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WO2001002356A1 - Dérivés d'indoline ou tétrahydroquinoline - Google Patents

Dérivés d'indoline ou tétrahydroquinoline Download PDF

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Publication number
WO2001002356A1
WO2001002356A1 PCT/JP2000/004333 JP0004333W WO0102356A1 WO 2001002356 A1 WO2001002356 A1 WO 2001002356A1 JP 0004333 W JP0004333 W JP 0004333W WO 0102356 A1 WO0102356 A1 WO 0102356A1
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group
piperidine
compound
pyridine
pyrrolidine
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PCT/JP2000/004333
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English (en)
Japanese (ja)
Inventor
Koichi Fujimoto
Fumitoshi Asai
Naoki Tanaka
Hayao Matsuhashi
Atsuhiro Sugidachi
Tatsuo Tanimoto
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Sankyo Company, Limited
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Priority to AU55709/00A priority Critical patent/AU5570900A/en
Publication of WO2001002356A1 publication Critical patent/WO2001002356A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to an indoline or tetrahydroquinoline derivative having an excellent activated blood coagulation factor X inhibitory activity, a pharmacologically acceptable salt thereof, and a blood coagulation containing them.
  • compositions for the treatment or prevention of solid diseases their use for the manufacture of a medicament for the treatment or prevention of blood coagulation diseases, and administration of a pharmacologically effective amount thereof to a warm-blooded animal
  • the present invention relates to a method for treating or preventing a blood clotting disease, or a method for producing the same.
  • thrombotic diseases such as cerebral infarction, myocardial infarction, and peripheral circulatory dysfunction not only directly lead to the cause of death, but also impose many personal and social burdens such as poor prognosis of patients and restrictions on their lives. become.
  • Anticoagulant therapy is expected to become increasingly important as a treatment for these thrombosis.
  • Blood coagulation undergoes a multi-step amplification process of an enzymatic reaction that is activated by some kind of stimulus. Generated by generating. Fibrin forms a clot with insoluble proteins. This process is known as the blood clotting cascade, and involves two pathways, intrinsic and extrinsic, each of which activates blood coagulation factor X and merges. As described above, the activated blood coagulation factor X produced is an enzyme that plays an important role in the blood coagulation cascade, and finally, divalent calcium ions, phospholipids, and activated blood coagulation factor V To form a complex with E.
  • Activated blood coagulation factor X is directly involved in the production of thrombin, and its inhibitors are known to exhibit anticoagulant effects, suggesting potential as new anticoagulants [e.g. , Vol. 49, pp. 856 (1995) [Drugs, 42, 856 (1995) j et al.].
  • new anticoagulants e.g. , Vol. 49, pp. 856 (1995) [Drugs, 42, 856 (1995) j et al.].
  • competitive competitive activated blood coagulation factor X inhibitors Japanese Patent Application Laid-Open Nos. 5-20946 and 09/166/940 are known. Further improvement is expected from the pharmacological point of view.
  • the present inventors have aimed for the development of a compound having an excellent activated blood coagulation factor X inhibitory effect, and as a result of long-term intensive studies on the pharmacological activity of various indulin or tetrahydroquinoline derivatives, Indoline or tetrahydroquinoline derivatives having an unusual structure have an excellent activated blood coagulation factor X inhibitory effect and are useful as prophylactic or therapeutic agents (especially therapeutic agents) for blood coagulation diseases.
  • the present invention has been completed.
  • the present invention relates to an indoline or tetrahydroquinoline derivative having an excellent activated blood coagulation factor X inhibitory activity, or a pharmaceutically acceptable salt thereof, and a composition for treating or preventing a blood coagulation disease containing the same.
  • the indolin or tetrahydroquinoline derivative of the present invention has the general formula
  • R 1 is a hydrogen atom; C “C 6 alkyl group; substituted C, _C 6 alkyl group (the substituent represents a halogen atom, a C ⁇ —C 6 alkoxy group, a hydroxyl group or a carboxyl group); C j-1 C 6 alkanoyl group; substituted 1 (: 6 alkanoyl group [the substituent is a hydroxyl group, c 6 —. 14 aryl group, c 6 — c 14 arylthio group, tetrazolylthio group, (c ⁇ - ⁇ 6 ⁇ alkyl) tetrazolylthio group, a carboxy (c -! c 6 alkyl) Chiomoto, (c -! c 6 alkoxy) carbonyl (d-C 6 alkyl) Chiomoto, carboxyl group and (C ⁇ - C - C
  • 6 alkoxy represents one or two substituents that are the same or different and are selected from the group consisting of a carbonyl group. ]; A C 6 alkylsulfonyl group; a substituted c 6 alkylsulfonyl group [the substituent is a halogen atom, a hydroxyl group, a carboxyl group or a (d-c 6 alkoxy) carboxyl group.
  • R 2 is one.
  • R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom, a d-C 6 alkyl group, a C 6 alkoxy group, a cyano group, a nitro group, a hydroxyl group or a C! -C 6 alkanoyloxy group;
  • A represents a single bond, a d—C 4 alkylene group, an oxygen atom, or a group having the general formula 10 (CH 2 ) m ⁇ (wherein, m represents an integer of 1 to 4);
  • the active ingredient of the therapeutic or prophylactic agent for a blood coagulation disease of the present invention is an indoline or tetrahydroquinoline derivative having the general formula (I).
  • the “rc, one C 6 alkyl group” part of “one C 6 alkyl group” and “substituted one c 6 alkyl group” is, for example, methyl Group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group,
  • 2-methylpentyl group 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group,
  • the “halogen atom” in the definition of the “substituted 1 C 6 alkyl group” in the above may be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C i-C 6 alkoxy group in the definition of the “substituted 1 C 6 alkyl group” for R 1 is, for example, a methoxy group, an ethoxy group, a propoxy group, Isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, Hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethyl Such as butoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-d
  • R 1 "(the substituent, a halogen atom, d-C 6 alkoxy group, a hydroxyl group, or carboxyl group.) d-C 6 alkyl group substituted" in the definition of, if example embodiment, Furuoromechiru group, Jifuruoromechiru group , Trifluoromethyl group, 2-fluoroethyl group, 2,2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 4-fluorobutyl Group, 6-fluorohexyl group, chloromethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, bromomethyl group, 3-bromopropyl group, dibromopentyl group, Methyl group, 2- Furuoro 1 one black port Echiru group, main Tokishimechiru group,
  • the “rc ⁇ —C 6 alkanoyl group” is preferably a C i-C 4 alkanoyl group, more preferably a formyl group or an acetyl group, and particularly preferably an acetyl group.
  • substituted d-C e Arukanoiru group "is good applicable, a C i-C 4 Arukanoiru group, more preferably a Asechiru group, a propionyl group, a butyryl group or valeryl group, more preferably the , It is an acetyl group or a propionyl group, particularly preferably an acetyl group.
  • C 6 —C 14 aryl group in the definition of “substituted C ⁇ —C 6 alkanoyl group” is, for example, a phenyl group, an indene-1-yl group
  • An aromatic hydrocarbon group having 6 to 14 carbon atoms such as a naphthalene-1-yl group, a naphthalene-12-yl group, a phenanthrene-11-yl group or an anthracene-19-yl group. It is preferably a phenyl group, a naphthalene-1-yl group or a naphthalene-12-yl group, more preferably a phenyl group.
  • a "C 6 - ⁇ 14 Ariruchio group” for example, phenylene group, a heteroarylthio group, indene one 1- Iruchi
  • An aromatic hydrocarbon group having 6 to 14 carbon atoms such as a thio group, a naphthylene-1-ylthio group, a naphthalene-12-ylthio group, a phenanthrene-1-ylthio group or an anthracene-9-ylthio group becomes a sulfur atom.
  • It may be a bonded group, preferably a phenylthio group, a naphthalene-1-ylthio group or a naphthalene-12-ylthio group, and more preferably a phenylthio group.
  • the definition of the substituent of “substituted d—C 6 alkanoyl group” of “ ⁇ C i—C ⁇ alkyl) tetrazolylthio group” is, for example, 1-methyltetrazol-5-ylthio Group, 1-ethyltetrazol-5-ylthio group, 1-propyltetrazol-15-ylthio group, 1-butyltetrazole-15-ylthio group, 1-pentyltetrazole-15-ylthio group or 1-hexyltetrazole
  • the “C i -C 6 alkyl” such as a 5-ylthio group may be a group bonded to a tetrazolylthio group, and is preferably a 1-methyltetrazole-5-ylthio group or a 1-ethyltetrazole-15- And is more preferably a 1-methyltetrazole-15-ylthio group.
  • Carboxy (d-CFI alkyl) Chiomoto includes, for example, carboxymethyl thio group, 2-carboxyanhydride Chez Ji thio group, 3-carboxypropyl thio group, such as 4 _ Karubokishibuchi thio group, 5-carboxy cyclohexylthio group to pentylthio group or a 6-carboxy, the carboxyl group is (C ⁇ - C 6 alkyl) It may be a group bonded to a thio group, preferably a carboxy (C i -C 4 alkyl) thio group, more preferably a carboxymethylthio group or a carboxyethylthio group, particularly preferably carboxymethylthio group.
  • the "group” is, for example, a methoxycarbonylmethylthio group, an ethoxycarbonylmethylthio group, a propoxycarbonylmethylthio group, a butoxycarbonylmethylthio group, Pentyloxycarbonyl methylthio group, hexyloxycarbonylmethylthio group, 2-methoxycarbonylethylthio group, 2-ethoxycarbonylethylthio group, 2-propoxyethoxycarbonylethylthio group, 2-butoxycarbonylethylthio group Or a 6-hexyloxy group, such as a carbonylylhexylthio group, wherein a (d—C 6 alkoxy) carbonyl group is bonded to a
  • Ci—Ce alkanol group a carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, and particularly preferably an ethoxycarbonyl group.
  • substituent is a hydroxyl group, C 6 —C 14 aryl, C 6 —C 14 arylthio] group, tetrazolylthio group, (C i one C 6 alkyl) tetrazolylthio group, a carboxy (C i-C 6 alkyl) Chiomoto, (C i-C 6 alkoxy) carbonyl (d-C 6 alkyl) Chiomoto, carboxyl Moto ⁇ And one or two substituents, which are the same or different and are selected from the group consisting of (d—C 6 alkoxy) carbonyl groups.]]
  • C 6 Al kill) tetrazolylthio group a carboxy (C i-C 6 alkyl) Chiomoto, (C i-C 6 alkoxy) carbonyl (one C 6 alkyl) Chiomoto, carboxyl group and (C ⁇ - (: 6 from the group consisting ⁇ alkoxy) carbonyl group, is selected same or different, one or two of the substituents Having, be a the C i-C 6 Arukanoiru group, preferably, hydroxyl, Hue group, naphthalene one 1 Iru group, naphthalene one 2-I group, phenylene group, a heteroarylthio group, naphthoquinone Ethylene-1-ylthio group, naphthalene-1-ylthio group, tetrazolylthio group, 1-methyltetrazole-5-ylthio group, carboxymethylthio group, methoxycarbonylmethylthio group, eth
  • phenylthioacetyl group phenylthioacetyl group, Rubokishiasechiru group, 3-carboxypropyl propionyl group, an ethoxycarbonyl ⁇ cetyl group or 3-E-butoxycarbonyl propionyl group or a 2 heat Dorokishi one 2- off
  • a phenylacetyl group most preferably a hydroxyacetyl group, a carboxylacetyl group or an ethoxycarbonylacetyl group.
  • “( ⁇ -1 C 6 alkylsulfonyl group” in the definition of R 1 is, for example, methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, isoprono, sulfonyl group, butanesulfonyl group, isobutane
  • the above-mentioned “( ⁇ -C 6 alkyl group)” may be a group bonded to a sulfonyl group, such as a sulfonyl group, a pentanesulfonyl group, an isopentanesulfonyl group, a neopentanesulfonyl group, a hexanesulfonyl group or an isohexanesulfonyl group.
  • a methanesulfonyl group Preferably a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group or a hexanesulfonyl group, more preferably a methanesulfonyl group, an ethanesulfonyl group or a butanesulfonyl group, Particularly preferably ethanesul Is a group.
  • halogen atom in the definition of the substituent of "substituted Ci-Cs alkylsulfonyl group” for R 1 has the same meaning as described above, and is preferably a fluorine atom or a salt.
  • the Ci-Cs alkoxy) carbonyl group in the definition of the substituent of the "substituted Ci-Cs alkylsulfonyl group" for R 1 has the same meaning as described above, and is preferably Is a (C ⁇ —C 4 alkoxy) carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, and particularly preferably an ethoxycarbonyl group.
  • substituted d—C 6 alkylsulfonyl group in the definition of R 1 [the substituent represents a halogen atom, a hydroxyl group, a carboxyl group, or a (d—C 6 alkoxy) carbonyl group.
  • Is for example, a fluoromethanesulfonyl group, a trifluoromethanesulfonyl group, a 2-fluoroethanesulfonyl group, a 3-fluoroprono, a" n-sulfonyl group, a 4-bromobutanesulfonyl group, a 5-chloropentanesulfonyl group , 6—Eord Hexanesulfonyl, hydroxymethanesulfonyl, 2-hydroxyethanesulfonyl, 3-hydroxypropanesulfonyl, 4-hydroxybutanesulfonyl, 5-hydroxypentanesulfonyl, 6 —Hydroxyhexanesulfonyl group, carboxymethanesulfonyl group, 2-carboxyethanesulfonyl group, 3-carboxypropanesulfonyl group, 4-carboxybutanes
  • the "arylsulfonyl group” moiety may be, for example, a benzenesulfonyl group, an indene-1-ylsulfonyl group, a naphthalene-11-ylsulfonyl group, a naphthalene-12-ylsulfonyl group, a phenanthrene-11-ylsulfonyl group or an anthracene-19-ylsulfonyl group.
  • a sulfonyl group may be bonded to the “C 6 -C 14 aryl group”, and a benzenesulfonyl group, a naphthalene-1-ylsulfonyl group or a naphthalene-12-ylsulfonyl group is particularly preferable.
  • a benzenesulfonyl group a benzenesulfonyl group.
  • “halogen atom” in the definition of the substituent of “substituted C 6 -C 14 arylsulfonyl group” has the same meaning as described above, and is preferably a fluorine atom or a salt.
  • the R 1 'C 6 substituted - C 14 ⁇ Li one Rusuruhoniru group "in” one C 6 alkyl group "in the definition of substituents have the same meanings as described above, preferably a d-C 4 alkyl group, more preferably a methyl group or Echiru group.
  • the “alkoxy group” in the definition of the substituent of “substituted C 6 — (: 14 arylylsulfonyl group” ”for R 1 has the same meaning as described above, and is preferably to is d one C 4 alkoxy group, more preferably a main butoxy group or an ethoxy group, and particularly good suitable a main butoxy group.
