WO2001089521A1 - Compositions medicinales contenant des derives du tiophene - Google Patents

Compositions medicinales contenant des derives du tiophene Download PDF

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WO2001089521A1
WO2001089521A1 PCT/JP2001/004298 JP0104298W WO0189521A1 WO 2001089521 A1 WO2001089521 A1 WO 2001089521A1 JP 0104298 W JP0104298 W JP 0104298W WO 0189521 A1 WO0189521 A1 WO 0189521A1
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group
compound
acid
reaction
ring
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PCT/JP2001/004298
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Japanese (ja)
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Tetsuo Hoshino
Masahiro Kawase
Atsushi Ohta
Tsuneo Yasuma
Shigeru Kamei
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Takeda Chemical Industries, Ltd.
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Priority to AU58808/01A priority Critical patent/AU5880801A/en
Publication of WO2001089521A1 publication Critical patent/WO2001089521A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel pharmaceutical composition containing a thiophene derivative and a biodegradable polymer compound, particularly to a medicament or composition for preventing or treating bone disease or cartilage disease.
  • osteoporosis is increasing toward an aging society, and the frequency of occurrence of osteoporosis-related limb fractures is increasing remarkably.
  • peptide bioactive substances such as bone morphophogetic protein (BMP) promote the healing of bone fractures (Procedureing National Academia Science, USA (Proceeding National Academy Science USA), Vol. 87, pp. 2220-2224, 1990).
  • BMP bone morphophogetic protein
  • such peptidic substances are rapidly metabolized in vivo and are physicochemically or biologically unstable.
  • various non-peptidic bone and cartilage formation promoting substances which are expected to be able to overcome these points have been proposed.
  • 9-263545 discloses an attempt to use a non-peptide bone / chondrogenesis promoting substance together with a biodegradable polymer as a pharmaceutical composition, especially a sustained release agent.
  • a pharmaceutical composition comprising a non-peptide bone promoting substance and a biodegradable polymer compound is described.
  • Japanese Patent Application Laid-Open No. 2000-72678 (WO 99/65474) describes a sustained-release preparation for preventing and treating cartilage diseases, comprising a benzozopine derivative or the like and a biodegradable polymer compound.
  • examples of the drug used in the pharmaceutical composition of the present invention include a condensed benzothiophene derivative represented by the general formula (I) .
  • a compound having a condensed benzothiophene derivative as a basic skeleton is described in the following literature. ing.
  • JP-A-8-245386 discloses 4,5-dihydro-8_ (methylthio) isoxosazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5_dihydro-8-unethylthio) isoxazolo [5 , 4-d] benzo [cj thienophene-6-carboxamide]
  • a cell differentiation-inducing factor action enhancer comprising a representative compound is described.
  • Japanese Patent Application Laid-Open No. 10-130271 discloses that osteoporosis, bone fracture, osteoarthritis, osteoarthritis, Fused thiophene compounds useful for the prophylactic treatment of bone diseases such as rheumatoid arthritis, arteriosclerosis, cancer metastasis and diseases based on neurodegeneration are described.
  • the present invention provides a pharmaceutical composition, a production method, and a use thereof, in which a physiologically active substance such as a substance for promoting bone cartilage formation, for example, is locally applied, and the effect is maintained for a long period of time.
  • a physiologically active substance such as a substance for promoting bone cartilage formation, for example
  • la general formula (la) having a characteristic of ring A
  • R 1 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 2 represents a cyano group, a formyl group.
  • a pharmaceutical composition comprising a compound represented by the formula or a salt thereof and a biodegradable polymer compound.
  • R 3 represents a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an amino group, a sulfonolene group or an acyl group.
  • Group 5 represents a 5-membered heterocyclic ring; ring B represents a 5- to 7-membered hydrocarbon ring which may have a substituent; ).
  • the lactic acid-glycolic acid copolymer is a lactic acid-glycolic acid copolymer having a composition ratio of lactic acid / glycolic acid of about 100/0 to 4060 (molar ratio).
  • R 1 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.
  • hydrocarbon residue in the hydrocarbon residue include an optionally substituted aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic monoaliphatic hydrocarbon residue, and an aromatic And a hydrocarbon residue or an aromatic monoaliphatic hydrocarbon residue (an aralkyl group).
  • aliphatic hydrocarbon residue examples include methyl, ethyl, propyl, isopropylinole, puynole, isobutynole, sec-pentinole, tert-butynole, pentinole, isopentinole, neopentyl, tert-pentinole, hexyl, isohexyl, C 1-8 saturated aliphatic hydrocarbon residues (eg, alkyl group) such as heptyl and octyl, for example, vinyl, aryl (allyl), 1-propenyl, 2-methyl-1-propenyl, 1 —Petinore, 2—Betini / le, 3—Betinore, 3—Methinore 21—Putnore, 1—Pentinore, 2—Pentinole, 3—Pentenigre, 4—Pentenole , 4-1 Mechinore 1-Penteninole, 1-Hex
  • alicyclic hydrocarbon residue examples include a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Alkyl group, etc.), 1-cyclopentenyl, 2-cyclopenteninole, 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2 —Cycloheptur,
  • C3-C7 unsaturated alicyclic hydrocarbon residues e.g., cycloalkenyl group, cycloalkadiele group, etc.
  • alicyclic hydrocarbon residues such as 3-cycloheptur, 2,4-cyclohexheptageninole, 1-indenyl, 2-Indul, 1-Indanole, 2-Indanyl, 1,2,3,4-Tetrahydro-1-naphthyl, 1,2,3,4-Tetrahydro-2-naphthyl, 1,2-Dihydro-1-naphthyl, 1 Partial saturation of 1,2-dihydro-1-naphthyl, 1,4-dihydro-1-naphthinole, 1,4-dihydro-12-naphthinole, 3,4-dihydro 1-naphthyl, 3,4-dihydro-2-naphthyl Fused bicyclic.
  • Hydrocarbon residue preferably C. - Partially saturated condensation Bicyclic hydrocarbon residue, etc. (5 And a 6-membered non-aromatic cyclic hydrocarbon group to which a benzene ring is bonded)].
  • alicyclic monoaliphatic hydrocarbon residue include those in which the above alicyclic hydrocarbon residue is bonded to an aliphatic hydrocarbon residue, for example, cyclopropylmethyl, cyclopropylethyl, cyclopeptinolemethy.
  • aromatic hydrocarbon residue examples include phenyl, 1-naphthyl, ⁇ -naphthyl, 4-indeninole, 5-indur, 41-indaninole, 5-indaninole, 5,6,7,8-tetrahydro-1-naphthyl , 5,6,7,8-tetrahydro-1-naphthyl, 5,6-dihydro-11-naphthyl, 5,6-dihydro-12-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro And aryl groups having 6 to 10 carbon atoms (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is fused to a
  • aromatic monoaliphatic hydrocarbon residue examples include benzyl, phenethyl, 1-phenylenoletinol, 1-phenylinolepropizole, 2-phenylinolepropinole, and phenyl CHalkyl such as 3-phenylinolepropyl.
  • Aralkyl groups having 7 to 14 carbon atoms such as naphthinolealkyl groups such as naphthylmethyl, naphthylethyl, ⁇ -naphthylmethyl, and ⁇ -naphthylethyl; Ali-Lu C Archi ),
  • styryl, cinnamyl and the like C 2 _ 4 alkenyl groups.
  • Aryl C 2 _ 4 alkyl group and the like.
  • the heterocyclic group of the optionally substituted heterocyclic group for R 1 includes, for example, (i) a 5- to 7-membered heterocyclic ring containing l sulfur atoms, 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 atom containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom (Iv) these heterocyclic groups are condensed with a 5- to 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom, and .
  • the heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be either aromatic or non-aromatic. You may.
  • heterocyclic group in the optionally substituted heterocyclic group for R 1 examples include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group.
  • heterocyclic group in the optionally substituted heterocyclic group for R 1 include: (i) an aromatic monocyclic heterocyclic group (eg, furyl, cheel, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl) , Imidazolyl, virazolinol, 1,2,3-oxadiazolyl, 1,2,4 monooxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 , 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyragel, triazinyl, etc.), (ii) fused aromatic heterocyclic group (eg, Benzofuranyl, isobenzofur
  • Surufieru group in substituted optionally Surufieru may be based, "hydrocarbon residue” in “each optionally substituted hydrocarbon residue or heterocyclic group” as R 1 mentioned above or " Heterocyclic group ”and one SO— bonded to each other.
  • Aromatic monocyclic heterocyclic group eg, furyl, cheel, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, virazolyl, 1,2,3-oxoxadiazolyl, 1,2,4- Oxadiazolyl, 1,3,4-thiaxazolyl, furazal, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4— Triazolyl, tetrazolyl, pyridyl, pyrimidur, pyridazyl, A group in which a sulfinyl group is bonded to a pyrazinyl or triazinyl group; an aromatic condensed heterocyclic group (eg, benzofuranyl, isobenofurael, benzo [b] chenyl,
  • Bok 8 alkyl and sulfinyl group bonded C ⁇ 8 alkylsulfinyl can be mentioned up.
  • R 1 it is a sulfonyl group in the optionally sulfonyl group which may be substituted, the above-mentioned as R 1 of the "each substituted or substituted hydrocarbon residue which may have heterocyclic group", “hydrocarbon residue” Or those in which a “heterocyclic group” and one so 2 — are bonded.
  • aromatic monocyclic heterocyclic group eg, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, villa Zolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 A group in which a thiadiazolyl, 1,2,3_triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidiel, pyridazinyl, pyrazyl, triazinyl, etc.) are bonded to a sulfonyl group; an aromatic fused heterocycl
  • C E _ 8 alkylsulfonyl C _ 8 alkyl and sulfonyl group is bonded in the cited et it is.
  • R 1 as the hydroxy group which may be substituted, hydroxyl group and optional substituents on the hydroxyl group, for example, “respectively optionally substituted carbon hydrocarbon residue or heterocyclic group represented by R 1 And a hydroxyl group substituted by ".
  • C- 8 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butynole, tert-butylinole, pentyl, isopentyl, neopentinole, tert-pentyl, hexinole, isohexyl, heptyl, octyl and the like.
  • C 6 More preferably, C 6 —e.
  • a hydroxyl group substituted with aryloxy (particularly preferably phenyl) or an aromatic monocyclic heterocyclic group (particularly preferably pyridyl) or an aromatic fused heterocyclic group (particularly preferably quinolyl) is exemplified.
  • the “heterocyclic group” is the same substituent as the “hydrocarbon residue” or the “heterocyclic group” in the “optionally substituted hydrocarbon residue or heterocyclic group” as R 1 described above. You may have each.
  • R 1 as the thiol group that may be substituted, an appropriate substituent, for example, represented by R 1 'may be substituted hydrocarbon residue or heterocyclic group to a thiol group and a thiol group And a thiol group substituted with Preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylinole, tert-butylinole, pentinole, isopenpentole, neopentinole, tert-pentinole, hexyl, isohexyl, heptyl, octyl and the like.
  • Arylthio aromatic monocyclic heterocyclic group (eg, furyl, cyenyl, pyrrolyl, oxazolinole, isoxoxolinole, thiazolinole, isotizazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl , 1,3,4_oxadizazolyl, 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, pyrazil, triazinyl, etc.
  • aromatic monocyclic heterocyclic group eg, furyl, cyenyl, pyrrolyl, oxazolinole, is
  • hydrocarbon residue or “heterocyclic group” as the substituent of the substituted thiol group exemplified here is the above-mentioned “optionally substituted hydrocarbon residue or heterocyclic group” as R 1. It may have the same substituent as the “hydrocarbon residue” or the “heterocyclic group” in the “group”.
  • methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec butynole, tert-butyl, pentynole, isopenpentole, neopentyl, tert-pentyl, hexyl, isohexyl, heptinole, octynole, etc. include C i _ 8 alkylthio substituted with 8 alkyl.
  • Examples of the amino group which may be substituted in R 1 include an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group.
  • the location is a substituted amino group, for example, be optionally substituted hydrocarbon group substituted (e.g., represented by R 1 Those similar to the conversion to hydrocarbons may be residues, more specifically, C M alkyl group, c 3 _ 7 cycloalkyl, c 2 _ 8 alkenyl, c 2 _ 8 alkynyl group, c 3 — 7 may have a cycloalkenyl group or a CH alkyl group.
  • R ′ represents a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively, wherein “a hydrocarbon residue or a heterocyclic group which may be respectively substituted” as R ′ Has the same substituent as the “hydrocarbon residue” or “heterocyclic group” in the above-mentioned “hydrocarbon residue or complex ring group which may be substituted” as R, respectively. ), Preferably c w .
  • Ashiru group e.g., c 2 _ 7 Arukanoiru, Benzoiru, Nikochinoiru etc.
  • amino group e.g. having a one or two substituents, Mechiruamino, Jimechiruamino, Echiruamino, Jechiruamino, dipropionate Piruamino, Jibuchiruamino, Jiariruamino, the consequent opening Xylamino, phenylamino, N-methyl-1-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino and the like.
  • two groups in the substituted amino group may combine to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, morpholino, thiomorpholino, etc.).
  • Hydrocarbon residue “heterocyclic group”, “sulfur group” in “hydrocarbon residue, heterocyclic group, sulfier group, sulfol group, which may be substituted” represented by R 1 Group “and” sulfonyl group "are:! May be substituted with up to three substituents.
