WO2011055843A1 - Retinoid compound - Google Patents

Retinoid compound Download PDF

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WO2011055843A1
WO2011055843A1 PCT/JP2010/069920 JP2010069920W WO2011055843A1 WO 2011055843 A1 WO2011055843 A1 WO 2011055843A1 JP 2010069920 W JP2010069920 W JP 2010069920W WO 2011055843 A1 WO2011055843 A1 WO 2011055843A1
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group
alkyl group
compound
hydrogen atom
salt
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PCT/JP2010/069920
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French (fr)
Japanese (ja)
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博貴 加来田
史宜 大澤
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国立大学法人 岡山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
    • C07C211/60—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton containing a ring other than a six-membered aromatic ring forming part of at least one of the condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention relates to an active substance (hereinafter also referred to as “retinoid compound”) for a retinoic acid receptor (RAR), which is a nuclear receptor.
  • retinoid compound an active substance for a retinoic acid receptor (RAR), which is a nuclear receptor.
  • Nuclear receptors are one of ligand-dependent transcriptional regulators that are responsible for maintaining cell proliferation, immune response, physiological functions such as sugar and / or lipid metabolism, and homeostasis.
  • the ligand corresponding to the nuclear receptor controls the transcription of the downstream gene.
  • Nuclear receptors are derived from the same primitive gene and form a superfamily (Non-patent Document 1).
  • RAR is a type of nuclear receptor that regulates gene transcription through the binding of agonists (hereinafter referred to as agonists). There are three subtypes, ⁇ , ⁇ , and ⁇ . At present, physiological actions are different (Non-patent Documents 2 and 3).
  • RAR ⁇ exists in various organizations.
  • RAR ⁇ selective agonists show differentiation-inducing action and are used for differentiation-inducing therapy of acute promyelocytic leukemia, but are known to show an increase in blood triglyceride (TG) level as a side effect (Non-Patent Literature) 4).
  • TG blood triglyceride
  • Non-Patent Literature 4 a side effect
  • RAR ⁇ is mainly localized in the skin.
  • RAR ⁇ selective agonists are known to show serious side effects such as toxicity to skin and bone and teratogenicity (Non-patent Document 2).
  • Non-patent Document 2 On the other hand, RAR ⁇ exists in the heart, lungs and spleen.
  • RAR ⁇ selective agonists are known to exert cell cycle regulation and apoptosis inducing action without exhibiting the side effects seen with RAR ⁇ and RAR ⁇ selective agonists. Therefore, RAR ⁇ selective agonists are targets of anticancer drugs that avoid the above-mentioned side effects, for example, therapeutic drugs for leukemia (Non-patent Documents 2 and 3).
  • Non-patent Document 5 When attention is paid to the X-ray crystal structure analysis data of RAR ⁇ and its ligand, it is known that the space where the ligand of RAR ⁇ binds is larger than that of other subtypes of RAR (Non-patent Document 5). In fact, many of the existing RAR ⁇ selective agonists have succeeded in producing RAR ⁇ selectivity by introducing a bulky fat-soluble substituent at a site corresponding to the space (Non-patent Documents 3 and 6). .
  • Patent Document 3 Patent Document 3
  • Patent Document 4 Patent Document 4
  • Patent Document 5 and Non-Patent Document 7 disclose naphthoic acid derivatives having a retinoid action, there is no description regarding RAR ⁇ selective compounds.
  • Patent Document 6 describes a rexinoid compound having an alkoxy group, but does not describe a retinoid compound selective for RAR ⁇ .
  • the object of the present invention is to provide a novel retinoid compound with reduced fat solubility, and more specifically, to provide a novel RAR ⁇ -acting substance with reduced fat solubility that can exert its RAR ⁇ selective action.
  • a compound having an acrylic acid structure has an activity on RAR, particularly RAR ⁇ , and the compound having an acrylic acid structure is lipophilic.
  • the present invention was completed by achieving reduction.
  • R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on the benzene ring to which they are bonded.
  • a 6-membered ring may be formed together with a carbon atom (the 6-membered ring has one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring. You may have).
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group
  • W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen)
  • R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group and a halogen
  • R 6 is a hydrogen atom or an alkyl group
  • Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group.
  • R 4 and R 5 may be hydrogen at the same time.
  • R 1 and R 2 are each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 together To form a 6-membered ring together with carbon atoms on the benzene ring to which they are bonded (the 6-membered ring is selected from a C 1 -C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring). And may have 1 or 2 or more substituents) 2.
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an alkylamino group and an arylamino group. 3.
  • R 6 is a hydrogen atom or a C 1 -C 4 alkyl group. 4).
  • R 4 , R 5 and R 6 are hydrogen atoms. 5.
  • R 1 and R 2 together form a 6-membered ring with the carbon atom on the benzene ring to which they are bonded (the 6-membered ring is a C 1 -C 4 alkyl group, alkyl halide on the ring) Or a salt thereof, which may have one or two or more substituents selected from a group and an oxo group), or a salt thereof. 6).
  • Formula II (In the formula, R 3 , W 1 , W 2 and Z are as defined in the preceding paragraph 1, and R 8 and R 9 are each independently a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl.
  • the compound of the present invention has excellent RAR activity and low hydrophobicity.
  • the compound of the present invention is excellent in RAR ⁇ selectivity, and is thought to be able to suppress the side effects of conventional RAR ⁇ agonists, RAR ⁇ agonists, etc., and is considered useful for the development of pharmaceuticals.
  • the compound of the present invention exhibits high RAR transcription activation ability at a low concentration, it is possible to provide a pharmaceutical product having the desired effect at a low dose.
  • FIG. 2 is a diagram showing a synthesis scheme of compounds of Intermediates 1 to 4.
  • Example 1 FIG. 2 is a diagram showing a synthesis scheme of compounds of intermediates 5 and 6.
  • Example 1 FIG. 3 is a diagram showing a synthesis scheme of intermediates 7 and 8 and target compounds 1 to 1c.
  • Example 1 FIG. 3 is a diagram showing a synthesis scheme of intermediates 9 to 13 and target compound 2.
  • Example 2 FIG. 3 is a diagram showing a synthesis scheme of intermediates 14 to 17 and target compound 3.
  • Example 3 It is a figure which shows the synthetic scheme of the intermediate bodies 18 and 19 and the target compounds 4 and 5.
  • FIG. Example 4 4 is a diagram showing a synthesis scheme of target compound 6.
  • FIG. Example 5
  • FIG. 5 Example 5
  • Example 3 is a diagram showing a synthesis scheme of intermediates 20 to 22 and target compound 7.
  • Example 6 It is a figure which shows the result of the reporter gene assay of compound 1a (HA-TMN).
  • Example 7) It is a figure which shows the result of the reporter gene assay of compound 1b (HAM-TMN).
  • Example 7) It is a figure which shows the result of the reporter gene assay of compound 1c (HAt-TMN).
  • Example 7) It is a figure which shows the result of the reporter gene assay of compound 2 (HA-3IP).
  • Example 7) It is a figure which shows the result of the reporter gene assay of compound 3 (HA-4IP).
  • Example 7 It is a figure which shows the result of the reporter gene assay of compound 4 (YA-TMN). (Example 7) It is a figure which shows the result of the reporter gene assay of compound 5 (MA-TMN). (Example 7) It is a figure which shows the result of the reporter gene assay of compound 6 (HHA-TMN). (Example 7) It is a figure which shows the result of having confirmed the blood transfer property at the time of orally administering compound 1a and 4.
  • FIG. (Example 10) It is a figure which shows the result of having confirmed the plasma triglyceride density
  • the novel retinoid compound of the present invention is a compound represented by the general formula I.
  • R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on the benzene ring to which they are bonded.
  • a 6-membered ring may be formed together with a carbon atom (the 6-membered ring has one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring.
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group
  • W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen)
  • R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group and a halogen
  • R 6 is a hydrogen atom or an alkyl group
  • Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group.
  • R 4 and R 5 may be hydrogen at the same time.
  • Alkyl is an atomic group represented by the general formula C n H 2n + 1 —.
  • alkyl means C 1 -C 20 linear or branched (chain) alkyl. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t- Examples include pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like. Further, in the following alkyl, methyl
  • alkenyl is an atomic group having one or more double bonds in the alkyl.
  • alkenyl means linear or branched C 2 -C 20 alkenyl. Examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,2-butadienyl, 1-pentenyl, 1,2-pentadienyl, 2-hexenyl, 1, Examples include 2-hexadienyl, 3-heptenyl, 1,5-heptadienyl and the like. Further, in the present invention, C 2 -C 6 linear or branched alkenyl is preferred.
  • Alkynyl is an atomic group having one or more triple bonds in the alkyl.
  • alkynyl means linear or branched C 2 -C 20 alkynyl. Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like. Further, in the present invention, C 2 -C 6 linear or branched alkynyl is preferred.
  • Alkoxy is an atomic group in which an alkyl group is bonded to an oxygen atom.
  • alkoxy means C 1 -C 6 alkoxy, and examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and the like.
  • acyl is an atomic group obtained by removing a hydroxyl group from an aliphatic carboxylic acid, and is represented by RCO— (R is a hydrocarbon group).
  • RCO— R is a hydrocarbon group.
  • acyl means C 1 -C 9 acyl, and examples thereof include formyl, acetyl, propionyl, butyryl, valeryl and the like.
  • Aryl means an atomic group obtained by removing one hydrogen atom from an aromatic ring including a single ring and a condensed ring.
  • aryl means a C 6 to C 14 monocyclic or condensed ring.
  • Aryl includes phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthryl (eg, 1-anthryl, 2-anthryl, 9-anthryl), phenanthryl (eg, 2-phenanthryl, 3-phenanthryl, 9-phenanthryl), fluorenyl (for example, 2-fluorenyl) and the like. In the present invention, phenyl is preferred.
  • Amino means an amino group of the general formula —NH 2 .
  • Alkylamino is one in which one or more (preferably one or two) hydrogen atoms of the above alkyl group are substituted with an amino group.
  • alkylamino include methylamino, propylamino, (1-methylethyl) amino, (2-methylbutyl) amino, dimethylamino, diethylamino, ethylmethylamino and the like.
  • Arylamino is one in which one or more (preferably one or two) hydrogen atoms on an aromatic ring are substituted with an amino group.
  • arylamino include phenylamino group, naphthylamino group, 4-methoxyphenylamino group, 3,4-dibromophenylamino group, 2-butylcarbonylphenylamino group, diphenylamino group and the like.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • halogenated alkyl is one in which one or more (preferably two or three) hydrogen atoms of the alkyl group are substituted with the halogen (preferably fluorine).
  • halogenated alkyl include trifluoromethyl, chloromethyl, bromomethyl, dichloromethyl, difluoromethyl, trichloromethyl, 2-chloroethyl and the like.
  • the carboxyl group is a group represented by —COOH
  • the esterified carboxyl group is a group represented by —COOR 12 (R 12 is an alkyl group, preferably a C 1 -C 4 alkyl group)
  • the acid group is a group represented by -CONHOH.
  • R 1 and R 2 may together form a 6-membered ring with the carbon atom on the benzene ring to which they are bonded.
  • the “six-membered ring” is a saturated or unsaturated ring structure having 6 atoms constituting the ring, and the ring-constituting atoms may be only carbon atoms, or in addition to carbon atoms, nitrogen atoms And 1 to 4 (preferably 1) heteroatoms (preferably nitrogen atoms) selected from oxygen atoms.
  • 6-membered ring in the present invention examples include cyclohexane, cyclohexene, cyclohexadiene, benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, and 1,2-dihydropyridine ring. These 6-membered rings are condensed with a benzene ring to which R 1 and R 2 are bonded to form a condensed ring group.
  • the 6-membered ring in the present invention may have 1 or 2 or more (preferably 1 to 4) substituents on the ring.
  • the substituents in the 6-membered ring are each independently selected from alkyl groups, halogenated alkyl groups, alkenyl groups, phenyl groups and oxo groups.
  • R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on a benzene ring to which they are bonded. You may form a 6-membered ring with a carbon atom.
  • the 6-membered ring may have one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring.
  • R 1 and R 2 are preferably each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 are Together, they form a 6-membered ring with the carbon atoms on the benzene ring to which they are attached.
  • the 6-membered ring may have one or more substituents selected from a C 1 -C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring.
  • R 1 and R 2 are each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 Together form a 6-membered ring with the carbon atom on the benzene ring to which they are attached.
  • the 6-membered ring contains 1 to 4 nitrogen atoms in addition to carbon atoms, and a substituent selected from a C 1 to C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring, 1 to 4 may be provided.
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group.
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group. More preferably, R 3 is selected from a hydrogen atom and an alkyl group.
  • W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen).
  • R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen.
  • W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group and halogen).
  • W 1 and W 2 are each independently selected from a nitrogen atom and CH.
  • R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group, and a halogen.
  • R 4 and R 5 are each independently a group selected from a hydrogen atom and an alkyl group. More preferably, R 4 and R 5 are hydrogen atoms.
  • R 6 is a hydrogen atom or an alkyl group.
  • R 6 is a hydrogen atom or a C 1 -C 4 alkyl group. More preferably, R 6 is a hydrogen atom.
  • Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group.
  • Z is selected from a carboxyl group and a hydroxamic acid group.
  • the novel retinoid compound of the present invention is a compound represented by the general formula II or the general formula III or a salt thereof.
  • R 3 , W 1 , W 2 and Z are as defined in the general formula I, and R 8 and R 9 are each independently a hydrogen atom, an alkyl group, a halogenated alkyl group. , An alkenyl group and a phenyl group.
  • R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, and a phenyl group, as described above.
  • R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group and a halogenated alkyl group. More preferably, R 8 and R 9 are each independently selected from a hydrogen atom, a C 1 -C 4 alkyl group and a halogenated alkyl group, and the halogen in the halogenated alkyl group is a fluorine atom.
  • R 3 , W 1 , W 2 and Z have the same definitions as in general formula I above.
  • the novel retinoid compounds of the present invention also include compounds represented by the following general formula IV.
  • W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen), R 10 and R 11 are an alkyl group or a halogenated alkyl group, Z is a carboxyl group, an esterified carboxyl group, or a hydroxamic acid group. )
  • novel retinoid compound of the present invention examples include compounds 1a, 1b, 1c, and 2 to 7 shown in Examples described later.
  • the novel retinoid compounds of the present invention are compounds 1a, 1b, 1c, 4-5, and compounds 1a, 4, 6 are preferred as RAR ⁇ agonists.
  • the novel retinoid compound in the present invention may be a pharmaceutically acceptable salt of the compound represented by the above general formulas I to III.
  • isomers for example, optical isomers, geometric isomers, and compatible isomers
  • the present invention includes these isomers. And also solvates, hydrates and crystals of various shapes.
  • the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts.
  • specific examples of such salts are as follows.
  • Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines.
  • Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts
  • tetramethylammonium salt tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, Quaternary ammonium salts such as tiger butyl ammonium salt; arginine; basic amino acid salts such as lysine salts.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate
  • Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate
  • sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate
  • the compound represented by any one of the general formulas I to III of the present invention has an action, that is, an action or an antagonistic action on RAR, particularly RAR ⁇ , and is used as a RAR action regulator (RAR ⁇ action regulator). It has a function.
  • the compound represented by any one of the general formulas I to III itself functions as a ligand for RAR and regulates the transcriptional activation ability of RAR, or other RAR administered to the living body or endogenous. It is considered to regulate the interaction between the ligand and RAR, and can be used as a RAR ligand action regulator.
  • RAR is a nuclear receptor involved in DNA transcription
  • a compound represented by any one of general formulas I to III can be used as a transcription regulator.
  • the term “modulation” or a similar term thereof should be interpreted in the broadest sense including enhancement (operation) or suppression of action. Whether the compound of the present invention has an enhancing (acting) action or an inhibitory action can be easily assayed according to the method specifically shown in the experimental examples of the present specification.
  • RAR agonists have physiological functions of retinoids such as cell differentiation and apoptosis. Therefore, these compounds are considered useful for the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissues, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers.
  • the retinoid compound of the present invention and the RXR agonist can be used in combination.
  • RAR functions together with a retinoid X receptor (RXR) (Non-patent Document 3).
  • RXR retinoid X receptor
  • the RAR-RXR heterodimer is known to exhibit a synergist effect when the RAR function is enhanced by the combined use of the RAR agonist and the RXR agonist (Non-patent Document 3). 6) It is useful.
  • a composition such as a reagent or a medicine containing the novel retinoid compound of the present invention is also included in the scope of the present invention.
  • the pharmaceutical composition containing the novel retinoid compound of the present invention can be used for the prevention and / or treatment of diseases involving RAR or other nuclear receptors, for example, anticancer agents and / or anti-inflammatory agents, anti-inflammatory agents, It can be used as an allergic agent.
  • the novel retinoid compound of the present invention can be used by being administered to a living body that requires treatment or treatment with the novel retinoid compound, but the dose to the living body is not particularly limited.
  • a retinoid compound such as retinoic acid as an active ingredient in combination with the retinoid compound of the present invention to control the action of retinoid, or without using a retinoid-containing drug, it already exists in the living body.
  • Appropriate doses can be easily selected in any administration method, such as when the retinoid compound of the present invention is administered to regulate the action of retinoic acid.
  • the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day.
  • the drug of the present invention can be administered either during the retinoid administration period and / or before or after that period. is there.
  • the agent of the present invention when used as an anticancer agent, the retinoid compound of the present invention described above may be used as an active ingredient, and a known anticancer agent may be included as an active ingredient.
  • anticancer agents include estrogen antagonistic anti-breast cancer agents and taxane anticancer agents, and specific examples include tamoxifen or taxol.
  • the agent of the present invention may contain a known anti-inflammatory agent as an active ingredient in addition to the above-described retinoid compound of the present invention as an active ingredient.
  • the anti-inflammatory agent may be steroidal or non-steroidal.
  • Non-steroidal anti-inflammatory agents include aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, And other types of structures may be selected.
  • Antiallergic agents include mediator release inhibitors, histamine H1-antagonists, thromboxane inhibitors, leukotriene antagonists, Th2 cytokine inhibitors, etc., specifically, mediator release inhibitors such as sodium cromoglycate and Tranilast, histamine H1-anti-antagonist, ketotifen fumarate, azelastine hydrochloride, thromboxane inhibitor, ozagrel hydrochloride (thromboxane A2 synthase inhibitor), seratrodast (thromboxane A2 antagonist), pranluca as leukotriene antagonist And sulatast tosilate as Th2 cytokine inhibitors.
  • mediator release inhibitors such as sodium cromoglycate and Tranilast, histamine H1-anti-antagonist, ketotifen fumarate, azelastine hydrochloride, thromboxane inhibitor, ozagrel hydrochloride (thromboxane A2 synthase inhibitor),
  • one or more substances selected from the compounds of the present invention may be administered as they are, but preferably, one or more of the above substances are used orally or non-containing. It is preferably administered as an oral pharmaceutical composition.
  • Oral or parenteral pharmaceutical compositions can be prepared using pharmaceutical additives available to those skilled in the art, that is, pharmacologically and pharmaceutically acceptable carriers.
  • one or more of the above substances can be blended in a medicine containing a retinoid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called mixture.
  • Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • the pharmaceutical composition suitable for parenteral administration includes for example, injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like can be mentioned.
  • Examples of pharmacologically and pharmaceutically acceptable carriers used in the production of the above pharmaceutical composition include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, Diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be mentioned.
  • the organic layer was washed with water (100 mL ⁇ 2) and saturated brine (100 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound 1a (173.5 mg, 83%) as yellow needle crystals.
  • Example 2 Synthesis of target compound 2
  • the target compound 2 was synthesized substantially as described in WO2008 / 105386.
  • a scheme of the production method is shown in FIG.
  • Example 3 Synthesis of target compound 3
  • the target compound 3 was synthesized substantially as described in WO2008 / 105386.
  • a scheme of the production method is shown in FIG.
  • the organic layer was washed with water (70 mL ⁇ 2) and saturated brine (70 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound 3 (52.5 mg, 77%) as yellow needle crystals.
  • the organic layer was washed with water (40 mL ⁇ 2) and saturated brine (40 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate to obtain the target compound 7 (07FO4-07) (9.2 mg, 49%) as a yellow disk crystal.
  • RAR activity evaluation 1 Measurement principle Since many nuclear receptors are transcription factors involved in transcriptional regulation, a reporter gene assay is performed as a means for measuring the transcriptional activity.
  • a RAR receptor protein expression plasmid and a reporter plasmid are introduced into cells such as COS-1 cells and HeLa cells to overexpress a fusion protein.
  • a RAR agonist ligand
  • transcription occurs in a ligand-dependent manner, producing a fusion protein downstream thereof, and production of downstream luciferase begins.
  • RAR agonist activity was measured.
  • DMEM Host cell culture Dulbecco's modified Eagle MEM medium
  • DMEM powder was dissolved in 1 L of ultrapure water (produced by Milli-Q (registered trademark)), sterilized by high-pressure heat (121 ° C., 15 minutes), returned to room temperature, Prepared by adding inactivated fetal bovine serum (FBS) to 10% (v / v), adding 10 mL of 10% NaHCO 3 sterilized by high-pressure heat sterilization, and then adding 10 mL of L-glutamine after filtration sterilization. did.
  • FBS inactivated fetal bovine serum
  • SEAP measurement was performed according to the method described in Methods in molecular biology, 63, pp. 49-60, 1997 / BD Great EscAPe SEAP User manual (BD bioscience). Specifically, it measured by the following method. 25 ⁇ L of dilution buffer was added to 25 ⁇ L of the supernatant on the fourth day, and then incubated at 65 ° C. for 30 minutes. Thereafter, the temperature was returned to room temperature, assay buffer (7 ⁇ L), 10 ⁇ MUP (0.3 ⁇ L) and dilution buffer (2.7 ⁇ L) were added, and incubated at room temperature in the dark for 60 minutes. Thereafter, the fluorescence intensity was measured at an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm using a microplate reader (Infinite TM (infinite) 200, manufactured by TECAN).
