WO2003000685A1 - Derives heterocycliques a 5 chainons - Google Patents

Derives heterocycliques a 5 chainons Download PDF

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Publication number
WO2003000685A1
WO2003000685A1 PCT/JP2002/006107 JP0206107W WO03000685A1 WO 2003000685 A1 WO2003000685 A1 WO 2003000685A1 JP 0206107 W JP0206107 W JP 0206107W WO 03000685 A1 WO03000685 A1 WO 03000685A1
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group
carbon atoms
optionally substituted
compound
hydrocarbon group
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PCT/JP2002/006107
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English (en)
Japanese (ja)
Inventor
Yu Momose
Tsuyoshi Maekawa
Hiroyuki Odaka
Hiroyuki Kimura
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Takeda Chemical Industries, Ltd.
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Publication of WO2003000685A1 publication Critical patent/WO2003000685A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a novel 5-membered heterocyclic derivative having an excellent blood glucose lowering action and blood lipid lowering action, and being useful as an agent for preventing and treating diabetes, hyperlipidemia, impaired glucose tolerance, and the like.
  • WO 00/64876 includes, as a PP AR ligand receptor binding agent,
  • W001 / 38325 includes a retinoid-related receptor function modulator
  • R 1 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X represents a bond, 0, S, —CO—, —CS—, one CR 4 (0R 5 ) —or—NR 6 —
  • R 4 and R 6 represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 5 represents a hydrogen atom or a hydroxyl-protecting group
  • the; Y is 0, S, one SO -, _ S0 2 _, -NR 7 -, _C0NR 7 _ or a NR 7 C0_ the (R 7 is a hydrogen atom or an optionally substituted hydrocarbon group);
  • Ring A may further have 1 to 3 substituents An aromatic ring; n is 1-8;
  • ring B is a nitrogen-containing 5-membered heterocyclic ring which may be further substituted with an alkyl group;
  • X 1 is a bond, 0, S, one SO—, one S0 2 — 1—S0 2
  • Peroxisome proliferator-activated receptor gamma is a member of the superfamily of nuclear hormone receptors represented by the steroid hormone receptor and thyroid hormone receptor. Its expression is induced and plays an important role in adipocyte differentiation as a master regulator. PPARr forms a dimer with the retinoid X receptor (RX) by binding to a ligand, and binds to the responsive site of the target gene in the nucleus to directly control (activate) the transcription efficiency.
  • RX retinoid X receptor
  • prostaglandin D 2 15-Dokishi - delta 12 ⁇ 14 prostaglandin J 2 are likely to be endogenous ligands for P PAR ⁇ suggested, furthermore, is represented cash to thiazolidinedione derivative
  • a kind of insulin sensitivity enhancer has the ligand activity of PPARa, and its strength is paralleled by its hypoglycemic action or adipocyte differentiation promoting action [Cell, 83, 803 (1995) Year); The Journal of Biological Chemistry, 270, 12953 (1995): Journal of Medicinal Chemistry, 39 655 pages (1996)].
  • PPART ligand inhibits the differentiation of 10T1 / 2 cells into adipocytes by PPARagogist [Proceedings of the National Academy of Sciences of The United States of America] [Procedings of the National Academy of Sciences of the United States of America] > 96, 610, 2 (1999)], 7) PPARr ligand inhibits the differentiation of 3T3-L1 cells into adipocytes by PPARr agonist [Molecular Endocrinology], 14 , 1425, (2000)].
  • the present invention is a.
  • R 1 is an optionally substituted hydrocarbon group or an optionally substituted
  • X and Y are the same or different bond, an oxygen atom, a sulfur atom, One CO-, One CS-, One SO- one S_ ⁇ 2 -, -CR 3 (OR 4 ) one one NR 5 - one CO NR 6 — or one NR 6 C ⁇ (R 3 is a hydrogen atom or a hydrocarbon group which may be substituted, R 4 is a hydrogen atom or a hydroxyl-protecting group, R 5 is a hydrogen atom, And R 6 represents a hydrogen atom or an optionally substituted hydrocarbon group N).
  • Q represents a divalent hydrocarbon residue having 1 to 20 carbon atoms
  • Ring A is an aromatic ring which may further have 1 to 3 substituents; n is an integer of 1 to 8;
  • Ring B is a nitrogen-containing 5-membered heterocyclic ring which may further have 1 to 3 substituents;
  • W represents a divalent hydrocarbon residue having 1 to 20 carbon atoms
  • V represents a bond, an oxygen atom, a sulfur atom, —SO—, one SO 2 —, — NR 7 — or one NR 7 CO— (R 7 represents a hydrogen atom or an optionally substituted hydrocarbon group )
  • R 2 is —PO (OR 8 ) (OR 9 ) (R 8 and R 9 are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 8 and R 9 are May form a ring which may be substituted), -COR 10 (R 1G represents a hydrogen atom or a hydrocarbon group which may be substituted), a hydrocarbon group which may be substituted or substituted A heterocyclic group which may be substituted.
  • R g and R h may be bonded to each other to form a ring).