  • substituents examples include a lower (C alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C 2 - 6) alkenyl [e.g., Bulle, Ariru (allyl), 1-propenyl, 2 one methyl one 1 one propenyl - le, 1 - 2-butenyl, 2-butenyl, 3-methyl-2-butul, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenole, 4-methynole , 1-hexeninole, 2-hexene-nore, 3- hexenyl, 4-hexenyl, 5-hexenyl, etc.], lower (C 2 _ 6 ) alk Nyl groups (e
  • Aroma with 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur A 5- or 6-membered heterocyclic group, (ii) an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a benzene ring or a nitrogen atom; Oxygen atom Fused bicyclic heterocyclic group in which an aromatic 5- or 6-membered heterocyclic ⁇ having 1-3 hetero atoms selected from sulfur atom to form condensed, (iii) 1Aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, 2benzene ring and 3selected from nitrogen atom, oxygen atom and sulfur atom Condensed tricyclic heterocyclic group formed by condensing an aromatic 5- or 6-membered heterocyclic or benzene ring having 1 to 3 heteroatoms], a non-aromatic heterocyclic group (eg
  • C 7 _ 14 Ararukiru group (example, benzyl, phenethyl, 1 one Fueniruechiru, 1 one Hue - Propyl, 2-phenylpropyl, 3 _ phenylpropyl, alpha-Na Fuchirumechiru one Nafuchiruechiru, beta one naphthylmethyl, etc..
  • Ariru one C W alkyl groups such as beta one naphthylene Honoré ethyl Honoré), amino group, N- monosubstituted amino group [e.g., Mechiruamino, Echiruamino, Ariru (allyl) amino, cyclohexyl amino, N- (C ⁇ 6 alkyl) amino groups such as Fueniruamino, N- (C 2 _ 6 Al Keninore) amino group, N _ (C 3 - 7 Shikuroanorekiru) amino group, N-- like ( ⁇ 6 10 Ari) amino groups], N, N-disubstituted amino group [e.g., Jimechiruamino, Jechiru amino, Jibuchiruamino, Jiariru (allyl) amino, such as N- methyl-one N- Fueyu Ruamino, C alkyl, C 2 _ 6 alkenyl, C 3 _ 7 cycloalkyl Contact and C 6
  • an amino group substituted with two substituents selected from an aryl group, etc. an amidino group, an acyl group (e.g., formyl, acetyl, propioyl, butyryl, isobutyryl, valeryl, isopaparyl, pino)
  • N- monosubstituted force Rubamoiru group e.g., methyl Scarpa moil, Echiru Power Rubamoiru, alkoxy carbamoyl cyclohexane, such as such as phenylene carbamoyl N - alkyl) force Rubamoiru group, N- (C 2 "6 Aruke - Le) force Rubamoiru group, N- (C 3 - 7 cycloalkyl) force Rubamoiru group , N— (C.aryl) carbamoyl group, etc.], N, N—disubstituted rubamoyl group [eg, dimethylcarbamoyl, dimethylcarbamoyl, dibut
  • N- methyl-one N- Hue - such as carbamoyl, C ⁇ 6 alkyl group, C 2 _ 6 alkenyl Le group, C 3 _ 7 consequent opening alkyl Contact Yopi C M.
  • N N over-disubstituted sulfamoyl group
  • sulfamoyl group e.g., dimethylsulfamoyl, Jefferies chill sul Famo I le, dibutylsulfamoyl, Jiariru (allyl) sulphamoyl, such as N- methylcarbamoyl Lou N- Hue acylsulfamoyl, 6 alkyl group, C 2 _ 6 Arukeeru group,
  • C 3 _ 7 cycloalkyl group and C ⁇ .
  • Sulfamoyl group substituted with two substituents selected from aryl groups, etc.) carboxyl group, lower (C) alkoxy-unrebonyl group (eg, methoxycarbol, ethoxycarbonyl, propoxycarbinole, isopropoxyca ⁇ bon / le, putoxycanolevone, isobutoxyka ⁇ boninole, sec-butoxycarbonyl, tert-butoxycanoleboninole, pentinoleoxycarbonyl, hexyloxycarbonyl, etc.), hydroxyl group, lower ( C, _ 6 ) Alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ⁇ ert-butoxy, pentinoreoxy, hexyloxy, etc.), lower (C 2 _ 6) ) Arke-loxy group [
  • C 3 _ 7 cycloalkyl O alkoxy group e.g., cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo alkoxy, cyclohexane Kishiruokishi, cyclohexylene, etc.
  • Puchiruokishi cycloalkyl O alkoxy group (e.g., cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo alkoxy, cyclohexane Kishiruokishi, cyclohexylene, etc. Puchiruokishi)
  • C 6 — K aryloxy group (eg, phenoxy, naphthyloxy, etc.), C 7 _ 14 7 ral cheloxy group (eg, phenyl alkyloxy, naphthyl-CM alkylo C 6 _i such as shore.
  • aryloxy group eg, phenoxy, naphthyloxy, etc.
  • C 7 _ 14 7 ral cheloxy group eg, phenyl alkyloxy, naphthyl-CM alkylo C 6 _i such as shore.
  • Aryl, CM alkyloxy, etc. mercapto, lower
  • (C ⁇ ) alkylthio group e.g., methylthio, Echiruchio, propylthio, isopropoxy port Pinorechio, Puchinorechio, Isobuchinorechio, sec Buchinorechio, tert- flop Chiruchio, pentylthio, Isopenchiruchio, neopentylthio, the like cyclohexylthio
  • C M4 Ararukiruchio group e.g. Phenyl-CH alkylthio, naphthyl-cw alkylthio, etc. cw. Aryl-cw alkylthio group, etc.), cw.
  • Arylthio group e.g., phenylthio, naphthylthio, etc.
  • lower (c ⁇ ) alkyl sulfier group e.g., methylsulfinyl, ethylsulfinyl, propylsulfyl, isopropylsulfiel, butylsulfiel, etc.
  • C 7 _ 14 ⁇ Lal kill sulfinyl group e.g., phenylene Lou CH ⁇ Ruki Angeles sulfide El, etc.
  • Arylsulfonyl group eg, phenylsulfonyl, naphthinolesulfoninole, etc.
  • sulfo group cyano group, azide group, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro group, nitroso group, esterification
  • a phosphono group eg, a ( 6- alkoxy) phosphoryl group such as a phosphono group or ethoxyphosphoryl, a di (Cw alkoxy) phosphoryl group such as a diethoxyphosphoryl group
  • an esterified phosphono group Lower (C ⁇ ) alkyl group substituted with a di (C ⁇ 6 alkoxy) phosphoryl C w alkyl group such as a phosphonoalkyl group, an alkoxyphosphorylalkyl group, and a diethoxyphosphorylmethyl group Etc.
  • c J- 6 alkylenedioxy such as methylenedioxy and ethylenedioxy may be formed.
  • C 6 ⁇ above.
  • C 6-1 as a substituent of an aryl group or an N, N-disubstituted amino group.
  • Aryl As a substituent of an aryl group or an N-monosubstituted sulfamoyl group.
  • Aryl the same as a substituent of an N, N-disubstituted sulfamoyl group.
  • the aryl group may be further substituted with 1 to 3 substituents.
  • substituents examples include a lower (C ⁇ ) alkyl group, an amino group, an N- (Cwalkyl) amino group, , N- di (Cw alkyl) amino group, amidino group, a force Luba moil group, N- (C-6 alkyl) force Rubamoiru group, N, N- di ( ⁇ DOO 6 alkyl) force Rubamoiru group, a sulfamoyl group, N -Alkyl) sulfamoyl group,
  • An azido group, a halogen atom, a nitro group, a nitroso group, an optionally esterified phosphono group [eg, a phosphono group, a 6- alkoxyphosphoryl group, a di (Cw alkoxy) phosphoryl group, etc.]; (Cw) alkyl group substituted with a good phosphono group
  • phosphono primary alkyl group, alkoxy phosphoryl primary alkyl group, and di (C ⁇ 6 alkoxy) phosphoryl one Cw al kill groups such as jet alkoxy phosphoryl methyl] and the like.
  • substituents a hydroxyl group and a lower (CJ alkoxy group as a substituent, when the contact may form a cw ⁇ Rukirenjiokishi such Mechirenjiokishi Oyopi Echirenjiokishi.
  • R 1 is preferably Represents an optionally substituted sulfier group, sulfel group, hydroxyl group or thiol group, that is, R 1 is a group represented by the formula: _SR 14 , -SOR 14 , —SO 2 R 14 or one OR 14 (wherein R 14 represent, respectively, an optionally substituted hydrocarbon residue or heterocyclic group.) in the group represented by the formula.
  • R 1 ′ is, among the optionally substituted hydrocarbon residue, heterocyclic group, sulfyl group, sulfonyl group, hydroxyl group, thiol group or amino group, a formula: 1 X, 1 W (wherein, X ′ represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally sulfur atom, and W ′ may be substituted A cyclic group or a carbon atom or a nitrogen atom having two or more substituents.).
  • an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group may be an optionally substituted hydrocarbon residue as R 1.
  • R 1 ′ the formula: 10 ⁇ , 1 W, (wherein X is a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an oxidized Represents a sulfur atom, may be substituted, and represents a cyclic group or a carbon atom or a nitrogen atom having two or more substituents.)
  • X is a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an oxidized
  • Represents a sulfur atom may be substituted, and represents a cyclic group or a carbon atom or a nitrogen atom having two or more substituents.
  • the substituent may be a substituent that the “hydrocarbon residue” or “heterocyclic group” in the above “optionally substituted hydrocarbon residue or heterocyclic group” as R 1 has And R 1 include the same groups as the “optionally substituted hydrocarbon residue or heterocyclic group”.
  • the “sulfur atom which may be oxidized” represented by X ′ is one s _, S O— or one
  • a cyclic group in the ⁇ good hydrocarbon residue or heterocyclic group '' for example, an optionally substituted alicyclic hydrocarbon residue, an optionally substituted aromatic hydrocarbon residue, and an optionally substituted And a heterocyclic group (aromatic monocyclic heterocyclic group, aromatic condensed heterocyclic group, non-aromatic heterocyclic group).
  • the substituent which the “cyclic group” may have is R.
  • the same substituents as the “hydrocarbon residue” or “heterocyclic group” in the “hydrocarbon residue or heterocyclic group which may be substituted” as 1 may be mentioned. .
  • 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” represented by W is, for example, tert-butyl, isopropyl And the same or different 2 to 3 substituents are bonded to the carbon atom as described above (in other words, those having 0 to 1 hydrogen atom on the atom are mentioned.
  • hydrocarbon residue or "heterocyclic group” substituent
  • Contact Yopi R 1 which may have the in "each optionally substituted by hydrocarbon residue or heterocyclic group” as R 1 which is And the same groups as those described above for “a hydrogen residue or a heterocyclic group which may be substituted”.
  • the nitrogen atom having two or more substituents is an N, N-disubstituted amino group.
  • substituents in the “N, N-disubstituted amino group” include the same substituents as the “amino group I” in the “optionally substituted amino group” for R 1 described above. No.
  • R 1 ′ is, among the optionally substituted hydrocarbon residue, heterocyclic group, sulfinyl group, sulfonyl group, hydroxyl group, thiol group or amino group, a formula: one X, one W (wherein, X 'Represents an oxygen atom or a sulfur atom which may be oxidized, and represents a cyclic group which may be substituted.) Is a group represented by the following formula:
  • R 2 is a cyano group, a formyl group, a thioformyl group or a formula: one Z 1 —? 2 (wherein Z 1 represents one CO—, one CS—, one SO— or one S0 2 —, and Z 2 represents Represents an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group.
  • Z 1 in R 2 is preferably one CO— or one CS—, more preferably one CO—.
  • R 2 is represented by one CO—Z 2 ′ (wherein, Z 2 ′ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group, or a hydroxyl group). The group is preferred.
  • the optionally substituted hydrocarbon group which may be substituted in Z 2 is you Keru substituted R 1 Les, be good Le, the same as the hydrocarbon residue.
  • the optionally substituted hydrocarbon residue in Z 2 is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isopti / re, sec And saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl) such as -butyl, tert-butyl, pentyl, isopenpentyl, neopentynole, tert-pentyl, hexyl, isohexynole, heptinole, and octyl. . .
  • Examples of the optionally substituted heterocyclic group for Z 2 include the same as the optionally substituted heterocyclic group for R 1 .
  • Examples of the optionally substituted amino group for Z 2 include, for example, the same as the optionally substituted amino group for R 1 .
  • Examples of the optionally substituted amino group preferably include an amino group and an amino group having one or two C w alkyl groups as substituents (eg, methylamino, dimethinorealamino, ethylamino, getylamino, dibutylamino, etc.). .
  • the optionally substituted hydroxyl group in Z 2 is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butylinole, pentinole, isopentyl, neopentyl, neopentyl, tert-pentyl , Kishinore, hexyl I Seo, heptyl, is C i-8 alkyl Ruokishi substituted with ⁇ ⁇ 8 alkyl such Okuchiru like to.
  • Z 2 is is a an amino group or substituted or optionally substituted in R 2 les is preferably a hydroxyl group.
  • R 2 is amino group which may be substituted more preferred.
  • Z 2 in R 2 is Amino group or an amino group having a C i_ 8 Arukinore group as one or two substituents, (e.g., Mechiruamino, Jimechiruamino, Echiruamino, Jechiruamino, Jibuchiruamino etc.) are preferable.
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfol group or an acyl group.
  • Examples of the optionally substituted hydrocarbon residue in R 3 include, for example, the same as the optionally substituted hydrocarbon residue in R 1 .
  • the hydrocarbon residue which may be substituted in R 3 is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptizle, sec-butyl, tert-butyl, Examples thereof include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl group) such as pentinole, isopentinole, neopentinole, tert-pentyl, hexinole, isohexinole, heptinole, and octyl.