  • the assay buffer was prepared by the following method. L-homoarginine (0.45 g) and magnesium chloride (0.02 g) were dissolved in 50 mL of ultrapure water (produced by Milli-Q (registered trademark)), and diethanolamine (21 mL) was added. Then, after adjusting the pH to 9.8 with hydrochloric acid, the volume was adjusted to 100 mL with ultrapure water and stored at 4 ° C.
  • Dilution buffer was prepared by the following method. Sodium chloride (4.38 g) and Tris Base (2.42 g) were dissolved in 90 mL of ultrapure water (produced with Milli-Q (registered trademark)). Thereafter, the pH was adjusted to 7.2 with hydrochloric acid to prepare a 5-fold concentration dilution buffer, which was stored at 4 ° C. Dilution buffer was prepared by diluting it 5 times immediately before use.
  • 4-Methylumbelliferyl phosphate was dissolved in ultrapure water (produced with Milli-Q (registered trademark)) to 25 mM and stored at ⁇ 20 ° C. to make 10 ⁇ MUP.
  • Table 2 shows ClogP obtained by ChemDraw® Ultra® 7.0.
  • Example 9 Evaluation of RAR activity Using the same method as in Example 7, RAR activity was evaluated for compounds 1a, 2, 3, 4, and 5. The results are shown in Table 3 below. It was found that the introduction of an alkoxy group can be expected to significantly reduce fat solubility. It was also found that partial agonist activity to RAR ⁇ or ⁇ was observed by introducing a pyridine ring into the acidic site.
  • Example 10 Blood transferability Compound 1a or compound 4 was orally administered to mice, the blood concentration was measured, and blood transferability was confirmed.
  • 1) Preparation of plasma sample for HPLC analysis For a group of mice (n 7-8), a solution of compound 1a or compound 4 was administered at a dose of 30 mg / kg (1% ethanol and 0.5% CMC dissolved in distilled water). Orally administered at 10 mL / kg. At a predetermined time, 1.0 mL of blood was collected by cardiac puncture under diethyl ether anesthesia. Each blood sample was centrifuged at 4400 g for 5 minutes at 4 ° C. to obtain a plasma sample.
  • HPLC system is equipped with SCL-10A system controller, LC-10AD pump, SPD-10AV UV-Vis spectrophotometric detector, SIL-10AD autoinjector, CTO-6A column oven, DGU-14A degasser and C-R7A Chromatopac. Shimadzu liquid chromatography system. Samples (20 ⁇ L each) were injected at 10 ° C. using a refrigerated autosampler while being kept at 10 ° C. For the chromatographic analysis, Inertsil ODS-3 (4.6 i.d. ⁇ 250 mm, 5 ⁇ m, GL Sciences) and guard column Inertsil ODS-3 (4.0 i.d. ⁇ 10 mm, 5 ⁇ m, GL Sciences) were used.
  • the mixture was kept at 40 ° C. using methanol: 25 mM ammonium acetate (adjusted to pH 5.0 with acetic acid) (80:20, v / v) as the mobile phase.
  • the flow rate was 0.7 mL / min, and the absorbance at 280 nm was monitored.
  • Example 11 In vivo blood triglyceride level In the same manner as in Example 10, Compound 1a or Compound 4 was administered to mice, and plasma samples were collected and prepared. The blood triglyceride level assay was performed according to the product protocol using the obtained plasma sample and an assay kit (Triglyceride E-Test Wako) purchased from Wako Pure Chemical.
  • RAR agonistic compounds have higher transcriptional activation ability and reduced lipophilicity compared to the activities of existing RAR agonists. . Furthermore, compounds 4 and 6 not only activate RAR ⁇ activity at low concentrations, but also show partial agonist activity against RAR ⁇ . Therefore, these compounds can be expected to avoid an increase in blood concentration of triglycerides accompanying RAR ⁇ activation even at high concentrations. Since the compound of the present invention can be expected to act as an active ingredient of anticancer agents, anti-inflammatory agents, and antiallergic agents, it can be used as such a medicament. It can also be used as a biochemical test reagent.

Abstract

Disclosed is a substance (a retinoid compound represented by the formula), which acts on a retinoic acid receptor that is a nuclear receptor. (In the formula, R1 and R2 each independently represents a group selected from among an NH2 group, an alkyl group and an alkoxy group, or R1 and R2 may combine together with carbon atoms on the benzene ring, to which the R1 and R2 are bonded, and form a six-membered ring that may be substituted by an alkyl group or the like; R3 represents a group selected from among a hydrogen atom, an alkyl group and the like; W1 and W2 each independently represents a group selected from among a nitrogen atom and a CR7 group (wherein R7 represents a hydrogen atom or the like); R4 and R5 each independently represents a group selected from among a hydrogen atom, an alkyl group and a halogen atom; R6 represents a hydrogen atom or an alkyl group; and Z represents a group selected from among a carboxyl group, an esterified carboxyl group and a hydroxamic acid group.)

Description

レチノイド化合物Retinoid compounds
　本発明は、核内受容体であるレチノイン酸受容体（retinoic acid receptor; RAR）に対する作用性物質（以下「レチノイド化合物」と称することもある）に関する。 The present invention relates to an active substance (hereinafter also referred to as “retinoid compound”) for a retinoic acid receptor (RAR), which is a nuclear receptor.
　本出願は、参照によりここに援用されるところの日本特許出願　特願２００９－２７３９４５号の優先権を請求する。 This application claims the priority of Japanese Patent Application No. 2009-273945, which is incorporated herein by reference.
　核内受容体は、細胞増殖や免疫応答、糖及び／又は脂質代謝等の生理機能、恒常性の維持を担っているリガンド依存性の転写調節因子のひとつである。核内受容体に対応するリガンドにより、その下流にある遺伝子の転写を制御している。核内受容体は、同一の原初遺伝子から派生しており、スーパーファミリーを形成する（非特許文献１）。 Nuclear receptors are one of ligand-dependent transcriptional regulators that are responsible for maintaining cell proliferation, immune response, physiological functions such as sugar and / or lipid metabolism, and homeostasis. The ligand corresponding to the nuclear receptor controls the transcription of the downstream gene. Nuclear receptors are derived from the same primitive gene and form a superfamily (Non-patent Document 1).
　RARは、作動性物質（以下、アゴニストと記す）の結合により遺伝子転写を制御する核内受容体の一種で、α、β、γの３つのサブタイプが存在し、サブタイプ毎にその体内局在、生理作用が異なっている（非特許文献２、３）。 RAR is a type of nuclear receptor that regulates gene transcription through the binding of agonists (hereinafter referred to as agonists). There are three subtypes, α, β, and γ. At present, physiological actions are different (Non-patent Documents 2 and 3).
　RARαは種々の組織に存在する。RARα選択的アゴニストは、分化誘導作用を示し、急性前骨髄球系白血病の分化誘導療法に使用されるが、副作用として血中トリグリセリド（TG）値上昇を示すことが知られている（非特許文献４）。RARγは主に皮膚に局在する。RARγ選択的アゴニストは、皮膚、骨に対する毒性や催奇形性などの重篤な副作用を示すことが知られている（非特許文献２）。一方、RARβは心臓や肺、脾臓に存在する。RARβ選択的アゴニストは、RARαやRARγの選択的アゴニストでみられるような副作用を示さずに、細胞周期の調節やアポトーシス誘導作用を発揮することが知られている。したがって、RARβ選択的アゴニストは、前述の副作用を回避した抗がん薬、例えば白血病治療薬のターゲットとなっている（非特許文献２、３）。 RARα exists in various organizations. RARα selective agonists show differentiation-inducing action and are used for differentiation-inducing therapy of acute promyelocytic leukemia, but are known to show an increase in blood triglyceride (TG) level as a side effect (Non-Patent Literature) 4). RARγ is mainly localized in the skin. RARγ selective agonists are known to show serious side effects such as toxicity to skin and bone and teratogenicity (Non-patent Document 2). On the other hand, RARβ exists in the heart, lungs and spleen. RARβ selective agonists are known to exert cell cycle regulation and apoptosis inducing action without exhibiting the side effects seen with RARα and RARγ selective agonists. Therefore, RARβ selective agonists are targets of anticancer drugs that avoid the above-mentioned side effects, for example, therapeutic drugs for leukemia (Non-patent Documents 2 and 3).
　RARβとそのリガンドとのX線結晶構造解析データに注目すると、RARβのリガンドが結合する空間は、他のサブタイプのRARと比べて大きいことが知られている（非特許文献５）。事実、既存のRARβ選択的アゴニストの多くは、その空間に相当する部位にかさ高い脂溶性の置換基を導入することでRARβ選択性を生み出すことに成功している（非特許文献３、６）。 When attention is paid to the X-ray crystal structure analysis data of RARβ and its ligand, it is known that the space where the ligand of RARβ binds is larger than that of other subtypes of RAR (Non-patent Document 5). In fact, many of the existing RARβ selective agonists have succeeded in producing RARβ selectivity by introducing a bulky fat-soluble substituent at a site corresponding to the space (Non-patent Documents 3 and 6). .
　以下に、代表的なRARβアゴニストの分子構造を示す。なお、各化合物に関するCLogPは、ChemDrawPro 11により求められたものであり、値が大きいほど脂溶性の高いことを示す。 The molecular structure of typical RARβ agonists is shown below. In addition, CLogP regarding each compound was calculated | required by ChemDrawPro-11, and it shows that fat solubility is so high that a value is large.
Figure JPOXMLDOC01-appb-C000004
 （特許文献１）
Figure JPOXMLDOC01-appb-C000004
 (Patent Document 1)
Figure JPOXMLDOC01-appb-C000005
 （特許文献２）
Figure JPOXMLDOC01-appb-C000005
 (Patent Document 2)
Figure JPOXMLDOC01-appb-C000006
 （特許文献３）
Figure JPOXMLDOC01-appb-C000006
 (Patent Document 3)
Figure JPOXMLDOC01-appb-C000007
 （特許文献４）
Figure JPOXMLDOC01-appb-C000007
 (Patent Document 4)
　しかしながら、上記の化合物のほとんどが高脂溶性であり、非特異的な蛋白質結合を生じやすいことなどから、上記化合物を医薬として使用する際には体内動態的な問題が懸念される。従って、低脂溶性であって、効率よく製造できる新規なRAR作用性物質の開発が望まれている。
　なお、特許文献５及び非特許文献７にはレチノイド作用を有するナフトエ酸誘導体が開示されているが、RARβ選択的な化合物に関する記載はない。
　また、特許文献６にはアルコキシ基を有するレキシノイド化合物が記載されているが、RARβに選択的なレチノイド化合物は記載されていない。 However, since most of the above compounds are highly lipophilic and easily cause non-specific protein binding, there are concerns about pharmacokinetic problems when using the above compounds as pharmaceuticals. Therefore, development of a novel RAR-active substance that is low in fat solubility and can be produced efficiently is desired.
Although Patent Document 5 and Non-Patent Document 7 disclose naphthoic acid derivatives having a retinoid action, there is no description regarding RARβ selective compounds.
Patent Document 6 describes a rexinoid compound having an alkoxy group, but does not describe a retinoid compound selective for RARβ.
ＷＯ１９９６／０２０９３０WO1996 / 020930 ＷＯ２０００／０１７１４７WO2000 / 0117147 ＷＯ１９９２／１９５８３WO1992 / 19583 ＷＯ２００７／００９０８３WO2007 / 009083 ＥＰ７２２９２８ＢEP72229B ＷＯ２００８／１０５３８６WO2008 / 105386
　本発明は、脂溶性が低減した新規レチノイド化合物の提供、詳細には、RARβ選択的に作用を発揮し得る、脂溶性が低減した新規RARβ作用性物質を提供することを目的とする。 The object of the present invention is to provide a novel retinoid compound with reduced fat solubility, and more specifically, to provide a novel RARβ-acting substance with reduced fat solubility that can exert its RARβ selective action.
　本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、アクリル酸構造を有する化合物がRAR、中でもRARβに対する作用性を有することを見出し、アクリル酸構造を有する化合物において脂溶性の低減を達成させることにより、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that a compound having an acrylic acid structure has an activity on RAR, particularly RARβ, and the compound having an acrylic acid structure is lipophilic. The present invention was completed by achieving reduction.
　即ち本発明は、以下よりなる。
１．　一般式I：
Figure JPOXMLDOC01-appb-C000008
 （式中、R1及びR2は、各々独立してNH2、アルキル基及びアルコキシ基から選択される基であるか、R1及びR2は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成してもよく（該６員環は環上に、アルキル基、ハロゲン化アルキル基、アルケニル基、フェニル基及びオキソ基から選択される置換基を、１又は２以上有していてもよい。）、
R3は、水素原子、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基及びアリールアミノ基から選択され、
W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基、アルコキシ基及びハロゲンから選択される。）から選択され、
R4及びR5は、各々独立して水素原子、アルキル基及びハロゲンから選択される基であり、
R6は、水素原子又はアルキル基であり、
Zは、カルボキシル基、エステル化カルボキシル基、及びヒロドキサム酸基から選択される。但し、R4とR5は同時に水素であってもよい。）
で表される化合物又はその塩。
２．　R1及びR2は、各々独立してアルキル基及びアルコキシ基から選択される基である（但し、R1とR2は同時にアルキル基ではない）か、又は、R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成しており（該６員環は環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１又は２以上を有していてもよい）、
R3が水素原子、アルキル基、アルケニル基、アルキニル基、アシル基、アルキルアミノ基及びアリールアミノ基から選択される、前項１記載の化合物又はその塩。
３．　R6が水素原子又はC1～C4アルキル基である、前項１又は２に記載の化合物又はその塩。
４．　R4、R5及びR6が水素原子である、前項１又は２に記載の化合物又はその塩。
５．　R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成している（該６員環は環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１又は２以上を有していてもよい）、前項１～４のいずれか１に記載の化合物又はその塩。
６．　一般式II：
Figure JPOXMLDOC01-appb-C000009
 （式中、R3、W1、W2及びZは、前項１記載の定義と同意義であり、R8及びR9は、各々独立して水素原子、アルキル基、ハロゲン化アルキル基、アルケニル基及びフェニル基から選択される。）
で表される、前項１記載の化合物又はその塩。
７．　一般式III：
Figure JPOXMLDOC01-appb-C000010
 （式中、R3、R6、W1、W2及びZは前項１記載の定義と同意義である。）
で表される化合物又はその塩。
８．　前項１～６のいずれか１項に記載の化合物又はその塩を含有する、レチノイン酸受容体（RAR）リガンド作用調節剤。
９．　前項１～６のいずれか１項に記載の化合物又はその塩を含有する、医薬組成物。
１０．　抗がん剤、抗アレルギー剤及び／又は抗炎症剤である、前項８に記載の医薬組成物。 That is, this invention consists of the following.
1. Formula I:
Figure JPOXMLDOC01-appb-C000008
 Wherein R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on the benzene ring to which they are bonded. A 6-membered ring may be formed together with a carbon atom (the 6-membered ring has one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring. You may have).
R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group,
W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen);
R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group and a halogen;
R 6 is a hydrogen atom or an alkyl group,
Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group. However, R 4 and R 5 may be hydrogen at the same time. )
Or a salt thereof.
2. R 1 and R 2 are each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 together To form a 6-membered ring together with carbon atoms on the benzene ring to which they are bonded (the 6-membered ring is selected from a C 1 -C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring). And may have 1 or 2 or more substituents)
2. The compound according to item 1 or a salt thereof, wherein R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an alkylamino group and an arylamino group.
3. 3. The compound or a salt thereof according to item 1 or 2, wherein R 6 is a hydrogen atom or a C 1 -C 4 alkyl group.
4). 3. The compound or a salt thereof according to item 1 or 2, wherein R 4 , R 5 and R 6 are hydrogen atoms.
5. R 1 and R 2 together form a 6-membered ring with the carbon atom on the benzene ring to which they are bonded (the 6-membered ring is a C 1 -C 4 alkyl group, alkyl halide on the ring) Or a salt thereof, which may have one or two or more substituents selected from a group and an oxo group), or a salt thereof.
6). Formula II:
Figure JPOXMLDOC01-appb-C000009
 (In the formula, R 3 , W 1 , W 2 and Z are as defined in the preceding paragraph 1, and R 8 and R 9 are each independently a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl. Selected from groups and phenyl groups.)
The compound or its salt of the preceding clause 1 represented by these.
7). Formula III:
Figure JPOXMLDOC01-appb-C000010
 (In the formula, R 3 , R 6 , W 1 , W 2 and Z have the same meaning as defined in the preceding paragraph 1).
Or a salt thereof.
8). A retinoic acid receptor (RAR) ligand action modulator comprising the compound or salt thereof according to any one of items 1 to 6.
9. 7. A pharmaceutical composition comprising the compound or salt thereof according to any one of items 1 to 6.
10. 9. The pharmaceutical composition according to item 8 above, which is an anticancer agent, antiallergic agent and / or antiinflammatory agent.
　本発明の化合物は優れたRAR作用性を有し、さらに疎水性が低いものである。また、本発明の化合物はRARβ選択性に優れており、従来のRARαアゴニストや、RARγアゴニストなどの持つ副作用を抑えることが可能であると考えられ、医薬品の開発に有用であると考えられる。さらに、本発明の化合物は低濃度で高いRAR転写活性化能を示すので、低用量で所期の効果を奏する医薬品を提供することができる。 The compound of the present invention has excellent RAR activity and low hydrophobicity. In addition, the compound of the present invention is excellent in RARβ selectivity, and is thought to be able to suppress the side effects of conventional RARα agonists, RARγ agonists, etc., and is considered useful for the development of pharmaceuticals. Furthermore, since the compound of the present invention exhibits high RAR transcription activation ability at a low concentration, it is possible to provide a pharmaceutical product having the desired effect at a low dose.
中間体１～４の化合物の合成スキームを示す図である。（実施例１）FIG. 2 is a diagram showing a synthesis scheme of compounds of Intermediates 1 to 4. Example 1 中間体５、６の化合物の合成スキームを示す図である。（実施例１）FIG. 2 is a diagram showing a synthesis scheme of compounds of intermediates 5 and 6. Example 1 中間体７、８および目的化合物１～１ｃの合成スキームを示す図である。（実施例１）FIG. 3 is a diagram showing a synthesis scheme of intermediates 7 and 8 and target compounds 1 to 1c. Example 1 中間体９～１３および目的化合物２の合成スキームを示す図である。（実施例２）FIG. 3 is a diagram showing a synthesis scheme of intermediates 9 to 13 and target compound 2. (Example 2) 中間体１４～１７および目的化合物３の合成スキームを示す図である。（実施例３）FIG. 3 is a diagram showing a synthesis scheme of intermediates 14 to 17 and target compound 3. (Example 3) 中間体１８、１９および目的化合物４および５の合成スキームを示す図である。（実施例４）It is a figure which shows the synthetic scheme of the intermediate bodies 18 and 19 and the target compounds 4 and 5. FIG. Example 4 目的化合物６の合成スキームを示す図である。（実施例５）4 is a diagram showing a synthesis scheme of target compound 6. FIG. (Example 5) 中間体２０～２２および目的化合物７の合成スキームを示す図である。（実施例６）FIG. 3 is a diagram showing a synthesis scheme of intermediates 20 to 22 and target compound 7. (Example 6) 化合物１ａ（HA-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 1a (HA-TMN). (Example 7) 化合物１ｂ（HAM-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 1b (HAM-TMN). (Example 7) 化合物１ｃ（HAt-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 1c (HAt-TMN). (Example 7) 化合物２（HA-3IP）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 2 (HA-3IP). (Example 7) 化合物３（HA-4IP）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 3 (HA-4IP). (Example 7) 化合物４（YA-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 4 (YA-TMN). (Example 7) 化合物５（MA-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 5 (MA-TMN). (Example 7) 化合物６（HHA-TMN）のレポータージーンアッセイの結果を示す図である。（実施例７）It is a figure which shows the result of the reporter gene assay of compound 6 (HHA-TMN). (Example 7) 化合物１ａおよび４を経口投与した際の、血中移行性を確認した結果を示す図である。（実施例１０）It is a figure which shows the result of having confirmed the blood transfer property at the time of orally administering compound 1a and 4. FIG. (Example 10) 化合物１ａおよび４を、経口投与した際の、血漿トリグリセリド濃度を確認した結果を示す図である。（実施例１１）It is a figure which shows the result of having confirmed the plasma triglyceride density | concentration at the time of administering compound 1a and 4 orally. (Example 11)
　本発明の新規レチノイド化合物は、一般式Iにより表わされる化合物である。
Figure JPOXMLDOC01-appb-C000011
 The novel retinoid compound of the present invention is a compound represented by the general formula I.
Figure JPOXMLDOC01-appb-C000011
（式中、R1及びR2は、各々独立してNH2、アルキル基及びアルコキシ基から選択される基であるか、R1及びR2は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成してもよく（該６員環は環上に、アルキル基、ハロゲン化アルキル基、アルケニル基、フェニル基及びオキソ基から選択される置換基を、１又は２以上有していてもよい）、
R3は、水素原子、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基及びアリールアミノ基から選択され、
W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基、アルコキシ基及びハロゲンから選択される）から選択され、
R4及びR5は、各々独立して水素原子、アルキル基及びハロゲンから選択される基であり、
R6は、水素原子又はアルキル基であり、
Zは、カルボキシル基、エステル化カルボキシル基、及びヒロドキサム酸基から選択される。但し、R4とR5は同時に水素であってもよい。） Wherein R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on the benzene ring to which they are bonded. A 6-membered ring may be formed together with a carbon atom (the 6-membered ring has one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring. You may have),
R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group,
W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen);
R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group and a halogen;
R 6 is a hydrogen atom or an alkyl group,
Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group. However, R 4 and R 5 may be hydrogen at the same time. )
　まず、本明細書において用いられる各種語句の定義を以下に説明する。 First, definitions of various terms used in this specification will be described below.