  • e —c 6 alkoxy carbonyl group in the definition of the substituent of the “substituted c 6 -c 14 arylsulfonyl group” has the same meaning as described above, and is preferably the a (C -C ⁇ alkoxy) carbonyl group, in further preferably a main Tokishikarubo alkylsulfonyl group or an ethoxycarbonyl group, particularly preferably at a the ethoxycarbonyl group, in the definition of R 1 "Substituted C 6 -C 14 arylsulfonyl group [the substituent is a halogen atom, a C 1, -C 6 alkyl group, a C 6 alkoxy group, a carboxy group or a (C i -Cs alkoxy) carbonyl] Represents a group.] Is, for example, 2-fluorobenzenesulfonyl group, 3-fluorobenzen
  • C 6 C 14 ⁇ Li - Rusuruhoniru be a group, suitably the group consisting of halogen atom, C i-C 4 alkyl group, C i-C 4 alkoxy group, a carboxyl group, and (d-C 4 alkoxy) carbonyl group
  • “(( ⁇ —. 6 alkoxy) carbonylsulfamoyl group” in the definition of R 1 is, for example, a methoxycarbonylsulfamoyl group, an ethoxycarbonylsulfamoyl group, a propoxycarbonylsulfamoyl group.
  • R 2 a in the definition of "C 3 -. - cycloalkyl group” and “cycloalkyl group substituted C 3.”
  • halogen atom in the definition of the substituent of “substituted C 3 —.cycloalkyl group” for R 2 has the same meaning as described above, and is preferably a fluorine atom or It is a chlorine atom, particularly preferably a chlorine atom.
  • Cycloalkyl group (the substituent is a halogen atom or an amino group)” in the definition of R 2 is, for example, 2-fluorocyclopropyl 2-, 2-chlorocyclopropyl, 2-bromocyclopropyl, 2-hydrocyclopropyl, 2-aminocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2 —Chlorocyclobutyl, 3 —chlorocyclobutyl, 2 —bromocyclobutyl, 3 —bromocyclobutyl, 2-odocyclobutyl, 3 —odocyclobutyl, 2 —aminocyclobutyl Group, 3-aminocyclobutyl group, 2-fluorocyclopentyl group, 3-fluorocyclopentyl group, 2-bromocyclopentene Tyl group, 3-bro
  • a substituent selected from the group consisting of a halogen atom and an amino group such as a 2-aminoadamantan-11-yl group; It may be a cycloalkyl group, preferably a 2-fluorocyclopentyl group, a 3-fluorocyclopentyl group, a 2-chlorocyclopentyl group, a 3-chlorocyclopentyl group, a 2-bromocyclopentyl group,
  • substituted C 6 —C 14 aryl group (the substituent represents an amidino group or a guanidino group)” in the definition of R 2 is, for example, a 2-amidinophenyl group, Amidinophenyl, 4-amidinofenyl, 2-guanidinophenyl, 3-guanidinophenyl, 4-guanidinophenyl, 5-amidinoindene1-1-yl, 5-guanidinoindene1-1— Yl group, 6-amidinonaphthalene-1-yl group, 6-guanidinonaphthalene-1-yl group, 6-amidinonaphthalene-12-yl group, 6-guanidinonaphthalene-12-yl group Group, 6-amidinophenanthrene-1-yl group, 6-guanidinophenanthrene-12-yl group, 9-amidinoanthracene-1 10-yl group or 9-guanidinoanthracene-1 10
  • the "substituted Amino group""one C 6 7 alkyl group” in the definition of substituents have the same meanings as described above, preferably with d-C 4 alkyl group Yes, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
  • the “hydroxy C 2 —C 6 alkyl group” in the definition of the “substituted amino group” of R 2 is, for example, a 2-hydroxyethyl group, a 2-hydroxypropyl group , 3-hydroxypropyl group, 2-hydroxyisopropyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 2-hydroxyisobutyl group, 2-hydroxy-1-s-butyl group, 2-hydroxy 1-t-butyl group, 2-hydroxypentyl group, 3-hydroxypentyl group, 4-hydroxypentyl group, 5- Hydroxypentyl, 3-hydroxy-2-methylbutyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6- It may be a group in which a hydroxyl group is bonded to a linear or branched alkyl group having 2 to 6 carbon atoms, such as a hydroxyhexyl group or a 5-hydroxy-4-methylp
  • substituted amino group (the substituent is a group consisting of a C i—C ⁇ T alkyl group, a hydroxy C 2 —C 6 alkyl group and an acetimidoyl group) Represents the same or different and represents one or two substituents.)
  • Is for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, Butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, 4-methylpentylamino Group, 3-methylpentylamino group, 2-methylpentylamino group, 1-methylpenty
  • the “4- to 6-membered saturated cyclic amino group” portion of the “4- to 6-membered saturated cyclic amino group” is, for example, an azetidine-11-yl group, an azetidine-12-yl group, an azetidine-13- 1-yl group, pyrrolidine 1-yl group, pyrrolidine 1-2-yl group, pyrrolidine 1-3-yl group, imidazolidine 1-1-yl group, imidazolidine 1-2-yl group, imidazolidin 1-41 y , Pyrazolidine-1-yl, pyrazolidine-4-yl, pyridino, pyridin-12-yl, pyridin-13-yl, Pyridine-1-yl, piperazine-1-yl, piperazine-12-yl, morpholin-12-yl, morpholin-3-y
  • a pyrrolidinyl group, a pyridyl group, a piperazinyl group or a morpholinyl group more preferably an azetidine-13-yl group, a pyrrolidine-12-yl group, a pyrrolidine-13-yl group, A lysine-1-yl group, a piperidine-3-yl group, a piperidine-14-yl group, a piperazine-11-yl group or a morpholine-12-yl group, more preferably Is a pyrrolidine-12-yl group, a pyrrolidine-13-yl group, a piperidine-12-yl group, a piperidine-13-yl group or a piperidine-14-yl group, particularly preferably Is a pyrrolidine-1-yl group or a pyridin-14-yl group.
  • a in the definition of the substituents of "substituted 4- to 6-membered saturated cyclic amino group""( ⁇ one C 6 Arukanoiru group” have the same meanings as described above, preferably is a CC 4 Arukanoiru group, more preferably a formyl group, an Asechiru group or propionate group, particularly preferably a Asechiru group.
  • Amino C i -C 6 alkanoyl group in the definition of the substituent of "membered saturated cyclic amino group” includes, for example, carbamoyl group, aminoacetyl group, 2-aminopropionyl group, 3-aminopropionyl group, 2-aminobutyryl group, 3-aminobutyryl group, 4-aminobutyryl group, 3-aminoisobutyryl group,
  • the above d-C 6 alkanoyl group such as a 3-aminobivalyl group, a 5-aminovaleryl group, a 4-aminoisovaleryl group or a 6-aminohexanoyl group, may be a group in which an amino group is substituted.
  • the “5- to 6-membered aromatic heterocyclic group” in the definition of the “substituted 4- to 6-membered saturated cyclic amino group” for R 2 is, for example, a 1-pyrrolyl group , 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-phenyl, 3-phenyl, imidazole-1-yl, imidazole-2-yl, imidazole — 4-yl, pyrazol-1,1-yl, pyrazol_3-yl, pyrazole-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole— 5-yl group, isoxazole-3-yl group, isoxazole-4-yl group, isoxazole-5-yl group, thiazol-12-yl group, thiazol-4-yl group Group, thiazole-5-yl group, isothiazol-1-yl
  • a Jiniru group even more preferably, a pyridyl group, particularly preferably a pyridine one 2-I le group.
  • R 2 “substituted 4- to 6-membered saturated cyclic amino group (wherein the substituent is an acetimidoyl group, a C ⁇ —C 6 alkanoyl group, an amino 1 1 ⁇ 6 Arcanoy And a 5- or 6-membered aromatic cyclic amino group.
  • Means for example, 1-acetimidylazetidine-12-yl group, 1-acetylazetidine-12-yl group, 1-carbamoylazetidine-12-yl group, 1-aminoacetyla Zetidine 1-2-yl group, 1- (2-amino-pionyl) azetidine-12-yl group, 1- (pyridine-12-yl) azetidine 1-2-yl group, 1-acetimidylylazetidine 1-3-yl group, 1-acetyl azetidine-1-3-yl group, 1-potassium azemoylazetidine-1-3-yl group, 1-aminoacetylazetidine-1-3-yl group, 1- (2-a Minopropionyl) azetidine-3-yl group, 1- (pyridine-12-yl) azetidine-13-yl group, 1-acetimidylpyrrolidine-12-yl group, 1-acetylpyr
  • 2-yl group 5- (pyridine-2-yl) piperidine-1-yl group, 6- (pyridine-2-yl) piperidine-1-2-yl group, 1-acetoimidylpi Peridine-3-yl group, 1-formylpiperidine-3-yl group, 1-acetylbiperidine-13-yl group,
  • 2-yl) piperidin-3-yl group 4- (pyridine-1-2-yl) piperidin-1-3-yl group, 5- (pyridine-1-2-yl) piperidin-1 3 —Yl group, 6— (pyridin-1-yl) piperidine-1-3-yl group, 1—acetoimidoylpyridin-1--4-yl group,
  • 1-formylpiperidine-1-yl group 1-acetylbiperidine-14-yl group, 1-propionylbiperidine-14-yl group, 1-valerylpiperidine-14-yl group, 1-1-to Xanoylbiperidine-1-yl group, 1-force rubamoylbiperidine-1-4-yl group, 2-force-type rubamoylpiperidine-1-4-yl group, 3-force-type rubamoylpiperidine-1-4-yl group 1-aminoacetylbiperidine-1-4-yl group, 1- (2-aminopropionyl) piperidine-1-4-yl group, 1- (3-aminopropionyl) piperidine-1-4 Yl group,
  • an acetimidoyl group isoxazolyl group, thia 'zolyl group, isothiazolyl group.
  • pyridyl group Selected from the group consisting of pyridyl group, pyrazinyl group, pyrimidinyl group and pyridazinyl group
  • 2-yl) pyrrolidine-3-yl group 1-acetimidoylpiperidine-1-yl group, 1-formylpiperidine-1-yl group, 1-acetylbiperidine-1-2-yl Group, 1-propionylpiperidin-1-yl group, 1-propaneylpiperidin-12-yl group,
  • halogen atom in the definition of R 3 and R 4 has the same meaning as described above, and is preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.
  • the r C ⁇ alkyl group in the definition of R 3 and R 4 has the same meaning as described above, is preferably a C 4 alkyl group, more preferably a methyl group or The It is a tyl group, particularly preferably a methyl group.
  • the “rC Ce alkoxy group in the definition of R 3 and R 4 ” has the same meaning as described above, is preferably a C 4 alkoxy group, and more preferably a methoxy group. It is.
  • one alkanoyloxy group in the definition of R 3 and R 4 is, for example, a formyloxy group, an acetoxy group, a propionyloxy group, a ptyryloxy group, an isobutyryloxy group, a bivaloyloxy group And a group in which an oxygen atom is bonded to the above-mentioned C ⁇ -Cs alkanoyl group, such as a noryloxy group, an isovaleryloxy group or a hexanoyloxy group, and is preferably a formyloxy group or an acetoxy group. Is an acetyloxy group.
  • ( ⁇ -C 4 alkylene group” in the definition of A is, for example, a methylene group, a methylmethylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, a 1-methyltrimethylene group. It may be a linear or branched alkylene group having 1 to 4 carbon atoms, such as a 2-methyltrimethylene group or a 3-methyltrimethylene group, and is preferably a methylene group, an ethylene group or a trimethylene group. And particularly preferably a methylene group.
  • preferred compounds are those represented by the general formula (I) of the present invention.
  • the compound having the general formula (I) of the present invention can be converted into a corresponding pharmacologically acceptable salt by treating the compound with an acid according to a conventional method.
  • the compound (I) is treated with a corresponding acid for 5 to 30 minutes at room temperature in a solvent (for example, ethers, esters or alcohols, preferably ethers or alcohols) in a solvent.
  • the crystals can be obtained by filtering the crystals obtained or distilling off the solvent under reduced pressure.
  • Such salts include carbonates; mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; Sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; acetate, propionate, butyrate, fumarate, succinate Salts, carboxylates such as citrate, tartrate, oxalate or maleate or benzoate; or amino acid salts such as glutamate or aspartate.
  • mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate
  • Sulfonates such as methanesulfonate, trifluoromethanesulfonate,
  • the compound having the general formula (I) of the present invention can be converted into the corresponding pharmacologically acceptable salt by treating with a base according to a conventional method, for example, when R 1 contains a carboxyl group.
  • a base for example, ethers, esters or alcohols, preferably alcohols
  • compound (I) is treated with a corresponding base in a solvent (for example, ethers, esters or alcohols, preferably alcohols) at room temperature for 5 to 30 minutes, and the precipitated crystals are filtered. Or by distilling off the solvent under reduced pressure.
  • a solvent for example, ethers, esters or alcohols, preferably alcohols
  • Such salts include, for example, alkali metal salts such as sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt, copper salt Metal salts such as salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine Salts, guanidine salts, getylamine salts, triethylamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, chlorinated proforce salts, proforce salts, diethanolamine salts, N-benzylphenethylamine salts , Piperazine salt, tetramethylammonium salt, Scan obtained an
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may have a cis or trans geometric isomer, and may have an asymmetric carbon atom in the molecule. If having, R coordination, the force that may be present stereoisomers strength is S configuration?, each or both of which are encompassed by the present invention in any proportion of compounds thereof.
  • stereoisomers can be obtained, for example, by synthesizing compound (I) using an optically resolved starting compound or, if desired, subjecting synthesized compound (I) to optical resolution using a conventional optical resolution or separation method. can do.
  • the compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof absorbs water by being left in the air or recrystallized, and adsorbs water, or becomes a hydrate.
  • the compound salt containing such water may be included in the present invention.