  • X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR 3 (OR 4 ) — or —NR 5 —
  • R 3 is a hydrogen atom Or an optionally substituted hydrocarbon group
  • R 4 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 5 represents a hydrogen atom, an optionally substituted hydrocarbon group or a protecting group for an amino group
  • Y is a bond, an oxygen atom, a sulfur atom, - SO -, one S0 2 -, -NR 6 -, one C ONR 6 - or - NR 6 CO- (R 6 is not good be hydrogen atom or a substituent The compound according to the above 1), which represents a hydrocarbon group);
  • R 2 gar PO (OR 8) (OR 9 ) (R 8 and R 9 are the same or different dates Te hydrogen atom or an optionally substituted hydrocarbon group, and R 8 and R
  • R 9 may be bonded to form an optionally substituted ring), —COR 10 (R 1Q represents a hydrogen atom or an optionally substituted hydrocarbon group) or may be substituted The compound according to the above 1), which is a good heterocyclic group;
  • composition according to the above 11 which is a preventive or therapeutic agent for hyperlipidemia
  • composition according to the above 11 which is an agent for preventing and treating obesity
  • a retinoid-related receptor function modulator comprising the compound according to 1) or a salt thereof or a prodrug thereof;
  • An insulin sensitizer comprising the compound according to 1) or a salt thereof or a prodrug thereof;
  • a method for treating diabetes in a mammal comprising administering the compound according to 1) or a salt thereof or a prodrug thereof to a mammal; 21) the compound according to 1) or a salt thereof or a prodrug thereof. 22.
  • a method for treating hyperlipidemia in a mammal which comprises administering the drug to the mammal; 22) administering the compound according to 1) or a salt thereof or a prodrug thereof to the mammal.
  • examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 1 include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an alicyclic monoaliphatic. Aromatic hydrocarbon groups, araliphatic hydrocarbon groups, and aromatic hydrocarbon groups. The number of carbon atoms in these hydrocarbon groups is preferably 1 to 14.
  • an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable.
  • the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, and octyl.
  • Saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, alkyl group); for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- Methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexagenyl, 5 —Hexenyl, 1 to 1 • penyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-he
  • an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable.
  • the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl (eg, cycloalkyl group, etc.); For example, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, And unsaturated alicyclic hydrocarbon groups having 5 to 7 carbon atoms such as 2,4-cycloheptagenyl (eg, cycloalkenyl group, cycloalkadienyl group, etc.).
  • Examples of the alicyclic monoaliphatic hydrocarbon group include those in which the alicyclic hydrocarbon group is bonded to an aliphatic hydrocarbon group (eg, a cycloalkyl monoalkyl group, a cycloalkenyl alkyl group, and the like). Above all, alicyclic monoaliphatics having 4 to 9 carbon atoms Hydrocarbon groups are preferred. Examples of the alicyclic monoaliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, and 2-cyclopentylmethyl.
  • Examples include cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, and cycloheptylethyl.
  • an araliphatic hydrocarbon group having 7 to 13 carbon atoms eg, an aralkyl group having 7 to 13 carbon atoms, an aralkyl alkenyl group having 8 to 13 carbon atoms
  • an araliphatic hydrocarbon group having 7 to 13 carbon atoms eg, an aralkyl group having 7 to 13 carbon atoms, an aralkyl alkenyl group having 8 to 13 carbon atoms
  • Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; Naphthylalkyl having 11 to 13 carbon atoms such as methyl, ⁇ -naphthylethyl, / 3-naphthylmethyl, i3-naphthylethyl; phenylalkenyl having 8 to 10 carbon atoms such as styryl; 2 — (2-naphthylvinyl And naphthylalkenyl having 12 to 13 carbon atoms.
  • an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group) is preferable.
  • the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, with phenyl, 1-naphthyl and 2-naphthyl being preferred.
  • hydrocarbon groups described above cyclic hydrocarbon groups such as alicyclic hydrocarbon groups and aromatic hydrocarbon groups are preferable.
  • the hydrocarbon group is more preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, particularly preferably fuel, naphthyl and the like.
  • the heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 includes, for example, an oxygen atom, a sulfur atom and a nitrogen atom other than a carbon atom as a ring-constituting atom.
  • a 5- to 7-membered monocyclic heterocyclic group or fused heterocyclic group containing 1 to 4 heteroatoms selected from The fused heterocyclic group includes, for example, a 5- to 7-membered monocyclic heterocyclic group and one or two nitrogen atoms.
  • a group in which a 6-membered ring containing a benzene ring or a 5-membered ring containing one sulfur atom is condensed.
  • heterocyclic group examples include, for example, furyl (2-furyl, 3-furyl), phenyl (2-phenyl, 3-phenyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (1 1-imidazolyl, 2r-midazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isooxazolyl (3-isoxoxazolyl, 4-isoxazolyl, 5- ⁇ ⁇ oxoxazolyl) , Isothiazolyl (3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (2-thiazolyl, 4-dithiazolyl, 5-diazolyl), oxazozolyl (2-diluted xazolyl, 4-diluted xazolyl, 5-digested xazo
  • the heterocyclic group is preferably an aromatic heterocyclic group.
  • the hydrocarbon group and the heterocyclic group represented by R 1 may each have 1 to 5, preferably 1 to 3 substituents at substitutional positions.
  • substituents include “halogen atom”, “nitro group”, “optionally substituted aliphatic hydrocarbon group”, “optionally substituted alicyclic hydrocarbon group”, 'Optionally substituted aromatic hydrocarbon group', 'optionally substituted aromatic heterocyclic group', 'optionally substituted non-aromatic heterocyclic group', 'acyl group', ' An optionally substituted amino group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally esterified or amidated propyloxyl group And the like.