　「アルキル」とは、一般式CnH2n+1-で表わされる原子団である。本発明において「アルキル」とは、C1～C20の直鎖状又は分枝（鎖）状のアルキルを意味する。アルキルとしては、例えば、メチル、エチル、ｎ―プロピル、ｉ―プロピル、ｎ―ブチル、ｉ―ブチル、ｓ―ブチル、ｔ―ブチル、ｎ―ぺンチル、ｉ―ぺンチル、ネオぺンチル、ｔ―ぺンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシル、ノナデシル、イコシル等が挙げられる。さらに本発明においては、C1～C6の直鎖状又は分枝状のアルキルが好ましい。 “Alkyl” is an atomic group represented by the general formula C n H 2n + 1 —. In the present invention, “alkyl” means C 1 -C 20 linear or branched (chain) alkyl. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t- Examples include pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like. Further, in the present invention, C 1 -C 6 linear or branched alkyl is preferred.
　「アルケニル」とは、上記アルキルに１個又はそれ以上の二重結合を有する原子団である。本発明おいて「アルケニル」とは、直鎖または分枝状のC2～C20アルケニルを意味する。アルケニルとしては、例えば、ビニル、１―プロペニル、２―プロペニル、１―ブテニル、２―ブテニル、３―ブテニル、１，２―ブタジエニル、１―ペンテニル、１，２―ペンタジエニル、２―ヘキセニル、１，２―ヘキサジエニル、３―ヘプテニル、１，５―ヘプタジエニル等が挙げられる。さらに本発明においては、C2～C6の直鎖状又は分枝状のアルケニルが好ましい。 “Alkenyl” is an atomic group having one or more double bonds in the alkyl. In the present invention, “alkenyl” means linear or branched C 2 -C 20 alkenyl. Examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,2-butadienyl, 1-pentenyl, 1,2-pentadienyl, 2-hexenyl, 1, Examples include 2-hexadienyl, 3-heptenyl, 1,5-heptadienyl and the like. Further, in the present invention, C 2 -C 6 linear or branched alkenyl is preferred.
　「アルキニル」とは、上記アルキルに１個又はそれ以上の三重結合を有する原子団である。本発明おいて「アルキニル」とは、直鎖または分枝状のC2～C20アルキニルを意味する。アルキニルとしては、例えば、エチニル、１―プロピニル、２―プロピニル、１―ブチニル、２―ブチニル、３―ブチニル等が挙げられる。さらに本発明においては、C2～C6の直鎖状又は分枝状のアルキニルが好ましい。 “Alkynyl” is an atomic group having one or more triple bonds in the alkyl. In the present invention, “alkynyl” means linear or branched C 2 -C 20 alkynyl. Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like. Further, in the present invention, C 2 -C 6 linear or branched alkynyl is preferred.
　「アルコキシ」とは、酸素原子にアルキル基が結合した原子団である。本発明において「アルコキシ」とは、C1～C6のアルコキシを意味し、例えば、メトキシ、エトキシ、ｎ―プロポキシ、ｉ―プロポキシ、ｎ―ブトキシ等が挙げられる。 “Alkoxy” is an atomic group in which an alkyl group is bonded to an oxygen atom. In the present invention, “alkoxy” means C 1 -C 6 alkoxy, and examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and the like.
　「アシル」とは、脂肪族カルボン酸から水酸基を除いた原子団であり、RCO-（Rは炭化水素基）で表わされるものである。本発明において「アシル」とは、C1～C9のアシルを意味し、例えば、ホルミル、アセチル、プロピオニル、ブチリル、バレリル等が挙げられる。 “Acyl” is an atomic group obtained by removing a hydroxyl group from an aliphatic carboxylic acid, and is represented by RCO— (R is a hydrocarbon group). In the present invention, “acyl” means C 1 -C 9 acyl, and examples thereof include formyl, acetyl, propionyl, butyryl, valeryl and the like.
　「アリール」とは、単環および縮合環を含む芳香環において水素原子１個を除いた原子団を意味する。本発明において「アリール」とは、C6～C14の単環又は縮合環を意味する。「アリール」としては、フェニル、ナフチル（例えば、１―ナフチル、２―ナフチル）、アンスリル（例えば、１―アンスリル、２―アンスリル、９―アンスリル）、フェナンスリル（例えば、２―フェナンスリル、３―フェナンスリル、９―フェナンスリル）、フルオレニル（例えば、２―フルオレニル）等が挙げられる。本発明においては、フェニルが好ましい。 “Aryl” means an atomic group obtained by removing one hydrogen atom from an aromatic ring including a single ring and a condensed ring. In the present invention, “aryl” means a C 6 to C 14 monocyclic or condensed ring. “Aryl” includes phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthryl (eg, 1-anthryl, 2-anthryl, 9-anthryl), phenanthryl (eg, 2-phenanthryl, 3-phenanthryl, 9-phenanthryl), fluorenyl (for example, 2-fluorenyl) and the like. In the present invention, phenyl is preferred.
　「アミノ」は、一般式-NH2のアミノ基を意味する。 “Amino” means an amino group of the general formula —NH 2 .
　「アルキルアミノ」とは、上記アルキル基の水素原子１個以上（好ましくは１個もしくは２個）がアミノ基に置換したものである。アルキルアミノとしては、例えば、メチルアミノ、プロピルアミノ、（１－メチルエチル）アミノ、（２－メチルブチル）アミノ、ジメチルアミノ、ジエチルアミノ、エチルメチルアミノ等が挙げられる。 “Alkylamino” is one in which one or more (preferably one or two) hydrogen atoms of the above alkyl group are substituted with an amino group. Examples of alkylamino include methylamino, propylamino, (1-methylethyl) amino, (2-methylbutyl) amino, dimethylamino, diethylamino, ethylmethylamino and the like.
　「アリールアミノ」とは、芳香環上の水素原子の１個以上（好ましくは１個もしくは２個）がアミノ基に置換したものである。アリールアミノとしては、例えば、フェニルアミノ基、ナフチルアミノ基、４－メトキシフェニルアミノ基、３，４－ジブロモフェニルアミノ基、２－ブチルカルボニルフェニルアミノ基、ジフェニルアミノ基等が挙げられる。 “Arylamino” is one in which one or more (preferably one or two) hydrogen atoms on an aromatic ring are substituted with an amino group. Examples of arylamino include phenylamino group, naphthylamino group, 4-methoxyphenylamino group, 3,4-dibromophenylamino group, 2-butylcarbonylphenylamino group, diphenylamino group and the like.
　「ハロゲン」とは、フッ素、塩素、臭素、ヨウ素を意味する。 “Halogen” means fluorine, chlorine, bromine and iodine.
　「ハロゲン化アルキル」とは、上記アルキル基の水素原子の１個以上（好ましくは２個もしくは３個）が上記ハロゲン（好ましくはフッ素）に置換したものである。ハロゲン化アルキルとしては、例えば、トリフルオロメチル、クロルメチル、ブロモメチル、ジクロルメチル、ジフルオロメチル、トリクロルメチル、２－クロルエチル等が挙げられる。 The “halogenated alkyl” is one in which one or more (preferably two or three) hydrogen atoms of the alkyl group are substituted with the halogen (preferably fluorine). Examples of the halogenated alkyl include trifluoromethyl, chloromethyl, bromomethyl, dichloromethyl, difluoromethyl, trichloromethyl, 2-chloroethyl and the like.
　カルボキシル基とは-COOHで表わされる基であり、エステル化カルボキシル基とは-COOR12（R12は、アルキル基、好ましくはC1～C4アルキル基である）で表わされる基であり、ヒドロキサム酸基とは、-CONHOHで表わされる基である。 The carboxyl group is a group represented by —COOH, the esterified carboxyl group is a group represented by —COOR 12 (R 12 is an alkyl group, preferably a C 1 -C 4 alkyl group), and hydroxam The acid group is a group represented by -CONHOH.
　上記一般式Iにおいて、R1とR2は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成してもよい。当該「６員環」とは、環を構成する原子数が６個である飽和もしくは不飽和の環構造であり、環構成原子が炭素原子のみであってもよいし、炭素原子以外に窒素原子および酸素原子から選択されるヘテロ原子（好ましくは窒素原子）を１～４個（好ましくは１個）有していてもよい。本発明における６員環は、シクロヘキサン、シクロヘキセン、シクロヘキサジエン、ベンゼン環、ピリジン環、ピラジン環、ピリミジン環、ピリダジン環、１，２－ジヒドロピリジン環等が挙げられる。これらの６員環は、R1とR2が結合するベンゼン環と縮合して縮合環基を形成するものである。 In the above general formula I, R 1 and R 2 may together form a 6-membered ring with the carbon atom on the benzene ring to which they are bonded. The “six-membered ring” is a saturated or unsaturated ring structure having 6 atoms constituting the ring, and the ring-constituting atoms may be only carbon atoms, or in addition to carbon atoms, nitrogen atoms And 1 to 4 (preferably 1) heteroatoms (preferably nitrogen atoms) selected from oxygen atoms. Examples of the 6-membered ring in the present invention include cyclohexane, cyclohexene, cyclohexadiene, benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, and 1,2-dihydropyridine ring. These 6-membered rings are condensed with a benzene ring to which R 1 and R 2 are bonded to form a condensed ring group.
　さらに本発明における６員環は、環上に置換基を１又は２以上（好ましくは１～４個）有していてもよい。６員環における置換基は、各々独立にアルキル基、ハロゲン化アルキル基、アルケニル基、フェニル基およびオキソ基から選択される。 Furthermore, the 6-membered ring in the present invention may have 1 or 2 or more (preferably 1 to 4) substituents on the ring. The substituents in the 6-membered ring are each independently selected from alkyl groups, halogenated alkyl groups, alkenyl groups, phenyl groups and oxo groups.
　前述のとおり、R1及びR2は、各々独立してNH2、アルキル基及びアルコキシ基から選択される基であるか、R1及びR2は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成してもよい。該６員環は環上に、アルキル基、ハロゲン化アルキル基、アルケニル基、フェニル基及びオキソ基から選択される置換基を、１又は２以上有していてもよい。
　R1及びR2は、好ましくは各々独立してアルキル基及びアルコキシ基から選択される基である（但し、R1とR2は同時にアルキル基ではない）か、又は、R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成している。ここで、該６員環は環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１又は２以上を有していてもよい。
　より好ましくはR1及びR2は、各々独立してアルキル基及びアルコキシ基から選択される基である（但し、R1とR2は同時にアルキル基ではない）か、又は、R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成している。ここで、該６員環は、炭素原子以外に窒素原子を１～４個含み、環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１～４有していてもよい。 As described above, R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on a benzene ring to which they are bonded. You may form a 6-membered ring with a carbon atom. The 6-membered ring may have one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring.
R 1 and R 2 are preferably each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 are Together, they form a 6-membered ring with the carbon atoms on the benzene ring to which they are attached. Here, the 6-membered ring may have one or more substituents selected from a C 1 -C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring.
More preferably, R 1 and R 2 are each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 Together form a 6-membered ring with the carbon atom on the benzene ring to which they are attached. Here, the 6-membered ring contains 1 to 4 nitrogen atoms in addition to carbon atoms, and a substituent selected from a C 1 to C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring, 1 to 4 may be provided.
　前述のとおり、R3は、水素原子、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基及びアリールアミノ基から選択される。
　好ましくはR3は、水素原子、アルキル基、アルケニル基、アルコキシ基、アシル基、アルキルアミノ基及びアリールアミノ基から選択される。
　より好ましくはR3は、水素原子及びアルキル基から選択される。 As described above, R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group.
Preferably R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group.
More preferably, R 3 is selected from a hydrogen atom and an alkyl group.
　前述のとおり、W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基、アルコキシ基及びハロゲンから選択される）から選択される。
　好ましくは、W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基及びハロゲンから選択される）から選択される。
　好ましくは、W1及びW2は、各々独立して窒素原子及びCHから選択される。 As described above, W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen).
Preferably, W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group and halogen).
Preferably, W 1 and W 2 are each independently selected from a nitrogen atom and CH.
　前述のとおり、R4及びR5は、各々独立して水素原子、アルキル基及びハロゲンから選択される基である。
　好ましくは、R4及びR5は、各々独立して水素原子及びアルキル基から選択される基である。
　より好ましくは、R4及びR5は水素原子である。 As described above, R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group, and a halogen.
Preferably, R 4 and R 5 are each independently a group selected from a hydrogen atom and an alkyl group.
More preferably, R 4 and R 5 are hydrogen atoms.
　前述のとおり、R6は水素原子又はアルキル基である。好ましくは、R6が水素原子又はC1～C4アルキル基である。より好ましくは、R6が水素原子である。 As described above, R 6 is a hydrogen atom or an alkyl group. Preferably, R 6 is a hydrogen atom or a C 1 -C 4 alkyl group. More preferably, R 6 is a hydrogen atom.
　前述のとおり、Zは、カルボキシル基、エステル化カルボキシル基、及びヒロドキサム酸基から選択される。
　好ましくは、Zは、カルボキシル基及びヒロドキサム酸基から選択される。 As described above, Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group.
Preferably Z is selected from a carboxyl group and a hydroxamic acid group.
　好ましくは、本発明の新規レチノイド化合物は、一般式II又は一般式IIIにより表わされる化合物又はその塩である。
Figure JPOXMLDOC01-appb-C000012
 　一般式II中、R3、W1、W2及びZは、上記一般式Iにおける定義と同意義であり、R8及びR9は、各々独立して水素原子、アルキル基、ハロゲン化アルキル基、アルケニル基及びフェニル基から選択される。 Preferably, the novel retinoid compound of the present invention is a compound represented by the general formula II or the general formula III or a salt thereof.
Figure JPOXMLDOC01-appb-C000012
 In the general formula II, R 3 , W 1 , W 2 and Z are as defined in the general formula I, and R 8 and R 9 are each independently a hydrogen atom, an alkyl group, a halogenated alkyl group. , An alkenyl group and a phenyl group.
　一般式IIにおいてR8及びR9は、前述のとおり、各々独立して水素原子、アルキル基、ハロゲン化アルキル基、アルケニル基及びフェニル基から選択される。
　好ましくは、R8及びR9は、各々独立して水素原子、アルキル基及びハロゲン化アルキル基から選択される。
　より好ましくは、R8及びR9は、各々独立して水素原子、C1～C4アルキル基及びハロゲン化アルキル基から選択され、当該ハロゲン化アルキル基におけるハロゲンがフッ素原子である。 In the general formula II, R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, and a phenyl group, as described above.
Preferably, R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group and a halogenated alkyl group.
More preferably, R 8 and R 9 are each independently selected from a hydrogen atom, a C 1 -C 4 alkyl group and a halogenated alkyl group, and the halogen in the halogenated alkyl group is a fluorine atom.
Figure JPOXMLDOC01-appb-C000013
 　一般式III中、R3、W1、W2及びZは上記一般式Iにおける定義と同意義である。
Figure JPOXMLDOC01-appb-C000013
 In general formula III, R 3 , W 1 , W 2 and Z have the same definitions as in general formula I above.
　また本発明の新規レチノイド化合物として、下記一般式IVにて示される化合物も含まれる。
Figure JPOXMLDOC01-appb-C000014
 （一般式IV中、W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基、アルコキシ基及びハロゲンから選択され）から選択され、
R10、R11は、アルキル基又はハロゲン化アルキル基であり、
Zは、カルボキシル基、エステル化カルボキシル基、又はヒロドキサム酸基である。） The novel retinoid compounds of the present invention also include compounds represented by the following general formula IV.
Figure JPOXMLDOC01-appb-C000014
 (In General Formula IV, W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen),
R 10 and R 11 are an alkyl group or a halogenated alkyl group,
Z is a carboxyl group, an esterified carboxyl group, or a hydroxamic acid group. )
　本発明の新規レチノイド化合物として具体的には、後述の実施例で示す化合物１ａ，１ｂ，１ｃ，２～７が挙げられる。好ましくは、本発明の新規レチノイド化合物は、化合物１ａ，１ｂ，１ｃ，４～５であり、RARβアゴニストとしては化合物１ａ，４，６が好適である。 Specific examples of the novel retinoid compound of the present invention include compounds 1a, 1b, 1c, and 2 to 7 shown in Examples described later. Preferably, the novel retinoid compounds of the present invention are compounds 1a, 1b, 1c, 4-5, and compounds 1a, 4, 6 are preferred as RARβ agonists.
　本発明における新規レチノイド化合物は、上記一般式I～IIIで表される化合物の薬学的に許容される塩であってもよい。また、一般式I～IIIで表される化合物又はその塩において、異性体（例えば光学異性体、幾何異性体及び互換異性体）などが存在する場合は、本発明はそれらの異性体を包含し、また溶媒和物、水和物及び種々の形状の結晶を包含するものである。 The novel retinoid compound in the present invention may be a pharmaceutically acceptable salt of the compound represented by the above general formulas I to III. In addition, in the compounds represented by the general formulas I to III or salts thereof, when isomers (for example, optical isomers, geometric isomers, and compatible isomers) exist, the present invention includes these isomers. And also solvates, hydrates and crystals of various shapes.
　本発明において、薬学的に許容される塩とは、薬理学的及び製剤学的に許容される一般的な塩が挙げられる。そのような塩として、具体的には以下が例示される。
　塩基性付加塩としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩；例えばカルシウム塩、マグネシウム塩等のアルカリ土類金属塩；例えばアンモニウム塩；例えばトリメチルアミン塩、トリエチルアミン塩；ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩等の脂肪族アミン塩；たとえばＮ，Ｎ－ジベンジルエチレンジアミン等のアラルキルアミン塩；例えばピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等の複素環芳香族アミン塩；例えばテトラメチルアンモニウム塩、テトラエチルアモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第４級アンモニウム塩；アルギニン塩；リジン塩等の塩基性アミノ酸塩等が挙げられる。 In the present invention, the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts. Specific examples of such salts are as follows.
Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines. Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts For example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, Quaternary ammonium salts such as tiger butyl ammonium salt; arginine; basic amino acid salts such as lysine salts.
　酸付加塩としては、例えば塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩；例えば酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩；例えばメタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩等のスルホン酸塩；例えばアスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等を挙げることができる。 Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.
　本発明の、一般式I～IIIのいずれかで表される化合物は、RAR、中でもRARβに対し作用性、すなわち作動性もしくは拮抗性を有し、RAR作用調節剤（RARβ作用調節剤）としての機能を有する。また一般式I～IIIのいずれかで表される化合物は、それ自体がRARのリガンドとして機能してRARの転写活性化能を調節する、または、生体に投与された若しくは内因性の他のRARリガンドとRARとの相互作用を調節するものと考えられ、RARリガンド作用調節剤として使用することができる。
　さらにRARはDNAの転写に関わる核内受容体であることから、一般式I～IIIのいずれかで表される化合物は転写調節剤として使用することが可能である。
　なお、本明細書において「調節」という用語又はその類似語は、作用の増強（作動）又は抑制を含めて最も広義に解釈する必要がある。本発明の化合物が増強（作動）作用又は抑制作用のいずれを有するかは、本明細書の実験例に具体的に示した方法に従って容易に検定可能である。 The compound represented by any one of the general formulas I to III of the present invention has an action, that is, an action or an antagonistic action on RAR, particularly RARβ, and is used as a RAR action regulator (RARβ action regulator). It has a function. In addition, the compound represented by any one of the general formulas I to III itself functions as a ligand for RAR and regulates the transcriptional activation ability of RAR, or other RAR administered to the living body or endogenous. It is considered to regulate the interaction between the ligand and RAR, and can be used as a RAR ligand action regulator.
Furthermore, since RAR is a nuclear receptor involved in DNA transcription, a compound represented by any one of general formulas I to III can be used as a transcription regulator.
In the present specification, the term “modulation” or a similar term thereof should be interpreted in the broadest sense including enhancement (operation) or suppression of action. Whether the compound of the present invention has an enhancing (acting) action or an inhibitory action can be easily assayed according to the method specifically shown in the experimental examples of the present specification.
　本発明の新規レチノイド化合物のうちRARアゴニストは、レチノイドの生理作用、例えば細胞分化作用、アポトーシス作用などを有する。そのため、これらの化合物はビタミンＡ欠乏症、上皮組織の角化症、リウマチ、遅延型アレルギー、骨疾患、及び白血病やある種の癌の治療や予防に有用であると考えられる。 Among the novel retinoid compounds of the present invention, RAR agonists have physiological functions of retinoids such as cell differentiation and apoptosis. Therefore, these compounds are considered useful for the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissues, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers.
　本発明のレチノイド化合物とRXRアゴニストとは、併用して用いることもできる。RARはレチノイドX受容体（RXR）とともに機能する（非特許文献３）。RAR-RXRのヘテロダイマーは、RARアゴニストとRXRアゴニストの併用により、RARの機能が増強されるため、RARアゴニストとRXRアゴニストの併用はシナジスト効果を発揮することが知られており（非特許文献３，６）、有用である。 The retinoid compound of the present invention and the RXR agonist can be used in combination. RAR functions together with a retinoid X receptor (RXR) (Non-patent Document 3). The RAR-RXR heterodimer is known to exhibit a synergist effect when the RAR function is enhanced by the combined use of the RAR agonist and the RXR agonist (Non-patent Document 3). 6) It is useful.
　本発明の新規レチノイド化合物を含む試薬又は医薬等の組成物も、本発明の範囲に含まれる。本発明の新規レチノイド化合物を含む医薬組成物は、RARもしくはその他の核内受容体が関与する疾患の予防及び／又は治療に用いることがき、例えば、抗がん剤及び／又は抗炎症剤、抗アレルギー剤として用いることができる。 A composition such as a reagent or a medicine containing the novel retinoid compound of the present invention is also included in the scope of the present invention. The pharmaceutical composition containing the novel retinoid compound of the present invention can be used for the prevention and / or treatment of diseases involving RAR or other nuclear receptors, for example, anticancer agents and / or anti-inflammatory agents, anti-inflammatory agents, It can be used as an allergic agent.