  • suitable compounds include, for example, (1) R 1 methyl or ethyl; fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl Group, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxethyl, hydroxymethyl, 2-hydroxyethyl, 'carboxymethyl or 2-carboxyethyl Alkanoyl group; hydroxyl group, phenyl group, naphthalene-1-yl group, naphthalene-12-yl group, phenylthio group, naphthalene-11-ylthio group, naphthalene-12-ylthio group, tetrazolylthio group, 1-methyltetrazo 5-ylthio, carboxymethylthio, methoxycarbonylmethylthio, ethoxy An acetyl,
  • R 1 methyl or ethyl group; trifluoromethyl group, methoxymethyl group, hydroxymethyl group or carboxymethyl group; formyl group or acetyl group; hydroxyacetyl group, phenylacetyl group, phenylthioacetyl group , (1-methyltetrazole-5-ylthio) acetyl, carboxyacetyl, 3-carboxypropionyl, 4-carboxybutyryl, 5-carboxyvaleryl, ethoxycarbonyl acetyl, 3-ethoxycarbonyl Propionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonylvaleryl, 2-hydroxy-12-phenylacetyl, 3-hydroxy-13-phenylpropionyl or 4-hydroxy-4-phenylbutyryl Group: methanesulfonyl group, ethanesulfonyl group Group, Purono, "Nsuruho two group, butanes
  • R 1 force formyl group, acetyl group, hydroxyacetyl group, phenylthioacetyl group, carboxyacetyl group, 3-carboxypropionyl group, 4-carboxybutyryl group, 5-carboxyvaleryl group, ethoxycarbonyl group Cetyl group, 3-ethoxycarbonylpropionyl group, 2-hydroxy-2-phenylacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, hydroxymethanesulfonyl group, 2-hydroxyethanesulfonyl group, carboxy Methanesulfonyl group, 2-carboxyethanesulfonyl group, 3 carboxypropanesulfonyl group, 4 carboxybutanesulfonyl group, 5-carboxypentanesulfonyl group, methoxycarbonylmethanesulfonyl group,
  • R 1 force, acetyl group, hydroxyacetyl group, phenylthioacetyl group, carbonyloxyacetyl group, 3-carboxypropionyl group, ethoxycarbonylacetyl group, 3-ethoxycarbonylpropionyl group, 2-hydroxy-12- Phenylasetti Methanesulfonyl, ethanesulfonyl, butanesulfonyl, 2-hydroxyethanesulfonyl, carboxymethanesulfonyl, 3 carboxypropanesulfonyl, 5-carboxypentanesulfonyl, ethoxycarbonylmethanesulfonyl, A compound that is a 3-ethoxycarbonylpropanesulfonyl group, a 5-ethoxycarbonylpentanesulfonyl group or a 4-methoxycarbonylbenzenesulfonyl group,
  • R 1 s , acetyl group, hydroxyacetyl group, carboxyacetyl group, ethoxycarbonylacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, carboxymethanesulfonyl group or ethoxycarbonylmethanesulfonyl group
  • acetyl group hydroxyacetyl group, carboxyacetyl group, ethoxycarbonylacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, carboxymethanesulfonyl group or ethoxycarbonylmethanesulfonyl group
  • R 2 is a pyrrolidine-12-yl group, a pyrrolidine-13-yl group, a pyridin-12-yl group, a pyridin-13-yl group, a pyridin-14-yl 1-acetoimidoylpyrazetidine-1-3-yl group, 1-acetoimidoylpyrrolidine-12-yl group, 1— Acetimidoylpyrrolidine-1-3-yl group, 1-acetoimidoylpyridine-1-3-yl group, 1 _acetimidoylpyrrolidine-1-4-yl group, 1-acetimylbiperidine-1-4-yl group, 1 —Hyrbamoylbiperidine-1-4-yl group, 1-aminoacetylbiperidine-1-4-yl group, 1- (2-aminopropionyl) piperidine-1-4-yl group, 1— ( A compound which is a pyridin-1-yl group, a
  • R 3 and R 4 are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a C 4 alkyl group, A compound which is an alkoxy group, a cyano group, a nitro group, a hydroxyl group, a formyloxy group or an acetoxy group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a methoxy group, a cyano group, a hydroxyl group or an acetyloxy group;
  • R 4 is a hydrogen atom or a chlorine atom compounds
  • R 2 force, cyclopentyl or cyclohexyl group; 2-fluorocyclohexyl group, 3-fluorocyclohexyl group, 4-fluorocyclohexyl group, 2-chlorocyclohexyl group, 3-chlorocyclohexyl group, 4-chlorocyclo Hexyl group, 2-aminocyclohexyl group, 3-aminocyclohexyl group or 4-aminocyclohexyl group; phenyl group or naphthalenyl group; 2-amidinophenyl group, 3-amidinophenyl group, 4-amidinophenyl group, 2 —Guanidinophenyl, 3-guanidinophenyl or 4-guanidinophenyl; amino; methylamino, ethylamino, N, N-dimethylamino, hydroxymethylamino, 1-hydroxyxamino Tilamino group, 2-hydroxythitylamino group,
  • R 1 force methyl group or ethyl group; trifluoromethyl group, methoxymethyl group, hydroxymethyl group, or carboxymethyl group; formyl group or acetyl group; , (1-methyltetrazol-5-ylthio) acetyl group, carboxyacetyl group, 3-carboxypropionyl group, 4-carboxybutyryl group, 5-carboxyvaleryl group, ethoxycarbonylbonacetyl group, 3-ethoxycarbonylpropionyl Group, 4-ethoxycarbonylbutyryl group, 5-ethoxycarbonylvaleryl group 2-hydroxy-12-phenylacetyl group, 3-hydroxy-13-phenylpropionyl group or 4-hydroxy-14-phenylbutyryl group; Methanesulfonyl group, ethanesulfonyl , Propanesulfonyl group, butanesulfonyl group, pentane sulfonyl group, or
  • R 2 force cyclohexyl group; 4-cyclohexyl group a hexyl group or a 4-amino-cyclo Kuroroshikuro; phenyl groups; 4 Amijinofueniru group; Amino group; Mechiruamino group, N, N- dimethylamino group or N- Asetoimi Doyl-N-methylamino group; azetidine-13-yl group, pyrrolidine-12-yl group, pyrrolidine-13-yl group, piperidine-12-yl group, piperidine-13-yl group, Piperidine-14-yl, piperazine-11-yl or morpholine-12-yl; or acetimidoyl, formyl, acetyl, propionyl, carbamoyl, aminoacetyl An azetidine-13-yl group, a pyrrolidine-12-yl group, and a pyrrolidine-13-yl group having
  • R 3 force? Hydrogen atom
  • R 4 forces a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, Echiru group, main butoxy group, compounds which are Shiano group, hydroxyl group or Asetokishi group,
  • R 1 force Formyl group, acetyl group, hydroxyacetyl group, phenylthioacetyl group, carboxyacetyl group, 3-carboxypropionyl group, 4-carboxybutyryl group, 5-carboxyvaleryl group, ethoxycarbonyl group Cetyl group, 3-ethoxycarbonylpropionyl group, 2-hydroxy-1-phenylacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, hydroxymethanesulfonyl group, 2-hydroxyethanesulfonyl group, carboxy Methanesulfonyl group, 2-carboxyethanesulfonyl group, 3-carboxypropanesulfonyl group, 4-carboxybutanesulfonyl group, 5-carboxypentanesulfonyl group, methoxycarbonylmethanesulfonyl
  • R 2 force azetidine-13-yl group, pyrrolidine-12-yl group, pyrrolidine-13-yl group, piperidine-12-yl group, piperidine-13-yl group, piperidine 1- 4-yl group, piperazine- 1-yl group, morpholine- 1- 2-yl group, 1-acetoimidoylazetidine 1- 3-yl group, 1-formylazetidine 13-yl group, 1- Acetyl-azetidine 1-3-yl group, 1-propionylazetidine 1-3-yl group, 1-potassium azetidine 1-3-yl group, 1-aminoacetylazetidine 1-3 —Yl group, 1— (2-aminobutionyl) azetidine-3-yl group, 1— (pyridin-2-yl) azetidine_ 3 —yl group, 1 —acetimidoylpyrrolidine-1-yl Group, 1-formylpyrrolidine-12-y
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, Mf, a single bond, a methylene group, an ethylene group, a trimethylene group, an oxygen atom or a general formula 10 (CH 2 ) a compound having a group having m- (wherein, m represents 1 or 2),
  • R 1 R acetyl group, hydroxyacetyl group, phenylthioacetyl group, carboxyacetyl group, 3-carboxypropionyl group, ethoxycarbonylacetyl group, 3-ethoxycarbonylpropionyl group, 2-hydroxy1-2 —Phenylacetyl, methanesulfonyl, ethanesulfonyl, butanesulfonyl, 2-hydroxyethanesulfonyl, carboxymethanesulfonyl, 3-carboxypropanesulfonyl, 5-carboxypentanesulfonyl, ethoxycarbonyl A methanesulfonyl group, a 3-ethoxycarbonylpropanesulfonyl group, a 5-ethoxycarbonylpentanesulfonyl group or a 4-methoxycarbonylbenzenesulfonyl group,
  • R 2 force pyrrolidine-12-yl group, pyrrolidine-13-yl group, piperidine-12-yl group, piperidine-13-yl group, piperidine-14-yl group, 1- Asetomi Doylua Zetidine-1-3-yl group, 1-acetoimidoylpyrrolidine-12-yl group, 1-acetoimidoylpyrrolidine-1-3-yl group, 1-acetoimidoylpiperidine-13-yl group, 1-acetimimi Doylpiperidine-1-4-yl group, 1-acetylbiperidine-1-4-yl group, 1-ylrubamoylbiperidine-1-4-yl group, 1-aminoacetylpiperidine-14-yl group, 1— (2-aminopropionyl) piperidin-4-yl group, 1- (pyridin-2-yl) piperidine-1-4-yl group, 4-acetoimidoylpyrazine-11-yl group or 4-aceto
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a chlorine atom
  • R 1 acetyl group, hydroxyacetyl group, carboxyacetyl group, ethoxycarbonyl acetyl group, methanesulfonyl group, ethanesulfonyl group, butansulfonyl group, carboxymethanesulfonyl group, 3-carboxypropanesulfonyl group, A 5-carboxypentane sulfonyl group, an ethoxycarbonylmethanesulfonyl group, a 3-ethoxycarbonylpropanesulfonyl group, a 5-ethoxycarbonylpentane sulfonyl group or a 4-methoxycarbonylbenzenesulfonyl group,
  • R 2 s ' 1-acetoimidoylpyrrolidine- 1-yl group, 1-acetoimidoylpyrrolidine 1- 3-yl group, 1-acetoimidoyl-doylpyridine- 1-yl group, 1-acetoimidoylpyridin A 4-pyridine group or a 1-hydroxyl-birmoylpyridin-4-yl group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a chlorine atom
  • a force An oxygen atom or a group having the general formula — 0 (CH 2 ) m — (wherein m represents 1);
  • R 1 acetyl group, hydroxyacetyl group, carboxyacetyl group, ethoxycarbonyl acetyl group, methanesulfonyl group, ethanesulfonyl group, butanth A sulfonyl group, a carboxymethylsulfonyl group or an ethoxycarbonylmethanesulfonyl group,
  • R 2 is a 1-acetimidylpyrrolidine-1-3-yl group or a 1-acetimidylpyrrolidine-1-4-yl group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a chlorine atom
  • Representative compounds of the present invention include, for example, compounds listed in the following table. The present invention is not limited to these compounds.
  • preferred compounds are exemplified compound numbers 1-75, 117-176, 1-104, 1-105, 1-1. 9 5, 1—1 96, 1—276, 1—2 77, 1—358, 1—520, 1—600, 1—60 1, 1—662, 1—663, 1—675, 1—687, 1—688, 1—690, 1—706, 1—7 1 3, 1—728, 1—732, 1—73 3, 1—734, 1—735, 1—761, 1—762, 1— 764, 1—77 1, 1—783, 1—784, 1—786, 1—788, 1—789, 1—790, 1—880, 1—88 1, 1—946, 1—993, 1— 1 074, 1—1 1 55, 1 1 243, 1—1 244, 1—1 250, 1—1 296, 1—1 324, 1—1 325, 1—1405, 1—1 40
  • Illustrative Compound No. 1 1 244 [5- (1-acetimidoylpyridinidine-4-yloxy) 1-2- (7-amidinonaphthalene-1-yl) indoline-1-ylsulfonyl] Ethyl acetate
  • the compound having the general formula (I) of the present invention can be easily produced according to the following method. it can,
  • R 1 R 2 , R 3 , RA and n have the same meanings as described above, and R 5 has the same meaning as R 2 except that the amino group is optionally protected.
  • R 8 has the same meaning as R 1 except that the hydroxyl group is protected.
  • the “protecting group for an amino group” of R 5 is not particularly limited as long as it is a group generally used as a protecting group for an amino group, for example, a formyl group, an acetyl group, and a propionyl group.
  • C, —C 6 alkanol groups such as butyryl group, isobutyryl group, pentanoyl group, bivaloyl group, norryl group, isonorelyl group or hexanoyl group; octaacetyl group, dichloroacetyl group, trichloroacetyl group, triflur Oroasechiru group, 3 full O Ropuro propionyl group, 4, 4-dichloro-butyryl group, main Tokishiasechiru group, Butokishiasechiru group, such as ethoxy propionyl group or a propoxy Petit Lil group, halogen or d-C 4 alkoxy in one substituted C 4 Arukanoiru group; ⁇ acryloyl group, propioloyl group, methacryloyl , Kurotono I group or Isokuro Tonoiru unsaturated CC 4 Arukanoiru groups such as;.
  • Benzoiru group "A naphthoyl Group, /?-Naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro- ⁇ -naphthoyl group, 4-toluoyl group, 4—Propylbenzoyl group, 41 t—Butylbenzoyl group, 2,4,6_trimethylbenzoyl group, 6—Ethyl-1- ⁇ -naphthyl group, 4-anisyl group, 4-propoxybenzoyl group, 4_t —Butoxybenzoyl group, 6-ethoxy ⁇ -naphthoyl group, 2 —ethoxycarbonylbenzoyl group, 4-t —butoxycarbonylbenzoyl group, 6-methoxycarbonyl ⁇ -naphthyl group, 4-phenyl Enylbenzoyl group, 4-pheny
  • hydroxyl protecting group where generally a group used as a protecting group for a hydroxyl group, a force that can specifically limited use rather than?, For example, a formyl group, Asechiru group, propionic group, butyryl group, isobutyryl Group, pentanoyl group, bivaloyl group, nor-s-relyl group, isovaleryl group, octanoyl group, nonanoyl group, decanoyl group, 3-methylnonanoyl group, 8-methylnonanoyl group, 3-ethylnonanoyl group, 3, 7-dimethylo ctanoyl group, decanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pendecanyl group, hexadecanoyl group, 1-methylpentadecanoyl group, 14-methylpentadecanoyl group, 13, 13-di
  • Method A is a method for producing a compound having the general formula (I).
  • Step A1 is a step of producing a compound having the general formula (I),
  • reaction for converting a cyano group to an amidino group is generally performed according to a method well known in the art.
  • reaction (a) (1) is a two-step reaction.
  • the first step is a reaction in which a nitrile group is reacted with an alcohol in the presence of an acid to obtain an imino ether compound.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Aliphatic hydrocarbons aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene Hydrogens; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether; ketones such as acetone, 2-butanone or methylethyl ketone; methyl acetate or ethyl acetate Esters such as nitromethane Oral compounds; formamide, N
  • this reaction may be carried out in an excess of alcohols (for example, methanol, ethanol, propanol, isopropanol, butanol or isobutanol, etc.) also as a solvent, preferably methanol or ethanol. It can be done by Normally, the reaction is carried out in alcohol unless there is a problem.
  • alcohols for example, methanol, ethanol, propanol, isopropanol, butanol or isobutanol, etc.
  • Examples of the acid used include mineral acids such as hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, and ethanesulfonic acid.
  • Acid a sulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid; or a Lewis acid such as boron trifluoride, aluminum chloride, iron chloride (111), zinc chloride, mercury (II) chloride, and the like.
  • a mineral or Lewis acid particularly preferably hydrogen chloride o
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 10 ° C to 100 ° C, preferably from Ot: to 50 ° C.