  • the heterocyclic group which may be substituted in R 3, for example, in R 1 The same thing as the heterocyclic group which may be substituted is mentioned.
  • Examples of the optionally substituted hydroxyl group for R 3 include, for example, the same as the optionally substituted hydroxyl group for R 1 .
  • Examples of the optionally substituted amino group for R 3 include the same as the optionally substituted amino group for R 1 .
  • the optionally substituted sulfonyl group for R 3 includes, for example, the same as the optionally substituted sulfonyl group for R 1 .
  • the optionally substituted acyl group for R 3 is preferably, for example, a group in which the ⁇ optionally substituted hydrocarbon residue or heterocyclic group '' represented by R 1 is bonded to a carbonyl group.
  • the hydrocarbon residue represented by R 1 heterocyclic group, sulfinyl group, those similar to the Ashiru group as a substituent of the sulfonyl group levator only ⁇ is.
  • R 3 ′ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group.
  • the hydrogen atom of R 3 ′ an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group
  • the hydrogen atom of R 3 an optionally substituted hydrocarbon residue
  • Examples include the same as a ring group, a sulfonyl group or an acyl group.
  • R 3 ′′ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfol group or an acyl group.
  • R 3 each optionally substituted hydrocarbon group which may be substituted ", a heterocyclic group, the Sunorehoniru group or Ashiru group, each optionally substituted hydrocarbon group which may be substituted R 3, a heterocyclic group, sulfonyl And the same as the above-mentioned groups or acyl groups.
  • R 4 represents a substituted hydroxyl group.
  • the substituted hydroxyl group for R 4 may be a substituted hydroxyl group represented by R 1 A substituted hydroxyl group in an optionally substituted hydroxyl group, e.g., an appropriate substituent for the hydroxyl group, e.g., a ⁇ substituted hydrocarbon residue or heterocyclic group which may be substituted '' represented by R 1 Hydroxyl group.
  • C 6 — substituted with an aryl group.
  • alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptinole, octinole, etc.
  • Substituted alkyloxy more preferably substituted with methyl, ethyl, propyl, isopropyl. ⁇ 3 alkynoleoxy.
  • heterocyclic group may be the “hydrocarbon residue” or the “heterocyclic group” in the aforementioned “optionally substituted hydrocarbon residue or heterocyclic group” as R 1. V, each of which may have the same substituent as the substituent.
  • R 5 represents the optionally substituted sulfinyl group or snorlefur group in R 1 .
  • R 6 has the same meaning as the substituted or substituted thiol group in R 1 .
  • R 7 has the same meaning as the substituent of the optionally substituted amino group in R 1 .
  • R 8 has the same meaning as R 2 .
  • R 9 has the same meaning as Z 2 above.
  • R 1G represents a protecting group for a lipoxyl group.
  • the carboxyl protecting group represented by R 1 0, for example, include substituted similar such as substituted hydrocarbon residue which may have groups shown in R 1.
  • R 11 represents an amino group which may be substituted.
  • the substituted amino group include, for example, an optionally substituted hydrocarbon residue (for example, the same as the optionally substituted hydrocarbon residue represented by R 1 , more specifically, 8 alkyl group, C._ 7 consequent opening Anorekiru group, C 2 _ s alkenyl, C 2 _ 8 alkynyl group, C 3 _ 7 cycloalkenyl group, which may have an alkyl group C 6 ⁇ .
  • An aryl group an optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R 1 ), or a compound represented by the formula: Represents a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively, wherein the “hydrocarbon residue or heterocyclic group which may be respectively substituted” as R ′ is as defined above.
  • R ′ has the same substituent as the “hydrocarbon residue” or “heterocyclic group” in the “optionally substituted hydrocarbon residue or heterocyclic group” as R ′ or.), preferably C H0 Ashiru group (e.g., C 2 _ 7 Arukanoiru, Benzoiru, two Kochinoiru etc.), an amino group (e.g.
  • an N, N-disubstituted amino group eg, dimethylamino, getylamino, dipropylamino, dibutylamino, diarylamino, N-methyl-1-N-phenylamino, etc.
  • N, N-diC ⁇ is more preferable, and N, N-diC ⁇ is more preferable.
  • 3 alkylamino groups eg, dimethylamino, getylamino, dipropylamino, etc.).
  • two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, monoreholino, thiomorpholino, etc.).
  • R 13 represents an optionally substituted amino group or a substituted hydroxyl group.
  • the R 1 3, include the same groups as the R 4 or the R 1 1.
  • R 13 ′ represents an optionally substituted amino group or hydroxyl group.
  • R 13 ′ includes a 7k acid group, R 4 and the same groups as R 11 .
  • X represents a halogen atom such as fluorine, chlorine, bromine, and iodine
  • Z 5 indicates one CO—.
  • Z 6 has the same meaning as the optionally substituted amino group in Z 2 .
  • Z 7 indicates one CO—.
  • z 8 has the same meaning as the optionally substituted hydrogen residue or heterocyclic group in z 2 .
  • Ring Aa represents a 5- to 7-membered ring which may be substituted.
  • the optionally substituted 5- to 7-membered 5- to 7-membered ring in ring Aa 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 either an alicyclic ring or an aromatic ring.
  • 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 Aromatic hydrocarbon ring (eg, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene , 2, C 5 _ 7 consequent opening alkenes such Putajen like to 4 consequent opening, and a C 5 _ 7 cycloalkadienes).
  • 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 heterocyclic ring containing a nitrogen atom, or (iii) a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms and one sulfur or oxygen atom is exemplified.
  • 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.
  • ring Aa is an aromatic 5-membered heterocyclic ring represented by the following ring A.
  • an optionally substituted hydrocarbon residue represented by R 3 an optionally substituted hydrocarbon residue represented by R 3 , a heterocyclic group, a hydroxyl group, an amino group, Examples are the same as the sulfonyl group or the acyl group.
  • Ring A is
  • R 3 represents 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 represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a cyano group or an amino group, an acyl group, a hydrocarbon residue or a heterocyclic group which may be substituted, R may be substituted together with the ring-constituting atoms of the thiophene ring and the ring Aa! / May form a hydrocarbon ring or a heterocyclic ring.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • Examples of the optionally substituted amino group for R include, for example, the same as the optionally substituted amino group for R 1 .
  • Examples of the optionally substituted acyl group for R include the same as the optionally substituted acyl group for R 3 .
  • Examples of the optionally substituted hydrocarbon residue in R include, for example, the same as the optionally substituted hydrocarbon residue in R 1 .
  • the heterocyclic group which may be substituted in R for example, location for R 1
  • the same thing as the heterocyclic group which may be substituted is mentioned.
  • the optionally substituted hydrocarbon ring formed by R together with the thiophene ring and the ring-constituting atoms (preferably ring-constituting carbon atoms) of ring Aa may be alicyclic or aromatic. Further, 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 B. Ring B represents a 5- to 7-membered hydrocarbon ring which may have a substituent.
  • the 5- to 7-membered hydrocarbon ring of the 5- to 7-membered hydrocarbon ring which may have a substituent in ring B is an alicyclic or aromatic 5- to 7-membered hydrocarbon ring, Is also good.
  • the alicyclic 5-7 membered hydrocarbon ring, C 5 - 7 saturated alicyclic hydrocarbon ring (e.g., cyclopentane, hexane consequent opening, C 5 _ 7 Shikuroaruka emissions such Sik port heptane) and C 5 _ 7 unsaturated alicyclic hydrocarbon ring for example, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene,
  • 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).
  • R is preferably a 5- to 14-membered heterocyclic ring which may be substituted with a thiophene ring and a ring-constituting atom of ring Aa (preferably, a ring-constituting carbon atom), and more preferably It is a 5- to 7-membered heterocyclic ring.
  • the heterocyclic ring is preferably, for example, (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom; To 7-membered heterocyclic ring, or (iii):! To 5 to 7-membered heterocyclic ring containing two nitrogen atoms and one sulfur or oxygen atom.
  • heterocyclic rings exemplified in (i) to (iii) may be either saturated or unsaturated, and the unsaturated heterocyclic groups may be aromatic or non-aromatic. It may be. Having substituents on rings B, B-1, C, D, D-2, D-3, D-4, D, D, -1, D'-2, D, -3 Examples of the substituent of the 5- to 7-membered hydrocarbon ring include those similar to the substituent of the “optionally substituted hydrocarbon residue” in R 1 .
  • an aliphatic hydrocarbon residue is used, and more preferably, for example, methyl, ethanol, propyl, isopropyl , Butyl, isoptyl, sec-butyl, tert-butynole, pentynole, isopenpentole, pentosepentinole, tert-pentyl, hexyl, isohexyl, heptyl, octyl and other saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (Eg, an alkyl group).
  • It represents a good 5- to 7-membered hydrocarbon ring preferably a 5- to 7-membered hydrocarbon ring having no substituent. More preferably, a 5- to 7-membered saturated hydrocarbon ring having no substituent is exemplified. More preferably, a 6-membered saturated hydrocarbon ring having no substituent is exemplified.
  • a compound represented by the formula (I) is preferable.
  • R 1 is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group
  • R 2 is one Z i — Z 2 (where Z 1 is
  • Ring A is
  • R 3 has the same meaning as described above.
  • R 1 is each substituted with an alkyl-bound sulfier group or sulfonyl group, a thiol group optionally substituted with Ci-s alkyl, or substituted with 1 to 3 substituents, respectively. May be C 6 — i.
  • Ariru (particularly preferably phenyl), an aromatic monocyclic Hajime Tamaki (particularly preferably pyridyl) or an aromatic fused Hajime Tamaki (particularly preferably quinolyl) optionally hydroxyl group which may be substituted with; is R 2 , - ⁇ ⁇ - ⁇ 2 (wherein ⁇ 1 represents one co—, and z 2 represents an optionally substituted hydroxyl group or an amino group, respectively); Ring A:
  • 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); and a compound or a salt thereof, wherein ring B is a C 5 _ 7 saturated alicyclic hydrocarbon ring, preferable.
  • ring B is a C 5 _ 7 saturated alicyclic hydrocarbon ring, preferable.
  • R 1 is an optionally substituted sulfiel group, sulfonyl group, hydroxyl group or thiol group
  • R 2 is one Z i— Z 2 (where Z 1 is one CO— or One CS—, Z 2 each represents a substituted or unsubstituted hydroxyl group or an amino group.)
  • R 4 is an alkyloxy; and ring C may have a substituent.
  • Compounds that are hydrocarbon rings or salts thereof are preferred.
  • R 1 is a sulfiel group or a sulfonyl group bonded with alkyl, a thiol group optionally substituted with alkyl, or 1 to 3 substituents, respectively. May be C 6 — i.
  • an aromatic monocyclic Hajime Tamaki particularly preferably pyridyl
  • aromatic Zokuchijimigo Hajime Tamaki particularly preferably quinolyl
  • hydroxyl group which may be substituted with
  • R 2 One Z 1 —Z 2 (wherein, Z 1 represents one CO—, and Z 2 each represents an optionally substituted hydroxyl group or an amino group);
  • R 4 is C alkyloxy;
  • C 5 _ 7 is a saturated compound is alicyclic hydrocarbon ring, or a salt thereof is more preferable.
  • a compound represented by the formula (Ia) [hereinafter referred to as compound (Ia).
  • the salt of the raw material compound for producing the salt is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or And salts with acidic amino acids.
  • a pharmaceutically acceptable salt for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or And salts with acidic amino acids.
  • Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salts, ammonium salts and the like.
  • salt with an organic base examples include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, jetanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ ′-dibenzylethylenediamine and the like. And salts thereof.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, triflic acid / leoacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, ⁇ -toluenesulfonic acid, and the like.
  • 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, glutamic acid, and the like. Salts.
  • Compound (Ia) or a salt thereof may be a prodrug thereof.
  • a prodrug of compound (I) 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, or hydrolysis.
  • a compound or a salt thereof for example, a compound in which a hydroxyl group of the ligate compound (la) or a salt thereof is acylated, alkylated, phosphorylated, or borated
  • a compound in which the carboxyl group of the compound (la) or a salt thereof is esterified or amidated for example, the compound (la) or the salt thereof Ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyshethyl esteranol, phthalidyl ester (5-Methyl-1-oxo-1,3-dioxolen-1-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound or its salt, etc.
  • prodrugs can be produced according to a method known per se or a method analogous thereto. .
  • the prodrug of compound (Ia) or a salt thereof can be prepared under the physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Vol. It may change to its salt.
  • the compound (la) or a salt thereof in the present invention 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.
  • each of them or a mixture thereof is included in the compound used in the present invention. included.
  • the compound used in the present invention or a salt thereof has a stereoisomer due to having an asymmetric carbon in the molecule or the like, the positional deviation of each of them or a mixture thereof is also included in the compound used in the present invention. It is.
  • the method for producing the compound used in the present invention will be described.
  • the compound (la) or a salt thereof can be prepared by a method known per se (for example, see JP-A-2000-3).
  • R is a compound (la).
  • R represents a thiophene ring and a ring A a.
  • the compound (Ia) or a salt thereof is, for example, a method A to F shown below or a method analogous thereto. Can be manufactured.
  • compound (III) represents hydroxylamine or monosubstituted hydrazine (R 3 'NHNH 2 ) or a salt thereof, and other symbols have the same meanings as described above.
  • compound (I) is produced by reacting compound (II) 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 hydrides such as sodium hydride, sodium hydroxide, and hydrogenation hydride, potassium t-toxide, sodium acetate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7 — Organic bases such as pendecene and sodium methoxide.
