hei 3-232880 (Japanese Patent Application Publication No. 3771697). ), Japanese Patent Application Laid-Open No. Hei 4-3641979 (European Patent Application Publication No. 460,488), Japanese Patent Application Laid-Open No. Hei 8-2341569 (Kyoto)
  • the method can be produced by the same method as described in Japanese Patent Application Laid-Open Publication No. 7119782, a method similar thereto, or a method analogous thereto.
  • the wetting agent used in the present invention may be a pharmacologically acceptable substance, and may be a sugar or a sugar derivative, a phospholipid, a surfactant (anionic surfactant, cationic surfactant). Agents, nonionic surfactants), amphiphilic polymers, proteins, inorganic salts, polyethylene glycol and the like. These may be used alone or in combination of two or more.
  • sugar or sugar derivative examples include, for example, monosaccharides such as glucose, fructose, galactose, and mannose; disaccharides such as manoletose, lactose, sucrose, and tre / perose; starch, cellulose, mannitol, and carboxymethylcellulose.
  • monosaccharides such as glucose, fructose, galactose, and mannose
  • disaccharides such as manoletose, lactose, sucrose, and tre / perose
  • starch cellulose, mannitol, and carboxymethylcellulose.
  • Methanol or its alkali metal salts croscarmellose or its alkali metal salts, sodium carboxymethyl starch, carboxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.
  • the phospholipid may be any pharmacologically acceptable substance, for example, lecithin, phosphatidylcholine, phosphatidinoleethanolamine, derived from the composition of egg yolk soybean or other animals and plants.
  • phosphatidylcholine preferably C 1 2 _ 2 6 Jiashirufosufu Achijinorekorin, more preferably Flip 1 4 - 1 8 Zia Sino les phosphatidylcholine (eg example, distearoyl phosphatidylcholine, Jiparumi toyl phosphatidyl di Norecoline, dimyristoylphosphatidylcholine, dilauroylphosphatidinorecholine, gioleylphosphatidylcholine, 1 _myristoyl-1 2 —Noremi, toluphophosphatidylcholine, 1 _palmitoyl 2 —myristoinophofofa Thidinolecoline, 1-normi toyl 2-stearoylphosphatidylcholine, 1-stearoyl2-palmitoylphosphatidylcholine, etc.) are used.
  • phosphatidylcholine eg example, distearoyl phosphati
  • phosphatidylethanolamine ⁇ Min preferably C 1 2 2 6 Jiashi Le phosphatidylethanolamine ⁇ Min, more preferably C 1 4 1 8 Jiashirufosu phosphatidyl ethanol ⁇ Min (e.g., Jiparumi toyl phosphatidyl E Tano Luamine, dimyrutoylphosphatidylethanolamine, etc.) are used.
  • phosphatidic acids preferably C 1 2 2 6 di ⁇ sill phosphatidyl Gin acid, more preferably C 1 4 1 8 di ⁇ sill phosphatidic acid (e.g., Jiparu Mi twig Le phosphatidic acid, di Myristoylphosphatidic acid) is used.
  • phosphatidyl glycerol preferably C 1 2 2 6 Jiashirufu O scan phosphatidyl glycerides port Lumpur, more preferably C E 4 - E 8 di ⁇ sill phosphatidyl di Le glycerol (e.g., distearoyl Honoré Foss Fatidyl glycerol, dipanolemi toyl phosphatidyl glycerol, dimyristoyl phosphatidyl glycerolone, dilauroynole phosphatidino glycerolone, dioleoinolefos fatidyl glycerol, etc.).
  • sill phosphatidyl di Le glycerol e.g., distearoyl Honoré Foss Fatidyl glycerol, dipanolemi toyl phosphatidyl glycerol, dimyristoyl phosphatidyl
  • the above phosphatidylinositols are all phosphatidylinositol Razz, which may be its monophosphate and diphosphate and the like, as the phosphatidyl di Louis waves * Torr, preferably C 2 _ 26 di ⁇ sill phosphatidylinositol, more preferably C i 4 - i 8 di A phosphatidylinositol is used.
  • Diacylphosphatidylserine more preferably, Cm (for example, dipalmitoylphosphatidylserine, dimyristoylphosphatidylserine, brainfosfatidylserine, etc.) is used.
  • Cm for example, dipalmitoylphosphatidylserine, dimyristoylphosphatidylserine, brainfosfatidylserine, etc.
  • the staple Ingo myelin preferably C 12 _ 26 di ⁇ sill sphingomyelinase Erin, more preferably C 14 _ 18 di ⁇ Sils fins dust Erin (e.g., Bray Nsu fins dust Erin, Jiparumi toyl sphingomyelin, Jisutearoirusu Erin and the like).
  • the hydrogenation for obtaining the hydrogenated lecithin can be carried out by a method known per se.
  • a phospholipid not modified with polyethylene glycol is preferred.
  • the phospholipid preferably C 12 - phospholipid having two phospholipids with i 8 Ashiru group, further preferably c 12 _ 26 Ashiru group, - phospholipids, more preferred properly the ci 4 with 26 Ashiru group especially preferably the phospholipid is used having two C i 4 _ i 8 Ashiru group.