  • the reaction time varies depending on the starting material, the reagent and the reaction temperature, but is usually from 10 minutes to 48 hours, preferably from 1 hour to 15 hours.
  • the second step of the reaction (a) (1) is a reaction in which the iminoether compound produced in the first step is decomposed with caro ammonia. This reaction is usually performed in an inert solvent in the presence of ammonium ion.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; water; or a mixed solvent of alcohols and water, preferably methanol, ethanol, water, hydrated methanol or hydrated ethanol. And particularly preferably ethanol, water or hydrous ethanol.
  • the source of ammonium ions of the ammonium ions used can be, for example, aqueous ammonia, ammonium chloride, ammonium carbonate or a mixture thereof, preferably ammonium chloride.
  • the pH in the reaction is neutral to weakly basic, and is preferably ammonia water and hydrochloric acid.
  • the pH is 7 to 9.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 10 to 100, preferably from 0 to 50 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 1 hour to 15 hours, depending on the starting material, the reagent and the reaction temperature.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or after the reaction is completed, water is added to the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added, and the target compound is added.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer was washed with water, after drying with anhydrous magnesium sulfate or the like, the target compound mosquitoes? distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Reaction (a) (2) is a two-step reaction.
  • the first step is a reaction in which a nitrile group is reacted with hydroxylamine in an inert solvent in the presence of a base, if desired, to obtain an amidoxime compound.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • hexane, cyclohexane, heptane, lignin, or petroleum ether Aromatic hydrocarbons such as benzene, toluene or xylene; halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene.
  • Ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, 2-butanone or methylethyl ketone; nitromethane Nito-oral compounds; acetonitrile or isobutyronitrile Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N- Amides such as methyl-2-pyrrolidinone; dimethyl Sulfoxides such as sulfoxides or sulfolanes; or water, preferably alcohols (particularly methanol or ethanol).
  • Examples of the source of hydroxyamine used include an aqueous solution of hydroxyamine, a solution of an organic solvent, and a salt with an acid.
  • the base used is not particularly limited as long as it can neutralize a salt of hydroxylamine with an acid.
  • a salt of hydroxylamine is used directly, , but not necessarily), for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or lithium hydroxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine , 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N Getylanilin, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DAB CO) or 1,8-diazabicyclo [5.4.0] ] It can be
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually 0 ° C to 150 ° C, preferably 50 ° C to 100 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 24 hours, preferably 5 hours to 12 hours.
  • the second step of (2) is a reaction for hydrolyzing the amidoxime compound produced in the first step.
  • acetylation is usually carried out in acetic acid, or using acetic anhydride. If necessary, it can be carried out in a solvent.
  • the solvent used for the acetylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hexane, cyclohexane, heptane, lignin and petroleum ether.
  • Aliphatic hydrocarbons aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; ketones such as acetone, 2-butanone or methyl ethyl ketone; nitro compounds such as nitromethanekind; or Acetonito It can be a nitrile such as lyl or isobutyronitrile, preferably a halogenated hydrocarbon (particularly dichloromethane) or an ether (particularly tetrahydrofuran).
  • the reaction temperature of the acetylation varies depending on the starting compound, the reagent and the like, but is usually 0 to 150, preferably 50 to 100 ° C.
  • the reaction time of the acetylation is 5 ', usually 1 hour to 24 hours, preferably 5 hours to 12 hours, which depends on the starting compound, the reagent and the reaction temperature.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent after completion of the reaction).
  • a conventional method for example, a method of distilling off the solvent after completion of the reaction.
  • Hydrogenolysis of the amidoxime compound is usually performed continuously without changing the reaction solvent. If desired, the solvent can be distilled off once, and the resulting residue can be dissolved again in an inert solvent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Aliphatic hydrocarbons aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Halogenated hydrocarbons such as tan, chlorobenzene or dichlorobenzene; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl ethane or diethylene glycol dimethyl ether; acetone, 2-butanone or methylethyl Ketones such as ketones; Nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; alcohols such
  • the catalyst used in the hydrogenolysis is not particularly limited as long as it is used in a usual catalytic reduction reaction.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 10 ° C to 100 ° C, preferably from 0 ° C to 80 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 24 hours, preferably 5 hours to 12 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the catalyst is removed by filtration, and then the solvent is distilled off.
  • the catalyst is removed by filtration, and then water is added to the reaction solution, and a water-immiscible solvent (for example, benzene , Ether, ethyl acetate, etc.) to extract the desired compound, wash the extracted organic layer with water, dry using anhydrous magnesium sulfate, etc., and distill off the solvent to obtain the desired compound.
  • a water-immiscible solvent for example, benzene , Ether, ethyl acetate, etc.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • reaction for removing a protected amino group is generally carried out as follows according to a method well known in the art of synthetic organic chemistry.
  • the protecting group of the amino group is formyl group, acetyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-1-t-butoxycarbonyl group, 2 , 2-dibutene tert-butoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxy carbonyl group, p-methoxy When it is a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group, it can be removed by treating with an acid in an inert solvent or an aqueous solvent.
  • the target compound can also be obtained as a salt.
  • the acid used can be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, Hydrofluoric acid or trifluoroacetic acid.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene
  • getyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether
  • esters such as methyl acetate or ethyl acetate
  • alcohols such as methanol, ethanol, propanol, isopropanol or butanol
  • formamide Amides such as dimethylformamide, dimethylacetamide or
  • the reaction temperature varies depending on the starting compound, the solvent or the acid used, but is usually from 110 to 1501: preferably from 0 ° C to 100 ° C.
  • the reaction time varies depending on the starting compound, the solvent and the acid used, but is usually 5 minutes to 48 hours, preferably 10 minutes to 15 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the target compound precipitated in the reaction solution is collected by filtration, or the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (for example, benzene, ether, Then, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the protecting group for the amino group is an alkanol, arylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aryldicarbonyl, aralkyl or aralkyloxycarbonyl. It can be removed by treating with a base in a solvent or an aqueous solvent.
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, lithium hydrogen carbonate or lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium methoxide Alkali metal alkoxides such as potassium butoxide or lithium methoxide; Mercaptan alkali metals such as methyl mercaptan sodium or ethyl mercaptan sodium; hydrazine, methylamine, dimethylamine, ethylamine, Triethylamine, G Buchiruamin, diisopropyl E Ji Ruamin, N _ methylmorpholine, pyridine, 4 one (N, N-Jimechiruamino) pyridinium Jin, N, N-
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene or dichlorobenzene
  • getyl ether, diisopropyl ether, tetrahi Ethers such as drofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether
  • alcohols such as methanol, ethanol, propanol, isopropanol or butanol
  • formsamide, dimethylformamide, dimethyla Setami Amides such as amide or hexamethylphosphoric triamide
  • the reaction temperature varies depending on the starting compound, the solvent or the base used, but is usually from 10 to 50 ° C, preferably from -5 to 10 ° C.
  • the reaction time varies depending on the parent compound, the solvent or the base used, but is usually 5 minutes to 20 hours, preferably 10 minutes to 3 hours.
  • the target compound of interest is collected from the reaction mixture according to a conventional method.
  • the power to filter out the target compound precipitated in the reaction solution, or the power to distill off the solvent pour water into the reaction solution, make the aqueous layer alkaline, and filter the precipitate, or Immiscible solvents (e.g., For example, benzene, ether, ethyl acetate, etc.) are added and extracted.
  • the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the protecting group for the amino group is a tertiary-butoxycarbonyl group, it can also be removed by treating with a silyl compound or a Lewis acid, particularly in an inert solvent.
  • silyl compound used for example, trimethylsilylchloride Li de, trimethylene Rushiriruiodi de or trimethylsilyl triflate Ruo b methane sulfonates Rukoto force like an bets? Can, as the Lewis acid used, and Ageruko for example, aluminum chloride Can be.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Ethers such as getyl ether, tetrahydrofuran or dioxane; or nitriles such as acetonitrile; preferably, hydrogenated hydrocarbons (particularly dichloromethane or chloroform) or nitrile. (Especially acetonitrile).
  • halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride
  • Ethers such as getyl ether, tetrahydrofuran or dioxane
  • nitriles such as acetonitrile
  • hydrogenated hydrocarbons particularly dichloromethane or chloroform
  • nitrile preferably, hydrogenated hydrocarbons (particularly dichloromethane or chloroform) or nitrile.
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent, and the like, but is usually from 120 to 100 G, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent, the solvent, the reaction temperature and the like, but is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is extracted and extracted.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the protecting group of the amino group when it is an aryloxycarbonyl group, it can be removed in the same manner as the removal method by the catalytic reduction reaction particularly in the case of an aralkyl group or the like. That is, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.
  • the protecting group for the amino group is an aralkyl group or a C 7 -C aralkyloxycarbonyl group, it is usually contacted with a reducing agent in an inert solvent (preferably in the presence of a catalyst). (Catalytic reduction) or a method of removing with an oxidizing agent.
  • the force is not particularly limited as long as it does not participate in the reaction?
  • aliphatic such as hexane hexane or cycloheteroalkyl carbide Hydrogens
  • aromatic hydrocarbons such as toluene, benzene or xylene
  • ethers such as geethylether, tetrahydrofuran or dioxane
  • esters such as ethyl acetate or propyl acetate
  • methanol, ethanol or isopropa for example, aliphatic such as hexane hexane or cycloheteroalkyl carbide Hydrogens; aromatic hydrocarbons such as toluene, benzene or xylene; ethers such as geethylether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; methanol, ethanol or isopropa.
  • Alcohols such as ethanol; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, and ethers. , Esters, alcohols, fatty acids or a mixed solvent of these organic solvents with water, and more preferably alcohols (Particularly methanol or ethanol), fatty acids (particularly formic acid or acetic acid), or a mixed solvent of these organic solvents and water.
  • the catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction.
  • Examples include palladium-carbon, raney-nickel, rhodium aluminum monoxide or palladium barium sulfate. It is preferably palladium-carbon or Raney-nickel.
  • the pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm.
  • the reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like.
  • reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours, depending on the raw material compound, the solvent, the reducing agent used or the reaction temperature.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, acetic acid).
  • E Chi le, etc. was added extracted, washed with water and the organic layer containing the desired compound, drying with anhydrous magnesium sulfate, the resulting s objective compound force by distilling off the solvent.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction.
  • Examples thereof include ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride.
  • Nitriles such as acetonitrile; ethers such as getyl ether, tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotri'amide; Sulfoxides such as dimethyl sulfoxide; or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides Or a mixed solvent of these organic solvents and water, more preferably a ketone ( Acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide) or their organic compounds It is a mixed solvent of a solvent and water.
  • the oxidizing agent used can be, for example, potassium persulphate, sodium persulphate, ammonium cerium nitrate (CAN) or 2,3-dichloro-1,5,6-dicyanol p-benzoquinone (DDQ), preferably , CAN or DDQ.
  • CAN ammonium cerium nitrate
  • DDQ 2,3-dichloro-1,5,6-dicyanol p-benzoquinone
  • the reaction temperature varies depending on the raw material compound, the solvent, the oxidizing agent used and the like, and is usually 0 ° C. to 150 ° C., and preferably 10 ° C. to 50 ° C.
  • the reaction time varies depending on the compound, solvent, oxidizing agent used, etc. Minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (eg, benzene, ether, acetic acid)
  • the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • acetimidylation of an amino group is performed by reacting a starting compound in an inert solvent in the presence or absence of a base (preferably in the presence of a base), ethylacetimidate or ethyl. It is achieved by reacting with acetimidate hydrochloride (preferably ethyl acetimidate hydrochloride).
  • the solvent used in the reaction (c) is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • examples thereof include hexane, cyclohexane, heptane, lignin and petroleum.
  • Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethane, ethane, cyclobenzene or dichlorobenzene.
  • Halogenated hydrocarbons such as, for example; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; such as acetone, 2-butanone or methylethyl ketone Ketones; nitro compounds such as nitromethane; acetonitrile or Nitriles such as sobutyronitrile; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide Or amides such as N-methyl-12-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably alcohols (particularly ethanol).
  • ethers such as getyl ether, diisopropyl ether, tetrahydr
  • the base used in the reaction (c) is, for example, sodium carbonate, potassium carbonate or carbonate.
  • Alkali metal carbonates such as lithium; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; alkali metal bicarbonate such as sodium hydroxide, lithium hydroxide or lithium hydroxide Oxides; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N —Jetylaniline, 1,5-diazabicyclo [4.3.0] nona5_en, 1,4-diazabicyclo [2.2.2] octane (DABC ⁇ ) or 1,8-diazabicyclo [5.4. 0]
  • Organic bases such as dex-7-ene (DBU), preferably alkali metal carbonates (sodium or potassium carbonate
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 to 10.0, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 1 hour to 48 hours, preferably from 5 hours to 15 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off.
  • the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the target compound.
  • the resulting target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • the desired (d) reaction “hydrolysis of ester” is generally carried out according to a method well-known in the art of synthetic organic chemistry, by reacting the starting compound with an acid or base in an inert solvent or in the absence of a solvent. In the following, it is achieved by hydrolysis, but hydrolysis by acid is more preferable.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, such as methanol, ethanol, propanol, and isopropanol. It may be a mixed solvent of alcohol and water such as ethanol, butanol or isobutanol, and is preferably hydrated methanol or hydrated ethanol.
  • Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenesulfone. Acid or a sulfonic acid such as p-toluenesulfonic acid; or a carboxylic acid salt such as fumaric acid, conodic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably a mineral acid (particularly hydrochloric acid). ).
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid
  • methanesulfonic acid trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenes
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or water It can be an alkali metal hydroxide such as sodium oxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.
  • the reaction temperature is usually 0 ° C. to 150 ° C. (preferably 50 ° C. to 100 ° C.) for a reaction using an acid or an acid which varies depending on the starting compound, the reagent, etc. Is usually -10 to 50 ° C (preferably -5 to 10 ° C).
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but in the case of a reaction using an acid, it is usually 1 hour to 48 hours (preferably 3 hours to 15 hours), and a The reaction is generally performed for 5 minutes to 10 hours (preferably 10 minutes to 3 hours).
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or after the completion of the reaction, the reaction solution is acidified with an acid (for example, hydrochloric acid), and the precipitated target compound is collected by filtration or immiscible with water.
  • the target compound is extracted by adding a solvent (for example, benzene, ether, ethyl acetate, etc.), the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and then the solvent is distilled off. Power s obtained.
  • a solvent for example, benzene, ether, ethyl acetate, etc.
  • the carbonate of the target compound can also be obtained by passing carbon dioxide gas through an aqueous solvent or adding sodium carbonate or potassium carbonate. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • the desired (e) reaction “ester reduction reaction”, is generally achieved by reducing a starting compound in an inert solvent in the presence of a reducing agent according to a method well known in the art of synthetic organic chemistry. Is done.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; Hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, cyclobenzene or dichlorobenzene Halogenated hydrocarbons; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol, ethanol, prono.