  • the amount of the acid compound (III) to be used is preferably about 1 to about 5 molar equivalents relative to the compound (II).
  • Solvents that do not adversely affect the reaction include, for example, water, methanol, ethanol, propanol, and other alcohols; ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated carbons such as chloroform and dichloromethane. Hydrogenated hydrocarbons; 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 generally about _50 to about 150 ° C, preferably about 0 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • R 3 ′ on ring A generated by this reaction can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R 3 using a method known per se. .
  • the compound (I) 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 (II) used as a starting compound in the above-mentioned method A is a novel compound, and the compound (IV):
  • the amount of orthoformate used is preferably about 1 to about 10 molar equivalents.
  • 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, disoptylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, and the like.
  • the amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).
  • solvents that does not adversely affect the reaction 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 generally about 1100 to about 150 ° C, preferably about 170 to about 0.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (II) 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.
  • separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compounds (IV) used as the starting compounds for example, the compound (I
  • compound (V) is produced by reacting 1,3-cycloalkanedione with alkyl isothiocyanate or arylaryl isothiocyanate in the presence of a base.
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, N, N
  • amides such as 7-diene; metal hydrides such as lithium hydride and sodium hydride; sodium methoxide; Alkyl metal alkoxides such as sodium methoxide and t-butoxy potassium.
  • the amount of the reactant used is preferably about 1 to 3,3-cycloalkanedione.
  • the amount of the base used is preferably about 1 to about 1 based on 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.
  • Compound (V) 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 and the like.
  • compound (VI) is produced by reacting compound (V) with compound (VI I). 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 haloacetic 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).
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethylamine, N, N
  • Amines such as vinyl chloride; metal hydrides such as hydrogen hydride and sodium hydride; sodium methoxide, sodium ethoxy And alkali metal alkoxides such as 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 chlorophonolem and dichloromethane.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and getyl ether
  • halogenated hydrocarbons such as chlorophonolem and dichloromethane.
  • Amides such as N, N-dimethylformamide;
  • the reaction temperature is usually about 150 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 (VI) 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 (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.
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethynoleamine, N, N-dimethinorea diline, 1,8-diazabicyclo [5.4] [0] Amines such as amide 7-ene; metal hydrides such as hydrogen hydride and sodium hydride; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide No.
  • alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate
  • pyridine triethynoleamine, N, N-dimethinorea diline, 1,8-diazabicyclo [5.4]
  • Amines such as amide 7-ene
  • metal hydrides such as hydrogen hydride and sodium hydride
  • metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t
  • 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, benzene, toluene, xylene Aromatic hydrocarbons such as methane; ethers such as tetrahydrofuran, dioxane, and getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethinoresulfoxide And the like. 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 110 to about 100 ° C.
  • the reaction time is usually from 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.
  • the compound (IV-2) is acylated to produce the compound (IV-3).
  • This method is performed using a method of appropriately reacting compound (IV-2) with an acylating agent.
  • acylating agent examples include acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides, and mixed acid anhydrides (eg, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, and the like). Is mentioned.
  • the amount of these acylating agents to be used is preferably about 1 to about 5 molar equivalents relative to the 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; Amides such as N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and the like. 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
  • Amides such as N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide
  • 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 (IV-3) 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. it can.
  • the compound (1-1) is produced by reacting the compound (1-2) with a nucleophilic reagent.
  • This reaction is carried out by a method known per se, for example, the method described in W098Z18792 or a method analogous thereto.
  • nucleophilic reagent examples include a metal phenolate, a metal alcoholate, a Grignard reagent, an alkyl metal reagent, an aryl metal reagent, and a thioalcolate.
  • the amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (1-2).
  • 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; 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 can be used by mixing at an appropriate ratio! / You may.
  • 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; sulfoxides such as dimethyl sulfoxide;
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about 110 to about 100 ° C.
  • the reaction time is usually 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.
  • Compound (I 2) used as a starting compound in the above-mentioned Method B can be produced by the following method.
  • compound (1-2) is produced using compound (I-13) and an oxidizing agent.
  • This reaction is carried out by a method known per se, for example, as an oxidizing agent, manganese diacid, permanganic acid, chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide, organic peroxide, organic peracid , Sodium hydrogen monotungstate, oxygen, N-halocarboxylic acid amide, hypohalous acid ester, odosyl compound, nitric acid, dinitrogen tetroxide, dimethyl sulfoxide, ethyl azodicarboxylate, black base (III) acid, etc.
  • an oxidizing agent manganese diacid, permanganic acid, chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide, organic peroxide, organic peracid , Sodium hydrogen monotungstate, oxygen, N-halocarboxylic acid amide
  • This is performed by the method used, or by anodic oxidation 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.
  • an oxidizing agent for example, m-chloroperbenzoic acid, peracetic acid and the like are preferable.
  • Solvents which do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chlorophonolem and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. 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 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 (1-2) 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. .
  • compound (1-5) is produced by the elimination reaction of the carboxyl protecting group.
  • carboxyl protecting group for this reaction, 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.
  • 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.
  • Suitable bases include, for example, alkali metal hydroxide (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 (sodium bicarbonate, potassium bicarbonate, etc.), alkaline metal acetates (eg, sodium acetate, potassium acetate, etc.) ), Alkaline earth metal phosphate (eg magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate Inorganic bases such as (for example, disodium hydrogen phosphate and diammonium hydrogen phosphate), trialkylamines (eg, trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 5-Dia
  • 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 depending on the type of carboxyl protecting group and the elimination method.
  • the elimination using a Lewis acid can be carried out by reacting compound (1-4) or a salt thereof with a Lewis acid, Boron halide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, titanium tetrabromide, etc.), aluminum halide (eg, aluminum chloride, bromide, etc.) Aluminum And trihaloacetic acid (for example, trichloroacetic acid, trifluoroacetic acid, etc.).
  • a Lewis acid eg, boron trichloride, boron trifluoride, etc.
  • titanium tetrahalide eg, titanium tetrachloride, titanium tetrabromide, etc
  • This elimination reaction is preferably performed in the presence of a cation scavenger (eg, anisol, phenol, etc.), and usually, nitroalkyl (eg, nitromethane, nitroethane, etc.), alkylene / , Ethyl chloride, etc.), getyl ether, carbon disulfide, and other solvents that do not adversely affect the reaction.
  • a cation scavenger eg, anisol, phenol, etc.
  • nitroalkyl eg, nitromethane, nitroethane, etc.
  • alkylene / ethyl chloride, etc.
  • getyl ether e.g, carbon disulfide, and other solvents that do not adversely affect the reaction.
  • solvents may be used as a mixture thereof.
  • the elimination by reduction is preferably applied to the elimination of protecting groups such as halogenated alkyl (for example, 2-odoethyl, 2,2,2-trichloroethyl) ester and aralkyl (for example, benzyl) ester.
  • the reduction method used in the present elimination reaction includes, for example, a metal (eg, zinc, zinc amalgam, etc.) or a salt of a chromium compound (eg, chromium (I), organic or inorganic). Combination with a salt (eg, acetic acid, propionic acid, hydrochloric acid, etc.); conventional catalytic reduction in the presence of a conventional metal catalyst (eg, 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.
  • the compound (1-5) 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.
  • R 2 is represented by the formula: Z 5 — Z 6 (wherein, Z ⁇ S—CO—, Z 6 represents an optionally substituted amino group).
  • the compound (1-6) is produced, for example, by the following Method D.
  • the compound (1-5) 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 form the compound (1-5).
  • Suitable reactive derivatives in the amino group of the compound (VI II) include a Schiff base imino or an enamine tautomer thereof formed by the reaction of the compound (VIII) with a carbonyl compound such as an aldehyde or a ketone.
  • Suitable reactive derivatives at the carboxyl group of the compound (I-15) include, specifically, acid nodogenates, acid anhydrides, activated amides, activated esters and the like.
  • the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, and nodogen phosphoric acid.
  • substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, and nodogen phosphoric acid.
  • Suitable salts of the reactive derivative of the compound (1-5) 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, for example, trimethylamine And base salts such as organic salts such as salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts and the like.
  • the reaction is usually carried out in water, for example, alcohols such as methanol, ethanol, etc., as well as common use such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • alcohols such as methanol, ethanol, etc.
  • common use such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water.
  • N -hexylhexylcarbodiimide; N-cyclohexylcarbodiimide; N'-morpholinoethyl carbodiimide; N-cyclohexyl-N '-(4-ethylethylaminohexyl) carbodiimide; ⁇ , ⁇ '-getyl carbodiimide, ⁇ , ⁇ '-disopropylpyrucarbodiimide, ⁇ -ethyl-N '-(3-dimethylaminopropyl) carbodiimide; ⁇ , N'-carbo-bis (2-methylimidazole); pentamethyleneketene- ⁇ - Cyclohexylimine; Diphenylketylene-N-cyclohexylimine; Ethoxyacetylene; 1-Alkoxy-1-cycloethylene; Trialkyl
  • 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 the compound (VIII) to be used is 0:! To 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (1-5).
  • the reaction temperature is usually 30 ° C to 100 ° C.
  • the reaction time is usually 0.5 to 20 hours.
  • a mixed acid anhydride e.g, the compound (1-5) and a carbonic acid ester (eg, methyl methyl carbonate, ethyl methyl carbonate, isoptyl carbonic acid carbonate, etc.) are converted to a base (eg, triethylamine, N—
  • a base e.g, triethylamine, N—
  • the reaction is carried out in the presence of methyl morpholine, N, N-dimethinorea diphosphorus, sodium hydrogen carbonate, sodium carbonate, carbonated carbonate, etc.), and further reacted with compound (VI II).
  • the amount of the compound (VIII) to be used is generally:! 110 molar equivalents, preferably 0.3-3 molar equivalents.
  • 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 (1-8) is produced from compound (I-17) in the presence of a dehydrating agent.
  • This reaction is performed using a method of appropriately reacting compound (1-7)) with a dehydrating agent.
  • the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, hydric pentate, and thiol chloride.
  • the amount of the dehydrating agent to be used is from 0.1 to: L 00 molar equivalents based on the compound (1-7), preferably:! ⁇ 10 molar equivalents.
  • the reaction temperature is usually from 30 ° 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 compound in the above method E is produced by the above method D or B.
  • the reaction adversely affects the reaction in the presence of a base. It is performed in a solvent that does not.
  • solvents that do not adversely affect the reaction include ethers such as ethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chlorophonolene 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. These solvents may be used in a mixture at an appropriate ratio.
  • compound (1-10) is produced by reacting nucleophilic reagent with compound (1-9).
  • nucleophilic reagent for example, metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, thioalcolate and the like are used.
  • the amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to the compound (1-9).
  • 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. Amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethylsulfoxide. These solvents are mixed at an appropriate ratio. They may be used in combination.
  • the reaction temperature is usually about 170 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 known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Can be.
  • the compound (1-9) used as a starting compound in the above Method F can be produced by the Method D.
  • Compound (I) can also be obtained by the following production method other than the above production method.
  • (IX-1) is produced by reacting compound (IV) with an amide acetal.
  • the amide acetal include an active acetal form of N, N-dialkylformamide, preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide dodecyl acetal, Butoxybisdimethylaminomethane, Trisdimethylaminomethane, N, N-Dimethinoleformamidodipropylacetate, N, N-Dimethylformamidobis (2-trimethylsilylethyl) acetal, N, N-Dimethylformamid Dojibenzyl acetal, N, N-dimethylformamide -1-Butyl acetal, N, N-Dimethinolehonorem, N, N-N-dimethylformamide N, N-Dimethylformamide
  • the active acetal is used, more preferably N, N-dimethylformamide dimethyl ace
  • 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, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated carbon Hydrogens (eg, dichloromethane, etc.), ethers (diethylenoate, diisopropinoleate, ethylene glycolone resin methinolate, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethyl) N, N-diC, 3- alkylformamides such as formamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), (Eg, acetonitrile, etc.), sulfoxides (eg, dimethylsulfoxide, etc.) alone
  • 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.
  • 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.
  • Any of the amide acetal described herein is known per se and can be easily obtained as a commercial product.
  • Compound (IV) can be prepared by a known method, for example, the article of D. Prim et al.
  • Compound (IX-2) is produced by a dealcoholation reaction of compound (II). 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.
  • the base is hydrogenated Hydride metal or alkaline earth metal hydrides, such as sodium, lithium metal hydride, lithium hexamethyl disilazide, lithium hexamethyl disilazide, sodium hexamethyl disilazide, etc.
  • Metal amides sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.Alkali metals or alkaline earth metal lower alkoxides, such as potassium hydroxide, sodium hydroxide, etc. Metal or alkaline earth metal hydroxides, carbonated lime, sodium carbonate, cesium carbonate, etc. Carbonates, potassium hydrogencarbonate, sodium hydrogencarbonate and other alkaline metal or alkaline earth metal bicarbonates, triethylamine, diisopropylamine, pyridine, dimethylaminopyridine, 1,8-diazabisik mouth [5 , 4,0] -7-Pendecene and the like.
  • 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
  • 1 mole of compound (II) Is used in an amount of 0.1 to 100 mol, preferably 1 to 30 mol.
  • any solvent can be used as long as it does not inhibit the reaction.
  • alcohols e.g., methanol, ethanol, d _ 3 alcohols, such as-propanol
  • the above-mentioned acid or base may be used also as a solvent.
  • This reaction is carried out at a reaction temperature of 0 to 50 ° (preferably 0 to 30 ° C) for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
  • the compound represented by the general formula (I) is obtained by converting the compound (VII) to hydroxylamine or a salt thereof, or hydra represented by R 3 'NHNH 2 (R 3 ' has the same meaning as described above). It is produced by ring closure with gins or salts thereof.