　本発明の新規レチノイド化合物は、当該新規レチノイド化合物による治療・処理等を必要とする生体に投与して用いることが可能であるが、生体への投与量は特に限定されない。例えばレチノイン酸などのレチノイドを有効成分として含む医薬と本発明のレチノイド化合物とを併用することにより、レチノイドの作用を調節する場合、あるいは、レチノイドを含む医薬を併用せずに、生体内に既に存在するレチノイン酸の作用調節のために本発明のレチノイド化合物を投与する場合など、あらゆる投与方法において適宜の投与量が容易に選択できる。例えば、経口投与の場合には有効成分を成人一日あたり０．０１～１０００ｍｇ程度の範囲で用いることができる。レチノイドを有効成分として含む医薬と本発明の薬剤とを併用する場合には、レチノイドの投与期間中、及び／又はその前若しくは後の期間のいずれにおいても本発明の薬剤を投与することが可能である。 The novel retinoid compound of the present invention can be used by being administered to a living body that requires treatment or treatment with the novel retinoid compound, but the dose to the living body is not particularly limited. For example, by using a retinoid compound such as retinoic acid as an active ingredient in combination with the retinoid compound of the present invention to control the action of retinoid, or without using a retinoid-containing drug, it already exists in the living body. Appropriate doses can be easily selected in any administration method, such as when the retinoid compound of the present invention is administered to regulate the action of retinoic acid. For example, in the case of oral administration, the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day. When a drug containing a retinoid as an active ingredient is used in combination with the drug of the present invention, the drug of the present invention can be administered either during the retinoid administration period and / or before or after that period. is there.
　本発明の薬剤を抗がん剤として用いる場合は、上記本発明のレチノイド化合物を有効成分とする他、公知の抗がん剤を有効成分として含んでいてもよい。抗がん剤としては、エストロゲン拮抗性抗乳がん剤やタキサン系抗がん剤が挙げられ、具体的にはタモキシフェン又はタキソールなどが挙げられる。 When the agent of the present invention is used as an anticancer agent, the retinoid compound of the present invention described above may be used as an active ingredient, and a known anticancer agent may be included as an active ingredient. Examples of anticancer agents include estrogen antagonistic anti-breast cancer agents and taxane anticancer agents, and specific examples include tamoxifen or taxol.
　本発明の薬剤を抗炎症剤として用いる場合は、上記本発明のレチノイド化合物を有効成分とする他、公知の抗炎症剤を有効成分として含んでいてもよい。抗炎症剤はステロイド系であっても非ステロイド系であってもよい。非ステロイド系抗炎症剤は、アミノアリールカルボン酸誘導体類、アリール酢酸誘導体類、アリール酪酸誘導体類、アリールカルボン酸類、アリールプロピオン酸誘導体類、ピラゾール類、ピラゾロン類、サリチル酸誘導体類、チアジンカルボキサミド 類、及び他の構造を有する種類の中から選択し得る。 When the agent of the present invention is used as an anti-inflammatory agent, it may contain a known anti-inflammatory agent as an active ingredient in addition to the above-described retinoid compound of the present invention as an active ingredient. The anti-inflammatory agent may be steroidal or non-steroidal. Non-steroidal anti-inflammatory agents include aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, And other types of structures may be selected.
　本発明の薬剤を抗アレルギー剤として用いる場合は、上記本発明のレチノイド化合物を有効成分とする他、公知の抗アレルギー剤を有効成分として含んでいてもよい。抗アレルギー剤としては、メディエーター遊離抑制薬、ヒスタミンH1-拮抗薬、トロンボキサン阻害薬、ロイコトリエン拮抗薬、Th2サイトカイン阻害薬等が挙げられ、具体的には、メディエーター遊離抑制薬として、クロモグリク酸ナトリウムやトラニラスト、ヒスタミンH1-措抗薬 として、フマル酸ケトチフェンや塩酸アゼラスチン、トロンボキサン阻害薬として、塩酸オザグレル（トロンボキサンA2合成酵素阻害薬）やセラトロダスト（トロンボキサンA2拮抗薬）、ロイコトリエン拮抗薬としてプランルカスト、Th2サイトカイン阻害薬としてトシル酸スプラタストなどが挙げられる。 When the agent of the present invention is used as an antiallergic agent, the retinoid compound of the present invention described above may be used as an active ingredient, and a known antiallergic agent may be included as an active ingredient. Antiallergic agents include mediator release inhibitors, histamine H1-antagonists, thromboxane inhibitors, leukotriene antagonists, Th2 cytokine inhibitors, etc., specifically, mediator release inhibitors such as sodium cromoglycate and Tranilast, histamine H1-anti-antagonist, ketotifen fumarate, azelastine hydrochloride, thromboxane inhibitor, ozagrel hydrochloride (thromboxane A2 synthase inhibitor), seratrodast (thromboxane A2 antagonist), pranluca as leukotriene antagonist And sulatast tosilate as Th2 cytokine inhibitors.
　本発明の薬剤として、本発明の化合物から選ばれる１種又は２種以上の物質をそのまま投与してもよいが、好ましくは、上記の物質の１種又は２種以上を含む、経口用あるいは非経口用の医薬組成物として投与することが好ましい。経口用あるいは非経口用の医薬組成物は、当業者に利用可能な製剤用添加物、即ち薬理学的及び製剤学的に許容しうる担体を用いて製造することができる。例えば、レチノイン酸などのレチノイドを有効成分として含む医薬に上記の物質の１種又は２種以上を配合して、いわゆる合剤の形態の医薬組成物として用いることもできる。 As the drug of the present invention, one or more substances selected from the compounds of the present invention may be administered as they are, but preferably, one or more of the above substances are used orally or non-containing. It is preferably administered as an oral pharmaceutical composition. Oral or parenteral pharmaceutical compositions can be prepared using pharmaceutical additives available to those skilled in the art, that is, pharmacologically and pharmaceutically acceptable carriers. For example, one or more of the above substances can be blended in a medicine containing a retinoid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called mixture.
　経口投与に適する医薬用組成物としては、例えば、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤等を挙げることができ、非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、坐剤、吸入剤、点眼剤、点鼻剤、軟膏剤、クリーム剤、及び貼付剤等を挙げることができる。上記の医薬組成物の製造に用いられる薬理学的及び製剤学的に許容しうる担体としては、例えば、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤、コーティング剤、色素、希釈剤、基剤、溶解剤ないし溶解補助剤、等張化剤、ｐＨ調節剤、安定化剤、噴射剤、及び粘着剤等を挙げることができる。 Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes For example, injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like can be mentioned. Examples of pharmacologically and pharmaceutically acceptable carriers used in the production of the above pharmaceutical composition include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, Diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be mentioned.
　本明細書の実施例に、本発明の式Iに示される好ましい化合物の製造方法を具体的に説明する。これらの製造方法において用いられた出発原料及び試薬、並びに反応条件などを適宜修飾ないし改変することにより、本発明の範囲に包含される化合物はいずれも製造可能である。本発明の化合物の製造方法は、実施例に具体的に説明されたものに限定されるものではない。 In the examples of the present specification, a method for producing a preferable compound represented by the formula I of the present invention will be specifically described. Any of the compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials and reagents used in these production methods and reaction conditions. The manufacturing method of the compound of this invention is not limited to what was specifically demonstrated by the Example.
　以下、本発明を実施例によりさらに具体的に説明するが、本発明は下記の実施例の範囲に限定されることはない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the scope of the following examples.
　[実施例１]目的化合物１ａ～１ｃの合成
　本実施例における製造方法のスキームを図１～図３に示した。 [Example 1] Synthesis of target compounds 1a to 1c The scheme of the production method in this example is shown in Figs.
　１）中間体１の合成
　濃塩酸（３５０ｍＬ）に２，５‐ジメチル‐２，５‐ヘキサンジオール（２６ｇ、１７５ｍｍｏｌ）を溶解させた後、室温で激しく１５分攪拌した。生じた沈澱を濾取した後、ジクロロメタン（３００ｍＬ）に再溶解させた。有機層を水（２００ｍＬ×２）で洗浄し、無水硫酸マグネシウムで乾燥させた。減圧下にて溶媒留去し、白色結晶の中間体１（２９ｇ、９０％）を得た。 1) Synthesis of Intermediate 1 2,5-Dimethyl-2,5-hexanediol (26 g, 175 mmol) was dissolved in concentrated hydrochloric acid (350 mL) and then vigorously stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration and redissolved in dichloromethane (300 mL). The organic layer was washed with water (200 mL × 2) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Intermediate 1 (29 g, 90%) of white crystals.
　２）中間体２の合成
　中間体１（５．７ｇ、３０ｍｍｏｌ）を無水ベンゼン（１３０ｍＬ）に溶解後、塩化アルミニウム（０．４ｇ、３．１ｍｍｏｌ）を加え、２４時間加熱還流した。１００ｍＬの氷水にあけ、ｎ－ヘキサン（１００ｍＬ×２）で抽出した。有機層を水（１００ｍＬ×２）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、減圧蒸留（１２７℃、３０ｍｍＨｇ）により無色オイルの中間体２（４．３ｇ、７４％）を得た。 2) Synthesis of Intermediate 2 Intermediate 1 (5.7 g, 30 mmol) was dissolved in anhydrous benzene (130 mL), aluminum chloride (0.4 g, 3.1 mmol) was added, and the mixture was heated to reflux for 24 hours. The mixture was poured into 100 mL of ice water and extracted with n-hexane (100 mL × 2). The organic layer was washed with water (100 mL × 2) and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, colorless oil intermediate 2 (4.3 g, 74%) was obtained by distillation under reduced pressure (127 ° C., 30 mmHg).
　1H NMR (300 MHz, CDCl3) δ :7.33-7.11 (m, 4 H), 1.69 (s, 4 H), 1.28 (s, 12 H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.33-7.11 (m, 4 H), 1.69 (s, 4 H), 1.28 (s, 12 H).
　３）中間体３の合成
　濃硝酸（１２ｍＬ）と濃硫酸（１８ｍＬ）を混合し、－１０℃に保ちながら中間体２（１１ｇ、５９ｍｍｏｌ）を滴下し４０分攪拌した。ＴＬＣプレート（ｎ‐ヘキサン）により反応の終了を確認した後、飽和炭酸水素ナトリウム水溶液（１００ｍＬ）にあけ、酢酸エチル（５０ｍＬ×４）で抽出した。有機層を水（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧にて溶媒留去し、フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ-ヘキサン＝１：１００）を行い、淡黄色結晶の中間体３（１１ｇ、８３％）を得た。 3) Synthesis of Intermediate 3 Concentrated nitric acid (12 mL) and concentrated sulfuric acid (18 mL) were mixed, and while maintaining at −10 ° C., Intermediate 2 (11 g, 59 mmol) was added dropwise and stirred for 40 minutes. After confirming the completion of the reaction with a TLC plate (n-hexane), the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (100 mL) and extracted with ethyl acetate (50 mL × 4). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 100) was performed to obtain a pale yellow crystalline intermediate 3 (11 g, 83%).
　1H NMR (300 MHz, CDCl3) δ :8.18 (d, 1 H, J = 2.5 Hz), 7.95 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.44 (d, 1 H,J = 8.5 Hz), 1.73 (s, 4 H), 1.33 (s, 6 H), 1.31 (s, 6 H). 1 H NMR (300 MHz, CDCl 3 ) δ: 8.18 (d, 1 H, J = 2.5 Hz), 7.95 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.44 (d, 1 H, J = 8.5 Hz), 1.73 (s, 4 H), 1.33 (s, 6 H), 1.31 (s, 6 H).
　４）中間体４の合成
　中間体３（４．７ｇ、２０ｍｍｏｌ）を酢酸エチル（２０ｍＬ）に溶解後、１０％パラジウム活性化炭素（触媒量）を加え、１時間水素雰囲気下で室温攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：１０）で反応終了を確認後、セライト濾過を行った。減圧下で溶媒留去することで白色結晶の中間体４（４．１ｇ、ｑ．ｙ．）を得た。 4) Synthesis of Intermediate 4 Intermediate 3 (4.7 g, 20 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium-activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 10), Celite filtration was performed. The solvent was distilled off under reduced pressure to obtain intermediate 4 (4.1 g, qy.) Of white crystals.
　1H NMR (300 MHz, CDCl3) δ :7.11 (d, 1 H, J = 8.5 Hz), 6.66 (d, 1 H, J = 2.5 Hz), 6.54 (dd, 1 H, J = 8.5 Hzand 2.5 Hz), 3.81 (R s, 2 H), 1.65 (s, 4 H), 1.25 (s, 6 H), 1.23 (s, 6 H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.11 (d, 1 H, J = 8.5 Hz), 6.66 (d, 1 H, J = 2.5 Hz), 6.54 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 3.81 (R s, 2 H), 1.65 (s, 4 H), 1.25 (s, 6 H), 1.23 (s, 6 H).
　５）中間体５の合成
　4-ヒドロキシ桂皮酸（１．６ｇ、１０．０ｍｍｏｌ）を無水メタノール（２０．０ｍＬ）に溶解し、濃硫酸（２．０ｍＬ）を攪拌しながら加え、１００℃で１０時間３０分還流した。ＴＬＣ（酢酸エチル：ｎ－ヘキサン＝１：２）で反応の進行を確認した後、反応を停止させ、減圧下にて溶媒留去した。炭酸水素ナトリウム水溶液（５０ｍＬ）を加えて中和し、水（５０ｍＬ）にあけ、酢酸エチル（６０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ×２）、飽和食塩水（８０ｍＬ）で洗浄した。硫酸マグネシウムで乾燥、減圧下にて溶媒留去し、白色の粗生成物（１．８ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：４→１：３→１：２）を行い、白色結晶の中間体５（１．５ｇ、８５％）を得た。 5) Synthesis of Intermediate 5 4-Hydroxycinnamic acid (1.6 g, 10.0 mmol) was dissolved in anhydrous methanol (20.0 mL) and concentrated sulfuric acid (2.0 mL) was added with stirring. Refluxed for 30 minutes. After confirming the progress of the reaction by TLC (ethyl acetate: n-hexane = 1: 2), the reaction was stopped and the solvent was distilled off under reduced pressure. Sodium hydrogen carbonate aqueous solution (50 mL) was added to neutralize, poured into water (50 mL), and extracted with ethyl acetate (60 mL × 3). The organic layer was washed with water (80 mL × 2) and saturated brine (80 mL). The extract was dried over magnesium sulfate and evaporated under reduced pressure to give a white crude product (1.8 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 4 → 1: 3 → 1: 2) was performed to obtain Intermediate 5 (1.5 g, 85%) of white crystals.
　1H NMR (300 MHz, CDCl3) δ :7.64 (d, 1H, J = 16.0 Hz), 7.44 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz),6.31 (d, 1H, J = 16.0 Hz), 5.14 (s, 1H), 3.80 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.64 (d, 1H, J = 16.0 Hz), 7.44 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 6.31 ( d, 1H, J = 16.0 Hz), 5.14 (s, 1H), 3.80 (s, 3H).
　６）中間体６の合成
　中間体５（８９０．９ｍｇ、５．０ｍｍｏｌ）を無水ジクロロメタン（１０．０ｍＬ）に溶解し、氷冷下で無水ピリジン（１．２ｍＬ）を加え、アルゴン雰囲気下で撹拌した。トリフルオロメタンスルホン酸無水物（１．２ｍＬ、７．５ｍｍｏｌ）を滴下し、氷冷下で２０分撹拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、２規定の塩酸（５０ｍＬ）にあけ、ジクロロメタン（３０ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×２）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒留去し、白色オイル状の粗生成物（１．６ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：５）を行い、無色針状結晶の中間体６（１．６ｇ、ｑ．ｙ．）を得た。 6) Synthesis of Intermediate 6 Intermediate 5 (890.9 mg, 5.0 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), anhydrous pyridine (1.2 mL) was added under ice cooling, and the mixture was stirred under an argon atmosphere. did. Trifluoromethanesulfonic anhydride (1.2 mL, 7.5 mmol) was added dropwise and stirred for 20 minutes under ice cooling. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was poured into 2N hydrochloric acid (50 mL) and extracted with dichloromethane (30 mL × 3). The organic layer was washed with water (100 mL × 2) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white oily crude product (1.6 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 5) was performed to obtain colorless needle crystal intermediate 6 (1.6 g, qy).
　1H NMR (300 MHz, CDCl3) δ :7.64 (d, 1H, J = 16.0 Hz), 7.61 (dd, 2H, J = 7.0 Hz and 2.0 Hz), 7.31 (dd, 2H,J = 7.0 Hz and 2.0 Hz), 6.44 (d, 1H, J = 16.0 Hz), 3.83 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.64 (d, 1H, J = 16.0 Hz), 7.61 (dd, 2H, J = 7.0 Hz and 2.0 Hz), 7.31 (dd, 2H, J = 7.0 Hz and 2.0 Hz), 6.44 (d, 1H, J = 16.0 Hz), 3.83 (s, 3H).
　７）中間体７の合成
　中間体６（３１０．３ｍｇ、１．０ｍｍｏｌ）、中間体４（２８４．７ｍｇ、１．４ｍｍｏｌ）を無水ジオキサン（３．０ｍＬ）に溶解後、（±）‐２，２’‐ビス（ジフェニルホスフィノ）‐１，１’‐ビナフチル（４６．７ｍｇ、０．０７５ｍｍｏｌ）、炭酸セシウム（４５６．２ｍｇ、１．４ｍｍｏｌ）、酢酸パラジウム（II）（１１．２ｍｇ、０．０５ｍｍｏｌ）を加え２時間加熱還流した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、セライト濾過を行い、２規定の塩酸（２０ｍＬ）、水（５０ｍＬ）にあけ洗浄した。有機層を水（７０ｍＬ）、飽和食塩水（７０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、茶色オイル状の粗生成物（７２１．８ｍｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ‐ヘキサン＝１：８）を行い、黄色針状結晶の中間体７（３５４．５ｍｇ、９８％）を得た。 7) Synthesis of Intermediate 7 Intermediate 6 (310.3 mg, 1.0 mmol) and Intermediate 4 (284.7 mg, 1.4 mmol) were dissolved in anhydrous dioxane (3.0 mL), (±) -2, 2'-bis (diphenylphosphino) -1,1'-binaphthyl (46.7 mg, 0.075 mmol), cesium carbonate (456.2 mg, 1.4 mmol), palladium (II) acetate (11.2 mg, 0. 05 mmol) was added and heated to reflux for 2 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was filtered through Celite, washed in 2N hydrochloric acid (20 mL) and water (50 mL) and washed. The organic layer was washed with water (70 mL) and saturated brine (70 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily crude product (721.8 mg). Flash column chromatography (ethyl acetate: n-hexane = 1: 8) was performed to obtain yellow needle crystal intermediate 7 (354.5 mg, 98%).
　1H NMR (300 MHz, CDCl3) δ7.63 (d, 1 H, J = 16.0 Hz), 7.40 (d, 2 H, J = 8.5 Hz), 7.24 (s, 1 H), 7.07 (d,1 H, J = 2.5 Hz), 6.97-6.94 (m, 3 H), 6.26 (s, 3 H), 3.79 (s, 4 H), 1.69 (s, 4H), 1.28 (s, 6 H), 1.27 (s, 6 H). 1 H NMR (300 MHz, CDCl 3 ) δ7.63 (d, 1 H, J = 16.0 Hz), 7.40 (d, 2 H, J = 8.5 Hz), 7.24 (s, 1 H), 7.07 (d, 1 H, J = 2.5 Hz), 6.97-6.94 (m, 3 H), 6.26 (s, 3 H), 3.79 (s, 4 H), 1.69 (s, 4H), 1.28 (s, 6 H), 1.27 (s, 6 H).
　８）目的化合物１ａの合成
　中間体７（２１８．０ｍｇ、０．６ｍｍｏｌ）をメタノール（１５．０ｍＬ）、テトラヒドロフラン（４．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（５．０ｍＬ）を加え、６０℃で１時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：２）で反応終了を確認後、減圧下で濃縮を行い、２規定の塩酸（７０ｍＬ）にあけ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、酢酸エチル／ｎ‐ヘキサンで再結晶を行い、黄色針状結晶の目的化合物１ａ（１７３．５ｍｇ、８３％）を得た。 8) Synthesis of target compound 1a Intermediate 7 (218.0 mg, 0.6 mmol) was dissolved in methanol (15.0 mL) and tetrahydrofuran (4.0 mL), and then 2N aqueous sodium hydroxide solution (5.0 mL) was added. In addition, the mixture was heated and stirred at 60 ° C. for 1 hour. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the mixture was concentrated under reduced pressure, poured into 2N hydrochloric acid (70 mL), and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound 1a (173.5 mg, 83%) as yellow needle crystals.
　1H NMR (300 MHz, DMSO-d6) δ 12.02 (Rs, 1 H), 8.44 (s, 1 H), 7.48 (d, 2 H J = 8.5 Hz), 7.46 (d, 1 H, J = 16.0 Hz),7.23 (d, 1 H, J = 8.5 Hz), 7.01 (d, 1 H, J = 2.5 Hz), 6.96 (d, 2 H, J = 8.5Hz), 6.92 (d, 1 H, J = 2.5 Hz), 6.23 (d, 1 H, J = 16.0 Hz), 1.64 (s, 4 H), 1.23(s, 12 H).
　Anal. Calcd for C23H27NO2 : C,79.05; H, 7.79; N, 4.01. Found: C, 79.15; H, 7.86; N, 3.97.
　MS : FAB-MS m/z: 349 [M]+, 350 [M + H]+,
　Mp : 241.5-242.8 ℃ 1 H NMR (300 MHz, DMSO-d6) δ 12.02 (Rs, 1 H), 8.44 (s, 1 H), 7.48 (d, 2 HJ = 8.5 Hz), 7.46 (d, 1 H, J = 16.0 Hz ), 7.23 (d, 1 H, J = 8.5 Hz), 7.01 (d, 1 H, J = 2.5 Hz), 6.96 (d, 2 H, J = 8.5 Hz), 6.92 (d, 1 H, J = 2.5 Hz), 6.23 (d, 1 H, J = 16.0 Hz), 1.64 (s, 4 H), 1.23 (s, 12 H).