  • C 12 - 26 di ⁇ sill phosphatidyl Gino records phosphorus
  • C 14 _ 18 di ⁇ sill phosphatidylcholine e.g., distearoyl phosphatidylcholine, Gino Noremi toyl phosphatidylcholine , Dimyristoylphosphatidylcholine, dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, 1-myristoinole-1, 2-panoremitoylphosphatidylcholine, 1-palmitoyl1-2, myristoylphosphatidylcholine , 1-no, 1-norretoyl, 1-stearoylonephosphatidinolecoline, 1stearoyl-2-palmitoylphosphatidylcholine, etc.).
  • Surfactants include nonionic surfactants, anionic surfactants, and cations
  • Non-ionic surfactants include higher alcohol ethylene oxide adducts, alkyl phenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alkyl amines Ethylene oxide adducts, fatty acid amides Ethylene oxide adducts, Ethylenoxide adducts of fats and oils, Glycerin fatty acid esters, Pentaerythritol tongue moon Fatty acid esters, Polyhydric alcohol alkyl ethers, Alkanolamines A fatty acid amide is used.
  • 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 (polyethoxylated castor oil), poly Oxyethylene hard castor oil
  • Sorbitan fatty acid esters include, in particular, sorbitan monostearate (trade name: SS-10, Nikko Chemicals Co., Ltd.), sorbitan sesquioleate (trade name: SO-15, Nikko Chemicals Co., Ltd.), sorbitan trioleate (Trade name: S0-30, Nikko Chemicals Co., Ltd.) and the like are suitable.
  • polyoxyethylene sorbitan fatty acid esters in particular, polysorbate 20 (trade name: TL-10, Nikko Chemicals Co., Ltd.), 40 (trade name: TP-10, Nikko Chemicals Co., Ltd.), 60 ( Trade name: TS-10, Nikko Chemicals Co., Ltd.), 80 (trade name: $ 0-10, Nikko Chemicals Co., Ltd.) and the like are suitable.
  • polyethylene glycol fatty acid ester polyethylene glycol monolaurate (10E.0.) (Trade name: MYL-10, Nikko Chemicals Co., Ltd.) is particularly suitable.
  • sucrose fatty acid esters examples include sucrose palmitate esters (for example, trade name: S-1670, Mitsubishi Chemical Foods Co., Ltd.) and sucrose stearic acid esters (for example, trade name: P-1670, Mitsubishi Chemical Foods) And the like are preferred.
  • Polyoxylated castor oil is, in particular, polyoxyethylene glycerol triricinoleate 35 (Polyoxy 35 Castor Oil, trade name Cremo). Hall EL or EL_P, or BSF Japan Co., Ltd.) is suitable.
  • Polyoxylated hydrogenated castor oil is particularly suitable for polyoxyethylene hydrogenated castor oil.
  • Polyoxyethylene Hydrogenated Castor Oil 50 and Polyoxyethylene Hydrogenated Castor Oil 60 (Polyoxyethylene Hydrogenated Castor Oil 60) are suitable.
  • polyoxyethylene polyoxypropylene daricol copolymer a block copolymer of ethylene oxide and oxidized propylene
  • polyoxyethylene (160) polyoxypropylene (30) glycol (trade name: Punore Knick F -68, BASF Co., Ltd.), polyoxyethylene (196) polyoxypropylene (67) glycol (Product name: Pull Mouth Nick F-127, BASF Co., Ltd.), Pull Mouth Nick L-121 (BASF Co., Ltd.) are preferred.
  • glycerin fatty acid ester daliseryl monostearate (MGS series, Nikko Chemicals Co., Ltd.) and the like are suitable.
  • 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.
  • anionic surfactants include sulfates (eg, higher alcohol sulfates, higher alkyl ether sulfates, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, sulfated olefins), sulfonates (Eg, sodium alkyl benzene sulfonate, oil-soluble alkyl benzene sulfonate, a-olefin sulfonate, igepon T type, aerosol OT type), phosphate esters (eg, phosphoric acid of higher alcohol ethylene oxide adduct) Ester salts) and dithiophosphate salts.
  • sulfates eg, higher alcohol sulfates, higher alkyl ether sulfates, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, sulfated olefins
  • anionic surfactants preferred are, for example, bile salts such as sodium glycocholate and sodium deoxycholate, fatty acids such as sodium stearate and sodium phosphate, and salts thereof, and sodium laurinole sulfate.
  • cationic surfactant examples 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), and the like.
  • Grade Ammonium II Salt type cationic surfactants eg, quaternary ammonium salt type surfactants made from higher alkylamines, quaternary ammonium salt type surfactants made from lower alkylamines, such as benzalkonium chloride, etc. Is used.
  • 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 lecithins such as purified egg yolk lecithin (trade name: P100H, Cupy Corporation) and hydrogenated soybean lecithin (trade name: Resinol S-10, Nikko Chemicals Co., Ltd.) And the like are used.