  • Halogen atom includes fluorine, chlorine, bromine and iodine, Of these, fluorine and chlorine are preferred.
  • aliphatic hydrocarbon group in the “optionally substituted aliphatic hydrocarbon group” examples include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, for example, an alkyl group and an alkenyl group. And alkynyl groups.
  • alkyl group examples include an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1 Examples include monoethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, and decyl.
  • alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1 Examples include monoe
  • alkenyl group examples include alkenyl groups having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5- Hexenyl, 11-heptur, 1-octenyl and the like.
  • alkynyl group examples include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propyl, 2-propynyl, 1-butynyl, 2-butenyl, 3-butynyl, 1-pentynyl, 2-pentynyl, and 31-alkynyl.
  • alkynyl groups having 2 to 10 carbon atoms such as ethynyl, 1-propyl, 2-propynyl, 1-butynyl, 2-butenyl, 3-butynyl, 1-pentynyl, 2-pentynyl, and 31-alkynyl.
  • Examples include pentynyl, 4-pentynyl, 1-hexynyl, 21-hexynyl, 31-hexynyl, 4-hexynyl, 5-hexynyl, 1-1 heptynyl, and 11-year-old cutinyl
  • substituent in the “optionally substituted aliphatic hydrocarbon group” examples include a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), Aromatic heterocyclic groups (eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, piperazinyl, etc.), amino groups, Amino group, amidino group, mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.), an acyl group having 2 to 8 carbon atoms (eg, al
  • Examples of the alicyclic hydrocarbon group in the “optionally substituted alicyclic hydrocarbon group” include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, for example, a cycloalkyl group, Examples thereof include a cycloalkenyl group and a cycloalkadienyl group.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] noel, bicyclo [4.2.1] nonyl, Picicyclo [4.3.1] decyl.
  • cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bi
  • cycloalkenyl group examples include a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-11-yl, 3-Hexone 1 f.
  • cycloalkadienyl group examples include a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-cyclopentadiene-11-yl, 2,4-cyclohexadiene-1_yl, 2, 5-cyclohexadiene 1-yl and the like.
  • aromatic hydrocarbon group in the “optionally substituted aromatic hydrocarbon group” include an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group, etc.), for example, examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, biphenylyl and the like, with phenyl, 1.1-naphthyl, 2-naphthyl and the like being preferred.
  • aromatic heterocyclic group in the “optionally substituted aromatic heterocyclic group” examples include, for example, 1 to 5 heteroatoms selected from oxygen, sulfur, and nitrogen atoms in addition to carbon atoms as ring constituent atoms. And a monocyclic, bicyclic or tricyclic aromatic heterocyclic group.
  • Preferred examples of the monocyclic aromatic heterocyclic group include furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxaziazolyl (1,2,3-oxaziazolyl, 1,2,41-41).
  • bicyclic or tricyclic aromatic heterocyclic group examples include benzofuranyl, isobenzofuranyl, benzo [b] chenyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzozo Xazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalagel, naphthyridiel, purinyl, pteridinyl, carbazolyl, ⁇ —carborilyl, ⁇ -propanolyl, r-1 Luponiryl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, indolizini [1,2—b] pyridazin
  • non-aromatic heterocyclic group in the “optionally substituted non-aromatic heterocyclic group” examples include, for example, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. And 3 to 3 non-aromatic heterocyclic groups having 2 to 10 carbon atoms.
  • non-aromatic heterocyclic group examples include oxilanyl, azetidinyl, oxetanyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroviranyl, morpholinel, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholinomorpholino And the like.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine, etc.
  • C2 to C6 alkenyl group C3 to C10 cycloalkyl group which may be substituted by An aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), an aromatic heterocyclic group (eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), a non-aromatic heterocyclic group (eg, Eg, tetrahydrofuryl, morpholino, thio Ruholino, piperidino, pyrrolidiel, piperazinyl, etc.), aralkyl group having 7 to 9 carbon atoms, amino group, alkyl group having 1 to 4 carbon atoms, or acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.).
  • the hydrocarbon group is preferably an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkenyl group having 5 to 7 carbon atoms, There are 14 groups.
  • aromatic heterocyclic group for R 11 or R 12 , for example, those exemplified as the substituent for the aforementioned R 1 can be mentioned.
  • the aromatic heterocyclic group is preferably phenyl, furyl or pyridyl.
  • substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted aromatic heterocyclic group” for R 11 or R 12 are preferably 1 to 3 halogen atoms (eg, , Fluorine, chlorine, bromine, iodine, etc.) optionally substituted Ci-s alkyl group, 1-3 halogen atoms (eg, fluorine, chlorine, odor, etc.) , Iodine, etc.).
  • acryl group examples include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanyl carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, cycloheptanyl
  • Examples of the “optionally substituted amino group” include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, and a carbon atom having 3 to 1 carbon atoms.
  • Examples thereof include an amino group which may be mono- or di-substituted by a cycloalkenyl group having 0, an aryl group having 6 to 14 carbon atoms or an acyl group having 1 to 13 carbon atoms. Examples of these groups include those exemplified above as the substituent for R 1 .
  • the C 1 to C 13 acyl group is preferably a C 2 to C 10 alkanol group, a C 7 to C 13 arylcarbonyl group or the like.
  • substituted amino group examples include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, dibutylamino, diarylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino, and the like.