  • any solvent may be used as long as it does not inhibit the reaction.
  • alcohols eg, C ⁇ s alcohols such as methanol, ethanol, and propanol
  • a mixed system with another solvent 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. The reaction is carried out for 6 hours, preferably for 1 to 3 hours.
  • R 3 ′ on Ring A generated by this reaction can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R 3 using a method known per se. it can.
  • any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, alcohols such as methanol, ethanol, and propanol) are preferably used.
  • 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% or less.
  • a solvent having a water content of about 5% or less preferably a water content of about 3% or less.
  • the reaction is carried out using a 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 the 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.
  • a compound having a hydroxyl group in which R 13 ′ is substituted with a cyclic group can be obtained by a known method from the compound (IV), for example, a paper by D. Prim et al. (Synth. Coface un. , 25 volumes, 2449 pages,
  • the corrosiveness is considered to be a problem during the production of the compound (IX-3).
  • the target compound can be industrially and advantageously produced without using a compound such as a boron trifluoride etherate 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). It can be used in an amount of 2 to 10 mol per 1 mol of compound (1-12).
  • 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. Is desirable.
  • any solvent may be used for this reaction as long as it does not hinder the reaction.
  • the solvent include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), and halogenated compounds.
  • hydrocarbons e.g., dichloromethane, etc.
  • ethers di-Echiruetenore, diisopropyl ether Honoré, ethylene glycol dimethyl ether Honoré, as tetrahydrofuran, Jiokisan etc.
  • alcohols e.g., methanol, E ethanol, C _ Q alcohols propanol
  • Ami earth eg, N, N -. dimethyl formamide, etc.
  • esters Eg, ethyl acetate, methyl acetate, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, Such as methylsulfoxide, ketones (acetone, 2-butanone, 4-methyl-2-pentanone,
  • 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).
  • Examples of the base used in this reaction include the bases described in [Method H]. Among them, sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, hydrogen carbonate carbonate, Sodium hydrogen carbonate and the like are preferred, and 1 to 3 mol, preferably 1 to 2 mol, is used per 1 mol 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 (di Ethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, 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 Q represents a carboxyl-protecting group can be converted to the compound (1-7) in a single step by reacting with formamide in the presence of a base.
  • Formamide is usually used also as a solvent, and is used in an amount of 1 to 30 milliliters, preferably 2 to 10 milliliters per gram of compound (1-4).
  • Examples of the base used in this reaction include the bases described in [Method H]. Thorium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like are preferred. To 10 mol, preferably 1 to 5 mol.
  • any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, 3 alcohols such as methanol, ethanol, propanol, etc.), amides (eg, N, N-dimethylform) Amide, N, N-dimethylacetamide, N-methylpyrrolidone, formamide, etc.) are preferred.
  • alcohols eg, 3 alcohols such as methanol, ethanol, propanol, etc.
  • amides eg, N, N-dimethylform
  • Amide N, N-dimethylacetamide, N-methylpyrrolidone, formamide, etc.
  • 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) The force R may be substituted together with the ring-forming carbon atoms of the thiophene ring and ring Aa! / If the compound does not form a hydrocarbon ring or a heterocyclic ring, or a compound, the compound (la) or a salt thereof may be produced by, for example, the A 'method to the L' method shown below or a method analogous thereto. Can be.
  • R 16 represents an optionally substituted hydrocarbon residue corresponding to R
  • R 17 and R 18 each represent a hydrogen atom or each of the same substituted as exemplified for R 1
  • a 1 and A 2 are each a hydrogen atom or an optionally substituted hydrocarbon residue as exemplified for R 1
  • Hal represents a heterocyclic group
  • Hal represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
  • Q represents a sulfur atom, an oxygen atom or an NH group
  • R 15 is A hydrogen atom or an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group.
  • Other symbols have the same meaning as above.
  • compound (A) is halogenated by a method known per se to give compound (2), and then compound (A) is produced by reacting compound (2) with amide, thioamide or amidine. .
  • the reaction between compound () and compound (3) is performed in an appropriate solvent in the presence or absence of a base.
  • the solvent examples include aromatic hydrocarbons such as benzene, benzene, and xylene; dichloromethane, chloroform; carbon tetrachloride; 1,2-dichloroethane; 1,1,2,2-tetrachloroethane; Hydrogenated hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene glycol
  • aromatic hydrocarbons such as benzene, benzene, and xylene
  • dichloromethane chloroform
  • carbon tetrachloride 1,2-dichloroethane
  • 1,1,2,2-tetrachloroethane Hydrogenated hydrocarbons
  • ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane
  • the base examples 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.
  • Alkali metal alkoxides such as tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, alkali metal salts such as sodium hydrogen carbonate, sodium acetate, sodium acetate acetate, disodium hydrogen phosphate, dihydrogen hydrogen phosphate
  • Alkali metal hydrogen phosphates such as sodium hydride, alkali metal hydrides such as hydrogen hydride, trimethinoleamine, triethylamine, pyridine, picoline, N-methinolevine lysine, N-methylmorpholine, N, N—amines such as dimethylaniline, etc.
  • a base is appropriately selected and used.
  • the amount of the base used is preferably about 1 to about 5 molar equivalents relative to compound (2), and the amount of amide, thioamide or amidine () used is about 1 to 1 relative to compound (). ⁇ 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 (A) thus obtained can be obtained by a known separation and purification method, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography. It can be isolated and purified by one method.
  • the amidation reaction can be carried out, for example, by introducing 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 conjugate (6).
  • a halogenating agent such as oxalyl chloride or thionyl chloride
  • the reaction between the compound (5.) and the halogenating agent is usually carried out in a solvent.
  • 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 performed 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 about:! ⁇ 2 molar equivalents are preferred.
  • the obtained acid halide may be subjected to a reaction with the compound (6) after being separated by a usual separation and purification means, or the reaction mixture containing the acid halide may be subjected to a reaction with the compound () without separation. It can also be attached.
  • the reaction between the acid halide and the compound (0) is usually performed in a solvent.
  • the solvent examples include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane and the like, ethers such as getyl ether, dioxane, tetrahydrofuran, etc., acetone, acetonitrile, Ethyl acetate, N, N-dimethylformamide and the like.
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane and the like
  • ethers such as getyl ether, dioxane, tetrahydrofuran, etc.
  • acetone acetonitrile
  • Ethyl acetate N, N-dimethylformamide and the like.
  • Examples of the base include organic bases such as trimethylamine, triethynoleamine, pyridine, N, N-dimethinoleaniline, for example, sodium hydrogen carbonate, Examples include inorganic bases such as potassium carbonate.
  • the amount of the compound () 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 carried out at about 0 ° C. to about + 120 ° C. for about 30 minutes to about 24 hours.
  • compounds in which Q is an NH group can undergo isomerism like compound (A-1) and compound (4-2).
  • Compounds (-1) and (-2) are produced by subjecting the compound to a reaction with an element. This reaction is carried out in an appropriate solvent in the presence or absence of a base.
  • the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Mixed solvents and the like can be mentioned.
  • the base examples 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, potassium Alkali metal alkoxides such as tert-butoxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, sodium acetate, alkali metal salts such as potassium acetate, disodium hydrogen phosphate, dihydrogen phosphate Al-metal hydrogen phosphates such as potassium, alkali metal hydrides such as sodium hydride and potassium hydrogen, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N—Bases such as amines such as dimethyla-line
  • the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (A), and the amount of halogenated hydrocarbon (_ ⁇ _) used is different
  • conjugates (9.1-1) and (-2) are obtained by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Each can be isolated and purified.
  • a carboxylic acid anhydride (11) e.g., acetic anhydride, propionic anhydride, butyric anhydride
  • Isobutyric anhydride etc.
  • 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 getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; N, N-dimethylformamide; Carboxylic acid (eg, acetic acid, propionic acid, butyric acid, isobutyric acid, etc.) corresponding to the substance (11) or a mixed solvent thereof.
  • the reaction temperature is usually about 120 ° 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 (12) 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 (13) is produced by subjecting compound (12) to a reaction with phosphorus oxychloride in an appropriate solvent or without a solvent.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, Halogenated hydrocarbons such as tetrachlorosilane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, dimethyl sulfoxide, Examples include acetonitrile or a mixed solvent thereof. The amount of phosphorus used for the compound
  • 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 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 (1 3) in which R 2 is --COOH can be produced by subjecting the compound (1 3) in which R 2 is one COOR 16 to an acid or alkali hydrolysis known per se, and wherein R 2 is The compound (1 3) in which R 2 is _CONR 17 R 18 is produced by subjecting the i-OHOH compound (13), which is one COOH, to a known amidation reaction [reaction with the compound (6.)]. You can also. In this reaction, compound (')
  • reaction leading to compound (7) from the compound (5) can be carried out under the same conditions as the reaction leading to (5.).
  • R 19 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.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethenoles such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane, methanol, ethanol, propylene glycol, isopropanol, and the like.
  • Alcohols such as butanol, 2-methoxyethanol, ethylene glycol, N, N-dimethylformamide, ethyl acetate, or a mixed solvent thereof.
  • the reaction temperature is usually about 120 ° 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 a dithioester represented by the general formula (15) in an appropriate solvent or without a solvent.
  • a dithioester represented by the general formula (15) examples include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2.
  • the dithioester (15) is preferably used in an amount of about 1 to about 5 molar equivalents relative to the 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.
  • the compound (JD) is produced by reacting the compound (16) with phosphorus oxychloride in the same manner as in the method B ′.
  • R 2 is able to produce the compound (1 7) is an R 2 gar COOH by subjecting to an COOR 16, compound (1-7) per se known acid or alkali hydrolysis reaction, also, R 2 A compound (17) in which R 2 is --CONR 17 R 18 by subjecting the compound ( 17 ) in which is —COOH to an amidation reaction [reaction with the compound (6.)] known per se. Can also.
  • This reaction can be carried out under the same conditions as in the reaction for deriving the compound (7 ′) from the compound ( ⁇ ′) and the compound (7_) from the compound.
  • Q ′ represents an oxygen atom or NA 1.
  • Other symbols are as defined above.
  • compound (18) is produced by subjecting compound (II) to a reaction with oxychloride phosphorus 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, dimethoxyethane, etc. May be used, or a mixed solvent thereof.
  • the amount of the salt used is preferably about 1 to about 5 molar equivalents relative to the compound ( ⁇ ).
  • the reaction temperature is usually about 120 ° C.
  • the compound ( ⁇ 8) 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 (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; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane.
  • Examples include hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof.
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating power, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, and the like.
  • Alkali metal alkoxides such as sodium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate, aluminum acetate, sodium acetate, etc.
  • Metal phosphates such as disodium and dibasic hydrogen phosphate metal phosphates such as sodium hydride and lithium hydride metal hydrides, trimethylamine, triethylamine, pyridine, picoline, N-methyl Amines such as pyrrolidine, N-methylmorpholine, N, N-dimethylaniline
  • a base is appropriately selected and used.
  • the amount of the base used is preferably about 1 to about 5 molar equivalents relative to the compound ( ⁇ 8), and the amount of hydroxylamine or hydrazine (19) is About 1 to about 5 molar equivalents to 8) are preferred.
  • This reaction is generally carried out at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C.
  • the compound ⁇ 2_0) 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.
  • a compound (20) in which R 2 is one COOH can be produced.
  • Compound (20) wherein R 2 is --CONR 17 R 18 can also be produced by subjecting compound (20) wherein 2 is --COOH to an amidation reaction [reaction with compound (6.)] known per se. it can. This reaction can be carried out under the same conditions as those for the reaction for deriving the compound (A,) compound (5.) and for deriving the compound (! From the compound (J_).
  • compound (21) is produced by subjecting compound (18) to a reaction with sulfur and sodium sulfate in an appropriate solvent, and then treating with sulfuricfuryl chloride.
  • the solvent include ethers such as gethyle ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; , N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or a mixed solvent thereof.
  • the amount of sulfur and sodium sulfate 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, especially about + 30 ° C to about + 30 ° C. + 120 ° C is preferred 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, ethenoleatenole, ethers such as tetrahydrofuran, dioxane, and dimethoxetane, and a mixed solvent thereof.
  • the amount of the salted sulfuryl to be used is preferably about 1 to about 3 molar equivalents relative to compound (18).
  • the reaction temperature is usually about 120 ° 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 (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 alcohols such as ethenole ethers, tetrahydrofuran, dioxane, dimethoxyethane, etc., methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene glycol and the like. And the like.
  • 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 a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • R 2 Gar COOR 16 compound (22) can be prepared compound is R 2 gar COOH (22) by subjecting the known acid or alkali hydrolysis reaction, also, R 2 is one Compound (22) wherein R 2 is --CONR 17 R 18 can also be produced by subjecting compound (22) which is COOH to an amidation reaction [reaction with compound] known per se. This reaction can be carried out under the same conditions as those for deriving compound () from compound ( ⁇ ') and for deriving compound (JL) from compound (5.). [F, Law]
  • R 2 represents an ethoxycarbol group or a p-toluenesulfonyl group. Other symbols have the same meanings as described above.
  • the above compound ( ⁇ ) The compound (23) is subjected to a reaction with ethyl carbazinate or p-toluenesulfol-hydrazide in a solvent to produce a compound (24).
  • the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, tetrachlorosilane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like.
  • Alcohols such as halogenated hydrocarbons, ethynoles such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanol, propanolone, isopropanol, pptanolone, 2-methoxyethanol, and ethylene glycol;
  • Examples include N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate, or a mixed solvent thereof.