  • amphiphilic polymer examples include polyalkenylpyrrolidone such as polybutylpyrrolidone, polybutyl alcohol, and polyoxyethylenepolyoxypropylene glycol copolymer (a block copolymer of ethylene oxide and propylene oxide)
  • polyoxyethylene (160) polyoxypropylene (30) glycolone (trade name: Pull Mouth Nick F-68, BASF Corporation), polyoxyethylene (196) polypropylene (67) glycol (trade name) : Pull Mouth Nick F-127, BASF Co., Ltd.), Pull Mouth Nick 121 (BASF Co., Ltd.), polyalkylene glycol (eg, Polyethylene Lendacol) and the like.
  • Examples of the protein include glycine, fibrin, collagen, gelatin and the like.
  • inorganic salts include inorganic salts such as sodium chloride, sodium hydrogen phosphate, calcium silicate, magnesium aluminate metasilicate, light silicic anhydride, magnesium stearate, calcium stearate, tanolek, colloidal silica, magnesium oxide, and the like. And the like.
  • additives eg, a hydrophilic polymer, a preservative, an antioxidant, etc.
  • a hydrophilic polymer e.g., a hydrophilic polymer, a preservative, an antioxidant, etc.
  • hydrophilic polymer examples include copolymers of methacrylic acid and methacrylic acid such as methacrylic acid copolymer (Eudragit (registered trademark) L-100-55); and methacrylic acid copolymer L and copolymer of methacrylic acid S.
  • methacrylic acid copolymer Eudragit (registered trademark) L-100-55
  • methacrylic acid copolymer L and copolymer of methacrylic acid S examples include Metacri Ethyl acrylates such as copolymers of methyl acrylate and methacrylic acid, such as aminoalkyl methacrylate copolymers E; polyvinyl acetal ethyl methacrylate, methacrylic acid copolymers RL, methacrylic acid copolymers RS, etc.
  • the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydrosulfuric acid, and sorbic acid.
  • Antioxidants include, for example, sulfites, ascorbic acid and the like. These additives may be used alone or in combination of two or more. The content and concentration of the additive may be in the same range as that of the wettability improving agent described later.
  • the organic solvent used in the present invention is not particularly limited as long as the organic solvent is miscible with the aqueous solvent.
  • the organic solvent miscible in such an aqueous solvent varies depending on the type of the aqueous solvent. Examples thereof include acids (eg, acetic acid, hydrochloric acid, sulfuric acid), alcohols (eg, methanol, ethanol, diethyl alcohol, glycerin).
  • aqueous solvent used in the present invention is not particularly limited as long as it is miscible with an organic solvent solution containing a water-insoluble or poorly water-soluble drug.
  • examples of the aqueous solvent include water or a mixture of water and a hydrophilic organic solvent.
  • hydrophilic organic solvent examples include alcohols (methanol, ethanol, propanol, etc.); acetonitrile and the like. Such a hydrophilic organic solvent may be added in an amount of preferably about 0 to about 50 parts by weight, more preferably about 0 to about 10 parts by weight, based on 100 parts by weight of water.
  • the aqueous solvent used in the present invention water is preferably used.
  • the content of the wetting agent in the organic solvent is preferably about 0.01 to 100 parts by weight of the water-insoluble or poorly water-soluble drug.
  • the concentration of the wetting improver in the aqueous solvent is preferably about 0.001% to about 20% (w / w). More preferably, it is about 0.001% to about 10% (w / w), particularly preferably about 0.005% to about 5% (w / w).
  • the wetting agent may be contained in both the organic solvent and the aqueous solvent.
  • the content of the entire wetting agent used is 100 parts by weight of the water-insoluble or poorly water-soluble drug.
  • the amount is preferably about 0.01 to about 1000 parts by weight, which is used by dividing into both the organic solvent and the aqueous solvent in the above-mentioned ratio.
  • the concentration of the water-insoluble or poorly water-soluble drug in the organic solvent is preferably about 1 to about 100 mg / m, more preferably about 10 to about 500 mg / mL, and more preferably about 10 to about 500 mg / mL. It is 10 to about 25 O mgZmL.
  • mucoadhesive polymer for example, a carboxyvinyl polymer (trade name: Neubis Co., Wako Pure Chemical Industries, Ltd.), mucoadhesive properties can be imparted to the finely divided drug.
  • an acrylic polymer trade name: Eudragit series such as Eudragit S100, Higuchi Shokai
  • the elution of the drug from the fine drug can be controlled.
  • an aqueous solvent-miscible organic solvent solution containing a water-insoluble or poorly water-soluble drug in which a wetting agent is dissolved in at least one solvent is rapidly mixed with an aqueous solvent.
  • the step of mixing the organic solvent solution and the aqueous solvent may be performed by any method. For example, a method of adding an aqueous solvent to the organic solvent solution, a method of adding the organic solvent solution to the aqueous solvent, or a method of mixing the organic solvent solution and the aqueous solvent Including the method of transferring to another container at the same time.