  • Examples of the “optionally substituted hydroxy group” include, for example, an optionally substituted alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and a carbon number? And an aralkyl group having 1 to 13 carbon atoms, an acyl group having 1 to 13 carbon atoms, and a hydroxy group which may be substituted with an aryl group having 6 to 14 carbon atoms.
  • Examples of the alkyl group, alkenyl group, acyl group or aryl are those exemplified above as the substituent for R 1 .
  • Examples of the aralkyl group include those exemplified as R 1 above.
  • alkyl groups having 1 to 10 carbon atoms “alkenyl groups having 2 to 10 carbon atoms”, “aralkyl groups having 7 to 13 carbon atoms”, “acyl groups having 1 to 13 carbon atoms” and “ Examples of the substituent which the aryl group having 6 to 14 carbon atoms may have are, for example, octylogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and 1 to 3 halogen atoms (eg, fluorine , chlorine, bromine, optionally substituted C ⁇ etc.) iodine - 6 alkoxy group, hydroxy group, a nitro group, an amino group, and the like.
  • the number of substituents is, for example, 1 or 2.
  • Examples of the substituted hydroxy group include an optionally substituted alkoxy group, an alkenyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group, and the like.
  • alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neo Pentyloxy, hexyloxy, heptyloxy, nonyloxy and the like.
  • alkenyloxy group examples include an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, and 3-hexenyloxy.
  • cycloalkyloxy group examples include a cycloalkyloxy group having 3 to 7 carbon atoms, such as cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
  • cycloalkenyloxy group examples include a cycloalkenyloxy group having 5 to 7 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy.
  • Ararukiruokishi groups Ararukiruo alkoxy group number 7-1 0 carbon atoms, for example phenylene Lou C Bok 4 Arukiruokishi (eg, Benjiruokishi, Hue, etc. Nechiruokishi) and the like.
  • acyloxy group examples include an alkoxy group having 2 to 13 carbon atoms, More preferably, they include C 2-4 alkenyloxy (eg, acetyloxy, propionyloxy, petyryloxy, isoptyryloxy, etc.).
  • aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
  • the alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group have one or two substituents at substitutable positions.
  • substituents include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • an alkoxy group, a hydroxy group, a nitro group, an amino group and the like e.g, fluorine, chlorine, bromine, iodine, etc.
  • Examples of the optionally substituted thiol group include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, and a carbon atom having 1 to 10 carbon atoms. And a thiol group which may be substituted with an aryl group having 13 to 13 carbon atoms, an aryl group having 6 to 14 carbon atoms, or a heteroaryl group.
  • Examples of the alkyl group, cycloalkyl group, acyl group and aryl group include those exemplified as the substituent for R 1 .
  • Examples of the aralkyl group include those exemplified as the aforementioned R 1 .
  • heteroaryl group examples include pyridyl (eg, 2-pyridyl, 3-pyridyl), imidazolyl (eg, 2-imidazolyl), triazolyl (eg, 1,2,4-triazole-5-yl) and the like.
  • pyridyl eg, 2-pyridyl, 3-pyridyl
  • imidazolyl eg, 2-imidazolyl
  • triazolyl eg, 1,2,4-triazole-5-yl
  • substituted thiol group examples include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, and heteroarylthio.
  • alkylthio group examples include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. Butylthio, t. Butylthio, pentylthio, isopentylthio. , Neopentylthio, hexylthio, heptylthio, noni Luthio and the like.
  • alkylthio group having 1 to 10 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. Butylthio, t. Butylthio, pentylthio, isopentylthio. , Neopentylthio, hexylthio, heptylthio, noni Lu
  • cycloalkylthio group examples include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • Ararukiruchio group Ararukiruchio group having a carbon number of 7 to 0, for example, phenylene Lu ⁇ _ 4 alkylthio (e.g., benzylthio, Fuenechiruchi O, etc.) and the like.
  • phenylene Lu ⁇ _ 4 alkylthio e.g., benzylthio, Fuenechiruchi O, etc.
  • acylthio group examples include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
  • alkanolthio group having 2 to 4 carbon atoms
  • arylthio groups include arylthio groups having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
  • heteroarylthio group examples include pyridylthio (eg, 2-pyridylthio, 3-pyridylthio), imidazolylthio (eg, 2-imidazolylthio), triazolylthio (eg, 1,2,4-triazolylthio). Lou 5-ylthio) and the like.
  • the esterified ester group may be, for example, an alkoxyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxylponyl, ptoxycarponyl, etc.).
  • An aralkyloxycarbonyl group having 8 to 10 carbon atoms e.g., benzyloxycarbonyl, etc.
  • an alkyl group having 7 to 15 carbon atoms which may be substituted with 1 to 2 alkyl groups having 1 to 3 carbon atoms.
  • a ryloxycarbonyl group eg, phenoxycarbonyl, p-tolyloxycarbonyl
  • the amidated carboxyl group may be represented by the formula: —CON (R 13 ) (R 14 )
  • R 13 and R 14 are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 13 and R 13 14 forms a nitrogen-containing heterocyclic ring which may be substituted with an adjacent nitrogen atom. May be formed. ).
  • the "optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R 1 3 and R 1 4 are include those exemplified as the R 1.
  • the substituents on the hydrocarbon group and the heterocyclic group are preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ( ⁇ -6 alkyl group, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) alkoxy group, nitro group
  • the number of substituents is, for example, 1 to 3.