Anal. Calcd for C 23 H 27 NO 2 : C, 79.05; H, 7.79; N, 4.01. Found: C, 79.15; H, 7.86; N, 3.97.
MS: FAB-MS m / z: 349 [M] + , 350 [M + H] + ,
Mp: 241.5-242.8 ℃
　９）目的化合物１ｂの合成
　水素化ナトリウム（６０％ in オイル）（９．６ｍｇ、０．２４ｍｍｏｌ）をｎ－ヘキサンで洗浄後に無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を加えて懸濁させ、氷冷下で中間体７（７１．０ｍｇ、０．２０ｍｍｏｌ）を加えて５分間攪拌した。その後、ヨードメタン（１４．９μＬ、０．２４ｍｍｏｌ）を加えて室温で１５分攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：４）で反応終了を確認後、反応液を２規定の塩酸（７０ｍＬ）にあけ、酢酸エチル（４０ｍＬ×３）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（７０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒留去し、黄色オイル状の粗生成物（５６．２ｍｇ）を得ることで、次の反応に使用した。
　粗生成物（５６．２ｍｇ）をメタノール（７．０ｍＬ）、テトラヒドロフラン（２．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（２．５ｍＬ）を加え、６０℃で１．５時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、２規定の塩酸を用いて中和した後、水（７０ｍＬ）にあけ、酢酸エチル（６０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ×２）、飽和食塩水（８０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、ジクロロメタン／ｎ‐ヘキサンで再結晶を行い、黄色針状結晶の目的化合物１ｂ（５９．３ｍｇ、８４％）を得た。 9) Synthesis of target compound 1b Sodium hydride (60% in oil) (9.6 mg, 0.24 mmol) was washed with n-hexane and suspended in anhydrous N, N-dimethylformamide (2.0 mL). Intermediate 7 (71.0 mg, 0.20 mmol) was added under ice cooling, and the mixture was stirred for 5 minutes. Then, iodomethane (14.9 μL, 0.24 mmol) was added and stirred at room temperature for 15 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 4), the reaction mixture was poured into 2N hydrochloric acid (70 mL) and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with water (70 mL × 2) and saturated brine (70 mL), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a yellow oily crude product (56.2 mg), which was used for the next reaction.
The crude product (56.2 mg) was dissolved in methanol (7.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (2.5 mL) was added, and the mixture was stirred with heating at 60 ° C. for 1.5 hr. did. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), neutralized with 2N hydrochloric acid, poured into water (70 mL), and extracted with ethyl acetate (60 mL × 3). . The organic layer was washed with water (80 mL × 2) and saturated brine (80 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound 1b (59.3 mg, 84%) as yellow needle crystals.
　1H NMR (500 MHz, CDCl3) δ :7.70 (d, 1 H, J = 16.0 Hz), 7.38 (d, 2 H J = 9.0 Hz), 7.30 (d, 1 H, J = 8.5Hz), 7.12 (d, 1 H, J = 2.5 Hz), 6.94 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.76 (d,2 H, J = 9.0 Hz), 6.22 (d, 1 H, J = 16.0 Hz), 3.34 (s, 3 H), 1.70 (s, 4 H),1.30 (s, 6 H), 1.25 (s, 6 H).
　Anal. Calcd for C24H29NO2　・・・5H2O : C, 78.52; H, 8.07; N, 3.82. Found: C, 78.57; H,8.16; N, 3.83.
　MS : FAB-MS m/z: 363 [M]+, 364 [M + H]+ 1 H NMR (500 MHz, CDCl 3 ) δ: 7.70 (d, 1 H, J = 16.0 Hz), 7.38 (d, 2 HJ = 9.0 Hz), 7.30 (d, 1 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 2.5 Hz), 6.94 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.76 (d, 2 H, J = 9.0 Hz), 6.22 (d, 1 H, J = 16.0 Hz), 3.34 (s, 3 H), 1.70 (s, 4 H), 1.30 (s, 6 H), 1.25 (s, 6 H).
Anal. Calcd for C 24 H 29 NO 2・ ・ ・ 5H 2 O: C, 78.52; H, 8.07; N, 3.82. Found: C, 78.57; H, 8.16; N, 3.83.
MS: FAB-MS m / z: 363 [M] + , 364 [M + H] +
　１０）目的化合物１ｃの合成
　水素化ナトリウム（６０％ in オイル）（１４．１ｍｇ、０．３６ｍｍｏｌ）を ｎ－ヘキサンで洗浄後に無水Ｎ，Ｎ－ジメチルホルムアミド（３．０ｍＬ）を加えて懸濁させ、氷冷下で中間体７（１０９．０ｍｇ、０．３０ｍｍｏｌ）を加えて３０分間攪拌した。その後、ヨードエタン（２８．８μＬ、０．３６ｍｍｏｌ）を加えて室温で１時間攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：５）で反応終了を確認後、反応液を２規定の塩酸（１００ｍＬ）にあけ、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（７０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒留去し、黄色結晶の粗生成物（１７９．０ｍｇ）を得た。
　粗生成物（１７９．０ｍｇ）をメタノール（７．０ｍＬ）、テトラヒドロフラン（２．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（３．０ｍＬ）を加え、６０℃で１．５時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：５）で反応終了を確認後、２規定の塩酸を用いて中和した後、水（８０ｍＬ）にあけ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ×２）、飽和食塩水（８０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、酢酸エチル／ｎ‐ヘキサンで再結晶を行い、黄色針状結晶の目的化合物１ｃ（６７．７ｍｇ、６０％）を得た。 10) Synthesis of target compound 1c Sodium hydride (60% in oil) (14.1 mg, 0.36 mmol) was washed with n-hexane and then suspended in anhydrous N, N-dimethylformamide (3.0 mL). Under ice cooling, Intermediate 7 (109.0 mg, 0.30 mmol) was added and stirred for 30 minutes. Then, iodoethane (28.8 μL, 0.36 mmol) was added and stirred at room temperature for 1 hour. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into 2N hydrochloric acid (100 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (70 mL × 2) and saturated brine (70 mL), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (179.0 mg) of yellow crystals.
The crude product (179.0 mg) was dissolved in methanol (7.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 1.5 hr. did. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), neutralized with 2N hydrochloric acid, poured into water (80 mL), and extracted with ethyl acetate (50 mL × 3). . The organic layer was washed with water (80 mL × 2) and saturated brine (80 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound 1c (67.7 mg, 60%) as yellow needle crystals.
　1H NMR (300 MHz, DMSO-d6) δ : 12.00 (Rs, 1 H), 7.47-7.35 (m, 3 H), 7.23 (d, 1 H, J = 2.5 Hz), 6.94 (dd, 1 H, J = 8.5Hz and 2.5 Hz), 6.66 (d, 2 H, J = 9.0 Hz), 6.20 (d, 1 H, J = 16.0 Hz), 3.74 (q,2 H, J = 7.0 Hz), 1.66 (s, 4 H), 1.27 (s, 6 H), 1.22 (s, 6 H) 1.14 (t, 3 H, J =7.0 Hz).
　Anal. Calcd for C25H31NO2 : C,79.54; H, 8.28; N, 3.71. Found: C, 79.41; H, 8.45; N, 3.64.
　MS : FAB-MS m/z: 377 [M]+, 378 [M + H]+ 1 H NMR (300 MHz, DMSO-d6) δ: 12.00 (Rs, 1 H), 7.47-7.35 (m, 3 H), 7.23 (d, 1 H, J = 2.5 Hz), 6.94 (dd, 1 H , J = 8.5Hz and 2.5 Hz), 6.66 (d, 2 H, J = 9.0 Hz), 6.20 (d, 1 H, J = 16.0 Hz), 3.74 (q, 2 H, J = 7.0 Hz), 1.66 (s, 4 H), 1.27 (s, 6 H), 1.22 (s, 6 H) 1.14 (t, 3 H, J = 7.0 Hz).
Anal. Calcd for C 25 H 31 NO 2 : C, 79.54; H, 8.28; N, 3.71. Found: C, 79.41; H, 8.45; N, 3.64.
MS: FAB-MS m / z: 377 [M] + , 378 [M + H] +
　[実施例２]目的化合物２の合成
　目的化合物２は、実質上、ＷＯ２００８／１０５３８６の記載に従って合成した。製造方法のスキームを図４に示す。 [Example 2] Synthesis of target compound 2 The target compound 2 was synthesized substantially as described in WO2008 / 105386. A scheme of the production method is shown in FIG.
　１）中間体９の合成
　２－イソプロピルアニリン（２．７ｇ、２０．０ｍｍｏｌ）、濃硫酸（５ｍＬ）を氷浴上で冷却しながら混合し、混酸 （濃硝酸：濃硫酸＝２：５、７ｍＬ）を０℃より昇温しないように加えた。その後ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：２）で反応の終了を確認した。２規定の水酸化ナトリウム水溶液で中和した後、酢酸エチル（７０ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×２）、飽和食塩水（５０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、濃橙色のオイル状の中間体９（２．９ｇ、８１％）を得た。 1) Synthesis of Intermediate 9 2-Isopropylaniline (2.7 g, 20.0 mmol) and concentrated sulfuric acid (5 mL) were mixed while cooling on an ice bath, and mixed acid (concentrated nitric acid: concentrated sulfuric acid = 2: 5, 7 mL). ) Was added so as not to raise the temperature from 0 ° C. Thereafter, the completion of the reaction was confirmed on a TLC plate (ethyl acetate: n-hexane = 1: 2). The mixture was neutralized with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (70 mL × 3). The organic layer was washed with water (100 mL × 2) and saturated brine (50 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a deep orange oily intermediate 9 (2.9 g, 81%).
　1H NMR (500 MHz, CDCl3) δ :7.60 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.50 (d, 1 H, J = 2.5 Hz), 7.24 (d, 1 H,J = 8.5 Hz), 3.95 (R s, 2 H), 2.90 (sept, 1 H, J = 7.0 Hz), 1.29 (d, 6 H, J =7.0 Hz). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.60 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.50 (d, 1 H, J = 2.5 Hz), 7.24 (d, 1 H, J = 8.5 Hz), 3.95 (R s, 2 H), 2.90 (sept, 1 H, J = 7.0 Hz), 1.29 (d, 6 H, J = 7.0 Hz).
　２）中間体１０の合成
　中間体９（２．９ｇ、１６．０ｍｍｏｌ）を水（２０．０ｍＬ）と濃硫酸（４．０ｍＬ）に攪拌しながら混合し、０～５℃まで温度を下げ、そこへ４．５Ｍの亜硝酸ナトリウム水溶液（４．０ｍＬ）を５℃以上に昇温しないようにしながら滴下し、攪拌した。ヨウ化カリウムデンプン紙により、反応の進行状況を確認した後、１２０℃の熱浴 （濃硫酸：水＝４：３、７ｍＬ）に滴下した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：５）により反応の終了を確認後、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（５０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、黒色オイル状の残渣（２．７ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル： ｎ－ヘキサン＝１：５）を行い、橙色オイル状の中間体９（２．２ｇ、７５％）を得た。 2) Synthesis of Intermediate 10 Intermediate 9 (2.9 g, 16.0 mmol) was mixed with water (20.0 mL) and concentrated sulfuric acid (4.0 mL) with stirring, and the temperature was lowered to 0-5 ° C. A 4.5 M sodium nitrite aqueous solution (4.0 mL) was added dropwise thereto while preventing the temperature from rising to 5 ° C. or higher and stirred. After confirming the progress of the reaction with potassium iodide starch paper, it was added dropwise to a 120 ° C. hot bath (concentrated sulfuric acid: water = 4: 3, 7 mL). After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (70 mL × 2) and saturated brine (50 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a black oily residue (2.7 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 5) was performed to obtain an orange oily intermediate 9 (2.2 g, 75%).
　1H NMR (500 MHz, CDCl3) δ :7.78 (dd, 1 H, J = 8.5 Hz and 2.0 Hz), 7.63 (d, 1 H, J = 2.0 Hz), 7.33 (d, 1 H,J = 8.5 Hz), 5.35 (s, 1 H), 3.31 (sept, 1 H, J = 7.0 Hz), 1.28 (d, 6 H, J = 7.0Hz). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.78 (dd, 1 H, J = 8.5 Hz and 2.0 Hz), 7.63 (d, 1 H, J = 2.0 Hz), 7.33 (d, 1 H, J = 8.5 Hz), 5.35 (s, 1 H), 3.31 (sept, 1 H, J = 7.0 Hz), 1.28 (d, 6 H, J = 7.0 Hz).
　３）中間体１１の合成
　中間体１０（２．２ｇ、１２．０ｍｍｏｌ）を無水Ｎ，Ｎ-ジメチルホルムアミド（６．０ｍＬ）に溶解し、炭酸カリウム（３．３ｇ、２４．０ｍｍｏｌ）、２－ブロモプロパン（１．７ｍＬ、１８．０ｍｍｏｌ）、ヨウ化カリウム適量を攪拌しながら混合し、１．５時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：１０）により反応の終了を確認後、水（７０ｍＬ）にあけ、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×２）、飽和食塩水（４０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、橙色オイル状の粗生成物（２．３ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：１０）を行い、黄色澄明なオイル状の中間体１１（２．２ｇ、８３％）を得た。 3) Synthesis of Intermediate 11 Intermediate 10 (2.2 g, 12.0 mmol) was dissolved in anhydrous N, N-dimethylformamide (6.0 mL), potassium carbonate (3.3 g, 24.0 mmol), 2- Bromopropane (1.7 mL, 18.0 mmol) and an appropriate amount of potassium iodide were mixed with stirring, and heated and stirred for 1.5 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 10), the reaction mixture was poured into water (70 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (50 mL × 2) and saturated brine (40 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an orange oily crude product (2.3 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 10) was performed to obtain a yellow clear oily intermediate 11 (2.2 g, 83%).
　1H NMR (500 MHz, CDCl3) δ :7.76 (dd, 1 H, J = 8.0 Hz and 2.0 Hz), 7.66 (d, 1 H, J = 2.0 Hz), 7.31 (d, 1 H,J = 8.0 Hz), 4.67 (sept, 1 H, J = 6.0 Hz), 3.36 (sept, 1 H, J = 7.0 Hz), 1.34(d, 6 H, J = 6.0 Hz), 1.22 (d, 6 H, J = 7.0 Hz). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.76 (dd, 1 H, J = 8.0 Hz and 2.0 Hz), 7.66 (d, 1 H, J = 2.0 Hz), 7.31 (d, 1 H, J = 8.0 Hz), 4.67 (sept, 1 H, J = 6.0 Hz), 3.36 (sept, 1 H, J = 7.0 Hz), 1.34 (d, 6 H, J = 6.0 Hz), 1.22 (d, 6 H, J = 7.0 Hz).
　４）中間体１２の合成
　中間体１１（２．２ｇ、１０ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、濃塩酸（０．５ｍＬ）、パラジウム炭素を適量加え、水素雰囲気下室温で１．５時間攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：１０）により反応の終了を確認した後、セライトろ過を行い、減圧下にて溶媒留去し、薄茶色板状結晶の中間体１２（１．６ｇ、８２％）を得た。 4) Synthesis of Intermediate 12 Intermediate 11 (2.2 g, 10 mmol) was dissolved in methanol (20 mL), concentrated hydrochloric acid (0.5 mL) and appropriate amounts of palladium on carbon were added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. did. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 10), the reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a light brown plate crystal intermediate 12 (1.6 g). 82%).
　1H NMR (500 MHz, DMSO-d6) δ : 9.84 (Rs, 2 H), 7.24 (d, 1 H, J = 8.0 Hz), 6.97 (s, 1 H), 6.85 (d, 1 H, J = 8.0 Hz),4.53 (sept, 1 H, J = 6.0 Hz), 3.20 (sept, 1 H, J = 7.0 Hz), 1.31 (d, 6 H, J =6.0 Hz), 1.15 (d, 6 H, J = 7.0 Hz). 1 H NMR (500 MHz, DMSO-d6) δ: 9.84 (Rs, 2 H), 7.24 (d, 1 H, J = 8.0 Hz), 6.97 (s, 1 H), 6.85 (d, 1 H, J = 8.0 Hz), 4.53 (sept, 1 H, J = 6.0 Hz), 3.20 (sept, 1 H, J = 7.0 Hz), 1.31 (d, 6 H, J = 6.0 Hz), 1.15 (d, 6 H , J = 7.0 Hz).
　５）中間体１３の合成
　中間体６（２０９．５ｍｇ、０．６７ｍｍｏｌ）、中間体１２（２１６．０ｍｇ、０．９４ｍｍｏｌ）を無水ジオキサン（１．４ｍＬ）に溶解後、（±）‐２，２'‐ビス（ジフェニルホスフィノ）‐１，１'‐ビナフチル（３１．５ｍｇ、０．０５ｍｍｏｌ）、炭酸セシウム（６５１．６ｍｇ、２．０ｍｍｏｌ）、酢酸パラジウム（II）（７．５８ｍｇ、０．０３４ｍｍｏｌ）を加え２時間加熱還流した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、セライト濾過を行った。減圧下にて溶媒留去し、２規定の塩酸（８０ｍＬ）にあけ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ×２）、飽和食塩水（８０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、茶色オイル状の粗生成物（４４４．４ｍｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ‐ヘキサン＝１：８）を行い、黄色針状結晶の中間体１３（１５７．３ｍｇ、６６％）を得た。 5) Synthesis of Intermediate 13 Intermediate 6 (209.5 mg, 0.67 mmol) and Intermediate 12 (216.0 mg, 0.94 mmol) were dissolved in anhydrous dioxane (1.4 mL), and (±) -2. 2'-bis (diphenylphosphino) -1,1'-binaphthyl (31.5 mg, 0.05 mmol), cesium carbonate (651.6 mg, 2.0 mmol), palladium (II) acetate (7.58 mg, .0. 034 mmol) was added and heated to reflux for 2 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), Celite filtration was performed. The solvent was distilled off under reduced pressure, poured into 2N hydrochloric acid (80 mL), and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (80 mL × 2) and saturated brine (80 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily crude product (444.4 mg). Flash column chromatography (ethyl acetate: n-hexane = 1: 8) was performed to obtain yellow needle crystal intermediate 13 (157.3 mg, 66%).
　1H NMR (500 MHz, CDCl3) δ :7.61 (d, 1 H, J = 16.0 Hz), 7.24 (d, 2 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0Hz), 6.95 (d, 2 H, J = 8.5 Hz), 6.68 (dd, 1 H, J = 8.0 Hz and 2.0 Hz), 6.65 (d,1 H, J = 2.0 Hz), 6.26 (d, 1 H, J = 16.0 Hz), 5.84 (R s, 1 H), 4.47 (sept, 1 H,J = 6.0 Hz), 3.78 (s, 3 H), 3.26 (sept, 1 H, J = 7.0 Hz), 1.34 (d, 6 H, J = 6.0Hz), 1.20 (d, 6 H, J = 7.0 Hz). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.61 (d, 1 H, J = 16.0 Hz), 7.24 (d, 2 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0 Hz) , 6.95 (d, 2 H, J = 8.5 Hz), 6.68 (dd, 1 H, J = 8.0 Hz and 2.0 Hz), 6.65 (d, 1 H, J = 2.0 Hz), 6.26 (d, 1 H, J = 16.0 Hz), 5.84 (R s, 1 H), 4.47 (sept, 1 H, J = 6.0 Hz), 3.78 (s, 3 H), 3.26 (sept, 1 H, J = 7.0 Hz), 1.34 (d, 6 H, J = 6.0 Hz), 1.20 (d, 6 H, J = 7.0 Hz).
　６）目的化合物２の合成
　中間体１３（６０．１ｍｇ、０．１７ｍｍｏｌ）をメタノール（７．０ｍＬ）、テトラヒドロフラン（２．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（３．０ｍＬ）を加え、６０℃で１時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、２規定の塩酸を用いて中和した後、水（６０ｍＬ）にあけ、酢酸エチル（４０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ・２）、飽和食塩水（８０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、ジクロロメタン／ｎ‐ヘキサンで再結晶を行い、黄色針状結晶の目的化合物２（５２．５ｍｇ、９１％）を得た。 6) Synthesis of target compound 2 Intermediate 13 (60.1 mg, 0.17 mmol) was dissolved in methanol (7.0 mL) and tetrahydrofuran (2.0 mL), and then 2N aqueous sodium hydroxide solution (3.0 mL) was added. In addition, the mixture was heated and stirred at 60 ° C. for 1 hour. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was neutralized with 2N hydrochloric acid, poured into water (60 mL), and extracted with ethyl acetate (40 mL × 3). . The organic layer was washed with water (80 mL · 2) and saturated brine (80 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound 2 (52.5 mg, 91%) as yellow needle crystals.
　1H NMR (500 MHz, DMSO-d6) δ : 12.01 (Rs, 1 H), 8.44 (R s, 1 H), 7.50-7.22 (m, 3 H), 7.07 (d, 1 H, J = 8.0 Hz), 6.99(d, 2 H, J = 8.5 Hz), 6.68 (dd, 1 H, J = 9.0 Hz and 2.0 Hz), 6.23 (d, 1 H, J =16.0 Hz), 4.50 (sept, 1 H, J = 6.0 Hz), 3.16 (sept, 1 H, J = 7.0 Hz), 1.29 (d,6 H, J = 6.0 Hz), 1.14 (d, 6 H, J = 7.0 Hz). 
　Anal. Calcd for C21H25NO3 : C,74.31; H, 7.42; N, 4.13. Found: C, 74.09; H, 7.52; N, 4.11.