  • the temperature of the organic solvent solution and the aqueous solvent may be any temperature at which the insoluble or poorly water-soluble drug can be decomposed and dissolved. To simplify production, For example, it may be performed at room temperature (1 to 30 ° C) or at room temperature (15 to 25 ° C). Mixing is performed by passing through a mixer (eg, a static mixer (Noritake Company)) together with compressed air, or, for example, in a closed system for about 0.1 second to 60 minutes, preferably about 1 second to 30 minutes.
  • a mixer eg, a static mixer (Noritake Company)
  • Shaking shaking and stirring
  • ultrasonic irradiation a Turbin type stirrer
  • a homogenizer eg, Polytron (Kinemachi Riki)
  • a high-pressure homogenizer e.g., Polytron (Kinemachi Riki)
  • a propeller type stirrer e.g., a propeller type stirrer, or the like
  • the mixture is stirred at 500 to 50,000 r111 for about 0.1 second to 60 minutes.
  • the mixing speed at this time is determined by mixing the water-insoluble or poorly water-soluble drug-containing organic solvent solution with about 0.0001 to 100 L / min, preferably about 0.001 to: L0L / min. Min, more preferably at a mixing speed of about 0.01 to 1 L / min, with respect to the aqueous solvent.
  • the volume of the aqueous solvent at this time is, for example, about 1 to about 100 times the volume of the organic solvent solution containing the water-insoluble or poorly water-soluble drug, more preferably about 3 to 500 times, and particularly preferably about 3 to 500 times. It is selected from about 5 to 100 times, particularly preferably about 5 to 50 times.
  • the organic solvent may be removed from the obtained mixture as needed.
  • the method includes, for example, the ability to filter using a filter or remove the supernatant after centrifugation, the ability to gradually reduce the pressure while stirring with a propeller-type stirrer, a magnetic stirrer, or the like;
  • the organic solvent may be removed by adjusting the degree of vacuum using a vaporizer or the like, or the solvent may be volatilized in a very short time by spraying into a drying chamber of a spray dryer (spray drying; etc.).
  • the organic solvent may be removed at the same time, or at the same time, the fine water-insoluble or poorly water-soluble drug may be solidified, and then, if necessary, by heating (under reduced pressure if necessary), the fine water-insoluble or poorly water-soluble drug may be added.
  • the fine particles of the water-insoluble or hardly water-soluble drug produced as described above may be further removed by removing the residual organic solvent or aqueous solvent therein.
  • the wettability improver contains or / and adheres to it, improving dispersibility.
  • an insoluble or poorly water-soluble drug may be present on the surface of the drug, may adhere to the entire surface of the drug, or may partially adhere to it.
  • This improves the dispersibility of the drug. That is, the ability of the drug particles to be connected in the absence of the wetting agent.
  • a wetting agent such as sodium carboxymethylcellulose (CMC-Na)
  • CMC-Na sodium carboxymethylcellulose
  • the drug release period of the finely divided water-insoluble or poorly water-soluble drug is, for example, about 1 day or more, preferably about 2 days to 3 months, more preferably about 3 days to 3 months, and more preferably about 1 week to 1 month. Months.
  • a water-insoluble or sparingly water-soluble drug can be prepared, for example, as a water-insoluble or sparingly water-soluble drug microparticle, or by formulating a water-insoluble or sparingly water-soluble drug microparticle as a raw material into various dosage forms, thereby preparing a parenteral drug (non-vascular Injections (eg, intra-articular, near-bone, intramuscular, subcutaneous, implant or implant or intravenous); intravascular injections or drops; nasal cavity, rectum, uterus, etc.
  • non-vascular Injections eg, intra-articular, near-bone, intramuscular, subcutaneous, implant or implant or intravenous
  • intravascular injections or drops nasal cavity, rectum, uterus, etc.
  • Transmucosal preparations for example, tablets, capsules (for example, hard capsules, soft capsules, seamless capsules (Morishita Nittan), etc.)), solid preparations such as granules and powders, suspensions, etc. Liquids, etc. These may be sustained release agents.
  • oral preparations for example, tablets, capsules (for example, hard capsules, soft capsules, seamless capsules (Morishita Nittan), etc.)
  • solid preparations such as granules and powders, suspensions, etc. Liquids, etc.
  • Liquids etc.
  • Can be administered. The administration of these preparations has the effect of maintaining the drug blood concentration with a single administration.
  • various medical devices such as artificial joints, artificial roots, artificial heart lungs, artificial hearts, artificial hearts, human skin, cultured skin, artificial organs, cultured organs, cell medicines, surgical adhesives (e.g., Focal Seal (Focal , Inc., USA), Tisir (Nihon Yakuhin), Bolhir (Fujisawa Pharmaceutical), Beriplast P (Hechist Japan), etc., calcium-containing surgical cement Leopipex (Mitsubishi Materials), etc. It can be used at the same time by binding, coating, embedding, dispersing, etc. In the field of regenerative medicine, it can be used for processing cells, tissues and organs.