  • nitrogen-containing heterocycle As the "nitrogen-containing heterocycle" of R 1 3 and R 1 4 is formed together with the adjacent nitrogen atom "nitrogen-containing heterocyclic ring but it may also be substituted", for example, as a ring-constituting atom, besides carbon atoms Examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains at least one nitrogen atom and may further contain 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • the “nitrogen-containing heterocycle” is preferably piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine and the like.
  • Preferred examples of the substituent for R 1 include:
  • alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a 1 to 3 halogen atom (eg, fluorine, C1-C6 alkoxy groups and halogen atoms (eg, fluorine, chlorine, odor) which may be substituted with chlorine, bromine, iodine, etc.
  • a nitro group, a hydroxy group and an amino group which may have 1 to 3 substituents, and may have 3 to 10 (preferably 3 to 7) cycloalkyl groups (preferably Is cyclohexyl);
  • alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, Selected from C1-C6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups, hydroxy groups and amino groups, which may be substituted with chlorine, bromine, iodine, etc.
  • An aryl group having 6 to 14 carbon atoms which may have 1 to 3 substituents (preferably phenyl, naphthyl, etc.);
  • alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, Selected from C1-C6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups, hydroxy groups and amino groups, which may be substituted with chlorine, bromine, iodine, etc.
  • Aromatic heterocyclic groups which may have 1 to 3 substituents (preferably furyl, phenyl, pyridyl, pyridinyl and the like); and the like.
  • R 1 is preferably an optionally substituted cyclic group.
  • examples of the cyclic group include the aforementioned cyclic hydrocarbon group and heterocyclic group.
  • R 1 is more preferably an optionally substituted heterocyclic group (preferably an aromatic heterocyclic group).
  • R 1 Preferred specific examples of R 1 include:
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, Selected from C1-C6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups, hydroxy groups and amino groups, which may be substituted with chlorine, bromine, iodine, etc.
  • An aryl group having 6 to 14 carbon atoms which may have 1 to 3 substituents (preferably, phenyl, naphthyl, etc.); and
  • alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, Selected from C1-C6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups, hydroxy groups and amino groups, which may be substituted with chlorine, bromine, iodine, etc.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • halogen atoms eg, fluorine, Selected from C1-C6 alkoxy groups
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • nitro groups hydroxy groups and amino groups, which may be substituted with chlorine, bromine, iodine, etc.
  • An aromatic heterocyclic group optionally having 1 to 3 substituents (preferably furyl, phenyl, pyridyl, pyrazinyl, etc.); and optionally having 1 to 3 substituents selected from 5- to 7-membered monocyclic aromatic heterocyclic group (preferably oxazolyl, thiazolyl, oxdiazolyl, thiadiazolyl, triazolyl, pyridyl, etc .; more preferably oxazolo Le, etc.) and the like.
  • an alkyl group having 1 to 4 carbon atoms preferably methyl, ethyl, etc.
  • an aryl group having 6 to 14 carbon atoms preferably phenyl, naphthyl, etc.
  • an aromatic heterocyclic group preferably furyl
  • a 5- to 7-membered monocyclic aromatic heterocyclic group preferably oxazolyl, thiazolyl, oxazidiazolyl
  • X and Y are the same or different bond, an oxygen atom, sulfur atom, -CO-, one CS-, one S_ ⁇ -, -S0 2 -, -CR 3 ( OR 4) —, NR 5 —, — CONR 6 — or — NR 6 C——
  • R 3 is a hydrogen atom or an optionally substituted hydrocarbon group
  • R 4 is a hydrogen atom or a hydroxyl-protecting group
  • R 5 Represents a hydrogen atom, an optionally substituted hydrocarbon group or an amino group-protecting group
  • R 6 represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • X is preferably a bond, an oxygen atom, a sulfur atom, —CO—, one CS—, one CR 3 (OR 4 ) one or —NR 5 — (R 3 , R 4 and R 5 are as defined above. More preferably a bond or —NR 5 _ (R 5 has the same meaning as described above); particularly preferably a bond.
  • the “optionally substituted hydrocarbon group” represented by R 3 and R 5 those exemplified as the aforementioned R 1 can be mentioned.
  • the ⁇ optionally substituted hydrocarbon group '' is preferably an optionally substituted alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, t.-butyl and the like.
  • the alkyl group may have 1 to 3 substituents at substitutable positions.
  • substituents examples include an octogen atom (eg, fluorine, chlorine, bromine, iodine), carbon Alkoxy groups of 1 to 4 (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, etc.), hydroxy group, nitro group, amino group, 1 to 4 carbon atoms And acyl groups (eg, alkanoyl groups having 1 to 4 carbon atoms such as formyl, acetyl, propionyl, etc.).
  • octogen atom eg, fluorine, chlorine, bromine, iodine
  • carbon Alkoxy groups of 1 to 4 eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, etc.
  • hydroxy group eg, methoxy, ethoxy, propoxy, isopropoxy
  • R 3 and R 5 are preferably a hydrogen atom or an alkyl having 1 to 4 carbons.
  • (vii 6 alkyl e.g., methylation, Echiru, propyl, isopropyl, heptyl, tert such as single heptyl), phenyl, trityl, C 7 _ 10 Ararukiru (e.g., Benzyl, etc.), formyl, ⁇ Alkyl-carbonyl (eg, acetyl, propionyl, etc.), benzoyl,.