  • Ethyl carpazate or p-toluenesulfonyl hydrazide (23) is preferably used in an amount of about 1 to about 2 molar equivalents with respect to the hydric compound ( ⁇ ).
  • the reaction temperature is usually 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 thus-obtained compound (24) is a known separation and purification means, for example, It can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (25) is produced by treating the compound (24) with a salted zionyl.
  • 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.
  • Examples include hydrocarbons, ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and mixed solvents thereof.
  • This reaction is generally carried out at about 120 ° C. to about + 180 ° C., preferably about 0 ° C.
  • 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.
  • compound (25) can be prepared compound is R 2 gar CO OH (25) by the subjected to per se known acid or alkali hydrolysis reaction, also, R 2 is Compound (25) wherein R 2 is --CONR 17 R 18 can also be produced by subjecting compound (25) which is one COOH to an amidation reaction [reaction with compound (6.)] known per se. This reaction can be performed under the same conditions as the reaction for deriving compound () from compound ( ⁇ ') and the reaction for deriving compound (7) from compound (5).
  • the compound (18) is subjected to a 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, and 1,1,2,2-tetrachloroethane.
  • Examples include hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, N-dimethinoleformamide, dimethyl sulfoxide, 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, sodium ethoxide, potassium tert.
  • Alkali metal alkoxides such as butoxide, sodium carbonate, sodium carbonate, hydrogencarbonate, sodium hydrogencarbonate, sodium acetate, sodium acetate, sodium metal phosphate, sodium phosphate, dihydrogen phosphate, dihydrogen phosphate
  • Alkali metal hydrogen phosphates such as potassium hydride, sodium hydride, alkaline metal hydrides such as lithium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N Salts such as amines such as N, N-dimethylaniline
  • the amount of these bases to I ⁇ product (1 8) from about 1 to about 5 molar equivalents to the preferred thiol (2.
  • the amount of 6_) to be used is preferably about 1 to about 3 molar equivalents relative to compound (18). 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 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, dichloromethane, chloroform, tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and the like.
  • Halogenated hydrocarbons such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, methanol, ethanol, prono-nore, isopropanol, butanol, 2-methoxyethanol, ethylene glycol, etc. Alcohol, acetonitrile, ethyl acetate or a mixed solvent thereof.
  • Examples of 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. And mixtures of carboxylic acids (acetic acid, benzoic acid, etc.) and the like (eg, pyrrolidine, piperidine).
  • the amount of the dehydrating reagent used is a catalyst amount or a large excess with respect to the conjugate (2JL), and the reaction temperature is usually about 0 ° C to about + 180 ° C, particularly about + 30 ° C to about + 120 ° C is preferred and the reaction time is from about 1 hour to about 50 hours.
  • the compound (2_8) 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 2 is able to R 2 to produce a compound of one CO OH (28) by subjecting to an COOR 16, compound (28) per se known acid or alkali hydrolysis reaction, also, R 2 is compound which is over COOH (28) known per se amidation reaction [compound (6) and reaction] 1 2 gar I Nyo be subjected to. Compound (28) which is 0 ⁇ 1 17 1 18 can also be produced.
  • the compound (4 ') The reaction can be carried out under the same conditions as those for the reaction leading to the compound (5.) and the reaction leading to the compound (! From the compound.
  • the above compound (2.) is subjected to a reaction of compound (29) with imine in an appropriate solvent in the presence of a base to produce compound (30).
  • a solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and a mixed solvent thereof.
  • the base for example, a base such as lithium getylamide or lithium diisopropylamide 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 the imine (29) with a base, and then adding the compound ().
  • the reaction temperature is usually about 80 ° C to about + 100 ° C, preferably about -80 ° C to about + 30 ° C, 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 2 Gar COOR 16 compound (30) R 2 by subjecting the known acid or alkali hydrolysis reaction can produce a compound of one COOH (30).
  • R 2 gar The compound (30) wherein R 2 is one CONR 17 R 18 can also be produced by subjecting the compound (30) which is COOH to an amidation reaction [reaction with the compound ()] known per se. This reaction is performed from the compound ('). The reaction can be carried out under the same conditions as the reaction for deriving compound (A) and the reaction for deriving compound (!) From compound (5).
  • compound (la) can also be produced according to the following I ′ method c
  • n 1 or 2, and each of the other symbols has the same meaning as described above.
  • 1,3-diketone is converted to a base, carbon disulfide, and a halogenated hydrocarbon (3
  • a dithioester of the compound (32) is produced. This reaction is performed in a solvent that does not adversely influence the reaction.
  • Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; N, N-dimethylformamide, dimethylsulfoxide; Examples include acetonitrile 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, sodium ethoxide, and the like.
  • Alkali metal alkoxides such as potassium tert-butoxide, sodium carbonate, sodium carbonate, sodium bicarbonate, sodium bicarbonate, sodium acetate, sodium acetate, sodium acetate, etc., disodium hydrogen phosphate, Hydrogen phosphate Alkali metal hydrogen phosphates such as dipotassium, sodium hydride, alkali metal hydrides such as hydrogen hydride, trimethylamine, triethylamine, pyridin, picoline, N-methinolepyrrolidine, N- Bases such as amines such as methyl monoreforin and N, N-dimethylaniline are appropriately selected and used.
  • the amount of these bases used is preferably about 1 to about 2 molar equivalents based on 1,3-diketone, and the amount of carbon disulfide used is preferably about 1 to about 2 molar equivalents based on 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 about ⁇ 20 ° C. to about + 100 ° C., for about 1 hour to about 24 hours.
  • the thus obtained compound (32) may 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. Can be.
  • Compound (34) is produced by subjecting compound (32) to a reaction with a halogenated hydrocarbon represented by general formula (33) in an appropriate solvent in the presence of a base.
  • a halogenated hydrocarbon represented by general formula (33) examples include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanolanol, propanol, isopropanol, butanol, and the like.
  • Alcohols such as 2-methoxyethanol and ethylene glycol; ketones such as cetone and methyl ethyl ketone; N, N-dimethylformamide, dimethyl snolefoxide, acetonitrile, ethyl acetate, and mixtures thereof.
  • the base examples 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 Alkali metal alkoxides such as sid, potassium tert-butoxide, sodium carbonate, lithium carbonate, sodium bicarbonate, aluminum chloride metal salts such as sodium hydrogen carbonate, sodium acetate, potassium acetate, disodium hydrogen phosphate, Metal hydrogen phosphates such as dihydrogen phosphate and alkali metal hydrides such as sodium hydride and hydrogen hydride, trimethylamine, triethylamine, pyridine, picolin, N-methinolepyrrolidine, N-methylmorpholine, N, N-dimethinorea Bases such as amines such as amines are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 10 molar equivalents, particularly preferably about 1 to about 5 molar equivalents,
  • the amount of the halogenated hydrocarbon (33) to be used is preferably about 1 to about 2 molar equivalents relative to the compound (32).
  • the reaction temperature is usually 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 ( ⁇ ) 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 (35) is produced by subjecting the compound (34) to an oxidation reaction.
  • the oxidizing agent used in this reaction peracids such as peracetic acid, pertrifluoroacetic acid, and m-chlorobenzoic acid, oxidized metals such as potassium permanganate and oxidized chromium, and hydrogen peroxide are used. .
  • the oxidizing agent is used in 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (34).
  • Any solvent can be used for this reaction as long as it does not hinder the reaction.
  • hydrocarbons such as n-hexane, N-heptane, benzene, toluene, xylene, etc .
  • Halogenated hydrocarbons such as carbon chloride, diethyl ether, diisopropyl ether, ethylene glycolone resin, ethers such as tetrahydrofuran, dioxane, 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 cyclohexaquinone.
  • halogenated hydrocarbons such as Shishidani carbon, getyl ether, Propyl ether, ethylene glycol / regimen Chino Les ether Honoré, as tetrahydrofuran, ethers such as Jioki acid. These solvents are used alone or as a mixture of two or more.
  • 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 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 is subjected to a reaction with various nucleophilic reagents to produce a compound (II).
  • the nucleophilic reagent for example, metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, thioalcoholate, amine and the like are used.
  • a base in some cases.
  • the base to be used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate, and the like.
  • Alkali metal salts such as potassium carbonate, sodium hydrogen carbonate, cesium fluoride, sodium acetate and potassium acetate; metal hydrogen phosphates such as disodium hydrogen phosphate and dihydrogen phosphate; sodium hydroxide Metal hydroxides such as oxidizing rims, triethylamine, pyridine,
  • Amines such as N-methylmorpholine are exemplified.
  • 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).
  • This reaction is usually performed in a solvent that does not adversely influence the reaction.
  • Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chlorophonolem and dichloromethane; 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 170 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 (II) 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 (20) can also be synthesized by the following method.
  • R 19 and R 2 Represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group, respectively, as exemplified for R 1 , and the other symbols have the same meanings as described above. ]
  • the compound (3) is produced by subjecting the above compound (1) to a reaction with a trialkyl orthoformate and a 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 tetrachlorocarbon are preferable.
  • the amount of the trialkyl orthoformate, boron trifluoride-ethyl ether complex and base used is preferably about 1 to about 10 molar equivalents relative to the compound (II)!
  • the reaction temperature is usually about 170 ° C.
  • the compound (31) thus obtained can be obtained by a known separation and purification means, for example, concentration, reduction, etc. Isolation and purification can be performed by pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (III) is reacted with N, N-dimethylformamide dialkyl acetal or trisdialkylaminomethane to produce the compound (32).
  • 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, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are preferable.
  • the compound (31) and the compound (32) thus obtained are reacted with a hydroxylamine derivative or a hydrazine derivative of the compound (19) to produce a compound (20).
  • 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, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like. Amides are preferred.
  • the amount of the acid used is preferably about 0.1 to about 10 molar equivalents based on the compound (1)! / ,.
  • the reaction temperature is usually about 0 ° C. to about 120 ° C., 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 a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (Ia) can also be synthesized by the following method.
  • Y is boronic acid, boronic ester, Indicates lead halide, copper halide, trialkyltin or triflate.
  • the starting material compound (36) of the present method is known from the literature [W02000047578, EP 676395, and Monatshef tefur Chemie, 120, 65 (1987)]. Can be produced by the method described in the above or a method analogous thereto.
  • 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), diacetoxy -Hackel (11), copper (I) chloride, copper (II) chloride, etc. are used.
  • phosphine for example, triphenylphosphine, tributylphosphine, 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; N, N-dimethylformamide; N, N-dimethylacetamide; Amides such as N-methylpyrrolidone are preferred.
  • the amount of the compound (37) used is about 1 to about 5 molar equivalents with respect to the compound (36).
  • the amount of the metal catalyst to be used is preferably about 0.1 to about 1 molar equivalent with respect to the compound (36).
  • the reaction temperature is usually about 170 ° C.
  • 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 of compound (la) can also be performed by the following method.
  • R ′ represents an optionally substituted hydrocarbon residue, and other symbols have the same meanings as described above.
  • the sulfidyl compound or the sulfonyl compound (40) is obtained by subjecting the sulfanyl group of the compound (3_9), which can be produced by the method K to the kappa A 'method by the K, method, to oxidation conditions.
  • the oxidizing agent used in the acid reaction include hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, pertrifluoroacetic acid, potassium permanganate, and chromium acid. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
  • ethers such as jeti / ether, tetrahydrofuran, and dioxane, and halogenated carbons such as dichloromethane, chlorophonolem, and carbon tetrachloride are preferable.
  • the amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound (3-9).
  • 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.
  • the compound ( ⁇ ) is produced by reacting the conjugated product (40) with a nucleophilic agent in the presence of a base, if necessary.
  • a nucleophilic agent 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 getyl ether, tetrahydrofuran and dioxane; halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as butane, toluene and xylene, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-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 ( ⁇ ) 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. 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 conjugate or a salt thereof used in the present invention can be isolated and purified by means of, for example, solvent extraction, concentration under reduced pressure, crystallization, recrystallization, distillation, chromatography and the like.
  • the obtained compound or its salt is used in the next step without any purification or as a reaction solution.
  • biodegradable in the biodegradable polymer compound used in the present invention refers to the body, that is, hard tissues such as soft tissues and osseous bones, such as subcutaneous and intramuscular, and in particular, fibers other than the digestive tract. It means that it has the property of being completely or partially degraded or metabolized by the bodily fluid in the tissue within the intended treatment period.
  • the “polymer compound” generally has a weight average molecular weight of about 3,000 to about 5, 0, 000, preferably from about 4, 000 to about, 4, 000, more preferably from about 5, 000 to about 3, 000. Also, the degree of dispersion (weight Average molecular weight Z number average molecular weight) Force Usually, a polymer compound having about 1.2 to about 4.0, more preferably about 1.5 to 3.5 is preferable.
  • the biodegradable polymer compound used in the present invention is, for example, a biodegradable polymer that is hardly soluble or insoluble in water.
  • the biodegradable polymer compound used in the present invention include, for example, fatty acid polyesters [eg, polyhydroxycarboxylic acids (eg, glycolic acid, diacid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid] , 2-hydroxy-3-methinobutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid, 2-hydroxycaprylic acid, etc., hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxy Tricarboxylic acids (eg, citric acid, etc.), one or more polymers such as lactic acid prolactone, parerolactone, copolymers, or mixtures thereof]; and derivatives thereof (eg, polylactic acid, polyglycolic acid, and the like) ⁇ Polyethylene glycol block polymer, etc.); Poly- ⁇ -cyano acrylate
  • Synthetic polymers can also be used.
  • biodegradable polymer conjugates may be used, or two or more copolymers or a simple mixture may be used.