　MS : FAB-MS m/z: 339 [M]+, 340 [M + H]+ 1 H NMR (500 MHz, DMSO-d6) δ: 12.01 (Rs, 1 H), 8.44 (R s, 1 H), 7.50-7.22 (m, 3 H), 7.07 (d, 1 H, J = 8.0 Hz), 6.99 (d, 2 H, J = 8.5 Hz), 6.68 (dd, 1 H, J = 9.0 Hz and 2.0 Hz), 6.23 (d, 1 H, J = 16.0 Hz), 4.50 (sept, 1 H, J = 6.0 Hz), 3.16 (sept, 1 H, J = 7.0 Hz), 1.29 (d, 6 H, J = 6.0 Hz), 1.14 (d, 6 H, J = 7.0 Hz).
Anal. Calcd for C 21 H 25 NO 3 : C, 74.31; H, 7.42; N, 4.13. Found: C, 74.09; H, 7.52; N, 4.11.
MS: FAB-MS m / z: 339 [M] + , 340 [M + H] +
　[実施例３]目的化合物３の合成
　目的化合物３は、実質上、ＷＯ２００８／１０５３８６の記載に従って合成した。製造方法のスキームを図５に示す。 [Example 3] Synthesis of target compound 3 The target compound 3 was synthesized substantially as described in WO2008 / 105386. A scheme of the production method is shown in FIG.
１）中間体１４の合成
　２－イソプロピルフェノール（２．７ｍＬ、２０．０ｍｍｏｌ）を酢酸エチル（２００ｍＬ）に溶解し塩化亜鉛（２．７ｇ、２０．０ｍｍｏｌ）を加えた後、超音波を与えながら濃硫酸（１．５ｍＬ）を滴下し、滴下終了後２０分間超音波を与え、ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：５）で反応の終了を確認した。水（２００ｍＬ）にあけ、酢酸エチル（１００ｍＬ）で抽出した。有機層を水（１５０ｍＬ×２）、飽和食塩水（１５０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、黒色オイル状の粗生成物（５．４ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ‐ヘキサン＝１：７）を行い、黄色針状結晶の中間体１４（２．２ｍｇ、６１％）を得た。 1) Synthesis of Intermediate 14 2-Isopropylphenol (2.7 mL, 20.0 mmol) was dissolved in ethyl acetate (200 mL), zinc chloride (2.7 g, 20.0 mmol) was added, and then ultrasonic waves were applied. Concentrated sulfuric acid (1.5 mL) was added dropwise, ultrasonic waves were applied for 20 minutes after completion of the addition, and the completion of the reaction was confirmed with a TLC plate (ethyl acetate: n-hexane = 1: 5). Poured into water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (150 mL × 2) and saturated brine (150 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a black oily crude product (5.4 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 7) was performed to obtain yellow needle crystal intermediate 14 (2.2 mg, 61%).
　1H NMR (500 MHz, CDCl3) δ :8.31 (d, 1 H, J = 2.5 Hz), 8.00 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 6.81 (d, 1 H,J = 9.0 Hz), 5.53 (s, 1 H), 3.25 (sept, 1 H, J = 7.0 Hz), 1.30 (d, 6 H, J = 7.0Hz). 1 H NMR (500 MHz, CDCl 3 ) δ: 8.31 (d, 1 H, J = 2.5 Hz), 8.00 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 6.81 (d, 1 H, J = 9.0 Hz), 5.53 (s, 1 H), 3.25 (sept, 1 H, J = 7.0 Hz), 1.30 (d, 6 H, J = 7.0 Hz).
　２）中間体１５の合成
　中間体１４（１．８ｇ、１０．０ｍｍｏｌ）を無水Ｎ，Ｎ-ジメチルホルムアミド（５．０ｍＬ）に溶解し、炭酸カリウム（２．８ｇ、２０．０ｍｍｏｌ）、２－ブロモプロパン（１．ｍＬ、１１．０ｍｍｏｌ）、ヨウ化カリウム適量を攪拌しながら混合し、４時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：１０）により反応の終了を確認後、２規定の塩酸（８０ｍＬ）にあけ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、黒色オイル状の粗生成物（２．０ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：１２）を行い、黄色澄明なオイル状の中間体１５（１．７ｇ、７４％）を得た。 2) Synthesis of Intermediate 15 Intermediate 14 (1.8 g, 10.0 mmol) was dissolved in anhydrous N, N-dimethylformamide (5.0 mL), and potassium carbonate (2.8 g, 20.0 mmol), 2- Bromopropane (1 mL, 11.0 mmol) and appropriate amounts of potassium iodide were mixed with stirring, and the mixture was heated and stirred for 4 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 10), the reaction mixture was poured into 2N hydrochloric acid (80 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a black oily crude product (2.0 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 12) was performed to obtain a yellow clear oily intermediate 15 (1.7 g, 74%).
　1H NMR (300 MHz, CDCl3) δ :8.10-8.05 (m, 2 H), 6.86 (d, 1 H, J = 9.0 Hz), 4.70 (sept, 1 H, J = 6.0 Hz),3.31 (sept, 1 H, J = 7.0 Hz), 1.40 (d, 6 H, J = 6.0 Hz), 1.24 (d, 6 H, J = 7.0Hz). 1 H NMR (300 MHz, CDCl 3 ) δ: 8.10-8.05 (m, 2 H), 6.86 (d, 1 H, J = 9.0 Hz), 4.70 (sept, 1 H, J = 6.0 Hz), 3.31 ( sept, 1 H, J = 7.0 Hz), 1.40 (d, 6 H, J = 6.0 Hz), 1.24 (d, 6 H, J = 7.0 Hz).
　３）中間体１６の合成
　中間体１５（４４６．５ｍｇ、２．０ｍｍｏｌ）をメタノール（７．０ｍＬ）に溶解し、パラジウム炭素を適量加え、水素雰囲気下室温で３０分攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：７）により反応の終了を確認した後、セライトろ過を行い、減圧下にて溶媒留去した。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：７）を行い、黄色澄明なオイル状の中間体１６（３５８．３ｍｇ、９３％）を得た。 3) Synthesis of Intermediate 16 Intermediate 15 (446.5 mg, 2.0 mmol) was dissolved in methanol (7.0 mL), an appropriate amount of palladium carbon was added, and the mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 7), the mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. Flash column chromatography (ethyl acetate: n-hexane = 1: 7) was performed to obtain a yellow clear oily intermediate 16 (358.3 mg, 93%).
　1H NMR (300 MHz, CDCl3) δ :6.70 (d, 1 H, J = 8.5 Hz), 6.60 (d, 1 H, J = 3.0 Hz), 6.49 (dd, 1 H, J = 8.5 Hzand 3.0 Hz), 4.34 (sept, 1 H, J = 6.0 Hz), 3.28 (sept, 1 H, J = 7.0 Hz), 1.29(d, 6 H, J = 6.0 Hz), 1.17 (d, 6 H, J = 7.0 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ: 6.70 (d, 1 H, J = 8.5 Hz), 6.60 (d, 1 H, J = 3.0 Hz), 6.49 (dd, 1 H, J = 8.5 Hz and 3.0 Hz), 4.34 (sept, 1 H, J = 6.0 Hz), 3.28 (sept, 1 H, J = 7.0 Hz), 1.29 (d, 6 H, J = 6.0 Hz), 1.17 (d, 6 H, J = 7.0 Hz).
　４）中間体１７の合成
　中間体６（３１０．３ｍｇ、１．０ｍｍｏｌ）、中間体１６（２７０．０ｍｇ、１．４ｍｍｏｌ）を無水ジオキサン（１．４ｍＬ）に溶解後、（±）‐２，２’‐ビス（ジフェニルホスフィノ）‐１，１’‐ビナフチル（４６．７ｍｇ、０．０７５ｍｍｏｌ）、炭酸セシウム（４５６．１ｍｇ、１．４ｍｍｏｌ）、酢酸パラジウム（II）（１１．２ｍｇ、０．０５ｍｍｏｌ）を加え３時間加熱還流した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：４）で反応終了を確認後、セライト濾過を行い、２規定の塩酸（７０ｍＬ）、水（７０ｍＬ）、飽和食塩水（７０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、茶色オイル状の粗生成物（６２３．８ｍｇ）を得た。
フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ‐ヘキサン＝１：９）を行い、黄色針状結晶の中間体１７（３５０．７ｍｇ、９９％）を得た。 4) Synthesis of Intermediate 17 After dissolving Intermediate 6 (310.3 mg, 1.0 mmol) and Intermediate 16 (270.0 mg, 1.4 mmol) in anhydrous dioxane (1.4 mL), (±) -2 2'-bis (diphenylphosphino) -1,1'-binaphthyl (46.7 mg, 0.075 mmol), cesium carbonate (456.1 mg, 1.4 mmol), palladium (II) acetate (11.2 mg, 0. 05 mmol) was added and the mixture was heated to reflux for 3 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 4), the mixture was filtered through Celite and washed with 2N hydrochloric acid (70 mL), water (70 mL), and saturated brine (70 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily crude product (623.8 mg).
Flash column chromatography (ethyl acetate: n-hexane = 1: 9) was performed to obtain yellow needle crystal intermediate 17 (350.7 mg, 99%).
　1H NMR (300 MHz, CDCl3) δ :7.62 (d, 1 H, J = 16.0 Hz), 7.38 (d, 2 H, J = 8.5 Hz), 7.01 (d, 1 H, J = 2.5Hz), 6.95 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.84 (d, 1 H, J = 8.5 Hz), 6.82 (d,2 H, J = 8.5 Hz), 6.24 (d, 1 H, J = 16.0 Hz), 5.76 (R s, 1 H), 4.50 (sept, 1 H,J = 6.0 Hz), 3.78 (s, 3 H), 3.32 (sept, 1 H, J = 7.0 Hz), 1.35 (d, 6 H, J = 6.0Hz), 1.19 (d, 6 H, J = 7.0 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.62 (d, 1 H, J = 16.0 Hz), 7.38 (d, 2 H, J = 8.5 Hz), 7.01 (d, 1 H, J = 2.5 Hz) , 6.95 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.84 (d, 1 H, J = 8.5 Hz), 6.82 (d, 2 H, J = 8.5 Hz), 6.24 (d, 1 H, J = 16.0 Hz), 5.76 (R s, 1 H), 4.50 (sept, 1 H, J = 6.0 Hz), 3.78 (s, 3 H), 3.32 (sept, 1 H, J = 7.0 Hz), 1.35 (d, 6 H, J = 6.0 Hz), 1.19 (d, 6 H, J = 7.0 Hz).
　５）目的化合物３の合成
　中間体１７（７０．７ｍｇ、０．２０ｍｍｏｌ）をメタノール（７．０ｍＬ）、テトラヒドロフラン（２．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（３．０ｍＬ）を加え、６０℃で３０分加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、減圧下で濃縮し、２規定の塩酸（７０ｍＬ）にあけ、酢酸エチル（４０ｍＬ×３）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（７０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、ジクロロメタン／ｎ‐ヘキサンで再結晶を行い、黄色針状結晶の目的化合物３（５２．５ｍｇ、７７％）を得た。 5) Synthesis of target compound 3 Intermediate 17 (70.7 mg, 0.20 mmol) was dissolved in methanol (7.0 mL) and tetrahydrofuran (2.0 mL), and then 2N aqueous sodium hydroxide solution (3.0 mL) was added. In addition, the mixture was stirred at 60 ° C. for 30 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was concentrated under reduced pressure, poured into 2N hydrochloric acid (70 mL), and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with water (70 mL × 2) and saturated brine (70 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound 3 (52.5 mg, 77%) as yellow needle crystals.
　1H NMR (300 MHz, DMSO-d6) δ : 11.95 (Rs, 1 H), 8.29 (R s, 1 H), 7.44 (d, 1 H, J = 16.0 Hz), 7.44 (d, 2 H, J = 8.5Hz), 6.95-6.86 (m, 5 H), 6.19 (d, 1 H, J = 16.0 Hz), 4.51 (sept, 1 H, J = 6.0Hz), 3.23 (sept, 1 H, J = 7.0 Hz), 1.28 (d, 6 H, J = 6.0 Hz), 1.16 (d, 6 H, J =7.0 Hz).
　Anal. Calcd for C21H25NO3 : C,74.31; H, 7.42; N, 4.13. Found: C, 74.09; H, 7.37; N, 4.11.
　MS : FAB-MS m/z: 339 [M]+, 340 [M + H]+ 1 H NMR (300 MHz, DMSO-d6) δ: 11.95 (Rs, 1 H), 8.29 (R s, 1 H), 7.44 (d, 1 H, J = 16.0 Hz), 7.44 (d, 2 H, J = 8.5Hz), 6.95-6.86 (m, 5 H), 6.19 (d, 1 H, J = 16.0 Hz), 4.51 (sept, 1 H, J = 6.0 Hz), 3.23 (sept, 1 H, J = 7.0 Hz), 1.28 (d, 6 H, J = 6.0 Hz), 1.16 (d, 6 H, J = 7.0 Hz).
Anal. Calcd for C 21 H 25 NO 3 : C, 74.31; H, 7.42; N, 4.13. Found: C, 74.09; H, 7.37; N, 4.11.
MS: FAB-MS m / z: 339 [M] + , 340 [M + H] +
　[実施例４]目的化合物４、５の合成
　本実施例における製造方法のスキームを図６に示した。 [Example 4] Synthesis of target compounds 4 and 5 The scheme of the production method in this example is shown in FIG.
１）中間体１８ａの合成
　中間体４（９１４．９ｍｇ、４．５ｍｍｏｌ）、２,５-ジブロモピリジン（１０６６．０ｍｇ、４．５ｍｍｏｌ）、パラトルエンスルホン酸一水和物（１１１２．７ｍｇ、５．８５ｍｍｏｌ）をジオキサン（２２．５ｍＬ）に溶解し、４８時間加熱還流した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：８）で反応の進行を確認し、反応を停止させた後、減圧下にて溶媒留去した。２規定の水酸化ナトリウム水溶液で中和した後、水（４０ｍＬ）にあけ、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（７０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥した。減圧下にて溶媒留去し、茶色オイル状の粗生成物（２０３５．４ｍｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：１０→１：８）を行い、白色結晶の中間体１８a（６１０．０ｇ、３８％）を得た。 1) Synthesis of Intermediate 18a Intermediate 4 (914.9 mg, 4.5 mmol), 2,5-dibromopyridine (1066.0 mg, 4.5 mmol), p-toluenesulfonic acid monohydrate (112.7 mg, 5 .85 mmol) was dissolved in dioxane (22.5 mL) and heated to reflux for 48 hours. The progress of the reaction was confirmed with a TLC plate (ethyl acetate: n-hexane = 1: 8), the reaction was stopped, and the solvent was distilled off under reduced pressure. The mixture was neutralized with 2N aqueous sodium hydroxide solution, poured into water (40 mL), and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (70 mL × 2) and saturated brine (70 mL), and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a brown oily crude product (2035.4 mg). Flash column chromatography (ethyl acetate: n-hexane = 1: 10 → 1: 8) was performed to obtain white crystal intermediate 18a (610.0 g, 38%).
　1H NMR (300 MHz, CDCl3) δ :8.16 (dd, 1 H, J = 2.5 Hz and 0.5 Hz), 7.54 (dd, 1 H, J = 9.0 Hz and 2.5 Hz),7.28 (d, 1 H, J = 8.5 Hz), 7.15 (d, 1 H, J = 2.5 Hz), 7.07 (dd, 1 H, J = 8.5 Hzand 2.5 Hz), 7.07 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.75 (dd, 1 H, J = 9.0 Hzand 0.5 Hz), 6.75 (br s, 1 H), 1.69 (s, 4 H), 1.28 (s, 6 H), 1.27 (s, 6 H). 1 H NMR (300 MHz, CDCl 3 ) δ: 8.16 (dd, 1 H, J = 2.5 Hz and 0.5 Hz), 7.54 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 7.28 (d, 1 H , J = 8.5 Hz), 7.15 (d, 1 H, J = 2.5 Hz), 7.07 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.07 (dd, 1 H, J = 8.5 Hz and 2.5 Hz) , 6.75 (dd, 1 H, J = 9.0 Hzand 0.5 Hz), 6.75 (br s, 1 H), 1.69 (s, 4 H), 1.28 (s, 6 H), 1.27 (s, 6 H).
　２）中間体１９ａの合成
　中間体１８ａ（６１０．０ｍｇ、１．７ｍｍｏｌ）、トリスジベンジリデンアセトンジパラジウム（７８．０ｍｇ、０．０８５ｍｍｏｌ）、トリトリルホスフィン（１０３．５ｍｇ、０．３４ｍｍｏｌ）、トリエチルアミン（１．２ｍＬ、８．５ｍｍｏｌ）をアルゴン雰囲気下無水Ｎ，Ｎ-ジメチルホルムアミド（２．０ｍＬ）に溶解し、アクリル酸ｔ－ブチル（０．３１ｍＬ、２．１ｍｍｏｌ）を滴下した。この混合液を１２０℃で２４時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：６）で反応の終了を確認した後、反応液をセライトろ過し、得たろ液を水（１００ｍＬ）にあけ酢酸エチル（６０ｍＬ×２）で抽出した。有機層を水（１２０ｍＬ×２）、飽和食塩水（１２０ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、橙色オイル状の粗生成物（１．２１ｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：１２→１０→１：８→１：６）を行い、白色結晶の中間体１９ａ（５６５．０ｇ、８２％）を得た。 2) Synthesis of intermediate 19a Intermediate 18a (610.0 mg, 1.7 mmol), trisdibenzylideneacetone dipalladium (78.0 mg, 0.085 mmol), tolylphosphine (103.5 mg, 0.34 mmol), triethylamine (1.2 mL, 8.5 mmol) was dissolved in anhydrous N, N-dimethylformamide (2.0 mL) under an argon atmosphere, and t-butyl acrylate (0.31 mL, 2.1 mmol) was added dropwise. The mixture was heated and stirred at 120 ° C. for 24 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 6), the reaction solution was filtered through Celite, and the obtained filtrate was poured into water (100 mL) and extracted with ethyl acetate (60 mL × 2). . The organic layer was washed with water (120 mL × 2) and saturated brine (120 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an orange oily crude product (1.21 g). Flash column chromatography (ethyl acetate: n-hexane = 1: 12 → 10 → 1: 8 → 1: 6) was performed to obtain an intermediate 19a (565.0 g, 82%) of white crystals.
　1H NMR (300 MHz, CDCl3) δ :8.21 (d, 1 H, J = 2.5 Hz), 7.69 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 7.47 (d, 1 H,J = 16.0 Hz), 7.31 (d, 1 H, J = 8.5 Hz), 7.19 (d, 1 H, J = 2.5 Hz), 7.10 (dd,1H, J = 8.5 Hz and 2.5 Hz), 6.85 (d, 1 H, J = 9.0 Hz), 6.22 (d, 1H, J = 16.0Hz), 1.70 (s, 4 H), 1.53 (s, 9 H), 1.29 (s, 6 H), 1.28 (s, 6 H). 1 H NMR (300 MHz, CDCl 3 ) δ: 8.21 (d, 1 H, J = 2.5 Hz), 7.69 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 7.47 (d, 1 H, J = 16.0 Hz), 7.31 (d, 1 H, J = 8.5 Hz), 7.19 (d, 1 H, J = 2.5 Hz), 7.10 (dd, 1H, J = 8.5 Hz and 2.5 Hz), 6.85 (d, 1 H, J = 9.0 Hz), 6.22 (d, 1H, J = 16.0 Hz), 1.70 (s, 4 H), 1.53 (s, 9 H), 1.29 (s, 6 H), 1.28 (s, 6 H ).
　３）中間体１９ｂの合成
　中間体４（２０３．０ｍｇ、１．０ｍｍｏｌ）、５-ブロモ２-クロロピリジン（１９３．０ｍｇ、１．０ｍｍｏｌ）を酢酸（２．０ｍＬ）に溶解し、９０℃で３時間加熱撹拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：４）で反応の終了を確認した後、飽和炭酸水素ナトリウム水溶液（８０ｍＬ）にあけ、酢酸エチル（８０ｍＬ×３）で抽出した。有機層を水（８０ｍＬ×２）、飽和食塩水（８０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧にて溶媒留去し橙色結晶の粗生成物（４９５．０ｍｇ）得ることで、次の反応に使用した。
　粗生成物（４９５．０ｍｇ）、酢酸パラジウム（II）（６．４ｍｇ、０．０３ｍｍｏｌ）、トリトリルホスフィン（２３．０ｍｇ、０．０７５ｍｍｏｌ）、トリエチルアミン（０．４１ｍＬ、３．０ｍｍｏｌ）をアルゴン雰囲気下で無水Ｎ，Ｎ-ジメチルホルムアミド（２．０ｍＬ）に溶解し、アクリル酸ｔ－ブチル（０．３４ｍＬ、２．３ｍｍｏｌ）を滴下した。この混合液を１００℃で８時間加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：４）で反応の終了を確認した後、反応液をセライトろ過し、得たろ液を水（１００ｍＬ）にあけ酢酸エチル（１００ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄した。得た有機層を硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、橙色結晶の粗生成物（５８５．０ｍｇ）を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝１：７→１：６→１：４→１：３）を行い、白色針状結晶の中間体１９ｂ（２９４．０ｍｇ、７２％）を得た。 3) Synthesis of intermediate 19b Intermediate 4 (203.0 mg, 1.0 mmol), 5-bromo-2-chloropyridine (193.0 mg, 1.0 mmol) was dissolved in acetic acid (2.0 mL) at 90 ° C. The mixture was heated and stirred for 3 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 4), the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (80 mL) and extracted with ethyl acetate (80 mL × 3). The organic layer was washed with water (80 mL × 2) and saturated brine (80 mL), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (495.0 mg) of orange crystals, which was used for the next reaction.