  • surgical adhesives e.g., Focal Seal (Focal , Inc., USA), Tisir (Nihon Yakuhin), Bolhir (Fujisawa Pharmaceutical), Beriplast P (Hechist Japan), etc.
  • Casir Nahon Yakuhin
  • Bolhir Bolhir
  • Beriplast P Hechist Japan
  • the finely divided water-insoluble or poorly water-soluble drug is preferably used as an injection as a suspension.
  • the finely divided water-insoluble or poorly water-soluble drug can be made into an aqueous suspension or an oil suspension using a dispersion medium such as water; vegetable oil; and medium-chain fatty acid triglyceride.
  • water-insoluble or poorly water-soluble drug microparticles may be added to a dispersant (for example, polysorbate 80 (polyoxysorbitan monooleate), Tween 80, HCO-60, a surfactant such as rheodol, carboxy).
  • a dispersant for example, polysorbate 80 (polyoxysorbitan monooleate), Tween 80, HCO-60, a surfactant such as rheodol, carboxy.
  • Polysaccharides such as sodium methylcellulose, sodium alginate, hyaluronic acid, etc.
  • preservatives eg, methylvalaben, propylparaben, etc.
  • tonicity agents eg, sodium chloride, sodium hydrogen phosphate, sodium phosphate Mannitol, sorbitol, glucose and the like
  • fine water-insoluble or poorly water-soluble drugs are mixed with vegetable oils such as sesame oil and corn oil, or a mixture of these with phospholipids such as lecithin, or medium-chain fatty acid tridaliceride (for example, miglyol 812).
  • vegetable oils such as sesame oil and corn oil, or a mixture of these with phospholipids such as lecithin, or medium-chain fatty acid tridaliceride (for example, miglyol 812).
  • An injection can be obtained by dispersing into an oily suspension.
  • injections into non-vessels are preferable, and injections into subcutaneous, intramuscular, intraarticular and fracture sites are particularly preferable.
  • sterilization by high-pressure steam A method of sterilizing with gamma ray, a method of adding a preservative, and the like, but are not particularly limited.
  • Various preparations obtained from a finely divided water-insoluble or poorly water-soluble drug and a finely divided water-insoluble or slightly water-soluble drug as raw materials have low toxicity.
  • various diseases in mammals including humans (eg, humans, pomas, porcines, pigs, dogs, cats, rats, mice, mice, etc.) It can be used as a preventive and therapeutic drug for
  • the compounds (Ia), (X) or salts thereof when used, they have an excellent activity of inducing lipophilic phosphatase, and an activity of promoting chondromodulin production and / or enhancing expression.
  • BMP action enhancing action is expected.
  • Such a differentiation-inducing and differentiation-inducing promoting action acts on not only osteoblast and chondrocyte differentiation but also differentiation induction of various cells.
  • compounds (Ia), (X) or salts thereof are expected to have an activity enhancing activity of neurotrophic factor.
  • compounds (Ia), (X) or salts thereof are expected to have anti-matrix metaoral protease (anti-MMP) activity.
  • Compound (Ia), (X) or a salt thereof has a strong osteogenesis promoting action, osteoblast differentiation induction and differentiation induction promoting action including progenitor osteoblasts, chondrogenesis promoting action, including precursor chondrocytes Since it is expected to induce chondrocyte differentiation and promote differentiation induction, and further enhance BMP activity, for example, bone formation promoters, bone disease prevention / treatment agents, fracture prevention / treatment agents, cartilage formation promotion agents, and cartilage disease prevention / treatment agents Specifically, in the field of orthopedic surgery, non-fractures such as simple fractures, intractable fractures, incomplete bone fusion, false joints, re-fractures, bone deformities and osteoporosis, osteosarcoma, myeloma, osteogenesis imperfections, scoliosis, etc.
  • non-fractures such as simple fractures, intractable fractures, incomplete bone fusion, false joints, re-fractures, bone deformities and osteoporosis, osteosarcoma, myel
  • Metabolic bone disease Bone defect, osteoporosis, osteomalacia, rickets, fibrous osteomyelitis, renal osteodystrophy, osteopetrophy, stiff myelitis, etc .; or osteoarthritis And similar diseases.
  • joint diseases typified cartilage diseases such as sex joint Riumachi, multiple myeloma, lung cancer, as a bone tissue repairing agent after surgery, such as breast cancer, can be used.
  • Compounds (Ia), (X) or salts thereof have an activity enhancing activity of neurotrophic factor. It is expected to have various neurodegeneration such as Alzheimer's dementia and general senile dementia, motor neuron disorders (such as amyotrophic lateral sclerosis), and diabetic peripheral neuropathy. The treatment and prevention of the disease based on it can be expected.
  • preparations containing compounds (Ia), (X) or salts thereof are expected to have anti-MMP activity, MMPs for osteoarthritis, rheumatoid arthritis, arteriosclerosis, cancer metastasis, etc.
  • MMPs for osteoarthritis MMPs for osteoarthritis
  • rheumatoid arthritis MMPs for osteoarthritis
  • arteriosclerosis arteriosclerosis
  • cancer metastasis etc.