  • alkyl e.g., methylation, Echiru, propyl, isopropyl, heptyl, tert such as single heptyl
  • phenyl trityl
  • C 7 _ 10 Ararukiru e.g., Benzyl, etc.
  • formyl e.g., Benzyl, etc.
  • ⁇ Alkyl-carbonyl eg, acetyl, propionyl, etc.
  • Aralkyl-carbonyl eg, benzylcarbonyl, etc.
  • 2-tetrahydropyrael 2-tetrahydrofuranyl
  • silyl eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butylethylsilyl, etc.
  • C 2 _ 6 alkenyl eg, 1-aryl
  • These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C- 6 alkyl (eg, methyl, ethyl, propyl, etc.), 6 alkoxy (eg, methoxy, ethoxy, Or a nitro group.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • C- 6 alkyl eg, methyl, ethyl, propyl, etc.
  • 6 alkoxy eg, methoxy, ethoxy, Or a nitro group.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • 6 alkoxy eg, methoxy, ethoxy, propoxy, etc.
  • R 6 As the “optionally substituted hydrocarbon group” for R 6 , those exemplified for the aforementioned R 1 can be mentioned. Among them, an alkyl group having 1 to 4 carbon atoms is preferable. R 6 is preferably a hydrogen atom.
  • Y is preferably a bond, an oxygen atom, a sulfur atom, — SO_, one S ⁇ 2 —, -N 6-one CONR 6 — or one NR 6 C ⁇ , (: R 6 is a hydrogen atom or a substituted More preferably an oxygen atom or one NR 6 — (R 6 has the same meaning as described above); particularly preferably an oxygen atom.
  • examples of the “divalent hydrocarbon group having 1 to 20 carbon atoms” represented by Q include “divalent acyclic hydrocarbon group” and “divalent cyclic hydrocarbon”. And a divalent group obtained by combining one or more divalent acyclic hydrocarbon groups with one or more divalent cyclic hydrocarbon groups.
  • examples of the “divalent acyclic hydrocarbon group” include alkylene having 1 to 20 carbon atoms, alkenylene having 2 to 20 carbon atoms, and alkynylene having 2 to 20 carbon atoms. .
  • ⁇ divalent cyclic hydrocarbon group '' there may be mentioned a cycloalkane having 5 to 20 carbon atoms, a cycloalkene having 5 to 20 carbon atoms or an aromatic hydrocarbon having 6 to 18 carbon atoms (e.g., benzene, And a divalent group obtained by removing any two hydrogen atoms from naphthalene, indene, and anthracene.
  • a cycloalkane having 5 to 20 carbon atoms
  • a cycloalkene having 5 to 20 carbon atoms
  • aromatic hydrocarbon having 6 to 18 carbon atoms
  • divalent group obtained by removing any two hydrogen atoms from naphthalene, indene, and anthracene e.g., benzene
  • Specific examples include 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, and 1,
  • Q is preferably a divalent hydrocarbon group having 1 to 6 carbon atoms, and among them, (DC 6 alkylene (for example, —C—, mono (CH 2 ) 2 —,-(CH 2 ) 3 —, _ (CH 2 ) 4 one, one (CH 2 ) 5 —, one (CH 2 ) 6 —, one CH (C3 ⁇ 4) —, one C (CH 3 ) 2 —, one (CH (CH 3 )) 2 —, One (CH 2 ) 2 C (CH 3 ) 2 —,-(CH 2 ) 3 C (CH 3 ) 2 etc.);
  • DC 6 alkylene for example, —C—, mono (CH 2 ) 2 —,-(CH 2 ) 3 —, _ (CH 2 ) 4 one, one (CH 2 ) 5 —, one (CH 2 ) 6 —, one CH (C3 ⁇ 4) —, one C (CH 3 ) 2 —, one (CH (CH 3 )) 2
  • C 2 - 6 alkynylene e.g., - C [identical to] C one, - C3 ⁇ 4 _C ⁇ C-, such as -CH 2 -C ⁇ C-CH 2 one CH 2 I
  • Q is more preferably a C alkylene or C 2 _ 6 alkenylene, among others, one CH 2 -, - (CH 2 ) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - CH-CH— and the like are preferable.
  • Q is particularly preferably —CH 2 —, — (CH 2 ) 2 — and the like.
  • the “aromatic ring” in the “aromatic ring optionally having one to three substituents” represented by ring A includes, for example, a benzene ring, a condensed aromatic hydrocarbon Ring, 5- or 6-membered aromatic heterocyclic ring, condensed aromatic heterocyclic ring and the like.
  • the “condensed aromatic hydrocarbon ring” includes, for example, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms. Specific examples include naphthalene, indene, fluorene, and anthracene.
  • Examples of the "5- or 6-membered aromatic heterocycle” include a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
  • fused aromatic heterocycle for example, a 9 to 14 membered (preferably 9 or 10 membered) containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom And fused aromatic heterocycles.
  • the “aromatic ring” is preferably a benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene or the like), a 5- or 6-membered aromatic heterocyclic ring (preferably Preferably, pyridine, oxazole, isoxazole, thiazole, oxdiazole, etc.).