  • the type of polymerization may be any of random, block, and graft.
  • Preferred examples of the biodegradable polymer conjugate are, for example, aliphatic polyesters.
  • synthesized from one or more ⁇ -hydroxycarbonic acids Polymers and copolymers are preferred from the viewpoint of biodegradability and biocompatibility, and specifically synthesized from one or more of lactic acid, glycolic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, and the like.
  • the used copolymer or a mixture thereof is used.
  • the biodegradable polymer compound in the present invention is produced by a method known per se, for example, a method described in JP-A-61-28521 or a method analogous thereto.
  • the ⁇ -hydroxycarboxylic acids may be any of a D-form, an L-form, and 0- and L-forms, but the D- and L-forms are preferred.
  • Examples of the homopolymers of monohydroxycarboxylic acids include homopolymers such as lactic acid, glycolic acid and 2-hydroxybutyric acid. As the hydroxycarboxylic acids, lactic acid is preferred.
  • copolymers of ⁇ -hydroxycarboxylic acids include copolymers of glycolic acid and other ⁇ -hydroxycarboxylic acids.
  • monohydroxycarboxylic acids examples include lactic acid and 2-hydroxybutyric acid. preferable. Specifically, for example, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer and the like, preferably lactic acid-glycolic acid copolymer and the like are used.
  • the composition ratio (mol 0/0) is preferably 100 / 0-40 Bruno 60, 100 / 0-50 / 50 Is particularly preferred.
  • the weight average molecular weight of the above lactic acid-glycolic acid copolymer is usually from about 3,000 to about 50,000, preferably from about 4,000 to about, 40,000, more preferably from about 5,000 to about 4,000. It is about 30,000.
  • the dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5.
  • the weight-average molecular weight, number-average molecular weight and dispersity in the present specification mean that the weight-average molecular weight is 1, 110,000, 707,000, 354,000, 189, 000, 156,000, 98, 900, 66.
  • This solution is titrated with an alcoholic solution of sodium hydroxide and potassium hydroxide, and the carboxy group is titrated.
  • the number average molecular weight obtained by quantification was calculated as the number average molecular weight obtained by quantification of the terminal group, while the number average molecular weight obtained by quantification of the terminal group was an absolute value.
  • a polymer synthesized from lactic acid and glycolic acid by a noncatalytic dehydration polycondensation method and having a free hydroxyl group at the terminal has a number average molecular weight determined by GPC
  • the number average molecular weight determined by the terminal group is almost the same as that of the lactic acid-glycolic acid copolymer when the number average molecular weight determined by the terminal group is about 0.2 of the number average molecular weight determined by the GPC measurement.
  • Non-catalytic dehydration polycondensation from acid Japanese Patent Application Laid-Open No. 61-28521
  • ring-opening polymerization using a catalyst from a cyclic substance such as lactide and glycolide
  • the polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but a polymer in which the polymer is chemically treated to have a free carboxyl group at its end (Journal Reb Control Releases (J. Controlled Release), Vol. 41, pp. 249-257, pp. 1996 can also be used.
  • the above-mentioned lactic acid-dalicholic acid copolymer having a free carboxyl group at its terminal can be prepared by a known production method (for example, a non-catalytic dehydration polycondensation method, see Japanese Patent Application Laid-Open No. 61-28521).
  • a polymer having a free carboxyl group which is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587).
  • a lactate-glycolic acid copolymer whose terminal has been converted into a free carboxyl group by a chemical treatment after ring-opening polymerization is, for example, Behringer-zingerheim
  • biodegradable polymer compounds may be used alone or as a mixture of two or more.
  • the form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include sustained-release agents that maintain its effects over a long period of time.
  • the form of the sustained-release preparation is not particularly limited, but a parenteral preparation is preferable, and a transdermal preparation, a transmucosal preparation, an implant, a microcapsule injection, and the like can be considered. Injectable preparations using microcapsules, which place little burden on patients, are preferred.
  • Preferred methods for producing the pharmaceutical composition of the present invention include a method of removing a solvent from a liquid containing compound (I) or a salt thereof and a biodegradable polymer compound.
  • the liquid containing compound (I) or a salt thereof may be a suspension.
  • a method for producing a sustained-release preparation in particular, a microcapsule (hereinafter sometimes referred to as a microsphere) is illustrated below.
  • an organic solvent solution of a biodegradable polymer compound is heated with an organic compound solution (I) or a salt thereof to prepare an organic solvent solution.
  • the compound (I) or a salt thereof may not be completely or partially dissolved in the organic solvent solution of the biodegradable polymer compound and may be dispersed, and may be a known compound such as a homogenizer or an ultrasonic wave. It is preferable to disperse finely in a short time by the above method. Also, depending on the solubility of the drug, water may be added to the organic solvent.
  • organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chlorophonolem, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, ⁇ Ethyl acid, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), acetonitrile, lower fatty acids (eg, acetic acid, propionic acid, etc.) are used.
  • halogenated hydrocarbons eg, dichloromethane, chlorophonolem, dichloroethane, trichloroethane, carbon tetrachloride, etc.
  • ethers eg, ethyl ether, is
  • An additive may be added to the above organic solvent solution. Examples of the additives include acetic acid, carbonic acid, oxalic acid, citric acid, phosphoric acid, phosphoric acid, hydrochloric acid, benzoic acid, ascorbic acid, tartaric acid, etc., as solubilizing agents for maintaining the stability and solubility of the drug.
  • Sodium hydroxide, arginine, lysine, aspartic acid or salts thereof may be added.
  • a drug stabilizing agent a polyol compound such as albumin, gelatin, cunic acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyethylene glycol, etc., or paraoxybenzoic acid, which is generally used as a preservative, is used. Estenoles (eg, methylparaben, propylparaben, etc.), benzyl alcohol, octabutanol, thimerosal, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like may be added.
  • the concentration of the biodegradable polymer compound in the organic solvent solution varies depending on the molecular weight of the biodegradable polymer and the type of the organic solvent.For example, when dichloromethane is used as the organic solvent, generally, It is selected from about 0.5 to about 70% by weight, more preferably about 1 to about 60% by weight, and particularly preferably about 2 to about 50% by weight.
  • an organic solvent solution of the biodegradable polymer compound containing the obtained compound (I) or a salt thereof was added to the aqueous phase to form an o (oil phase) / W (aqueous phase) emulsion. Thereafter, the solvent in the oil phase is evaporated to prepare microcapsules.
  • the volume of the aqueous phase at this time is generally about 1 to about 100,000 times the volume of the oil phase, more preferably about 5 to about 5,000 times, and particularly preferably about 10 to 100 times. It is selected from double to about 2000 times.
  • An emulsifier may be added to the above external water phase. In general, the emulsifier may be any one that can form a stable oZw emulsion.
  • anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
  • nonionic surfactants polyoxyethylene sorbitan fatty acid ester (Tween OVeen ) 80, Tween (IVeen) 60, Atlas powder One company), polyoxyethylene castor oil derivatives (HC0-60, HC0_50, Nikko Chemicals, etc.), polybutylpyrrolidone, polybutyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like. You may use one of these or a combination of two or more.
  • the concentration at the time of use is preferably in the range of about 0.01 to 10% by weight, more preferably in the range of about 0.05 to about 5% by weight.
  • An osmotic pressure regulator may be added to the above external aqueous phase.
  • the osmotic pressure adjusting agent may be any as long as it exhibits an osmotic pressure when used as an aqueous solution.
  • osmotic pressure adjusting agent examples include polyhydric alcohols, monohydric alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids, and derivatives thereof.
  • polyhydric alcohols examples include dihydric alcohols such as glycerin, pentahydric alcohols such as arabitol, xylitol and adtol, and hexahydric alcohols such as mannitol, sorbitol and dulcito tonle. . Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.
  • Examples of the above monohydric alcohols include methanol, ethanol, and isopropyl alcohol, and among them, methanol is preferable.
  • Examples of the above monosaccharides include pentoses such as arabinose, xylose, lipose, and 2-deoxyribose, and hexoses such as pudose, fructose, galactose, manose, sorbose, rhamnose, and fucose. Carbohydrates are preferred.
  • oligosaccharide for example, trisaccharides such as maltotriose and raffinose sugars, and tetrasaccharides such as stachyose are used, and among them, trisaccharides are preferable.
  • disaccharides and oligosaccharides for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.
  • any L-form amino acid can be used, and examples thereof include glycine, leucine, arginine and the like. Of these, L-arginine is preferred. These osmotic pressure regulators may be used alone or as a mixture.
  • osmotic pressure adjusting agents are used at a concentration such that the osmotic pressure of the external aqueous phase is about 1 Z50 to about 5 times, preferably about 1 to 25 to about 3 times the osmotic pressure of physiological saline.
  • a method for removing the organic solvent a method known per se or a method analogous thereto is used. For example, a method in which the organic solvent is evaporated at normal pressure or gradually reduced pressure while stirring with a propeller-type stirrer or a magnetic stirrer, etc., and the organic solvent is evaporated while adjusting the degree of vacuum using a rotary vaporizer. The method of making it do.
  • the micro force cell obtained in this way is separated by centrifugation or filtration, and then the physiologically active compound, drug-retaining substance, lactating agent, etc. adhering to the surface of the microcapsule are distilled water several times. Wash repeatedly, disperse again in distilled water and freeze-dry.
  • an anti-aggregation agent may be added to prevent aggregation of the particles.
  • the aggregation inhibitor include water-soluble polysaccharides such as mannitol, ratatose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Among them, mannitol is preferred.
  • the microcapsules may be heated under reduced pressure so that the microcapsules do not fuse with each other to remove water and organic solvents in the microforce capsule.
  • the polymer is heated at a temperature slightly higher than the midpoint glass transition temperature of the biodegradable polymer determined by a differential scanning calorimeter under a condition of a heating rate of 10 to 20 ° C per minute. . More preferably, the polymer is heated within a temperature range of about 30 ° C. higher than the midpoint glass transition temperature of the biodegradable polymer.
  • the temperature range is preferably higher than the midpoint glass transition temperature and 10 ° C higher than the midpoint glass transition temperature, and more preferably, medium. Heat in the temperature range above the midpoint glass transition temperature and 5 ° C above the midpoint glass transition temperature.
  • the heating time varies depending on the amount of microcapsules, etc. After the black capsule itself reaches a predetermined temperature, about 12 hours to about 168 hours, preferably about 24 hours to about 120 hours, particularly preferably about 48 hours to about 96 hours It is.
  • the heating method is not particularly limited as long as the assembly of micro force cells can be uniformly heated.
  • the heating and drying method for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.
  • a coacervation agent is added to an organic solvent solution of the biodegradable polymer compound containing the compound (I) or a salt thereof described in the above (I) in water drying method. Is added slowly with stirring to precipitate a micro force plate, which is then solidified.
  • the coacervation agent is used in an amount of about 0.01 to 1.0 times, preferably about 0.05 to 500 times, particularly preferably about 0.001 to! 200 times the oil phase volume. To be elected.
  • the coacervation agent is a polymer-based, mineral oil-based or vegetable oil-based compound which is miscible with an organic solvent and does not dissolve both the bioactive compound and the biodegradable polymer. If it is, there is no particular limitation. Specifically, for example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more.
  • washing is repeated with heptane or the like to remove bioactive compounds and coacervation agents other than the biodegradable polymer, and then dried under reduced pressure. I do.
  • washing may be performed in the same manner as described in the underwater drying method (I), followed by freeze-drying, and further, desolvation by heating and drying.
  • the organic solvent solution of the biodegradable polymer conjugate containing the compound (I) or the salt thereof described in the above-mentioned (I) in water drying method is sprayed with a nozzle.
  • Spray into the drying room of a spray dryer (spray dryer) the organic solvent in the atomized droplets is volatilized in a very short time to prepare microcapsules.
  • the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type. After that, if necessary, washing may be carried out in the same manner as described in the above-mentioned in-water drying method (I), followed by freeze-drying, and further, desolvation by heating and drying.
  • an organic solvent solution of the biodegradable polymer compound containing the compound (I) or a salt thereof described in the in-water drying method of the microcapsule production method (I) may be used, for example, by rotary. After evaporating the organic solvent and water to dryness while adjusting the degree of vacuum using an evaporator or the like, the powder may be ground into fine powder by a jet mill or the like.
  • the pulverized fine powder may be washed in the same manner as described in the in-water drying method of the microcapsule production method (I), followed by freeze-drying, and further, desolvation by heating and drying.
  • the drug release can be controlled in accordance with the decomposition rate of the biodegradable high molecular compound to be used and the type and amount of the compound (I) or its salt.
  • the sustained-release preparations thus obtained can be formulated as such or as a raw material in various dosage forms, and can be used in the periosteum, subperiosteum, near the bone, in the knee joint, in the shoulder joint, in the finger joint.
  • bone cement such as polymethyl methacrylate / calcium phosphate.
  • a dispersant eg, aniline
  • On-surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
  • non-ionic surfactants polyoxyethylene sorbitan fatty acid ester (Tween 80, Tween 60, Atlas powder) Co., Ltd.)
  • polyoxyethylene castor oil derivatives [HC0_60, HC0-50, Nikko Chemicals] etc.)
  • stearyltriethanolamine sodium lauryl sulfate, laurylaminopropionic acid, benzalkonium chloride, chloridenebenzetonium, monostearic acid
  • Surfactants such as glycerin; lecithin; gelatin; polybulpyridone; polybutyl alcohol; hyaluronic acid or a salt thereof (such as sodium salt); polysaccharides such as carboxymethylcellulose and sodium alginate; Examples
  • Aqueous suspensions Dispersed with vegetable oils such as sesame oil and corn oil
  • a sustained-release injection that can be actually used as an oily suspension can be obtained.