  • the dosage of the fine water-insoluble or poorly water-soluble drug varies depending on the type and content of the water-insoluble or poorly water-soluble drug to be used, the elution time of the drug, the animal to be administered, etc., but the effective amount of each drug I just need.
  • the amount of the water-insoluble or poorly water-soluble drug is, for example, about 0.1 mg or more, preferably about 0.2 mg to about 500 mg, more preferably about 0-5 mg to about 200 mg.
  • a compound (la) or its salt when used as a water-insoluble or poorly water-soluble drug, and it is administered intra-articularly as an aqueous suspension injection, one dose per adult (body weight 5 O kg) per person
  • the amount is preferably about 0.1 to 50 mL, more preferably about 0.2 to: L OmL, and more preferably about 0 to about 0.1 mL to 50 mL, more preferably about 0.2 to 50 mL, as the administration volume of the finely divided water-insoluble or poorly water-soluble drug dispersed in the aqueous medium. 5-5 mL.
  • a compound (la) or its salt when used as a water-insoluble or poorly water-soluble drug, and it is administered intra-articularly as an aqueous suspension injection, one dose per adult (body weight 5 O kg) per person
  • concentration of the active ingredient in the above is, for example, about 0.1 mg / mL or more, preferably about 0.1-300 mgZmL, more preferably about 0.1 mg / mL or more, as the concentration of the fine water-insoluble or poorly water-soluble drug dispersed in an aqueous medium.
  • Omg / mL 0 Omg / mL, more preferably about 0.5 to 50 mg, mL (eg, 2 Omg / mL, etc.).
  • compound (la) or a salt thereof is used as a water-insoluble or poorly water-soluble drug and administered intra-articularly as an aqueous suspension injection
  • one adult body weight: 5 O kg
  • the frequency of administration per once per day or more for example, preferably about once every 2 days to 3 months, more preferably about once every 3 days to about 3 months, even more preferably about 1 week to 1 month
  • One time interval preferably about once every 2 days to 3 months, more preferably about once every 3 days to about 3 months, even more preferably about 1 week to 1 month
  • the finely divided water-insoluble or poorly water-soluble drug can be stored stably for a long time without aggregation in a cold state (eg, in a refrigerator) or at room temperature in a suspended or dry state.
  • the organic layer is water, after aqueous sodium bicarbonate solution, washed and dried with saturated Japanese brine (MgSO 4), and evaporated.
  • the residual oil was subjected to column chromatography. From the fraction eluted from ethyl acetate-hexane (3: 2), the title compound (1.36 g, 84%) was obtained as colorless needles. Melting point: 138-139 ° C.
  • Reference Example 13 The compound of Reference Example 13 was synthesized by the method according to Reference Example 1.
  • Reference Example 13 The compound of Reference Example 13 was synthesized by the method according to Reference Example 1.
  • Example 2 In the same manner as in Example 1, a fine compound is prepared under the conditions shown in Table 1 to obtain a suspension.
  • Fine particles of the compound obtained in Reference Example 4 were prepared in the same manner as in Example 31 under the conditions shown in Table 3 to obtain a suspension.
  • the content of the compound obtained in Reference Example 4 and distearoyl phosphatidylcholine (DSPC) was measured.
  • DSPC distearoyl phosphatidylcholine
  • Example 67 a suspension in which the compound obtained in Reference Example 13 had a concentration of about 2 Omg / mL was obtained.
  • the suspension is allowed to stand at room temperature for 2 weeks, and then it is evaluated with a dispersibility evaluation device (a device that evaluates redispersibility by placing the suspension on a rotating arm and reversing and shaking it 180 degrees at 60 strok minutes for 30 seconds). Upon evaluation, the redispersibility was extremely good.
  • Example 68 When these microparticles are administered orally, intramuscularly, subcutaneously or intraarticularly, a continuous change in blood drug concentration can be obtained.
  • Example 68
  • Example 6 9 a filter (Kiriyama Seisakusho, filter paper No. 3) was filtered to collect the fine drug particles, and finally dispersed in 0.5% CMC_Na, 0.01% polysorbate 80, and 5% mannitol aqueous solution. Thereafter, the suspension was subjected to autoclave sterilization (121 ° C, 20 minutes) to obtain a suspension in which the compound obtained in Reference Example 4 had a concentration of about 2 OmgZmL. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated with a dispersibility evaluation apparatus. As a result, the redispersibility was very good.
  • Example 6 9 a filter (Kiriyama Seisakusho, filter paper No. 3) was filtered to collect the fine drug particles, and finally dispersed in 0.5% CMC_Na, 0.01% polysorbate 80, and 5% mannitol aqueous solution. Thereafter, the suspension was subjected to autoclave sterilization (121 ° C, 20 minutes
  • Example 70 After stirring for 1 hour, fine particles containing the compound obtained in Reference Example 4 were obtained. Thereafter, the solution was filtered through a filter (Kiriyama Seisakusho, filter paper No. 3) to collect the fine drug particles, and finally dispersed in 0.5% CMC-Na, 0.01% pluronic F68, and 5% mannitol aqueous solution. Thereafter, the suspension was subjected to autoclave sterilization (121 ° C., 20 minutes) to obtain a suspension in which the compound obtained in Reference Example 4 had a concentration of about 20 mg L. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated by a dispersibility evaluation apparatus. As a result, the redispersibility was good.