  • ⁇ substituent '' in the ⁇ aromatic ring which may further have 1 to 3 substituents '' for ring A, an optionally substituted aliphatic hydrocarbon group, an optionally substituted Examples include a good hydroxy group, a halogen atom, an acyl group, a nitro group, and an optionally substituted amino group.
  • substituents those exemplified as the substituent for R 1 can be used.
  • the substituent in the ring A is preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms (preferably methoxy), an aralkyloxy group having 7 to 10 carbon atoms, or an octylogen atom. is there.
  • Ring A preferably has 1 or 2 substituents selected from an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms (preferably methoxy) and a halogen atom.
  • a benzene ring or a 5- or 6-membered aromatic heterocyclic ring preferably pyridine
  • It is a 5- or 6-membered aromatic heterocycle (preferably pyridine).
  • n represents an integer of 1 to 8.
  • n is preferably an integer of 1 to 3, and more preferably 1.
  • the “nitrogen-containing 5-membered heterocyclic ring” represented by ring B includes, for example, at least one nitrogen atom other than a carbon atom as a ring-constituting atom, and includes an oxygen atom, a sulfur atom, and a nitrogen atom.
  • a 5-membered heterocyclic ring which may further contain 1 to 3 heteroatoms selected from
  • nitrogen-containing 5-membered heterocycle examples include nitrogen-containing 5-membered non-aromatic heterocycles such as pyrrolidine, imidazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine, isoxazolidine, and isothiazolidine. ; Nitrogen-containing 5-members such as pyrrole, imidazole, pyrazole, triazole, and tetrazole An aromatic heterocycle is mentioned.
  • the “nitrogen-containing 5-membered heterocycle” represented by ring B is preferably a nitrogen-containing 5-membered aromatic complex ring, and more preferably a pyrrole ring, an imidazole ring, a pyrazoyl ring and the like.
  • Ring B may have 1 to 3, preferably 1 to 2 substituents at substitutable positions.
  • substituents include, for example, "octogen",
  • substituents those exemplified as the substituent for R 1 can be used.
  • the “substituent” in ring B is preferably a hydrocarbon group, more preferably an alkyl group having 1 to 10 carbon atoms (preferably methyl or the like), an aralkyl group having 7 to 13 carbon atoms (eg, Benzyl, etc.) and aryl groups having 6 to 14 carbon atoms (preferably phenyl, naphthyl, etc.).
  • a monocyclic aromatic heterocyclic group preferably, furyl or phenyl is also preferable.
  • Ring B preferably has one or two substituents selected from an aryl group (preferably phenyl) having 6 to 14 carbon atoms and a monocyclic aromatic heterocyclic group (preferably furyl, phenyl). 5-membered aromatic heterocycle (optional) Or a pyrrol ring, an imidazole ring, or a pyrazole ring, and more preferably a pyrrol ring or a pyrazole ring).
  • examples of the “divalent hydrocarbon group having 1 to 20 carbon atoms” represented by W include those exemplified as the aforementioned Q.
  • W is preferably C _ 6 alkylene or C 2 _ 6 alkenylene, among others, single C -!
  • V is a bond, an oxygen atom, a sulfur atom,
  • S_ ⁇ one one S_ ⁇ 2 one, - NR 7 - or a NR 7 CO- R 7 is is hydrogen atom or a substituent Represents a hydrocarbon group which may be present).
  • R 7 As the “optionally substituted hydrocarbon group” for R 7 , those exemplified for the aforementioned R 1 can be mentioned. Among them, an alkyl group having 1 to 4 carbon atoms is preferable. R 7 is preferably a hydrogen atom. , V is preferably a bond.
  • R 2 is one PO (OR 8) (OR 9 ) (R 8 and R 9 represents a hydrocarbon group which may optionally be a hydrogen atom or a substituent same or different, and R 8 And R 9 may combine to form an optionally substituted ring), -COR 10 (R 1Q represents a hydrogen atom or an optionally substituted carbon hydride group), A hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
  • Examples of the “optionally substituted carbon hydride group” represented by RR 9 , R 1Q and R 2 include those exemplified as the aforementioned R 1 .
  • the “optionally substituted hydrocarbon group” represented by R 8 , 1 ⁇ 9 and 11 () is preferably an “alkyl group having 1 to 4 carbon atoms” and the like.
  • the “alkyl group having 1 to 4 carbon atoms” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. And methyl and ethyl are particularly preferred.
  • R 2 As the “optionally substituted heterocyclic group” for R 2 , those exemplified for the aforementioned R 1 can be mentioned. Among them, a 5- to 7-membered monocyclic aromatic heterocyclic group (preferably oxazolyl, thiazolyl, or the like) which may be substituted by an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, propyl) Oxaziazolyl, thiadiazolyl, triazolyl, pyridyl; more preferably thiazolyl, oxaziazolyl) and the like.
  • a 5- to 7-membered monocyclic aromatic heterocyclic group preferably oxazolyl, thiazolyl, or the like
  • an alkyl group having 1 to 4 carbon atoms preferably methyl, ethyl, propyl
  • the “optionally substituted ring” formed by R 8 and; 9 together with an adjacent oxygen atom and phosphorus atom is, for example, a compound represented by the formula:
  • alk represents an alkylene group having 1 to 10 carbon atoms which may be substituted.