  • Alcohols such as ethanol, butanol or isobutanol; or alcohols, which can be a mixed solvent of the above solvents, and when the reducing agent is hydrogenated aluminums or diborane, aliphatic hydrocarbons (particularly hexane) Or cyclohexane), aromatic hydrocarbons (especially benzene, toluene or xylene) or ethers (especially getyl ether, tetrahydrofuran or dioxane), and alcohols when the reducing agent is sodium borohydride. (Particularly methanol or ethanol) or a mixed solvent of halogenated hydrocarbons and alcohols (particularly a mixed solvent of dichloromethane and ethanol).
  • the reducing agent used may be an aluminum hydride compound such as lithium aluminum hydride or dibutyl hydride, sodium borohydride, lithium borohydride or diborane, etc., preferably lithium borohydride. is there.
  • the reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually from 178 to 100, preferably from 0 to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 10 minutes to 12 hours, preferably 1 hour to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is added to the obtained residue, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed.
  • the obtained organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • reaction to remove a protected hydroxyl group is described, for example, in Protective 'Groups in' Organic 'Synthesis, 3rd Edition, T.W. Green-and-P. G. M. Watts, John 'Wiley' and 'Sands Ink [Protective Groups in Organic Synthesis, 3rd edition, TWGreene &
  • the protecting groups for the hydroxyl groups are formyl, acetyl, benzoyl, tetrahydropyran-12-yl, 3-bromotetrahydropyran-1-2-yl, 4-methoxytetrahydropyran-1-4-yl and tetrahydrothiopyran-1 2-yl, 4-methoxytetrahydrothiofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-12-yl, methoxymethyl, 1,1-dimethyl-1-methyl Toximethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloro ethoxy) methyl group, 1-ethoxyethoxy
  • Acids used are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid O, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahi Ethers such as drofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; methanol, ethanol, prono.
  • Alcohols such as phenol, isopropanol or butanol; amides, such as formamide, dimethylformamide, dimethylacetamide or trimethyl hexamide; sulfoxides, such as dimethyl sulfoxide or sulfolane; formic acid or acetic acid And water or a mixed solvent of water and the above-mentioned solvent, preferably, halogenated hydrocarbons, ethers, esters, alcohols, fatty acids or water and the above-mentioned solvent.
  • a halogenated hydrocarbon particularly dichloromethane
  • an ether particularly tetrahydrofuran or dioxane
  • an ester particularly ethyl acetate
  • a fatty acid particularly acetic acid
  • water it is a mixed solvent of water and the above solvent.
  • the reaction temperature is usually from 1 ° C. to 150 ° C., preferably from 0 ° C. to 60 ° C., depending on the starting compound, the solvent or the acid used.
  • the reaction time is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours, depending on the starting compound, solvent or acid used.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.) is extracted and extracted.
  • a water-immiscible solvent for example, benzene, ether, ethyl acetate, etc.
  • the target compound can be obtained by washing the organic layer containing the target compound with water, drying it over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the protecting group for the hydroxyl group is an alkanol, a carboxylated alkanol, a halogenoalkanol, an alkoxyalkanol, an unsaturated alkanol, an arylcarbonyl, a halogenoarylcarbonyl, an alkylated arylcarbonyl, or a carboxylated aryl.
  • carbonyls, nitrated arylcarbonyls, alkoxycarbonylated arylcarbonyls or arylated arylcarbonyls they should be removed by treatment with a base in an inert solvent or an aqueous solvent. Can be.
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, lithium hydrogen carbonate or lithium hydrogen carbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium methoxide, potassium t Alkali metal alkoxides such as butoxide or lithium methoxide; alkali metal mercaptans such as methyl mercaptan sodium or ethyl mercaptan sodium; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, triethylamine Butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethyl'tylamino) pyridine, N, N-di
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent ', for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • Halogenated hydrocarbons such as dich
  • Ethers such as methanol; ethanols such as methanol, ethanol, propanol, isopropanol or butanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide; Sulfoxides such as dimethylsulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably a halogenated hydrocarbon, ether, alcohol, or a mixture of water and the above solvent.
  • a solvent even more preferably ethers (tetrahydrofuran especially or Jiokisan), alcohols (in particular methanol, ethanol), a mixed solvent of, or water and the solvent.
  • the reaction temperature is usually from 10 to 150 ° C, preferably from 0 to 50, depending on the starting compound, solvent or base used.
  • the reaction time varies depending on the starting compound, the solvent or the base used, and is usually 50 minutes to 20 hours, preferably 10 minutes to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is poured into the reaction solution, and a solvent that is immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is extracted and the organic layer containing the target compound is extracted.
  • the residue is dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group
  • it is usually obtained by contacting with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent.
  • a reducing agent preferably catalytic reduction in the presence of a catalyst
  • the removal method or the removal method using an oxidizing agent is preferable.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • aliphatic hydrocarbons such as hexane or cyclohexane
  • Aromatic hydrocarbons such as toluene, benzene or xylene Ethers such as getyl ether, tetrahydrofuran or dioxane
  • esters such as ethyl acetate or propyl acetate
  • alcohols such as methanol, ethanol or isopropanol
  • fatty acids such as formic acid or acetic acid
  • It can be a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids or these organic solvents and water.
  • the catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction, and may be, for example, palladium monocarbon, Raney nickel, rhodium aluminum monoxide or palladium barium monosulfate. Is palladium monocarbon or Raney nickel.
  • the pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm.
  • reaction temperature varies depending on the starting compound, solvent, reducing agent used, etc.
  • the temperature is from 0 ° C. to 100 ° C., preferably from 10 ° C. to 50 ° C.
  • Reaction time varies depending on the starting material, the solvent, the force s you change by the reducing agent or the reaction temperature and the like are used, usually from 1 5 minutes to 1 0 hours, preferably from 3 0 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by drying using magnesium sulfate or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction.
  • Examples thereof include ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride.
  • Nitriles such as acetonitrile; ethers such as getyl ether, tetrahydrofuran or dioxane; Amides such as methylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent of these organic solvents and water.
  • ketones are ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides, or mixed solvents of these organic solvents with water. More preferably, ketones (particularly acetone ), Halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexmethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide), or mixtures of these organic solvents with water Solvent.
  • the oxidizing agent used can be, for example, potassium persulphate, sodium persulphate, ammonium cerium nitrate (CAN) or 2,3-dichloro-1,6-dicyano-p-benzoquinone (DDQ). Is CAN or DDQ.
  • the reaction temperature varies depending on the starting compound, the solvent, the oxidizing agent used, and the like, but is usually from 0 ° C to 150 ° C, and preferably from 10 ° C to 50 ° C.
  • the reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours, depending on the compound, solvent or oxidizing agent used.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent for example, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by drying using magnesium acid or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound having the general formula (II), which is a starting compound of the present invention can be easily produced, for example, according to the following method. [Method B]
  • RR 2 , R 3 , R 4 , R 5 , R 8 , A and n have the same meanings as described above,
  • R 5a represents an amino group, a substituted amino group (the substituent is a C 6 alkyl group, One or two substituents selected from the same or different groups selected from the group consisting of a roxy c 2 -c 6 alkyl group and an acetimidoyl group. ), 4-membered to 6-membered saturated cyclic amino group, walk is 4-membered or 6-membered saturated cyclic amino group (said substituent is substituted, Asetoimi Doyle group, d-C 6 Arukanoiru group, amino It represents an alkanoyl group or a 5- or 6-membered aromatic complex ring group. (However, in R 5a , an amino group which does not participate in the reaction may be protected, and R 5a binds to an adjacent A via a nitrogen atom.)
  • R 6 represents a protecting group for a hydroxyl group
  • R 7 represents a halogeno d—C 6 alkanoyl group
  • R 8a represents an acetoxy (: 1 — C 6 alkanoyl group
  • R 8b is a substituted ⁇ C 6 alkanol group [the substituents may be C 6 -C 14 arylthio groups, tetrazolylthio groups, (C “C 6 alkyl) tetrazolylthio groups, carboxy (( ⁇ -1 C 6 alkyl) Chio group or (C ⁇ - C 6 alkoxy) indicates] indicates a carbonyl (d-C 6 alkyl) Ji O group.
  • R 8e represents a hydrogen atom
  • R 8d is a d-C 6 alkyl group; a substituted C "C 6 alkyl group (the substituent represents a halogen atom, a C ⁇ -C 6 alkoxy group, a protected hydroxyl group or a carboxyl group); one C 6 Arukanoiru groups; substituted C Cs Arukanoiru group [the substituent is a protected hydroxyl group, C 6 - (3 14 Ariru group, C 6 _ C 14 ⁇ Li one thio group, tetrazolylthio group, ( ⁇ — C 6 alkyl) tetrazolylthio, carboxy (C, — C 6 alkyl) thio, (C ⁇ — C 6 alkoxy) carbonyl (d—Cs alkyl) thio, carboxyl, and ( ⁇ -1 C 6 al.
  • halogen atom C ⁇ - C 6 alkyl group, C ⁇ - shows the C 6 alkoxy group, a carboxyl group or (d-Ce alkoxy) carbonylation Le group]; a sulfamoyl group; or, (C Ce alkoxy) carbonyl sul
  • a 1 represents a single bond or C ⁇ C 4 alkylene group
  • a 2 represents an oxygen atom or a group having the general formula —0 (CH 2 ) m — (wherein m has the same meaning as described above),
  • a 3 represents an oxygen atom or a group having the general formula — 0 (CH 2 ) m — (wherein m has the same meaning as described above),
  • a 4 represents a single bond, a C 3 alkylene group, an oxygen atom or a group having the general formula —0 (CH 2 ) m .— (wherein, m represents an integer of 1 to 3),
  • X represents a halogen atom
  • Y 1 represents a leaving group
  • Y 2 represents a hydrogen atom, CC 4 alkanesulfonyl group, halogeno C i-C 4 Arukansuru Honiru group or d-C 4 alkyl from 1 to 3 having C 6 _ C 10 7 may be Rirusuruho sulfonyl group ,
  • TMS represents a trimethylsilyl group.
  • a substituted amino group represented by R 5a wherein the substituent is the same or different, and is selected from the group consisting of a C 1, -alkyl group, a hydroxy C 2 -C 6 alkyl group and an acetimidoyl group; Represents two substituents.) ”Has the same meaning as described above, and is preferably a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butyramino group, an isobutylamino group, or an s- group.
  • the ⁇ 4- to 6-membered saturated cyclic amino group '' for R 5a has the same meaning as described above, and is preferably an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group or a morpholinyl group, more preferably Are azetidine-1-yl, pyrrolidine-12-yl, pyrrolidine-13-yl, piperidine-2-yl, piperidine-3-yl, piperidine-1
  • R 5a is a substituted 4- to 6-membered saturated cyclic amino group (the substituent is an acetimidyl group, a C, -C 6 alkanoyl group, an amino C, -C 6 alkanoyl group or a 5- to 6-membered Represents an aromatic heterocyclic group.)
  • the substituent is an acetimidyl group, a C, -C 6 alkanoyl group, an amino C, -C 6 alkanoyl group or a 5- to 6-membered Represents an aromatic heterocyclic group.
  • the “halogeno d—C 6 alkanoyl group” for R 7 includes, for example, a fluoroacetyl group, a chloroacetyl group, a bromoacetyl group, a lodoacetyl group, a 3-fluoropropionyl group, a 3-chloropropionyl group, a 4-chlorobutyryl group, 4-bromobutyryl, 3-chloroisobutyryl, 3-chlorobivaloyl, 5-chlorovaleryl, 5-dono, relyl, 4-chloroisonoleryl or 6-cyclohexanolyl like,
  • a halogen atom may be a group having 1 to 6 carbon atoms bonded to a linear or branched alkanoyl group, preferably a halogen atom.
  • An alkanoyl group particularly preferably a chloroacetyl group or a bromoacetyl group.
  • the “acetoxy, 1 C 6 alkanoyl group” of R 8a is, for example, an acetooxyacetyl group, a 3-acetoxypropionyl group, a 4-acetoxybutyryl group, a 3-acetoxyisobutyryl group, a 3-acetoxy group
  • R 8b “substituted C” C 6 alkanoyl group
  • the substituent is C 6 — ( 14 arylthio group, tetrazolylthio group, (C! —C 6 alkyl) tetrazolylthio group, carboxy (C 1, —C 6 alkyl) Represents a thio group or a (C i -C 6 alkoxy) carbonyl (C i -C s alkyl) thio group.]
  • Is for example, a phenylthioacetyl group, a 3-phenylthiopropionyl group, a 4-phenylthiobutyryl group , 5-phenylthiovaleryl, 6-phenylthiohexanoyl, indene 1-ylthioacetyl, naphthalene 1-ylthioacetyl, naphthalene 1-2-ylthioacetyl, phenanthrene 11
  • “1 C 4 alkylene group” of A 1 has the same meaning as described above, and may be preferably a methylene group, an ethylene group or a trimethylene group, and particularly preferably a methylene group.
  • the “di-C 3 alkylene group” of A 4 is, for example, a linear or branched alkylene having 1 to 3 carbon atoms such as a methylene group, a methylmethylene group, an ethylene group, a propylene group or a trimethylene group. It can be a methylene group, preferably a methylene group, an ethylene group or a trimethylene group, particularly preferably a methylene group.
  • halogen atom of X has the same meaning as described above, and is preferably a chlorine atom or a bromine atom.
  • the “leaving group” of Y 1 is not particularly limited as long as it is a group which is usually a nucleophilic residue. ? Force, for example, a chlorine atom, a halogen atom such as bromine atom or iodine atom; d-C ⁇ alkanesulfonyl, such as methanesulfonic Niruokishi group, ethanesulfonyl O alkoxy group, propanesulfonyl O alkoxy group or butane Suruhoniruokishi group O Xy group; trifluoromethanesulfonyloxy group, 2,2,2-trichloromouth ethanesulfonyloxy group, 3,3,3-tribromopropanesulfonyloxy group, or 4,4,4-trifluorobenzoyl sulfonylo A halogeno C ⁇ —C 4 alkanesulfonyloxy group, such as a
  • _Naphthylsulfonyloxy group p-toluenesulfonyl Oxy group, 4-t-butylbenzene sulfonyloxy group, mesitylenesulfonyloxy group or 6 — It may be a C 6 -C 10 arylsulfonyloxy group which may have 1 to 3 d-C 4 alkyl, such as ethyl-naphthylsulfonyloxy group, preferably halogen Atom, methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, 2,2,2-trichloromouth ethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group or mesitylenesulfonyl A chlorine atom, a bromine atom, an iodine
  • the rc—C 4 alkanesulfonyl group of Y 2 may be, for example, ', a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group or a butanesulfonyl group, and preferably a methansulfonyl group or an ethanesulfonyl group. And particularly preferably a methanesulfonyl group.
  • the “halogeno d—C 4 alkanesulfonyl group” of Y 2 is, for example, a trifluoromethansulfonyl group, a 2,2,2-trichloromouth ethanesulfonyl group, 3,3,3-tribromoprono. Or a 4,4,4-trifluorobutanesulfonyl group, preferably a trifluoromethanesulfonyl group or a 2,2,2-trichloroethane And a trifluoromethanesulfonyl group.