Crude product (495.0 mg), palladium (II) acetate (6.4 mg, 0.03 mmol), tolylphosphine (23.0 mg, 0.075 mmol), triethylamine (0.41 mL, 3.0 mmol) in an argon atmosphere The resultant was dissolved in anhydrous N, N-dimethylformamide (2.0 mL), and t-butyl acrylate (0.34 mL, 2.3 mmol) was added dropwise. This mixed solution was heated and stirred at 100 ° C. for 8 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 4), the reaction solution was filtered through Celite, and the obtained filtrate was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). . The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL). The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (585.0 mg) of orange crystals. Flash column chromatography (ethyl acetate: n-hexane = 1: 7 → 1: 6 → 1: 4 → 1: 3) was performed to obtain white needle crystal intermediate 19b (294.0 mg, 72%). .
　1H NMR (500 MHz, CDCl3) δ :8.54 (s, 2 H), 7.53 (s, 1 H), 7.44 (d, 1 H, J = 2.0 Hz), 7.42 (dd, 1 H, J = 8.5Hz and 2.0 Hz), 7.41 (d, 1 H, J = 16.0 Hz), 7.29 (d, 1H, J = 8.5 Hz), 6.29 (d,1 H, J = 16.0 Hz), 1.53 (s, 4 H), 1.30 (s, 9 H), 1.28 (s, 6 H). 1 H NMR (500 MHz, CDCl 3 ) δ: 8.54 (s, 2 H), 7.53 (s, 1 H), 7.44 (d, 1 H, J = 2.0 Hz), 7.42 (dd, 1 H, J = 8.5Hz and 2.0 Hz), 7.41 (d, 1 H, J = 16.0 Hz), 7.29 (d, 1H, J = 8.5 Hz), 6.29 (d, 1 H, J = 16.0 Hz), 1.53 (s, 4 H), 1.30 (s, 9 H), 1.28 (s, 6 H).
　５）目的化合物４の合成
　中間体１９ａ（６１．０ｍｇ、０．１５ｍｍｏｌ）をジクロロメタン（２．０ｍＬ）に溶解し、トリフルオロ酢酸（０．５ｍＬ）を加え室温で２時間攪拌した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝１：２）で反応の終了を確認した後、減圧下で溶媒留去後、メタノールで再結晶を行い、黄色針状結晶の目的化合物４のトリフルオロ酢酸塩（２９．０ｍｇ、４３％）を得た。 5) Synthesis of target compound 4 Intermediate 19a (61.0 mg, 0.15 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the solvent was distilled off under reduced pressure and then recrystallized with methanol to give trifluoroacetic acid as a target compound 4 as yellow needle crystals. The salt (29.0 mg, 43%) was obtained.
　1H NMR (300 MHz, DMSO-d6) δ : 9.56 (Rs, 1 H), 8.32 (d, 1 H, J = 2.5 Hz), 8.01 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 7.53(d, 1 H, J = 16.0 Hz), 7.48 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.43 (d, 1H, J =2.5 Hz), 7.27 (d, 1 H, J = 8.5 Hz), 6.86 (d, 1H, J = 9.0 Hz), 6.38 (d, 1 H, J =16.0 Hz), 1.64 (s, 4 H), 1.25 (s, 6 H), 1.24 (s, 6 H).
　Anal. Calcd for C22H26N2O2・C2F3O・1/6H2O: C, 61.66; H, 5.89; N, 5.99. Found: C, 71.63; H, 5.95; N, 6.14.
　MS : FAB-MS m/z: 351 [M + H]+, 
　R : 247.7-248.2 ℃ 1 H NMR (300 MHz, DMSO-d6) δ: 9.56 (Rs, 1 H), 8.32 (d, 1 H, J = 2.5 Hz), 8.01 (dd, 1 H, J = 9.0 Hz and 2.5 Hz), 7.53 (d, 1 H, J = 16.0 Hz), 7.48 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.43 (d, 1H, J = 2.5 Hz), 7.27 (d, 1 H, J = 8.5 Hz), 6.86 (d, 1H, J = 9.0 Hz), 6.38 (d, 1 H, J = 16.0 Hz), 1.64 (s, 4 H), 1.25 (s, 6 H), 1.24 (s, 6 H).
Anal.Calcd for C 22 H 26 N 2 O 2・ C 2 F 3 O ・ 1 / 6H 2 O: C, 61.66; H, 5.89; N, 5.99. Found: C, 71.63; H, 5.95; N, 6.14 .
MS: FAB-MS m / z: 351 [M + H] + ,
R: 247.7-248.2 ℃
　６）目的化合物５の合成
　中間体１９ｂ（４１．０ｍｇ、０．１０ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し、トリフルオロ酢酸（０．５ｍＬ）を加え室温で２時間攪拌した。ＴＬＣプレート（ジクロロメタン：メタノール＝２０：１）で反応の終了を確認した後、減圧下で溶媒留去後、メタノールで再結晶を行い、白色粒状結晶の目的化合物５（９．０ｍｇ、８５％）を得た。 6) Synthesis of target compound 5 Intermediate 19b (41.0 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hr. After confirming the completion of the reaction with a TLC plate (dichloromethane: methanol = 20: 1), the solvent was distilled off under reduced pressure, and then recrystallization was performed with methanol to obtain the target compound 5 (9.0 mg, 85%) as white granular crystals. Got.
　1H NMR (500 MHz, DMSO-d6) δ : 12.26 (Rs, 1 H), 8.77 (s, 2 H), 7.60 (d, 1 H, J = 2.5 Hz), 7.55(dd, 1 H, J = 8.5 Hz and2.5 Hz), 7.47 (d, 1 H, J = 16 Hz), 7.22 (d, 1H, J = 8.5 Hz), 6.51 (d, 1 H, J =16. Hz), 1.64 (s, 4 H), 1.24 (s, 6 H), 1.23 (s, 6 H).
Anal.Calcd for C21H25N3O2 : C, 71.77; H,7.17; N, 11.96. Found: C, 71.48; H, 7.12; N, 11.94.
MS :FAB-MS m/z: 352 [M + H]+ 1 H NMR (500 MHz, DMSO-d6) δ: 12.26 (Rs, 1 H), 8.77 (s, 2 H), 7.60 (d, 1 H, J = 2.5 Hz), 7.55 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 7.47 (d, 1 H, J = 16 Hz), 7.22 (d, 1H, J = 8.5 Hz), 6.51 (d, 1 H, J = 16.Hz), 1.64 ( s, 4 H), 1.24 (s, 6 H), 1.23 (s, 6 H).
Anal.Calcd for C 21 H 25 N 3 O 2 : C, 71.77; H, 7.17; N, 11.96.Found: C, 71.48; H, 7.12; N, 11.94.
MS: FAB-MS m / z: 352 [M + H] +
　[実施例５]目的化合物６の合成
　本実施例における製造方法のスキームを図７に示した。 [Example 5] Synthesis of target compound 6 The scheme of the production method in this example is shown in FIG.
　１）目的化合物６の合成
　中間体７（１６３．６ｍｇ、０．４５ｍｍｏｌ）をメタノール（０．５ｍＬ）、テトラヒドロフラン（２．５ｍＬ）に溶解後、氷冷下で５０％ヒドロキシルアミン水溶液（０．０３ｍＬ、４．１４ｍｍｏｌ）を滴下した。水酸化カリウム（０．９ｍＬ、１Ｍメタノール溶液）を滴下し室温で４時間撹拌した。
　ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：３）で反応終了を確認後、２規定の塩酸で中和し、水（３０ｍＬ）にあけ、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（７０ｍＬ×２）、飽和食塩水（７０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、酢酸エチルで再結晶を行い、黄色粒状結晶の目的化合物６（１５２．８ｍｇ、９３％）を得た。 1) Synthesis of target compound 6 Intermediate 7 (163.6 mg, 0.45 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (2.5 mL), and then 50% aqueous hydroxylamine solution (0.03 mL) under ice-cooling. 4.14 mmol) was added dropwise. Potassium hydroxide (0.9 mL, 1M methanol solution) was added dropwise and stirred at room temperature for 4 hours.
After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was neutralized with 2N hydrochloric acid, poured into water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (70 mL × 2) and saturated brine (70 mL), and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with ethyl acetate to obtain the target compound 6 (152.8 mg, 93%) as yellow granular crystals.
　1H NMR (500 MHz, DMSO-d6) δ : 10.54(br s, 1 H), 8.85 (br s, 1 H), 8.31 (br s, 1 H, ), 7.36 (d, 2 H J = 8.0 Hz),7.32 (d, 1 H, J = 16.0 Hz), 7.21 (d, 1 H, J = 8.5 Hz), 7.01 (s, 1 H), 6.97 (d,2 H, J = 8.5 Hz), 6.92 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.20 (d, 1 H, J = 16.0Hz), 1.63 (s, 4 H), 1.23 (s, 12 H). 
　Anal. Calcd for C23H28N2O2: C, 75.79; H, 7.74; N, 7.69. Found: C, 75.76; H, 7.79; N, 7.69. 1 H NMR (500 MHz, DMSO-d6) δ: 10.54 (br s, 1 H), 8.85 (br s, 1 H), 8.31 (br s, 1 H,), 7.36 (d, 2 HJ = 8.0 Hz ), 7.32 (d, 1 H, J = 16.0 Hz), 7.21 (d, 1 H, J = 8.5 Hz), 7.01 (s, 1 H), 6.97 (d, 2 H, J = 8.5 Hz), 6.92 (dd, 1 H, J = 8.5 Hz and 2.5 Hz), 6.20 (d, 1 H, J = 16.0 Hz), 1.63 (s, 4 H), 1.23 (s, 12 H).
Anal. Calcd for C 23 H 28 N 2 O 2 : C, 75.79; H, 7.74; N, 7.69. Found: C, 75.76; H, 7.79; N, 7.69.
　[実施例６]目的化合物７の合成
　本実施例における製造方法のスキームを図８に示した。 [Example 6] Synthesis of target compound 7 The scheme of the production method in this example is shown in FIG.
　１）中間体２０の合成
アセト酢酸エチル（１．３２ｍＬ、９．０ｍｍｏｌ）、ｐ－トルエンスルホン酸（２５．８ｍｇ、０．１５ｍｍｏｌ）をエタノール（１５ｍＬ）に懸濁させ、マイクロウェーブ条件下１６０℃で９０分間反応した。ＴＬＣプレート（酢酸エチル：ｎ－ヘキサン＝４：１）で反応の終了を確認した後、生じた黄色結晶をろ集することで中間体２０（09SY1-42）（４９８．３ｍｇ、２９％）を得た。 1) Synthesis of intermediate 20 Ethyl acetoacetate (1.32 mL, 9.0 mmol) and p-toluenesulfonic acid (25.8 mg, 0.15 mmol) were suspended in ethanol (15 mL) and subjected to microwave conditions at 160 ° C. For 90 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 4: 1), the produced yellow crystals were collected by filtration to obtain Intermediate 20 (09SY1-42) (498.3 mg, 29%). Obtained.
　1H NMR (500MHz, DMSO-d6) d : 10.09(s, 1 H), 7.15 (d, 1 H, J = 8.5 Hz), 6.54 (s, 1 H), 6.25 (dd, 1 H, J = 2.0 and8.5 Hz), 6.11 (d, 1 H, J = 2.0 Hz). 1 H NMR (500MHz, DMSO-d6) d: 10.09 (s, 1 H), 7.15 (d, 1 H, J = 8.5 Hz), 6.54 (s, 1 H), 6.25 (dd, 1 H, J = 2.0 and 8.5 Hz), 6.11 (d, 1 H, J = 2.0 Hz).
　２）中間体２１の合成
　水素化ナトリウム（６０％ｉｎオイル）（３９．６ｍｇ、０．９９ｍｍｏｌ）をｎ－ヘキサンで洗浄後、無水Ｎ，Ｎ-ジメチルホルムアミド（１ｍＬ）に懸濁させ、中間体２０（09SY1-42）（２０５．４ｍｇ、０．９ｍｍｏｌ）の無水Ｎ，Ｎ－ジメチルホルムアミド（８ｍＬ）溶液を氷冷下で加えて１０分間攪拌した。その後、ヨードメタン（５６μＬ、０．９０ｍｍｏｌ）を加えて氷冷下で１０分間攪拌した。ＴＬＣプレート（酢酸エチル：ｎ-ヘキサン＝４：１）で反応の終了を確認した後、水（８０ｍＬ）にあけ、酢酸エチル（６０ｍＬ×３）で抽出した。得た有機層を水（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄し、硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、黄色の残渣を得た。
　フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ－ヘキサン＝２：１）を行い、黄色固体状の中間体２１（07FO4-06）（１９３．６ｍｇ、８９％）を得た。 2) Synthesis of Intermediate 21 Sodium hydride (60% in oil) (39.6 mg, 0.99 mmol) was washed with n-hexane and then suspended in anhydrous N, N-dimethylformamide (1 mL). A solution of 20 (09SY1-42) (205.4 mg, 0.9 mmol) in anhydrous N, N-dimethylformamide (8 mL) was added under ice cooling and stirred for 10 minutes. Then, iodomethane (56 μL, 0.90 mmol) was added and stirred for 10 minutes under ice cooling. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 4: 1), the reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (60 mL × 3). The obtained organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a yellow residue.
Flash column chromatography (ethyl acetate: n-hexane = 2: 1) was performed to obtain a yellow solid intermediate 21 (07FO4-06) (193.6 mg, 89%).
　1H NMR (300 MHz, CDCl3) d : 7.64(dq, 1 H, J = 2.0 and 9.0 Hz), 6.82 (s, 1 H), 6.64 (dd, 1 H, J = 2.0 and 8.0Hz), 6.54 (d, 1 H, J = 2.0 Hz), 4.24 (br s, 2 H), 3.60 (s, 3 H). 1 H NMR (300 MHz, CDCl 3 ) d: 7.64 (dq, 1 H, J = 2.0 and 9.0 Hz), 6.82 (s, 1 H), 6.64 (dd, 1 H, J = 2.0 and 8.0 Hz), 6.54 (d, 1 H, J = 2.0 Hz), 4.24 (br s, 2 H), 3.60 (s, 3 H).
　３）中間体２２の合成
　中間体６（９３．１ｍｇ、０．３０ｍｍｏｌ）、中間体２１（07FO4-05）７２．６ｍｇ、０．３０ｍｍｏｌ）を無水ジオキサン（１．０ｍＬ）に溶解後、（±）‐２，２’‐ビス（ジフェニルホスフィノ）‐１，１’‐ビナフチル（１４．９ｍｇ、０．０２３ｍｍｏｌ）、炭酸セシウム（１３６．８ｍｇ、０．４２ｍｍｏｌ）、酢酸パラジウム（II）（３．３７ｍｇ、０．０１５ｍｍｏｌ）を加え２時間加熱還流した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝１：１）で反応終了を確認後、セライト濾過を行い減圧下にて溶媒を留去した。残渣を、水（６０ｍＬ）にあけ、塩化メチレン（６０ｍＬ×３）で抽出した。得た有機層を水（８０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥した後、減圧下にて溶媒留去し、黄色の残渣を得た。フラッシュカラムクロマトグラフィー（酢酸エチル：ｎ‐ヘキサン＝１：３→１：２→１：１）を行い、黄色粉状結晶の中間体２２（07FO4-06）（２２．４ｍｇ、１９％）を得た。 3) Synthesis of Intermediate 22 Intermediate 6 (93.1 mg, 0.30 mmol) and Intermediate 21 (07FO4-05) 72.6 mg, 0.30 mmol) were dissolved in anhydrous dioxane (1.0 mL), and (± ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (14.9 mg, 0.023 mmol), cesium carbonate (136.8 mg, 0.42 mmol), palladium (II) acetate (3. 37 mg, 0.015 mmol) was added and the mixture was heated to reflux for 2 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was poured into water (60 mL) and extracted with methylene chloride (60 mL × 3). The obtained organic layer was washed with water (80 mL × 2) and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a yellow residue. Flash column chromatography (ethyl acetate: n-hexane = 1: 3 → 1: 2 → 1: 1) was performed to obtain yellow powdery intermediate 22 (07FO4-06) (22.4 mg, 19%). It was.
　1H NMR (300 MHz, CDCl3) d : 7.75(dq, 1 H, J = 2.0 and 9.0 Hz), 7.68 (d, 1 H, J = 16.0 Hz), 7.47 (d, 2 H, J = 7.5Hz), 7.32 (s, 1 H), 7.22 (dd 2 H, J = 7.5 Hz), 7.07 (d, 1 H, J = 2.0 Hz), 7.02(dd, 1 H, J = 2.0 and 9.0 Hz), 6.92 (br s, 1 H), 6.39 (d, 1 H, J = 16.0 Hz),3.81 (s, 3 H), 3.66 (s, 3 H). 1 H NMR (300 MHz, CDCl 3 ) d: 7.75 (dq, 1 H, J = 2.0 and 9.0 Hz), 7.68 (d, 1 H, J = 16.0 Hz), 7.47 (d, 2 H, J = 7.5 Hz), 7.32 (s, 1 H), 7.22 (dd 2 H, J = 7.5 Hz), 7.07 (d, 1 H, J = 2.0 Hz), 7.02 (dd, 1 H, J = 2.0 and 9.0 Hz) , 6.92 (br s, 1 H), 6.39 (d, 1 H, J = 16.0 Hz), 3.81 (s, 3 H), 3.66 (s, 3 H).
　４）目的化合物７の合成 
　中間体２２（07FO4-06）（２２．４ｍｇ、０．０５６ｍｍｏｌ）をメタノール（３．０ｍＬ）、テトラヒドロフラン（３．０ｍＬ）に溶解後、２規定の水酸化ナトリウム水溶液（１．０ｍＬ）を加え、６０℃で３０分加熱攪拌した。ＴＬＣプレート（酢酸エチル：ｎ‐ヘキサン＝３：１）で反応終了を確認後、減圧下で濃縮し、２規定の塩酸（４０ｍＬ）にあけ、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（４０ｍＬ×２）、飽和食塩水（４０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒留去後、酢酸エチルで再結晶を行い、黄色盤状結晶の目的化合物７（07FO4-07）（９．２ｍｇ、４９％）を得た。 4) Synthesis of target compound 7
Intermediate 22 (07FO4-06) (22.4 mg, 0.056 mmol) was dissolved in methanol (3.0 mL) and tetrahydrofuran (3.0 mL), 2N aqueous sodium hydroxide solution (1.0 mL) was added, The mixture was heated and stirred at 60 ° C. for 30 minutes. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 3: 1), the mixture was concentrated under reduced pressure, poured into 2N hydrochloric acid (40 mL), and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (40 mL × 2) and saturated brine (40 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate to obtain the target compound 7 (07FO4-07) (9.2 mg, 49%) as a yellow disk crystal.
　1H NMR (300 MHz, DMSO-d6) d : 9.34 (s,1 H), 7.69 (d, 1 H, J = 2.0 Hz), 7.66 (d, 2 H, J = 8.5 Hz), 7.55 (d, 1 H, J = 16.0Hz), 7.31 (d, 2 H, J = 8.5 Hz), 7.20 (d, 1 H, J = 8.5 Hz), 7.17 (dd, 1 H, J = 2.0and 9.0 Hz), 6.81 (s, 3 H), 6.39 (d, 1 H, J = 16.0 Hz), 3.61 (s, 3 H). 1 H NMR (300 MHz, DMSO-d6) d: 9.34 (s, 1 H), 7.69 (d, 1 H, J = 2.0 Hz), 7.66 (d, 2 H, J = 8.5 Hz), 7.55 (d , 1 H, J = 16.0Hz), 7.31 (d, 2 H, J = 8.5 Hz), 7.20 (d, 1 H, J = 8.5 Hz), 7.17 (dd, 1 H, J = 2.0and 9.0 Hz) , 6.81 (s, 3 H), 6.39 (d, 1 H, J = 16.0 Hz), 3.61 (s, 3 H).
　[実施例７]RAR活性評価
　１）測定原理
　核内受容体の多くは転写調節に関わる転写因子であるため、その転写活性を測定する手段としてレポーター遺伝子アッセイ（reporter gene assay）が行われる。COS-1細胞やHeLa細胞などの細胞に、RAR受容体タンパク質発現プラスミド及びレポータープラスミドを導入し、融合タンパク質（fusion protein）を過剰発現させる。そこに、RAR作動性物質（リガンド）が受容体に結合すると、転写がリガンド依存的に起こり、その下流にある融合タンパク質が生成され、下流にあるルシフェラーゼの産生が始まる。このルシフェラーゼ活性を測ることにより、RAR作動活性を測定した。 [Example 7] RAR activity evaluation 1) Measurement principle Since many nuclear receptors are transcription factors involved in transcriptional regulation, a reporter gene assay is performed as a means for measuring the transcriptional activity. A RAR receptor protein expression plasmid and a reporter plasmid are introduced into cells such as COS-1 cells and HeLa cells to overexpress a fusion protein. There, when a RAR agonist (ligand) binds to the receptor, transcription occurs in a ligand-dependent manner, producing a fusion protein downstream thereof, and production of downstream luciferase begins. By measuring this luciferase activity, RAR agonist activity was measured.
　２）宿主細胞の培養
　細胞の増殖培地は、ダルベッコ変法イーグルMEM培地（DMEM）を用いた。まず、１Ｌの超純水（Milli-Q（登録商標）にて生成）にDMEM粉末を９．５ｇ溶解し、高圧加熱滅菌（１２１℃、１５分間）を行った後、室温に戻し、これを非働化したウシ胎児血清（FBS）を１０％（ｖ／ｖ）となるように加え、さらに高圧加熱滅菌した１０％ ＮａＨＣＯ３を１０ｍＬ添加し、その後Ｌ‐グルタミン　１０ｍＬをろ過滅菌後添加して調製した。 2) Host cell culture Dulbecco's modified Eagle MEM medium (DMEM) was used as a cell growth medium. First, 9.5 g of DMEM powder was dissolved in 1 L of ultrapure water (produced by Milli-Q (registered trademark)), sterilized by high-pressure heat (121 ° C., 15 minutes), returned to room temperature, Prepared by adding inactivated fetal bovine serum (FBS) to 10% (v / v), adding 10 mL of 10% NaHCO 3 sterilized by high-pressure heat sterilization, and then adding 10 mL of L-glutamine after filtration sterilization. did.