  • the particle size of the sustained-release preparation in the pharmaceutical composition of the present invention may be within a range that satisfies the dispersibility and the needle penetration property.
  • the average particle diameter About 0.01 to 300 ⁇ , preferably about 0.05 to 150 ⁇ m, and more preferably about 0.1 to 100 ⁇ .
  • the sustained-release preparation in the pharmaceutical composition of the present invention into a sterile preparation, a method for sterilizing the production process, a method for sterilizing with gamma rays, a method for combining these, or a method for adding a preservative, etc.
  • a method for sterilizing the production process a method for sterilizing with gamma rays, a method for combining these, or a method for adding a preservative, etc.
  • the compound (I) or a salt thereof used in the present invention has excellent alkaline phosphatase inducing activity and chondromodulin production promoting activity and / or expression enhancing activity.
  • osteoblast differentiation including progenitor osteoblasts, promoting differentiation induction, promoting chondrogenesis, including precursor chondrocytes
  • it is expected to have a chondrocyte differentiation-inducing and differentiation-inducing promoting action, and also a BMP action enhancing action. If such differentiation is induced, the differentiation induction promoting action acts on not only osteoblast and chondrocyte differentiation but also differentiation induction of various cells.
  • Compound (I) or a salt thereof is expected to have a neurotrophic factor action-enhancing activity. Further, compound (I) or a salt thereof is expected to have anti-matrix meta-oral protease (anti-MMP) activity.
  • Compound (I) or a salt thereof, which is used in the present invention has a strong osteogenesis promoting action, osteoblast differentiation induction and differentiation induction promoting action including precursor osteoblasts, chondrogenesis promoting action, cartilage including precursor chondrocytes Since the cell differentiation-inducing and differentiation-inducing action and the BMP action-enhancing action are expected, the pharmaceutical composition of the present invention may be used for, for example, an osteogenesis-promoting agent, an agent for preventing and treating bone disease, an agent for preventing and treating bone fracture, and cartilage.
  • cartilage diseases specifically, in the field of orthopedics, simple fractures, intractable fractures, incomplete bone fusion, false joints, refractures, bone deformities and osteoarthritis, osteosarcoma, myeloma, bone
  • Non-metabolic bone diseases such as dysplasia, scoliosis, etc .
  • Metabolic bone diseases such as;
  • As a prophylactic / therapeutic agent for osteoarthritis and similar diseases, and for joint diseases represented by cartilage diseases such as rheumatoid arthritis, as a bone tissue repair agent after surgery for multiple myeloma, lung cancer, breast cancer, etc.
  • dental field which can be used in combination with autologous bone grafting and artificial bone grafting in order to promote bone formation after bone resection, treatment of periodontal disease, tooth in periodontal disease It is also expected to be applicable to repair of peripheral tissue defects, stabilization of artificial dental roots, ridge formation, and repair of cleft lip.
  • compound (I) or a salt thereof used in the present invention is expected to have a neurotrophic factor action-enhancing activity, Alzheimer's disease and general senile dementia, motor-Euron's disorder Treatment and prevention of various neurodegenerative diseases such as (amyotrophic lateral sclerosis) and diabetic peripheral neuropathy can be expected.
  • the pharmaceutical composition containing the compound (I) of the present invention or a salt thereof is expected to have anti-MMP activity, it can be used for osteoarthritis, rheumatoid arthritis, arteriosclerosis, cancer Treatment and prevention of MMP-related diseases such as metastasis can be expected. Since the pharmaceutical composition of the present invention has low toxicity, it can be safely administered to mammals (eg, human, rat, mouse, dog, rabbit, cat, cat, pig, pig, etc.). You.
  • the dose of the pharmaceutical composition of the present invention depends on the type and content of the bioactive compound as the main drug, dosage form, administration route, duration of release of the bioactive compound, target disease, target animal, and subject to be treated. It varies depending on the condition of the animal and the like, but may be any effective amount of the physiologically active compound.
  • the daily dose of the pharmaceutical composition is, for example, about 0.1 mg to about 50 Omg, preferably in the case of oral administration per adult (body weight 50 kg) as a compound (I) or a salt thereof. Is in the range of about 1 mg to about 100 mg, for parenteral administration, for example, in the range of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 10 mg. Can be administered.
  • composition of the present invention is a sustained release preparation
  • Compound (I) or a salt thereof is released per adult (body weight 50 kg) per day, for example, about 0.0 Img to about 100 mg. As described above.
  • the frequency of administration of the pharmaceutical composition of the present invention depends on the type and content of the biologically active compound as the active ingredient, dosage form, administration route, duration of release of the biologically active compound, target disease, target animal, target animal to be treated, etc. Can be selected as appropriate, for example, once a week, once a few weeks, once a month, or once a few months (eg, 3 months, 4 months, 6 months, etc.) The times can be selected as appropriate.
  • the duration of release of the physiologically active compound can be obtained by appropriately selecting the type, composition and blending amount of the biodegradable polymer compound to obtain the required duration of release of the biologically active compound.
  • the pharmaceutical composition of the present invention comprises a cartilage disease healing promoting substance (eg, chondroitin, chondroitin sulfate, dextran sulfate, dalcosamine, dalcosamine darican, bone formation protein (BMP), transforming growth factor (TGF- / 3) ), An anti-inflammatory agent (such as cortisol palmitate) or a lubricating substance (such as hyaluronan), or as a single preparation, or at the same time or at intervals of time. it can.
  • a cartilage disease healing promoting substance eg, chondroitin, chondroitin sulfate, dextran sulfate, dalcosamine, dalcosamine darican, bone formation protein (BMP), transforming growth
  • the pharmaceutical composition of the present invention includes, for example, (1) a cyclooxygenase inhibitor (Cox-I, Cox-II inhibitor), (2) a disease-modifying antirheumatic drug and an immunosuppressant, and (3) a biologic. It can be administered simultaneously or at intervals with 4 analgesics and anti-inflammatory agents or 5 other prophylactic or therapeutic agents for bone or joint diseases.
  • the route of administration can be appropriately selected, and may be, for example, oral, topical or transdermal administration.
  • cyclooxygenase inhibitors include salicylic acid derivatives such as celecoxib, oral fuecoxib, and aspirin, diclofenac, indomethacin, loxoprofen, and the like.
  • the dosage of these oral preparations is, for example, about 100 to 20 Omg / day for celecoxib, about 10 to 30 mg / day for oral fuecoxib, about 1000 to 4500 mg / day for salicylic acid derivatives such as aspirin, and about 25 to 50 mg for diclofenac.
  • indomethacin is about 50 to 15 Omg / day
  • loxoprofen is about 60 to 180 mg / day.
  • Examples of disease-modifying antirheumatic drugs and immunosuppressants include methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, and oral gold preparations.
  • the dosage of these oral preparations is, for example, about 2.5 to 7.5 mg / week for methotrexate, about 20 to: leflunomide: about L0 Omg / day, about 1 to 5 mg / day for prograf, and about sulfasalazine for About 500-200 Omg / day, D
  • Penicillamine is about 100 to 600 mg / day, and oral gold is about 3 to 6 mg / day.
  • biologics include monoclonal antibodies (eg, anti-TNF- ⁇ antibody, anti-IL-12 antibody, anti-IL-16 antibody, anti-ICAM-I antibody, anti-CD4 antibody, etc.), soluble receptors (eg, , Soluble TNF-receptors, etc.) and proteinaceous ligands (IL-I receptor antagonists, etc.).
  • the dose of these oral preparations is, for example, about 0.1 to 5 Omg / kg / day, preferably 0.5 to 20 mg / kg / day.
  • Antiphlogistics include, for example, central analgesics (eg, morphine, codine, pentadisine, etc.), steroids (eg, prednisolone, dexamethazo) , Betamethasone, etc.), and anti-inflammatory enzyme agents (eg, promersin, lysozyme, proctase, etc.).
  • the dosage of these oral preparations is, for example, about 1 to 100 Omg / day for central analgesics, preferably about 5 to 30 Omg / day, and about 0 to 40 Omg / day for steroids. Days, preferably about 0.5 to: 10 Omg / day, the anti-inflammatory enzyme agent is about 1 to 10 Omg / day, preferably about 5 to 4 Omg / day.
  • 5Other bone or joint diseases [For example, if bone fracture, refracture, bone defect, osteoporosis, osteoarthritis, bone Behcet's disease, stiff myelitis, rheumatoid arthritis, osteoarthritis, etc.]
  • calcium preparations eg, calcium carbonate, etc.
  • calcitonin preparations eg, , ⁇ Nagi calcitonin, salmon calcitonin, porcine calcitonin, Abikatonin etc.
  • vitamin D 3 compounds e.g., 1 Fei - hydroxycarboxylic vitamin D 3, 1 a, 25-dihydrazide mud carboxymethyl vitamin D 3, Furoka Rushitorioru, Sekarushifu ⁇ roll, etc.
  • sex hormone-related compounds eg, tipolone, estrogen, estradi
  • Lactic acid-glycolic acid copolymer [hereinafter may be referred to as PLGA in the formulation shown in Table 1. Lactic acid-glycolic acid composition ratio (mol./.) 75/25, weight average molecular weight 11300, number average molecular weight 6.430 by GPC measurement, number average molecular weight 3,530 by terminal group determination, Wako Pure Chemical Industries] After preparing a dichloromethane solution or suspension with the compound obtained in Reference Example, a 0.1% aqueous solution of polybutyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Co., Ltd.) (hereinafter referred to as PVA) in the volume shown in Table 1 The solution was sometimes referred to as a solution), and it was converted to 0 / W emulsion at 7, OOOrpm using a turbine type homomixer.
  • EG-40 polybutyl alcohol
  • the pharmaceutical composition of the present invention contains a high content of a physiologically active substance such as a substance promoting bone and cartilage formation and can control the release rate thereof, so that the desired pharmacological action of the physiologically active compound can be maintained for a long period of time. Can be expected.
  • a physiologically active substance such as a substance promoting bone and cartilage formation
  • bone disorders in mammals such as bone fractures, refractures, intractable fractures, bone malunion, pseudoarthritis, osteomalacia, bone Behcet's disease, ankylosing spondylitis, autologous bone grafting, artificial bone grafting, deformity
  • a preventive or therapeutic agent for the destruction of bone and cartilage in osteoarthritis and similar diseases as a bone tissue repair material after surgery for multiple myeloma, lung cancer, breast cancer, etc., and periodontal disease It can be used safely as an agent for promoting regeneration of periodontal tissue, etc.
  • the pharmaceutical composition of the present invention can maintain a constant blood concentration regardless of day and night, the dose and the number of doses can be reduced, and furthermore, the local concentration and the blood drug concentration can be reduced. It is expected that the treatment effect will be more clear because there is little change in the condition and there will be no change in the condition due to discontinuation of taking the drug.

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Abstract

L'invention concerne des compositions médicinales qui permettent à une substance physiologiquement active, à effet promoteur d'oestéogénèse et de chondrogénèse, d'agir de manière continue durant une longue période sur une partie touchée. Ces compositions médicinales contiennent des composés de formule générale (Ia) ou leurs sels, ainsi qu'un composé polymère biodégradable.
PCT/JP2001/004298 2000-05-23 2001-05-23 Compositions medicinales contenant des derives du tiophene WO2001089521A1 (fr)

Priority Applications (1)

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AU58808/01A AU5880801A (en) 2000-05-23 2001-05-23 Medicinal compositions containing thiophene derivatives

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JP2000-155973 2000-05-23
JP2000155973 2000-05-23

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078673A1 (fr) * 2001-03-29 2002-10-10 Takeda Chemical Industries, Ltd. Procede de production d'un medicament sous forme de granules fins
WO2010032448A1 (fr) * 2008-09-17 2010-03-25 株式会社ネクスト２１ Feuillet cellulaire utilisable pour la réparation d'un site cartilagineux défectueux

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08245386A (ja) * 1995-03-09 1996-09-24 Takeda Chem Ind Ltd 細胞分化誘導因子作用増強剤
WO1996039134A1 (fr) * 1995-06-05 1996-12-12 Takeda Chemical Industries, Ltd. Composition pharmaceutique favorisant l'osteogenese
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
WO1999065474A2 (fr) * 1998-06-15 1999-12-23 Takeda Chemical Industries, Ltd. Composition traitant une maladie du cartilage
WO2000018765A1 (fr) * 1998-09-30 2000-04-06 Taisho Pharmaceutical Co., Ltd. Composes d'isoxazolylthiophene substitue

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08245386A (ja) * 1995-03-09 1996-09-24 Takeda Chem Ind Ltd 細胞分化誘導因子作用増強剤
WO1996039134A1 (fr) * 1995-06-05 1996-12-12 Takeda Chemical Industries, Ltd. Composition pharmaceutique favorisant l'osteogenese
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
WO1999065474A2 (fr) * 1998-06-15 1999-12-23 Takeda Chemical Industries, Ltd. Composition traitant une maladie du cartilage
WO2000018765A1 (fr) * 1998-09-30 2000-04-06 Taisho Pharmaceutical Co., Ltd. Composes d'isoxazolylthiophene substitue

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078673A1 (fr) * 2001-03-29 2002-10-10 Takeda Chemical Industries, Ltd. Procede de production d'un medicament sous forme de granules fins
WO2010032448A1 (fr) * 2008-09-17 2010-03-25 株式会社ネクスト２１ Feuillet cellulaire utilisable pour la réparation d'un site cartilagineux défectueux

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