  • the "(Ci-Ci. Arylsulfonyl group optionally having 1 to 3 alkyl groups)" for Y 2 is, for example, p-toluenesulfonyl group, 4-t-butylbenzenesulfonyl group, mesitylenesulfonyl Or a 6-ethylethylnaphthylsulfonyl group, preferably a p-toluenesulfonyl group.
  • A is an oxygen atom or a group having the general formula —0 (CH 2 ) ra _ (wherein m has the same meaning as described above).
  • Step B1 is a step of producing a compound having the general formula (V),
  • the solvent used in the step Bl (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • hexane, cyclohexane, heptane, lignin or Aliphatic hydrocarbons such as petroleum ether; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene; or getyl ether, diisopropyl ether And ethers such as tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether, preferably ethers (particularly tetrahydrofuran).
  • the reaction temperature in the step B1 (1) varies depending on the starting compounds, reagents and the like, but is usually from 178 ° C to 100, preferably from -50 to 50.
  • reaction time of step Bl (1) varies depending on the starting compounds, reagents and reaction temperature. It is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
  • the desired compound of the B l (1) step may be used in the next reaction without mosquitoes?, Particularly isolated and purified to be collected from the reaction mixture by conventional means.
  • the solvents used in Step B1 (2) are the same as those used in Step B1 (1).
  • the oxidizing agent used in the step B1 (2) is, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro_5,6-disocyano_p— It can be benzoquinone (DDQ), preferably DDQ.
  • the reaction temperature of Step B1 (2) varies depending on the starting compounds, reagents and the like, but is usually ⁇ 78 ° C. to 100 ° C., preferably ⁇ 50 ° C. to 50 ° C.
  • the reaction time of the step B1 (2) is usually from 5 minutes to 10 hours, preferably from 10 minutes to 3 hours, which depends on the starting compound, the reagent and the reaction temperature.
  • the target compound of Step B1 (2) is collected from the reaction mixture by a conventional method.
  • the solvent is distilled off, or after completion of the reaction, an aqueous solution of ammonium chloride is added to the reaction solution, and then diluted by adding water, and a solvent that is immiscible with water (eg, benzene, ether, , Etc.) to extract the target compound.
  • the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Step B2 is a step of producing a compound having the general formula (VI), and converting compound (V) into 7-formylnaphthalene-1-carbohydrate in an inert solvent in the presence of tetrabutylammonium fluoride. It is achieved by reacting with nitrile.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene Aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or ethers such as diethylene glycol dimethyl ether; or nitro compounds such as nitromethane, preferably ethers (particularly tetrahydrofuran).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 180 to 100 ° C, preferably from 120 to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • an aqueous solution of ammonium chloride is added to the reaction solution, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Step B3 is a step of producing a compound having the general formula (V I I), wherein the compound (V I) is
  • aliphatic hydrocarbons such as hexane, cyclohexane, heptane, lignin or petroleum ether; aromatics such as benzene, toluene or xylene Aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane, cyclobenzene or dichlorobenzene; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as dimethoxetane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; or a mixed solvent thereof.
  • alcohols especially 'Methanol Or a mixed solvent of ethers and alcohols (especially a mixed solvent of tetrahydrofuran and methanol or
  • the catalytic reduction catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction.
  • palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, Raney nickel It can be rhodium aluminum monoxide, palladium barium monosulfate, platinum oxide or platinum black, preferably palladium monocarbon.
  • the reaction temperature is different depending on the starting compounds, reagents and the like, usually from 10 ° C to 100 ° C, and preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, and is usually 10 minutes to 10 hours, preferably 30 minutes to 6 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the catalyst is removed by filtration, and the filtrate is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • the solvent used in the reduction with metal powder can be acetic acid, aqueous hydrochloric acid, water, alcohol or a mixture with an organic solvent soluble in water, preferably acetic acid.
  • the metal powder used can be, for example, zinc powder or iron powder, preferably zinc powder.
  • the reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between ⁇ 10 and 100. And preferably between 0 ° C and 50 ° C.
  • the reaction time the raw material compound, reagent, different force s' by the reaction temperature is usually for 10 minutes to 1 0 hours, preferably for 30 minutes to 3 hours.
  • Step B4 is a step of producing a compound having the general formula (IX),
  • a compound having the general formula (VIII) is reacted with a compound having the general formula (VIII) in an inert solvent in the presence or absence of a base (preferably in the presence of a base).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Hydrogens; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether
  • Ketones such as 2-butanone or methylethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-dimethylformamide, N And amides such as N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably halogenated hydrocarbons (particularly, Dichloromethane) or ethers (getyl ether or tetrahydrofuran).
  • halogenated hydrocarbons particularly, Dichloromethane
  • ethers getyl ether or tetrahydrofuran
  • the bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate.
  • Alkali metal bicarbonates such as titanium; Alkali metal acetates such as sodium acetate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; or, triethylamine, tributyl Amine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridinine, N, N-dimethylaniline, N, N-Jetylaniline, 1,5-diazabisik mouth [4.
  • organic bases can be used, preferably organic bases (especially, triethylamine, N, N-getylaniline or pyridine).
  • the reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually from 10 ° C to 100 ° C, and preferably from 0 ° C to 50 ° C. '
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 10 minutes to 24 hours, preferably 1 hour to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • the step B5 is a step for producing a compound having the general formula (X), and the solvent used is obtained by reacting the compound (IX) with a phosphine and an azo compound in an inert solvent.
  • a phosphine and an azo compound in an inert solvent.
  • the phosphines used include, for example, tri d-C 6 alkyl phosphines such as trimethyl phosphine, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tripentyl phosphine or trihexyl phosphine; triphenyl phosphine C 6 -c 10 aryl phosphine such as tri-, triindenyl phosphine or trinaphthyl phosphine; or tolyl diphenyl phosphine, tritolyl phosphine, trimesityl phosphine, tributyl phenyl phosphine or tri-6-ethyl Tri-C 6 -C 10 arylphosphine which may have d-C 4 alkyl as a substituent, such as 12-naphthylphosphine, and is preferably a
  • ⁇ zone compounds used are, for example, be a Azojikarubo two Rujipiperijin or Azoji force carboxylic acid dimethyl Azojikarubon acid Jechiru, Azojikarubon Sanjiichi C i-C 4 alkyl, such as Azojikarubon acid dipropyl or ⁇ zo di force carboxylic dibutyl
  • it is azodicarbodilpiperidine, dimethyl azodirubonate or getyl azodirubonate.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 150 to 100 ° C., preferably from ⁇ 10 ° C. to 30 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 15 minutes to 24 hours, preferably from 30 minutes to 6 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, if any insolubles are present, they are removed by filtration and the solvent is distilled off. Alternatively, after the reaction is completed, the solvent is distilled off, water is poured into the obtained residue, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added for extraction, and the extract is washed with water. and, after the organic layer was dried over anhydrous magnesium sulfate or the like, the target compound forces? obtained Te cowpea to distilling off the solvent.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • Step B6 is a step for producing a compound having the general formula (XI), which is achieved by removing the hydroxyl-protecting group of the compound (X), and comprising the desired (f) reaction in Step A1. The reaction is performed under the same conditions as in a certain “reaction for removing a protected hydroxyl group”.
  • Step B7 is a step of producing compound (IIa),
  • Step B7 (1) The compound (XI) is dehydrated and condensed with a compound having the general formula (XIII) (where Y 2 represents a hydrogen atom) in an inert solvent in the presence of a phosphine and an azo compound. It is achieved by reacting.
  • the solvent used in Step B7 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.Examples include hexane, cyclohexane, heptane, ligroin, and petroleum.
  • Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; double-mouthed compounds such as nitromethane; and acetates such as acetonitrile or isobutyronitrile Nitriles; formamide, N, N Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-12-pyrrolidinone; or It can be a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably an amide (especially formamide or N, N-dimethylformamide).
  • the base used in step B7 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; sodium bicarbonate, hydrogen carbonate or lithium hydrogen carbonate.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature.
  • the reaction time is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • the target compound of Step 7 (1) is collected from the reaction mixture by a conventional method.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the solvent is distilled off to obtain the target compound.
  • the desired compound can be obtained by standard methods, for example, reconstitution. It can be further purified by crystallization, reprecipitation, or chromatography.
  • the solvent used in step B7 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene
  • It may be an ether such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether, preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon or an ether.
  • halogenated hydrocarbons Dichloromethane
  • an ether particularly Jechirue one ether or as te
  • the phosphines used in the step B7 (2) are, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine or the like.
  • Tri C 6 —C i may have a C ⁇ —C ⁇ alkyl as a substituent, such as trimesityl phosphine, tributyl phenyl phosphine or tri-6-ethyl-12-naphthyl phosphine.
  • Ariruhosufi down preferably tri C i-C 6 alkyl phosphines (especially trimethyl phosphinate down, tri E chill phosphine, Toripuropiruho Sufin or tributylphosphine) or tri C 6 - ⁇ 10 Ariruhosufi emissions (in particular preparative Rifueniruhosu Fin, triindenylphosphine or trinaphthylphosphine), and more preferably tributylphosphine or triphenylphosphine.
  • tri C i-C 6 alkyl phosphines especially trimethyl phosphinate down, tri E chill phosphine, Toripuropiruho Sufin or tributylphosphine
  • tri C 6 - ⁇ 10 Ariruhosufi emissions in particular preparative Rifueniruhosu Fin, triindenylphosphine or trinaphthyl
  • the azo compound used in the step B7 (2) is, for example, dimethyl diazodicarboxylate, diacetyl azodicarboxylate, dipropyl azodicarboxylate such as dipropyl azodicarboxylate or dibutyl azodicarboxylate. And preferably dimethyl azodicarbonate or getyl azodicarboxylate.
  • Reaction temperature starting compound the force varies by a reagent such as is usually an 2 0 a to 1 0 0 ° C, preferably - 1 is 0 ° C to 5 0 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • the target compound of Step B7 (2) is collected from the reaction mixture by a conventional method. For example, if there is any insoluble matter, remove it by filtration and distill off the solvent, or pour water into the residue after distilling off the solvent, and add a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.). ), Extract, wash with water, dry over anhydrous magnesium sulfate, etc., and evaporate the solvent to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • Step C1 is a process for producing a compound (lib), This can be achieved by reacting the compound having the formula (XIV) with sodium acetate in an inert solvent.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • hexane Aliphatic hydrocarbons such as cyclohexane, heptane, rig-in or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1 Halogenated hydrocarbons such as 1,2-dichloroethane, cyclobenzene or dichlorobenzene; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl ethane or diethylene glycol dimethyl ether; Amides such as amide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-12-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane. It is possible and preferably amides (especially N, N-dimethylacetamide).
  • the reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually 0 to 150 ° C, and preferably 30 to 80 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the solvent is distilled off to obtain the desired compound strength.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Step C2 is a step of producing compound (lie).
  • Compound (XIV) is prepared by reacting compound (XIV) in an inert solvent in the presence of a base with C 6 -C 14 arylthiol, tetrazolylthiol, _C 6 This is achieved by reacting with (alkyl) tetrazolylthiol, carboxy (C i -C 6 alkyl) thiol or (C i -C 6 alkoxy) carbonyl (C ⁇ -C 6 alkyl) thiol.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene.
  • ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Nitriles such as tolyl or isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-1-pyrrolidinone; Alternatively, it may be a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably an amide (especially formamide or N, N-dimethylacetamide).
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; acetic acid Alkali metal acetates such as sodium; alkali metal hydrides such as lithium hydride, sodium hydride or lithium hydride; such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide Alkali metal alkoxides; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N —Jetylaniline, 1,5—Diazabicyclo [4.3.0]
  • Nona -Organic bases such as 5-ene, 1,4-diazabicyclo [2.2.2] octan
  • the “C 6 -C 14 arylthiol” used is, for example, benzenethiol, indene-11-ylthiol, naphthalene-11-ylthiol, naphthalene-12-ylthiol, phenanthrene-11-ylthiol or anthracene-9 —An aromatic hydrocarbon group having 6 to 14 carbon atoms such as ylthiol may be a group bonded to thiol, preferably benzenethiol, naphthalene-111-ylthiol or naphthalene-12-ylthiol, more preferably Is benzenethiol.
  • (CfCealkyl) tetrazolylthiol used is, for example, 1-methyltetrazole-5-ylthiol, 1-ethyltetrazole-5-ylthiol, 1-propyltetrazole-5-ylthiol, —Butyltetrazoyl 5-yl
  • Said “( ⁇ —C 6 alkyl)” may be a group bonded to tetrazolylthiol, such as thiol, 1-pentyltetrazole-5-ylthiol or 1-hexyltetrazo-l-ylthiol, preferably , 1-Mechirutetorazo one Roux 5 Iruchio Ichiru also 1 over E chill tetrazole - a Iruchioru, more preferably a 1-Mechiruteto Razoru one 5- Iruchio Ichiru '- 5.
  • the “carboxy (C i -C 6 alkyl) thiol” used is, for example, carboxymethylthiol, 2-carboxyethylthiol, 3-carboxypropylthiol, 4-carboxybutylthiol, 5-carboxypentylthiol or 6 —
  • a carboxyl group, such as carboxylhexyl thiol may be a group bonded to a (C i -C 6 alkyl) thiol, preferably a carboxy (C t -C ⁇ alkyl) thiol; Preferably it is carboxymethylthiol or carboxyethylthiol, particularly preferably carboxymethylthiol.
  • one C 4 Alkyl) thiol more preferably (C i-C ⁇ alkoxy) carbonylmethylthiol, even more preferably methoxycarbonylmethylthiol or ethoxycarbonylmethylthiol, Particularly preferred is ethoxycarbonylmethylthiol.
  • the reaction temperature varies depending on the starting compounds, reagents, and the like, and is usually from ⁇ 10 ° C. to 100 ° C., and preferably from ⁇ 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Method D is a method for compound (II) in which R 5 amino group, substituted amino group (the substituent is a group consisting of C 6 alkyl group, hydroxy C 2 —C 6 alkyl group and acetimidoyl group) Represents one or two substituents which are the same or different from each other), a 4- to 6-membered saturated cyclic amino group, or a substituted 4- to 6-membered saturated cyclic amino group (the substituent Yes it is Asetoimi Doyle group, C! -C ⁇ Arukanoiru group, amino Ji!
  • Step D1 is a step of producing a compound having the general formula (XVI), which is achieved by reacting the compound having the general formula (XV) with ethylene glycol in an inert solvent in the presence of an acid,
  • XVI general formula
  • XV Protective 'Group — Organic' Chemistry
  • H. J. E. Lowenthal Chapter 9, Protection 'Ob' Aldehyde 'and ⁇ Ketones, p.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Halogenated hydrocarbons such as benzene, cyclobenzene or dichlorobenzene; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as ditromethane Nitro compounds; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-12-pyrrolidinone; or amides such as dimethylsulfoxide
  • Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenesulfone. Acids or sulfonic acids such as p-toluenesulfonic acid; or carboxylic acids such as fumaric acid, conodic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably sulfonic acid (particularly p-toluenesulfonic acid). —Toluenesulfonic acid).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from ⁇ 10 ° C. to 100 ° C., preferably from 0 to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 20 hours, preferably from 30 minutes to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Step D2 is a step for producing a compound having the general formula (XVII).