  • Example 70 Example 70
  • Example 71 the drug fine particles were collected by filtration with a filter (Kiriyama Seisakusho, filter paper No. 3), and finally dispersed in 0.5% CMC-Na, 0.01% pull-mouth nick F 127, 5% mannitol aqueous solution. Thereafter, the suspension was subjected to autoclave sterilization (121 ° C, 20 minutes) to obtain a suspension in which the compound obtained in Reference Example 4 had a concentration of about 2 OmgZmL. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated by a dispersibility evaluation apparatus. As a result, the redispersibility was very good.
  • Example 71 the redispersibility was very good.
  • Example 72 Thereafter, the drug fine particles were collected by filtration with a filter (Kiriyama Seisakusho, filter paper No. 3), and finally dispersed in 0.5% CMC-Na, 0.01% pull-mouth nick L121, 5% mannitol aqueous solution. Thereafter, the mixture was subjected to autoclave sterilization (121 ° C, 20 minutes) to obtain a suspension in which the compound obtained in Reference Example 4 had a concentration of about 20 mg ZmL. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated by a dispersibility evaluation apparatus. As a result, the redispersibility was very good.
  • Example 72 Example 72
  • Example 73 A suspension in which the compound obtained in 4 had a concentration of about 2 Omg / mL was obtained. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated by a dispersibility evaluation apparatus. As a result, the redispersibility was good.
  • Example 73 A suspension in which the compound obtained in 4 had a concentration of about 2 Omg / mL was obtained. After the suspension was allowed to stand at room temperature for 2 weeks, it was evaluated by a dispersibility evaluation apparatus. As a result, the redispersibility was good.
  • Example 74 Example 74
  • test examples 1-3 were filtered to collect the drug microparticles, and finally 0.5% CMC-Na, Dispersed in 0.01% polysorbate 80, 5% mannitol aqueous solution.
  • the obtained microparticles are orally, intramuscularly, subcutaneously or intraarticularly administered to rats, a continuous change in blood drug concentration can be obtained.
  • Test examples 1-3 are orally, intramuscularly, subcutaneously or intraarticularly administered to rats, a continuous change in blood drug concentration can be obtained.
  • Example 6 A suspension equivalent to about 0.75 mg of the compound obtained in Reference Example 4 prepared in the same manner as in 7, 7, 71 and 72 was placed in a glass bottle using a microsyringe. Then, 15 mL of an elution test solution (20% phosphate buffer with 1% sodium dodecyl sulfate, pH 7) was added to the solution. This was sampled in 0.15 mL portions over time while shaking at 30 ° C and 60 strokes, and this was filtered (Acrodisc LC, Germanic Laboratory, diameter 13 mm, pore size 0.2). 2 ⁇ m) After filtration, the amount of drug eluted was determined by HPLC. Figure 2 shows the time course of the drug dissolution rate. As is clear from the figure, it was confirmed that the drug elution rate could be changed by the wetting agent to be added and the preparation method. Industrial applicability
  • ADVANTAGE OF THE INVENTION According to the manufacturing method of this invention, it is simple, the loss in the manufacturing process of the water-insoluble or poorly water-soluble drug used as a raw material is small, and a high yield is obtained. Can be manufactured.
  • the finely divided water-insoluble or poorly water-soluble drug obtained by the production method of the present invention is safe, less irritating to the administration subject, has a high content of the water-insoluble or poorly water-soluble drug, has excellent stability, Since it has excellent dispersibility in a dispersion medium and excellent drug sustained release effect, it is possible to provide an excellent pharmaceutical preparation.

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Abstract

L'invention concerne un procédé de production d'un médicament insoluble dans l'eau ou faiblement soluble dans l'eau sous la forme de granulés fins, ce médicament pouvant être administré par voie orale ou injecté. Ledit procédé consiste à mélanger rapidement un solvant aqueux avec une solution de solvant organique miscible avec un solvant aqueux et contenant un médicament insoluble dans l'eau ou faiblement soluble dans l'eau, ce médicament ayant été préalablement amélioré en termes de mouillabilité dans l'un au moins desdits solvants.
