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WO2011055843A1 - Composé rétinoïde - Google Patents

Composé rétinoïde Download PDF

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Publication number
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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alkyl group
compound
hydrogen atom
salt
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博貴 加来田
史宜 大澤
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Okayama University NUC
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Okayama University NUC
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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.

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Abstract

L'invention porte sur une substance (un composé rétinoïde représenté par la formule) qui agit sur un récepteur de l'acide rétinoïque qui est un récepteur nucléaire. (Dans la formule, R1 et R2 représentent chacun indépendamment un groupe choisi parmi un groupe NH2, un groupe alkyle et un groupe alcoxy, ou R1 et R2 peuvent se combiner conjointement avec les atomes de carbone sur le noyau benzénique auquel les R1 et R2 sont liés et former un noyau à six chaînons qui peut être substitué par un groupe alkyle et similaire ; R3 représente un groupe choisi parmi un atome d'hydrogène, un groupe alkyle et similaires ; W1 et W2 représentent chacun indépendamment un groupe choisi parmi un atome d'azote et un groupe CR7 (dans lequel R7 représente un atome d'hydrogène ou similaire) ; R4 et R5 représentent chacun indépendamment un groupe choisi parmi un atome d'hydrogène, un groupe alkyle et un atome d'halogène ; R6 représente un atome d'hydrogène ou un groupe alkyle ; et Z représente un groupe choisi parmi un groupe carboxyle, un groupe carboxyle estérifié et un groupe acide hydroxamique).
PCT/JP2010/069920 2009-11-09 2010-11-09 Composé rétinoïde Ceased WO2011055843A1 (fr)

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WO2015026990A3 (fr) * 2013-08-20 2015-05-07 University Of Washington Through Its Center For Commercialization Nouveaux inhibiteurs spécifiques de l'hydrolase d'acide rétinoïque cytochrome p450 26

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JPH05297638A (ja) * 1992-04-22 1993-11-12 Hodogaya Chem Co Ltd 負帯電性電子写真用トナー
JPH10182583A (ja) * 1996-12-25 1998-07-07 Mitsui Chem Inc 新規ヒドロキサム酸誘導体
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques
JP2008509075A (ja) * 2004-08-09 2008-03-27 アステラス製薬株式会社 ヒストンデアセチラーゼ（ｈｄａｃ）の阻害活性を有するヒドロキシアミド化合物
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015026990A3 (fr) * 2013-08-20 2015-05-07 University Of Washington Through Its Center For Commercialization Nouveaux inhibiteurs spécifiques de l'hydrolase d'acide rétinoïque cytochrome p450 26
US9963439B2 (en) 2013-08-20 2018-05-08 University Of Washington Through Its Center For Commercialization Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase
EP4083029A1 (fr) * 2013-08-20 2022-11-02 University of Washington through its Center for Commercialization Nouveaux inhibiteurs spécifiques de l'hydroxylase d'acide rétinoïque cytochrome p450 26

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