  • the (2) intermediate This is achieved by oxidizing the adduct formed as above with an oxidizing agent in an inert solvent, and can be carried out under the same conditions as in Step B1.
  • Step D3 is a step of producing a compound having the general formula (XVIII), and converting the compound (XVII) into an inert solvent in the presence of tetrabutylammonium fluoride in the presence of 7-formylnaphthalene-1- It is achieved by reacting with carbonitrile, and can be carried out under the same conditions as in Step B2.
  • Step D4 is a step for producing a compound having the general formula (XIX), and is accomplished by reacting compound (XVIII) with an acid in an inert solvent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, for example, hexane, cyclohexane, heptane, rigoin or petroleum ether.
  • ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether
  • ketones such as acetone, 2-butanone or methylethyl ketone
  • Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid. Acids or sulfonic acids such as p-toluenesulfonic acid; or carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably mineral acids (particularly hydrochloric acid). is there.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid
  • methanesulfonic acid trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid
  • the reaction temperature varies depending on the starting compounds, reagents, etc., and is usually between 110 and 100. Preferably, it is 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • Step D5 is a step for producing a compound having the general formula (XXI).
  • Compound (XIX) is reacted with sodium triacetoxybohydrate or sodium hydride in an inert solvent in the presence or absence of acetic acid.
  • the reaction is achieved by reacting with a compound having the general formula (XX) at pH 3 to 7 (preferably using acetic acid) using cyanoborohydride or the like.
  • the solvent used is There is no particular limitation as long as it does not hinder and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, rigoin or petroleum ether; Aromatic hydrocarbons such as toluene or xylene; halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene.
  • Hydrocarbons such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or methylene glycol dimethyl ether; double-mouthed compounds such as nitromethane; Nitrils such as nitriles; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide Or N-methyl-1-pyrrolidinone Sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above solvents, preferably halogenated hydrocarbons (particularly dichloromethane), ethers (particularly tetrahydrofuran), alcohols (Particularly, methanol or ethanol) or a mixed solvent thereof (particularly, tetrahydrofuran and methanol).
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 10 minutes to 24 hours, preferably 3 hours to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Step D6 is a step for producing a compound having the general formula (XXII).
  • Compound (XXI) is placed in an inert solvent under a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm). This can be achieved by reduction using a catalytic reduction catalyst, and can be performed under the same conditions as in Step B3.
  • Step D7 is a step for producing a compound having the general formula (XXIII), and converting the compound (XXII) into an inert solvent in the presence or absence of a base (preferably in the presence of a base) This is achieved by reacting with compound (VIII), and carried out under the same conditions as in Step B4.
  • Step D8 is a step of producing compound (IId), which is achieved by reacting compound (XXIII) with a phosphine and an azo compound in an inert solvent, and is the same as step B5.
  • Method E is a method for producing a compound having the general formula (VIIa) wherein n is 2 in compound (VII) which is an intermediate compound of method B.
  • Step E1 is a step for producing a compound having the general formula (XXVI), and combining the compound having the general formula (XXIV) with a compound having the general formula (XXV) in an inert solvent in the presence of a base. It is achieved by reacting.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.Examples include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene. Hydrogens; or ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (particularly tetrahydrofuran).
  • Bases used are, for example, metal hydrides such as lithium hydride, sodium hydride or lithium hydride; alkali metal hydrides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide.
  • Alkali metal alkoxides particularly sodium methoxide, sodium methoxide or potassium tert-butoxide
  • alkyllithiums particularly butyllithium
  • lithium alkylamides particularly lithium diisopropylamide.
  • the reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually from 18 to 30 and preferably from -70 to 0.
  • the reaction time varies depending on the starting compounds, reagents, and reaction temperature. Time, preferably 30 minutes to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the target compound forces by distilling off the solvent? obtained.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Step E2 is a step for producing a compound having the general formula (XXVII), and is achieved by reacting the compound (XXVI) with an acid in an inert solvent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • ethers such as methyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; double-mouthed compounds such as nitromethane; Rils; formamide, N, N-dimethylform And amides such as N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethylsulfoxide or sulfolane, and preferably ethers (particularly 1,2-dichloroethane). ).
  • Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid. Acids or sulfonic acids such as p-toluenesulfonic acid; or carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably sulfonic acid (particularly p-toluene Sulfonic acid).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 0 ° C to 150, preferably from 50 to 100.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the precipitated crystals are collected by filtration, or after completion of the reaction, water is added to the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added, and the target compound is added.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • the protecting group for the hydroxyl group of R 6 when a compound which can be removed with an acid is used as the protecting group for the hydroxyl group of R 6 , the protecting group for the hydroxyl group is removed under the conditions of Step E2. In such a case, after protecting the hydroxyl group again, it can be used for the next step. For example, when a hydroxyl group is protected again using a methoxymethyl group, it is achieved by reacting a starting compound with chloromethyl methyl ether in an inert solvent in the presence of a base.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene.
  • ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; Compounds; Nitriles such as tonitrile or isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; It can be a sulfoxide such as dimethyl sulfoxide or sulfolane, and preferably an amide (especially N, N-dimethylacetamide).
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate S , potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, lithium hydrogen carbonate or lithium hydrogen carbonate.
  • Salts Alkali metal acetates such as sodium acetate
  • Salts Alkali metal hydroxides such as sodium hydroxide, hydroxide hydroxide or lithium hydroxide; or triethylamine, tributylamine, diisopropylethylamine, N —Methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridin, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazavicik Mouth [4.3.0] Nona-5 1,4-diazabicyclo [2.2.2] octane
  • DBU CO 1,8-diazabicyclo [5.4.0] indene-7-ene
  • DBU 1,8-diazabicyclo [5.4.0] indene-7-ene
  • the reaction temperature varies depending on the starting compounds, reagents and the like, and is usually from 150 to 100 ° C, preferably from -20 to 30 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the solvent is distilled off to obtain the desired compound strength f.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Step E3 is a step for producing a compound having the general formula (XXV III), and is accomplished by reducing the compound (XXV II) in an inert solvent in the presence of a reducing agent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • examples include hexane, cyclohexane, heptane, lignin, and oil ethers.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene or dichlorobenzene.
  • Hydrogens ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol, ethanol, propanol, isoprono.
  • Alcohols such as ethanol, butanol or isobutanol; or an alcohol such as a mixture of the above solvents, and when the reducing agent is a hydrogenated aluminum or diborane, an aliphatic hydrocarbon (particularly hexane or cyclohexane).
  • Xan aromatic hydrocarbons (especially benzene, toluene or xylene) or ethers (especially getyl ether, tetrahydrofuran or dioxane), and alcohols (especially methanol or Ethanol) or a mixed solvent of halogenated hydrocarbons and alcohols (especially a mixed solvent of dichloromethane and ethanol).
  • the reducing agent used can be an aluminum hydride compound such as lithium aluminum hydride or dibutyl hydride, sodium borohydride or diborane, and preferably sodium borohydride.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 78 to 100, preferably from 0.1 to 50 ° C.
  • the reaction time the raw material compound, reagent, different forces s depending on the reaction temperature is usually for 10 minutes to 12 hours, preferably 1 hour to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is added to the obtained residue, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed.
  • the organic layer was washed with water, dried using anhydrous magnesium sulfate, etc., and the solvent was distilled off. By doing so, the target compound is obtained.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • the step E4 is a step for producing the compound (Vila).
  • the compound (XXVIII) is treated with a catalytic reduction catalyst in an inert solvent under a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm). This is achieved by reduction using
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, for example, hexane, cyclohexane, heptane, rigoin or petroleum ether.
  • Aliphatic hydrocarbons aromatic hydrocarbons such as benzene, toluene or xylene; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, cyclobenzene or dichlorobenzene.
  • Hydrocarbons ethers such as methyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol.
  • a mixture of the above solvents It is a solvent, preferably an alcohol (particularly methanol) or a mixture of ethers and alcohols (particularly Tetorahi de port furan and a mixed solvent of methanol or ethanol).
  • the catalytic reduction catalyst used is not particularly limited as long as it is used in a usual catalytic reduction reaction.
  • the reaction temperature varies depending on the starting compounds, reagents, and the like, and is usually from ⁇ 10 ° C. to 100 ° C., and preferably from 0 ° C. to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 12 minutes to 10 hours, preferably 30 minutes to 6 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the catalyst is removed by filtration, and the filtrate is distilled off to obtain the desired compound. It is.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Method F is a compound which is a raw material compound of Method C (XIV), or, in the starting compound der Ru compound of Method A (II), R 8 mosquito ⁇ CI- C 6 alkyl group; single substituted C 6 alkyl Le group (the substituent, a halogen atom, C t one C 6 alkoxy group, a protected hydroxy group or force Rupokishiru group.); C ⁇ - C 6 Arukanoiru group;!
  • the substituent is a protected hydroxyl group, a C 6 -C 14 aryl group, a C 6 -C 14 arylthio group, a tetrazolylthio group, a (C, 1C 6 alkyl) tetrazolylthio group, a carboxy (C i- c 6 alkyl) Chiomoto, (c -! c 6 alkoxy) carbonyl (c -! c 6 alkyl) Ji O group, from a carboxyl group and (Ci one c 6 alkoxy) group consisting of a carbonyl group, the same or different Indicates one or two substituents selected.
  • Step F1 is a step of producing a compound (XIV), which comprises converting a compound having the general formula (lie) wherein R 8 is a hydrogen atom in the compound (II), It is achieved by reacting with a compound having the general formula (XX IX) or a compound having the general formula (XXX) in an inert solvent in the presence or absence of a base (preferably in the presence of a base).
  • Solvent does not hinder the reaction and dissolves some starting materials But not by limitation, especially if those, for example, hexane, cyclohexane, heptane, aliphatic hydrocarbons such as rigs opening in or petroleum ether; benzene, such as toluene or xylene Kaoru Aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as toxiethane or diethylene glycol dimethyl ether; ketones such as acetone, 2-butanone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile;
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, lithium hydrogen carbonate or lithium hydrogen carbonate; Alkali metal acetates such as sodium acetate; Alali metal hydroxides such as sodium hydroxide, lithium hydroxide or lithium hydroxide; or triethylamine, tributylamine, diisopropylethylamine, N_ Methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridin, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazavicik Mouth [4.3.0] Nona-5-ene 1,4-Diazabicyclo [2.2.2] octane (DABCO) or 1,8-Diazabicyclo [5.4.0] pentane-7-ene (DBU) And preferably organic bases (especially triethylamine, N
  • the reaction temperature starting compound, the force varies by a reagent such as?, Usually Ri one 1 0 ° C to 1 0 o ° c der, preferably a 0 a to 5 0 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, and is usually 10 minutes to 24 hours, preferably 1 hour to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent for example, benzene or ether
  • a water-immiscible solvent for example, benzene or ether
  • Ethyl acetate, etc. to extract the desired compound
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • Step F2 is a step of producing compound (IIf).
  • Compound (lie) is prepared by reacting compound (lie) in an inert solvent in the presence or absence of a base (preferably in the presence of a base), a compound represented by the general formula (XXX I ) Or a compound having the general formula (XXXII), and is carried out under the same conditions as in Step F1.
  • Method G is a compound which is a raw material compound of Method C At a (XIV), A force, an oxygen atom or one general formula _0 (CH 2) m - show (where, m is the same meaning as described above?
  • This is a method for producing a compound having the general formula (XIVa), which is a group having the formula:
  • Step G1 is a step for producing a compound having the general formula (XXXIII).
  • the compound (VII) obtained as an intermediate compound of the method B is prepared in an inert solvent in the presence or absence of a base. (Preferably in the presence of a base), by reacting with compound (XXIX) or compound (XXX), and carried out under the same conditions as in Step B4.
  • Step G2 is a step of producing a compound having the general formula (XXX IV), which is achieved by reacting the compound (XXX III) with a phosphine and an azo compound in an inert solvent. The reaction is performed under the same conditions as in Step B5.
  • Step G3 is a step of producing a compound having the general formula (XXXV), which is achieved by removing the protecting group of the hydroxyl group of compound (XXXIV), and comprising the desired (f) reaction of step A1. The reaction is performed under the same conditions as in “Reaction to remove protected hydroxyl-protecting group”.
  • Step G4 is a step of producing compound (XIVa),
  • A is an oxygen atom or a group having the general formula —0 (CH 2 ) m — (wherein m has the same meaning as described above),
  • This is a method for producing a compound having the general formula (IIg).
  • the HI step is a step of producing a compound having the general formula (XXXV II), wherein the compound having the general formula (XXXV I) has the general formula (XII la) in an inert solvent in the presence of a base. It is achieved by reacting with a compound.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; Hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, halogen such as cyclobenzene or dichlorobenzene.
  • Ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; ketones such as acetone, 2-butanone or methyl ethyl ketone; nitrites such as nitromethane Oral compounds; acetonitrile or isobutyroni Nitriles such as ril; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or dimethylsulfoxide or It can be a sulfoxide such as sulfolane, preferably an amide (especially N, N-dimethyl Formamide or N, N-dimethylacetamide).
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate, carbonated lithium or lithium carbonate; alkali metal bicarbonates such as sodium hydrogencarbonate, hydrogenated carbonate or lithium hydrogencarbonate; acetic acid Alkali metal acetates such as sodium; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydrides such as sodium hydroxide, lithium hydroxide or lithium hydroxide Hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4— (N, N-dimethylamino) pyridine, N , N-Dimethylaniline, N, N-Jetylaniline, 1,5-Diazabicyclo [4,3.0] non-5-ene, 1,4-
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 10 ° C. to 10 ° C., preferably from 0 ° C. to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10 minutes to 24 hours, preferably 1 hour to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water for example, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • Step H2 is a step of producing a compound having the general formula (XXXV III),
  • Step H3 is a step of producing a compound having the general formula (XXXIX), and converting the compound (XXXVIII) into an inert solvent in the presence of tetrabutylammonium fluoride in 7-formylnaphthalene_ It is achieved by reacting with 2-carbonitrile and is carried out under the same conditions as in Step B2.
  • Step H4 is a process for producing a compound having the general formula (XXXX), wherein the compound (XXXI X) is
  • Step H5 is a step for producing a compound having the general formula (XXXXI), and the compound (XXXX) is reacted with the compound (XXXX) in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This is achieved by reacting with (VIII) and performed under the same conditions as in Step B4.
  • Step H6 is a step of producing compound (IIg), which is achieved by reacting compound (XXXXI) with a phosphine and an azo compound in an inert solvent. It is performed under similar conditions.