PCT/JP2002/003049 2001-03-29 2002-03-28 Procede de production d'un medicament sous forme de granules fins WO2002078673A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071711A2 (fr) 2005-12-22 2007-06-28 Glaxosmithkline Biologicals Sa Vaccin
WO2009000826A1 (fr) 2007-06-26 2008-12-31 Glaxosmithkline Biologicals S.A. Vaccin
EP2392346A1 (fr) 2006-04-07 2011-12-07 GlaxoSmithKline Biologicals SA Vaccin contre le Streptococcus pneumoniae
CN105705141A (zh) * 2013-03-15 2016-06-22 奥克伍德实验室有限责任公司 缓释微球及其制备方法
US9469630B2 (en) 2010-10-18 2016-10-18 Sumitomo Dainippon Pharma Co., Ltd. Sustained-release formulation for injection

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EP0781548A2 (fr) * 1995-12-15 1997-07-02 Takeda Chemical Industries, Ltd. Fabrication d'une préparation à libération prolongée pour injection
WO1997035563A2 (fr) * 1996-03-28 1997-10-02 Takeda Chemical Industries, Ltd. Preparation a liberation prolongee et production de cette preparation
EP0819431A1 (fr) * 1996-07-05 1998-01-21 Takeda Chemical Industries, Ltd. Médicament pour la prophylaxie et le traitement des troubles de la fonction visuelle
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JPH10167988A (ja) * 1996-10-09 1998-06-23 Takeda Chem Ind Ltd 経口液剤
WO1999037288A1 (fr) * 1998-01-21 1999-07-29 Takeda Chemical Industries, Ltd. Procede de lyophilisation de preparations a liberation prolongee
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WO2001089521A1 (fr) * 2000-05-23 2001-11-29 Takeda Chemical Industries, Ltd. Compositions medicinales contenant des derives du tiophene
WO2001097784A1 (fr) * 2000-06-23 2001-12-27 Takeda Chemical Industries, Ltd. Procede de production de medicaments contenant des phospholipides

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EP0484936A1 (fr) * 1990-11-08 1992-05-13 Fujisawa Pharmaceutical Co., Ltd. Suspensions à base de composés tricycliques
JPH05229941A (ja) * 1992-02-26 1993-09-07 Takeda Chem Ind Ltd フェノール誘導体を含有する注射用乳剤
JPH06183970A (ja) * 1992-12-16 1994-07-05 Fujisawa Pharmaceut Co Ltd 医薬用組成物
WO1996006617A1 (fr) * 1994-08-30 1996-03-07 Fujisawa Pharmaceutical Co., Ltd. Preparation de liposomes
EP0781548A2 (fr) * 1995-12-15 1997-07-02 Takeda Chemical Industries, Ltd. Fabrication d'une préparation à libération prolongée pour injection
WO1997035563A2 (fr) * 1996-03-28 1997-10-02 Takeda Chemical Industries, Ltd. Preparation a liberation prolongee et production de cette preparation
EP0819431A1 (fr) * 1996-07-05 1998-01-21 Takeda Chemical Industries, Ltd. Médicament pour la prophylaxie et le traitement des troubles de la fonction visuelle
WO1998009958A1 (fr) * 1996-09-06 1998-03-12 Takeda Chemical Industries, Ltd. 4,5,6,7-tetrahydrobenzo[c]thiopenes condenses utilises comme renforçateurs de l'action des facteurs induisant la differenciation cellulaire
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JPH10167988A (ja) * 1996-10-09 1998-06-23 Takeda Chem Ind Ltd 経口液剤
JPH10152438A (ja) * 1996-11-22 1998-06-09 Takeda Chem Ind Ltd １−アザキサントン誘導体またはその塩の安定化方法および１−アザキサントン誘導体含有組成物
WO1999037288A1 (fr) * 1998-01-21 1999-07-29 Takeda Chemical Industries, Ltd. Procede de lyophilisation de preparations a liberation prolongee
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WO2001074823A2 (fr) * 2000-03-31 2001-10-11 Takeda Chemical Industries, Ltd. Derives heterocycliques fondus, leur production et leur utilisation
WO2001089521A1 (fr) * 2000-05-23 2001-11-29 Takeda Chemical Industries, Ltd. Compositions medicinales contenant des derives du tiophene
WO2001097784A1 (fr) * 2000-06-23 2001-12-27 Takeda Chemical Industries, Ltd. Procede de production de medicaments contenant des phospholipides

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071711A2 (fr) 2005-12-22 2007-06-28 Glaxosmithkline Biologicals Sa Vaccin
EP2384765A2 (fr) 2005-12-22 2011-11-09 GlaxoSmithKline Biologicals S.A. Vaccin contre le Streptococcus pneumoniae
EP2402025A2 (fr) 2005-12-22 2012-01-04 GlaxoSmithKline Biologicals S.A. Vaccin
EP2392346A1 (fr) 2006-04-07 2011-12-07 GlaxoSmithKline Biologicals SA Vaccin contre le Streptococcus pneumoniae
WO2009000826A1 (fr) 2007-06-26 2008-12-31 Glaxosmithkline Biologicals S.A. Vaccin
US9469630B2 (en) 2010-10-18 2016-10-18 Sumitomo Dainippon Pharma Co., Ltd. Sustained-release formulation for injection
CN105705141A (zh) * 2013-03-15 2016-06-22 奥克伍德实验室有限责任公司 缓释微球及其制备方法
CN105705141B (zh) * 2013-03-15 2018-12-28 奥克伍德实验室有限责任公司 缓释微球及其制备方法

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