　各細胞の継代は、１００ｍｍ培養シャーレで培養した細胞の培養上清を除き、トリプシン処理により細胞を回収し、４℃、１０００ｒｐｍ、３分間遠心分離後、増殖培地を加えて細胞を分散させ、１００ｍｍ培養シャーレに細胞を分散した増殖培地を１５ｍＬ加え、３７℃、５％ＣＯ２存在下で培養した。
　形質転換はEffecteneTM Transfection Reagent（QIAGEN社）を用いて行った。RARの陽性コントロールとして、RARαおよびRARβにはAm80を、RARγにはall-trans retinoic acid（ATRA）を用いた。これらは、DMSO溶解したものをストック溶液とし、アッセイするプレートにおいて計測した。 For the passage of each cell, remove the culture supernatant of cells cultured in a 100 mm culture dish, collect the cells by trypsin treatment, centrifuge at 4 ° C., 1000 rpm for 3 minutes, add the growth medium, disperse the cells, 15 mL of a growth medium in which cells were dispersed in a 100 mm culture dish was added and cultured in the presence of 37 ° C. and 5% CO 2 .
Transformation was performed using Effectene ™ Transfection Reagent (QIAGEN). As RAR positive controls, Am80 was used for RARα and RARβ, and all-trans retinoic acid (ATRA) was used for RARγ. These were counted in the plates to be assayed as DMSO-dissolved stock solutions.
　３）転写活性の測定
（１日目）６０ｍｍ培養シャーレに、増殖培地１５ｍＬとともにCOS-1細胞を５０×１０４細胞を播種し、一晩培養した。
（２日目）EffecteneTM Transfection Reagent（QIAGEN社）を用いたリポフェクション法により形質転換を行った。
（３日目）１６～１８時間後、培養上清を除き、トリプシン処理により細胞を回収し、４ ℃、１０００ｒｐｍ、３分間遠心分離後、増殖培地を加えて細胞を分散し、２．０×１０４細胞／ウェルとなるように９６穴ホワイトプレートに播種した。その後、DMSO濃度が１％以下になるように各化合物を加えた。
（４日目）２４時間後、上清２５μＬをSEAP測定に用い、残りの細胞液はルシフェラーゼ活性測定に用いた。 3) Measurement of transcription activity (day 1) in 60mm culture dishes, the COS-1 cells with growth medium 15mL were seeded 50 × 10 4 cells and cultured overnight.
(Day 2) Transformation was performed by a lipofection method using Effectene ™ Transfection Reagent (QIAGEN).
(Day 3) After 16 to 18 hours, the culture supernatant is removed, the cells are collected by trypsin treatment, centrifuged at 4 ° C., 1000 rpm for 3 minutes, and then the growth medium is added to disperse the cells. It seed | inoculated to 96 well white plate so that it might become 10 < 4 > cell / well. Thereafter, each compound was added so that the DMSO concentration was 1% or less.
(Day 4) After 24 hours, 25 μL of the supernatant was used for SEAP measurement, and the remaining cell fluid was used for luciferase activity measurement.
　SEAP測定は、Methods in molecular biology, 63,pp.49-60, 1997/ BD Great EscAPe SEAP User manual (BD bioscience)に記載の方法に従い行った。
　具体的には、以下の方法で測定した。上記４日目の上清２５μＬに対して希釈用緩衝液を２５μＬ加えた後、６５℃で３０分インキュベートした。その後室温に戻し、アッセイ用緩衝液（７μＬ）、１０×ＭＵＰ（０．３μＬ）、希釈用緩衝液（２．７μＬ）を加え、暗所室温で６０分インキュベートした。その後、マイクロプレートリーダー（インフィニットTM (infinite)200、TECAN社製）を用い励起波長３６０ｎｍ、蛍光波長４６０ｎｍにより蛍光強度を測定した。 SEAP measurement was performed according to the method described in Methods in molecular biology, 63, pp. 49-60, 1997 / BD Great EscAPe SEAP User manual (BD bioscience).
Specifically, it measured by the following method. 25 μL of dilution buffer was added to 25 μL of the supernatant on the fourth day, and then incubated at 65 ° C. for 30 minutes. Thereafter, the temperature was returned to room temperature, assay buffer (7 μL), 10 × MUP (0.3 μL) and dilution buffer (2.7 μL) were added, and incubated at room temperature in the dark for 60 minutes. Thereafter, the fluorescence intensity was measured at an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm using a microplate reader (Infinite ™ (infinite) 200, manufactured by TECAN).
　アッセイ用緩衝液は、以下の方法で調製した。５０ｍＬの超純水（Milli-Q（登録商標）にて生成）にＬ－ホモアルギニン（０．４５ｇ）と塩化マグネシウム（０．０２ｇ） を溶解させ、ジエタノールアミン（２１ｍＬ）を加えた。その後、塩酸を用いてｐＨを９．８になるように調整後、超純水を用いて全量が１００ｍＬになるようにメスアップし、それを４℃で保存した。 The assay buffer was prepared by the following method. L-homoarginine (0.45 g) and magnesium chloride (0.02 g) were dissolved in 50 mL of ultrapure water (produced by Milli-Q (registered trademark)), and diethanolamine (21 mL) was added. Then, after adjusting the pH to 9.8 with hydrochloric acid, the volume was adjusted to 100 mL with ultrapure water and stored at 4 ° C.
　希釈用緩衝液は、以下の方法で調製した。９０ｍＬの超純水（Milli-Q（登録商標）にて生成）に塩化ナトリウム（４．３８ｇ）とTris Base（２．４２ｇ）を溶解させた。その後、塩酸を用いてｐＨが７．２になるように調整し、５倍濃度希釈用緩衝液を作製し、それを４℃で保存した。使用直前にそれを５倍希釈することで希釈用緩衝液を作製した。 Dilution buffer was prepared by the following method. Sodium chloride (4.38 g) and Tris Base (2.42 g) were dissolved in 90 mL of ultrapure water (produced with Milli-Q (registered trademark)). Thereafter, the pH was adjusted to 7.2 with hydrochloric acid to prepare a 5-fold concentration dilution buffer, which was stored at 4 ° C. Dilution buffer was prepared by diluting it 5 times immediately before use.
　４－メチルウンベリフェリルホスフェートを２５ｍＭになるように超純水（Milli-Q（登録商標）にて生成）に溶解させ、それを－２０℃で保存したものを、１０×MUPとした。 4-Methylumbelliferyl phosphate was dissolved in ultrapure water (produced with Milli-Q (registered trademark)) to 25 mM and stored at −20 ° C. to make 10 × MUP.
　ルシフェラーゼ活性は、NUNC社製の９６穴ホワイトプレートを用い、発光基質（Steady-Glo（登録商標） Luciferase Assay System、Promega社製）との反応産物との発光強度をマイクロプレートリーダー（インフィニットTM (infinite)200、TECAN社製）を用いて測定した。 Luciferase activity using the 96-well white plate manufactured by NUNC, luminescent substrate (Steady-Glo (TM) Luciferase Assay System, Promega Corp.) emission intensity of the reaction product a microplate reader with (Infinite TM (infinite ) 200, manufactured by TECAN).
　４）測定結果
　上記の測定結果を図８～１５に示した。
　測定結果は、RARの陽性コントロール（RARαおよびRARβにはAm80を、RARγにはall-transretinoic acid(ATRA)）を１μＭ反応させたときの転写活性を100%とし、相対活性を調べた。その結果、化合物１ａ，１ｂ，１ｃ，２－６について、転写活性を認めた。この結果は、本発明の化合物が低濃度で優れた活性を示すことを示している。 4) Measurement results The above measurement results are shown in FIGS.
As a result of the measurement, the transcriptional activity when the positive control of RAR (Am80 for RARα and RARβ and all-transretinoic acid (ATRA) for RARγ) was reacted at 1 μM was taken as 100%, and the relative activity was examined. As a result, transcriptional activity was recognized for compounds 1a, 1b, 1c, and 2-6. This result indicates that the compounds of the present invention exhibit excellent activity at low concentrations.
　[実施例８]化合物１～６のClogP値 [Example 8] ClogP values of compounds 1 to 6
　ClogPは、ChemDrawPro 11により求めた。結果を表１に示す。 ClogP was obtained from ChemDrawPro11. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　また、ChemDraw Ultra 7.0により求めたClogPを表２に示す。 In addition, Table 2 shows ClogP obtained by ChemDraw® Ultra® 7.0.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
　[実施例９]RAR活性評価
　実施例７と同様の手法を用いて、化合物１ａ，２，３，４，５について、RAR活性評価を行った。結果を下記の表３に示す。
Figure JPOXMLDOC01-appb-T000017
 　アルコキシ基の導入により脂溶性の大幅な低減が期待できることがわかった。また、酸性部位へのピリジン環導入によりRARαまたはγへのパーシャルアゴニスト活性が見られることがわかった。 [Example 9] Evaluation of RAR activity Using the same method as in Example 7, RAR activity was evaluated for compounds 1a, 2, 3, 4, and 5. The results are shown in Table 3 below.
Figure JPOXMLDOC01-appb-T000017
 It was found that the introduction of an alkoxy group can be expected to significantly reduce fat solubility. It was also found that partial agonist activity to RARα or γ was observed by introducing a pyridine ring into the acidic site.
　[実施例１０]血中移行性
　マウスに化合物１ａまたは化合物４を経口投与し、血中濃度を測定し、血中移行性の確認を行った。
　１）HPLC分析用の血漿試料の調製
 　マウス一群（ｎ＝７～８）に対し、化合物１ａまたは化合物４の溶液を、用量３０ｍｇ／ｋｇ（蒸留水中に１％エタノールおよび０．５％ＣＭＣを溶解したもの）となるように、１０ｍＬ／ｋｇで経口投与した。所定の時間に、血液１．０ｍＬをジエチルエーテル麻酔下にて心臓穿刺により回収した。各血液試料を、４４００ｇ、５分間、４℃にて遠心分離し、血漿試料を得た。
　得られた血漿１００μＬに、氷冷５ｍＭ酢酸アンモニウム１００μＬと、氷冷酢酸エチル１ｍＬを添加した。３０秒間ボルテックスした後、得られた混合物を、１０分間室温で静置した。その後、混合物を４４００ｇ、３０秒間、室温で遠心分離を行い、酢酸エチル相８００μＬを除去し、窒素もしくはアルゴンの気体を流すことにより、濃縮して乾燥させた。得られた残渣に、HPLCグレードメタノール１００μＬを添加した。溶液を、直接各化合物の濃度を測定するためにHPLC分析に供した。各化合物の濃度は、上記と同様の手法により調製した基準化合物１ａおよび４の結果を参照して、試料のピーク領域から算出した。 [Example 10] Blood transferability Compound 1a or compound 4 was orally administered to mice, the blood concentration was measured, and blood transferability was confirmed.
1) Preparation of plasma sample for HPLC analysis For a group of mice (n = 7-8), a solution of compound 1a or compound 4 was administered at a dose of 30 mg / kg (1% ethanol and 0.5% CMC dissolved in distilled water). Orally administered at 10 mL / kg. At a predetermined time, 1.0 mL of blood was collected by cardiac puncture under diethyl ether anesthesia. Each blood sample was centrifuged at 4400 g for 5 minutes at 4 ° C. to obtain a plasma sample.
To 100 μL of the obtained plasma, 100 μL of ice-cold 5 mM ammonium acetate and 1 mL of ice-cold ethyl acetate were added. After vortexing for 30 seconds, the resulting mixture was allowed to stand at room temperature for 10 minutes. Thereafter, the mixture was centrifuged at 4400 g for 30 seconds at room temperature, 800 μL of the ethyl acetate phase was removed, and the mixture was concentrated and dried by flowing nitrogen or argon gas. To the obtained residue, 100 μL of HPLC grade methanol was added. The solution was directly subjected to HPLC analysis to determine the concentration of each compound. The concentration of each compound was calculated from the peak area of the sample with reference to the results of reference compounds 1a and 4 prepared by the same method as described above.
　２）HPLC条件
　HPLCシステムは、SCL-10A system controller、LC-10AD pump、SPD-10AV UV-Vis spectrophotometric detector、SIL-10AD autoinjector、CTO-6A column oven、DGU-14A degasserおよびC-R7A Chromatopacを装備した島津液体クロマトグラフィシステムである。試料（各２０μＬ）を１０℃にrefrigerated autosamplerを用いて、１０℃に保ったまま注入した。クロマトグラフ解析は、Inertsil ODS-3（４．６ｉ．ｄ．×２５０ｍｍ、５μｍ、GL Sciences社）、ガードカラムInertsil ODS-3（４．０ｉ．ｄ．×１０ｍｍ、５μｍ、GL Sciences社）を用いて、４０℃に保って、メタノール：２５ｍＭ酢酸アンモニウム（酢酸によりｐＨ５．０に調整）（８０：２０、ｖ／ｖ）を移動相として用いて行った。流量は、０．７ｍＬ／ｍｉｎであり、２８０ｎｍの吸光度をモニタリングした。 2) HPLC conditions The HPLC system is equipped with SCL-10A system controller, LC-10AD pump, SPD-10AV UV-Vis spectrophotometric detector, SIL-10AD autoinjector, CTO-6A column oven, DGU-14A degasser and C-R7A Chromatopac. Shimadzu liquid chromatography system. Samples (20 μL each) were injected at 10 ° C. using a refrigerated autosampler while being kept at 10 ° C. For the chromatographic analysis, Inertsil ODS-3 (4.6 i.d. × 250 mm, 5 μm, GL Sciences) and guard column Inertsil ODS-3 (4.0 i.d. × 10 mm, 5 μm, GL Sciences) were used. The mixture was kept at 40 ° C. using methanol: 25 mM ammonium acetate (adjusted to pH 5.0 with acetic acid) (80:20, v / v) as the mobile phase. The flow rate was 0.7 mL / min, and the absorbance at 280 nm was monitored.
　結果を図１７に示す。化合物４は、良好な血中移行性を示すことがわかった（tmax=3hr、Cmax=24.3μM）。 The results are shown in FIG. Compound 4 was found to exhibit good blood transferability (t max = 3 hr, C max = 24.3 μM).
　[実施例１１]in　vivo血中トリグリセリド量
　実施例１０と同様の手法により、化合物１ａまたは化合物４をマウスに投与し、血漿試料を回収および調製した。血中トリグリセリド量のアッセイは、得られた血漿試料を用いて、和光純薬から購入したアッセイキット（トリグリセライドE-テストワコー）を用いて製品プロトコルに従って行った。 [Example 11] In vivo blood triglyceride level In the same manner as in Example 10, Compound 1a or Compound 4 was administered to mice, and plasma samples were collected and prepared. The blood triglyceride level assay was performed according to the product protocol using the obtained plasma sample and an assay kit (Triglyceride E-Test Wako) purchased from Wako Pure Chemical.
　結果を図１８に示す。化合物１ａおよび４ともに、血中のトリグリセリド量（TG値）の顕著な上昇を示さなかった。 Results are shown in FIG. Neither compound 1a nor 4 showed a significant increase in blood triglyceride level (TG value).
　以上詳述したように、本発明の化合物のうち、RAR作動性を有する化合物は、既存のRARアゴニストの活性と比較してその転写活性化能は高く、かつ脂溶性が低減されたものである。さらに、化合物４、６は、RARβ活性を低濃度で活性化するだけでなく、RARαに対しパーシャルアゴニスト活性を示す。従ってこれらの化合物は、高濃度においてもRARα活性化にともなうトリグリセリド血中濃度の上昇を回避することができると期待できる。本発明の化合物は、抗がん剤、抗炎症剤、抗アレルギー剤の有効成分としての作用が期待できるため、このような医薬として利用することができる。また、生化学試験用試薬としても利用することができる。 As described in detail above, among the compounds of the present invention, RAR agonistic compounds have higher transcriptional activation ability and reduced lipophilicity compared to the activities of existing RAR agonists. . Furthermore, compounds 4 and 6 not only activate RARβ activity at low concentrations, but also show partial agonist activity against RARα. Therefore, these compounds can be expected to avoid an increase in blood concentration of triglycerides accompanying RARα activation even at high concentrations. Since the compound of the present invention can be expected to act as an active ingredient of anticancer agents, anti-inflammatory agents, and antiallergic agents, it can be used as such a medicament. It can also be used as a biochemical test reagent.

Claims (10)

  1. 　一般式I：
    Figure JPOXMLDOC01-appb-C000001
     （式中、R1及びR2は、各々独立してNH2、アルキル基及びアルコキシ基から選択される基であるか、R1及びR2は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成してもよく（該６員環は環上に、アルキル基、ハロゲン化アルキル基、アルケニル基、フェニル基及びオキソ基から選択される置換基を、１又は２以上有していてもよい。）、
    R3は、水素原子、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基及びアリールアミノ基から選択され、
    W1及びW2は、各々独立して窒素原子及びCR7（R7は、水素原子、アルキル基、アルコキシ基及びハロゲンから選択される。）から選択され、
    R4及びR5は、各々独立して水素原子、アルキル基及びハロゲンから選択される基であり、
    R6は、水素原子又はアルキル基であり、
    Zは、カルボキシル基、エステル化カルボキシル基、及びヒロドキサム酸基から選択される。但し、R4とR5は同時に水素であってもよい。）
    で表される化合物又はその塩。     Formula I:
    Figure JPOXMLDOC01-appb-C000001
     Wherein R 1 and R 2 are each independently a group selected from NH 2 , an alkyl group and an alkoxy group, or R 1 and R 2 together are on the benzene ring to which they are bonded. A 6-membered ring may be formed together with a carbon atom (the 6-membered ring has one or more substituents selected from an alkyl group, a halogenated alkyl group, an alkenyl group, a phenyl group and an oxo group on the ring. You may have).
    R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group and an arylamino group,
    W 1 and W 2 are each independently selected from a nitrogen atom and CR 7 (R 7 is selected from a hydrogen atom, an alkyl group, an alkoxy group, and a halogen);
    R 4 and R 5 are each independently a group selected from a hydrogen atom, an alkyl group and a halogen;
    R 6 is a hydrogen atom or an alkyl group,
    Z is selected from a carboxyl group, an esterified carboxyl group, and a hydroxamic acid group. However, R 4 and R 5 may be hydrogen at the same time. )
    Or a salt thereof.
  2. 　R1及びR2は、各々独立してアルキル基及びアルコキシ基から選択される基である（但し、R1とR2は同時にアルキル基ではない）か、又は、R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成しており（該６員環は環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１又は２以上を有していてもよい）、
    R3が水素原子、アルキル基、アルケニル基、アルキニル基、アシル基、アルキルアミノ基及びアリールアミノ基から選択される、請求項１記載の化合物又はその塩。     R 1 and R 2 are each independently a group selected from an alkyl group and an alkoxy group (provided that R 1 and R 2 are not an alkyl group at the same time), or R 1 and R 2 together To form a 6-membered ring together with carbon atoms on the benzene ring to which they are bonded (the 6-membered ring is selected from a C 1 -C 4 alkyl group, a halogenated alkyl group, and an oxo group on the ring). And may have 1 or 2 or more substituents)
    The compound or a salt thereof according to claim 1, wherein R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an alkylamino group, and an arylamino group.
  3. 　R6が水素原子又はC1～C4アルキル基である、請求項１又は２に記載の化合物又はその塩。 The compound or a salt thereof according to claim 1 or 2, wherein R 6 is a hydrogen atom or a C 1 -C 4 alkyl group.
  4. 　R4、R5及びR6が水素原子である、請求項１又は２に記載の化合物又はその塩。 The compound or salt thereof according to claim 1 or 2, wherein R 4 , R 5 and R 6 are hydrogen atoms.
  5. 　R1及びR2が一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成している（該６員環は環上に、C1～C4アルキル基、ハロゲン化アルキル基、及びオキソ基から選択される置換基を、１又は２以上を有していてもよい）、請求項１～４のいずれか１に記載の化合物又はその塩。 R 1 and R 2 together form a 6-membered ring with the carbon atom on the benzene ring to which they are bonded (the 6-membered ring is a C 1 -C 4 alkyl group, alkyl halide on the ring) The compound or a salt thereof according to any one of claims 1 to 4, which may have one or two or more substituents selected from a group and an oxo group.
  6. 　一般式II：
    Figure JPOXMLDOC01-appb-C000002
     （式中、R3、W1、W2及びZは、請求項１記載の定義と同意義であり、R8及びR9は、各々独立して水素原子、アルキル基、ハロゲン化アルキル基、アルケニル基及びフェニル基から選択される。）
    で表される、請求項１記載の化合物又はその塩。     Formula II:
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 3 , W 1 , W 2 and Z are as defined in claim 1, and R 8 and R 9 are each independently a hydrogen atom, an alkyl group, a halogenated alkyl group, (Selected from alkenyl group and phenyl group.)
    The compound of Claim 1 represented by these, or its salt.
  7. 　一般式III：
    Figure JPOXMLDOC01-appb-C000003
     （式中、R3、R6、W1、W2及びZは請求項１記載の定義と同意義である。）
    で表される化合物又はその塩。     Formula III:
    Figure JPOXMLDOC01-appb-C000003
     (Wherein R 3 , R 6 , W 1 , W 2 and Z are as defined in claim 1).
    Or a salt thereof.
  8. 　請求項１～６のいずれか１項に記載の化合物又はその塩を含有する、レチノイン酸受容体（RAR）リガンド作用調節剤。 A retinoic acid receptor (RAR) ligand action regulator comprising the compound according to any one of claims 1 to 6 or a salt thereof.
  9. 　請求項１～６のいずれか１項に記載の化合物又はその塩を含有する、医薬組成物。 A pharmaceutical composition comprising the compound or a salt thereof according to any one of claims 1 to 6.
  10. 　抗がん剤、抗アレルギー剤及び／又は抗炎症剤である、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, which is an anticancer agent, an antiallergic agent and / or an anti-inflammatory agent.
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