  • Starting compounds of the present invention (1 1 1), (IV), (VIII), (XII), (XIII), (XV), (XX), (XX IV), (XXV), (XX IX), ( XXX).
  • (XXX I), (XX XII) and (XXXV I) etc. are known or easily produced according to known methods.
  • Vol. 2798 (1 981) [J. Org. Chem .. 46.2798 (1981)]
  • Bulltin Ob-The 'Chemical' Society 'of Japan Vol. 63, 1888 (1 990) [Bull. Chem. So in Jpn. R , 1888 (1990)] and others.
  • the NMR spectrum used tetramethylsilane as an internal standard, and the three values were represented by ppm and the coupling constant was represented by the J value (Hz) (approximate to 0.5 Hz unit).
  • the coupling pattern is
  • reaction solution was diluted with ethyl acetate, washed successively with water and brine, and then the ethyl acetate layer was dried using anhydrous magnesium sulfate.
  • 2- (7-Cyanonaphthalene-12-yl) -11-ethanesulfonylindoline 76 O mg (yield 51%) was obtained as an amorphous solid.
  • This solid was added to 5 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling stirring.
  • the reaction mixture was concentrated under reduced pressure, and the concentrate was pulverized in ethyl acetate, collected by filtration, washed, and dried to give the title compound.390 mg (yield 52%) as an amorphous solid Obtained.
  • This solid was dissolved in 2 O ml of ethyl acetate under ice cooling, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added. The resulting precipitate was collected by filtration, washed, and dried to give 21.5 mg (yield 55%) of the title compound as an amorphous solid.
  • reaction solution was diluted with ethyl acetate, washed successively with water and brine, and then the ethyl acetate layer was dried using anhydrous magnesium sulfate.
  • 2- (7-Cyanonaphthalene-1-yl) -11-ethanesulfonylindoline 49 O mg (55% yield) was obtained as an amorphous solid.
  • the obtained solid was dissolved in 2 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added thereto while stirring with ice cooling.
  • the reaction mixture was concentrated under reduced pressure, and the concentrate was pulverized in ethyl acetate, collected by filtration, washed with ethyl acetate and hexane, and dried to obtain 19 Omg (63% yield) of the title compound. Obtained as a shaped solid.
  • Example 15-Omg of 2- (7-amidinonaphthalene-12-yl) -11-ethanesulfonyl-5- (pyrrolidine-13-yloxy) indoline dihydrochloride obtained in Example 5 was dissolved in 1 Oml of ethanol.
  • the reaction was carried out in the same manner as in Example 2 by using 8 Omg of ethyl acetylamide hydrochloride and 0.4 Oml of triethylamine.
  • a solid was obtained. The obtained solid was dissolved in 1 Oml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring.
  • the obtained solid was dissolved in 5 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring.
  • the reaction mixture was concentrated under reduced pressure, and the concentrate was triturated in ethyl acetate, filtered, washed, and dried to give 535 mg (yield 60%) of the title compound as an amorphous solid As obtained.
  • Example 7 50 mg of 2- (7-amidinonaphthalene-12-yl) -11-ethanesulfonyl-5- (piperidine-13-ylmethoxy) indrin dihydrochloride obtained in Example 7 was added to 12 ml of ethanol. After dissolving and reacting in the same manner as in Example 4 using 22 O mg of ethyl acetimidate hydrochloride and 0.8 O ml of triethylamine, the reaction solution was concentrated under reduced pressure, and the concentrate was concentrated.
  • the obtained solid was dissolved in 10 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring.
  • 250 mg of the obtained solid was dissolved in 1 Oml of ethyl acetate, and 0.4 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring.
  • the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of water and lyophilized to obtain 287 mg of the title compound as an amorphous solid.
  • 14.6 mg of the obtained solid was dissolved in 15 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added. Then, the reaction solution was concentrated under reduced pressure. After drying the obtained concentrate, vinegar The residue was triturated with ethyl acetate and collected by filtration to obtain 132 mg (yield: 79%) of the title compound as an amorphous solid.
  • the obtained solid was dissolved in 1 ml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice cooling and stirring, and the reaction solution was concentrated under reduced pressure.
  • the obtained solid was dissolved in 1 Oml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added thereto while stirring at room temperature.
  • the reaction solution was concentrated under reduced pressure, and the concentrate was pulverized in ethyl acetate and collected by filtration.
  • the obtained powder was washed successively with ethyl acetate, dichloromethane and hexane, and dried to obtain 466 mg (yield 63%) of the title compound as an amorphous solid.
  • Omg was dissolved in 4 Oml of ethanol, and after adding 26 Omg of hydroxylamine hydrochloride and 18 Omg of sodium carbonate, the mixture was stirred at 80 ° C for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was stirred. The resulting precipitate was collected by filtration and dried to give 60 Omg of a colorless solid (87% yield). Next, the obtained solid is acetic acid 1
  • the 5- (1-acetylbiperidine-1-4-yloxy) 1-2- (7-cyanonaphthalene-1-2) obtained above was obtained.
  • 820 mg of 11-ethanesulfonylindoline was dissolved in 4 Oml of ethanol, 38 Omg of hydroxylamine hydrochloride and 26 Omg of sodium carbonate were added, and the mixture was stirred at 80 ° C for 10.5 hours.
  • the reaction solution was concentrated under reduced pressure, water was added to the concentrate, and the mixture was stirred.
  • the resulting precipitate was collected by filtration and dried to give 84 Omg (96% yield) of a colorless solid.
  • the obtained solid was dissolved in 1 Oml of ethyl acetate, and 1 ml of a 4N hydrogen chloride / ethyl acetate solution was added with stirring.
  • the reaction solution is concentrated under reduced pressure, and the concentrate is Crushed in chill.
  • the resulting powder was collected by filtration, washed with ethyl acetate and hexane, and dried to give the title compound (455 mg, yield 52%) as an amorphous solid.
  • the obtained solid was dissolved in ethyl acetate, and 5 ml of a 4N hydrogen chloride / monoethyl acetate solution was added with stirring.
  • the reaction solution was concentrated under reduced pressure, and the concentrate was dried, crushed in ethyl acetate, and collected by filtration to obtain 105 O mg (yield 84%) of the title compound as an amorphous solid.
  • a solid was obtained.
  • the obtained solid was dissolved in 5 ml of methanol, and 0.9 ml of a 4N hydrogen chloride / ethyl acetate solution was added.
  • the reaction mixture was concentrated under reduced pressure, the concentrate was dried, a small amount of methanol was added in ethyl acetate, and the mixture was stirred.
  • the resulting solid was collected by filtration, dried, and dried to give 59 lmg of the title compound (yield (57%) was obtained as an amorphous solid.
  • Melting point 188-198 ° C (softening);
  • Example 28 2- (7-amidinonaphthalene-1-yl) 1-1-methanesulfonyl-1-5- (piperidine_4-yloxy) indrin dihydrochloride obtained in Example 8 50 mg of hydrochloride was added to 50 mg of methanol 1 O ml The reaction was carried out in the same manner as in Example 2 by using 23 mg of ethyl acetylamide hydrochloride and 0.78 ml of triethylamine.
  • the obtained solid was suspended in 1 O ml of ethyl acetate, and 0.43 ml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring, followed by stirring for a while.
  • the reaction solution was concentrated under reduced pressure, and the obtained solid was pulverized in ethyl acetate and collected by filtration. The resulting powder was washed with ethyl acetate and hexane, and dried to give the title compound (283 mg, yield 85%) as an amorphous solid.
  • the obtained solid was dissolved in 5 ml of ethyl acetate, and 0.67 ml of a 4N hydrogen chloride-ethyl acetate solution was added. Concentrate the reaction mixture under reduced pressure and concentrate the concentrate in ethyl acetate. After stirring at, the resulting solid was collected by filtration and dried to give 504 mg (70% yield) of the title compound as an amorphous solid.
  • the obtained solid was suspended in 1 Oml of ethyl acetate, 0.4 Oml of a 4N hydrogen chloride / ethyl acetate solution was added under ice-cooling and stirring, and the mixture was stirred for a while.
  • Example 3 500 mg of 2_ (7-amidinonaphthalene-1-yl) -11-benzenesulfonyl-5- (piperidine-14-yloxy) indoline dihydrochloride obtained in Example 2 was added to ethanol 150 ml The reaction was carried out in the same manner as in Example 2 using 21 mg of ethyl acetimidate hydrochloride and 0.7 ml of triethylamine.
  • 392 mg (yield: 83%) of a solid was obtained.
  • the obtained solid is suspended in 1 O ml of ethyl acetate and dissolved in 4N hydrogen chloride / ethyl acetate while stirring under ice-cooling. 0.5 ml of the liquid was added, and the mixture was stirred for a while.
  • the obtained solid was dissolved in 1 ml of dioxane, and 0.7 ml of a 4N hydrogen chloride-dioxane solution was added.
  • the concentrate was stirred in ethyl acetate. The resulting solid was collected by filtration and dried to give the title compound (584 mg, yield 98%) as an amorphous solid.
  • Example 36 4- [2- (7-Amidinonaphthalene_2-2-yl) -1-5- (piperidine-1-4-yloxy) indoline-1 1-ylsulfonyl] ethyl butyrate 2 hydrochloride obtained in Example 36 was dissolved in 1 Oml of ethanol and reacted in the same manner as in Example 2 using 16 Omg of ethyl acetimidate hydrochloride and 0.55 ml of triethylamine. After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography.
  • reaction solution was extracted with ethyl acetate, the extract was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: hexane Z: ethyl acetate, 6- [5-( l_t-Butoxycarbonylbiperidine-14-yloxy) 1-2- (7-cyanonaphthalene-12-yl) indrin-1 1-ylsulfonyl] ethyl ethyl hexanoate 338 mg (82% yield) Obtained as an amorphous solid.
  • the obtained solid was dissolved in 20 ml of ethyl acetate, and 1.64 ml of a 4N hydrogen chloride / ethyl acetate solution was added.
  • Reduce reaction volume After concentration under pressure, the concentrate was stirred in ethyl acetate. The resulting solid was collected by filtration and dried to give 1395 mg (yield 96%) of the title compound as an amorphous solid.
  • the obtained solid was dissolved in 1 O ml of ethyl acetate, and 0.8 O ml of a 4 N hydrogen chloride / ethyl acetate solution was added to the solution under ice-cooling and stirring, followed by stirring for a while.
  • the solvent was concentrated under reduced pressure, and the obtained solid was triturated in ethyl acetate, filtered, and dried to obtain 62 O mg (yield: 84%) of the title compound as an amorphous solid.
  • the obtained solid was dissolved in 1 O ml of dioxane, 1.0 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was stirred for a while.
  • the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the concentrate, followed by stirring.
  • the resulting solid was collected by filtration and dried to give the title compound (307 mg, yield 91%).
  • the reaction solution was concentrated under reduced pressure, water was added to the concentrate, and the mixture was stirred.
  • the insoluble target product was collected by filtration and dried to obtain 115 O mg of a colorless solid.
  • the obtained solid was dissolved in acetic acid (20 ml), acetic anhydride (0.3 O ml) was added, the mixture was stirred for 20 minutes, and then 10% palladium-carbon catalyst (15 O mg) was added.
  • the mixture was stirred at room temperature for 10 hours.
  • the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography.
  • the obtained solid was dissolved in 10 ml of dioxane, and 0.8 ml of a 4N hydrogen chloride-dioxane solution was added thereto, followed by stirring at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the concentrate was stirred in ethyl acetate. The resulting solid was collected by filtration and dried to give 581 mg (99% yield) of the title compound as an amorphous solid. Obtained.
  • the obtained solid was added to 6 ml of methanol, and 0.57 ml of a 4N hydrogen chloride-dioxane solution was added under ice-cooling and stirring.
  • the reaction solution was concentrated under reduced pressure, and the concentrate was dried at 70 ° C for 2 days to obtain 442 mg (yield 72%) of the title compound as an amorphous solid.

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Abstract

L'invention porte sur des dérivés d'indoline ou de trétrahydroquinoline représentés par la formule générale (I) ou sur des sels de ceux-ci acceptables d'un point de vue pharmaceutique. Ces dérivés présentent une excellente activité inhibitrice du facteur X activé de coagulation sanguine et sont utiles comme médicaments dans le traitement ou la prévention des troubles de la coagulation sanguine. Dans cette formule, R1 représente hydrogène, alkyle éventuellement substitué, alcanoyle éventuellement substitué, alkylsufonyle éventuellement substitué, arylsufonyle éventuellement substitué ou sulfamoyle éventuellement substitué; R2 représente cycloalkyle éventuellement substitué, aryle éventuellement substitué, amino éventuellement substitué ou amino cyclique saturé éventuellement substitué; R3 et R4 représentent chacun hydrogène, halogéno, alkyle, alcoxy, cyano, nitro, hydroxyle ou alcanoyloxy; A est une liaison unique, alkylène, oxygène ou -O(CH¿2?)m- (m étant compris entre 1 et 4); et n vaut 1 ou 2.
PCT/JP2000/004333 1999-07-01 2000-06-30 Dérivés d'indoline ou tétrahydroquinoline WO2001002356A1 (fr)

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AU55709/00A AU5570900A (en) 1999-07-01 2000-06-30 Indoline or tetrahydroquinoline derivatives

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JP11/187805 1999-07-01

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085892A1 (fr) * 2001-04-20 2002-10-31 Wyeth Derives d'heterocyclyloxy-, -thioxy- et aminobenzazol servant de ligands de 5-hydroxytryptamine-6
US7138412B2 (en) 2003-03-11 2006-11-21 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
US7750038B2 (en) 2007-03-06 2010-07-06 Wyeth Llc Sulfonylated heterocycles useful for modulation of the progesterone receptor
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

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WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1998031661A1 (fr) * 1997-01-17 1998-07-23 Ajinomoto Co., Inc. Derives de benzamidine
WO1999011617A1 (fr) * 1997-09-01 1999-03-11 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de naphtamide et sels de ces derives

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JPS6417549A (en) * 1987-07-13 1989-01-20 Hitachi Ltd Network control unit
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels
WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1998031661A1 (fr) * 1997-01-17 1998-07-23 Ajinomoto Co., Inc. Derives de benzamidine
WO1999011617A1 (fr) * 1997-09-01 1999-03-11 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de naphtamide et sels de ces derives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085892A1 (fr) * 2001-04-20 2002-10-31 Wyeth Derives d'heterocyclyloxy-, -thioxy- et aminobenzazol servant de ligands de 5-hydroxytryptamine-6
US6815456B2 (en) 2001-04-20 2004-11-09 Wyeth Heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands
CN1293072C (zh) * 2001-04-20 2007-01-03 惠氏公司 作为5－羟色胺－6配体的杂环基氧基－、－硫代－和－氨基吲哚衍生物
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
US7138412B2 (en) 2003-03-11 2006-11-21 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
US7709646B2 (en) 2003-03-11 2010-05-04 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
US7750038B2 (en) 2007-03-06 2010-07-06 Wyeth Llc Sulfonylated heterocycles useful for modulation of the progesterone receptor

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