  • alkyl group having 1 to 10 carbon atoms which may be substituted examples include —C, — (CH 2 ) 2 —, one (CH 2 ) 3 —, one (CH 2 ) 4 —, _ (C) 5 —, one (C3 ⁇ 4) 6 — , One CH (C) —, one C (CH 3 ) 2 one, one (CH (C)) 2 —, one (C) 2 C (C3 ⁇ 4) 2 —, one (C3 ⁇ 4) 3 C (C3 ⁇ 4) 2 — , -CH (CH 3 ) -CH 2 , — CH 2 — CH (C) — C3 ⁇ 4—, — CH 2 — C (C) “C —, — C _ CH (CC) — C3 ⁇ 4, -CH ( CH 3 ) -CH 2 -1 CH (
  • alkylene group having 1 to 10 carbon atoms may have 1 to 3, preferably 1 to 2 substituents at substitutable positions.
  • substituents include a hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.).
  • R 2 is Konomareku one P_ ⁇ (OR 8) (OR 9) (R 8 and R 9 represents a were identical or different and represent a hydrogen atom or an optionally substituted hydrocarbon group and R 8 And R 9 may combine to form an optionally substituted ring), -COR 10 (R 1 Q represents a hydrogen atom or an optionally substituted hydrocarbon group) or A heterocyclic group which may be (OR 8 ) (OR 9 ) (R 8 and R 9 are as defined above) or an optionally substituted heterocyclic group.
  • R 2 is particularly preferably
  • R 8 and R 9 are the same or different and are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, propyl)];
  • a 5- to 7-membered monocyclic aromatic heterocyclic group (preferably oxazolyl, thiazolyl) which may be substituted by an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, propyl).
  • R 2 one (C 0) - R e (R e one 0R f (R f is a hydrogen atom or an optionally substituted hydrocarbon group shown) or a NR3 ⁇ 4 h (R g and R h are the same or different and each represents a hydrogen atom, an optionally substituted carbon hydrocarbon group, an optionally substituted heterocyclic group or optionally substituted ⁇ , And R g and R h may be combined to form a ring), but not a hydrocarbon group substituted with a substituent represented by the formula:
  • Preferable specific examples of the compound represented by the general formula (I) include the following compounds.
  • R 1 is an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, etc.), an aryl group having 6 to 14 carbon atoms (preferably phenyl, naphthyl, etc.) and an aromatic heterocyclic group (preferably furyl, phenyl, A 5- to 7-membered monocyclic aromatic heterocyclic group (preferably oxazolyl, thiazolyl, oxaziazolyl, thiadiazolyl, triazolyl) which may have 1 to 3 substituents selected from pyridyl, pyragel, etc. Pyridyl or the like; more preferably oxazolyl);
  • X is a bond
  • Q is C i _ 6 alkylene or C 2 - 6 alkenylene (preferably - CH 2 -, one (CH 2)
  • Y is an oxygen atom
  • a ring A in which a benzene ring or a 5- or 6-membered aromatic heterocycle (preferably pyridine) each of which may be substituted by an alkoxy group having 1 to 4 carbon atoms (preferably methoxy);
  • n is an integer of 1 to 3 (preferably 1);
  • Ring B may have 1 to 2 substituents selected from an aryl group having 6 to 14 carbon atoms (preferably phenyl) and a monocyclic aromatic heterocyclic group (preferably furyl, phenyl).
  • aryl group having 6 to 14 carbon atoms preferably phenyl
  • a monocyclic aromatic heterocyclic group preferably furyl, phenyl.
  • Good 5-membered aromatic heterocycle preferably pyrrole ring, imidazole ring, pyrazolyl ring, more preferably pyrrole ring, pyrazolyl ring
  • V is a bond
  • R 8 and R 9 are the same or different and are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, propyl)] or
  • a 5- to 7-membered monocyclic aromatic heterocyclic group (preferably oxazolyl or thiazolyl) which may be substituted by an alkyl group having 1 to 4 carbon atoms (preferably methyl, ethyl, or propyl).
  • a salt of the compound represented by the general formula (I) (hereinafter may be abbreviated as the compound (I)), a pharmacologically acceptable salt is preferable.
  • a salt with an inorganic base for example, a salt with an inorganic base, an organic base, And salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, ammonium salt and the like.
  • Preferred examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Salts.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumanoleic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, P- Examples thereof include salts with toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, orditin and the like. '
  • salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid and the like.
  • a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in vivo, that is, a compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. Or a compound that undergoes hydrolysis or the like due to stomach acid or the like to change to compound (I).
  • Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonyl).
  • the prodrug of compound (I) can be obtained under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Vol. 7, Molecular Design, pp. 163 to 198. (I) may be changed.
  • the compound (I) may be labeled with an isotope (eg,% H C, 35 S, I 25 I, etc.).
  • an isotope eg,% H C, 35 S, I 25 I, etc.
  • the compound (I) may be an anhydride or a hydrate.
  • Compound (I) or a salt thereof (hereinafter may be simply abbreviated as the compound of the present invention) has a low toxicity and is used as it is or as a mixture with a pharmacologically acceptable carrier to form a pharmaceutical composition. As a result, it can be used as a preventive / therapeutic agent for various diseases described below in mammals (eg, humans, mice, rats, puppies, dogs, cats, cats, puppies, pigs, monkeys, etc.). .
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as drug substances are used, and excipients, lubricants, binders, disintegrants in solid preparations, and solvents in liquid preparations It is formulated as a solubilizer, suspending agent, isotonic agent, buffer, soothing agent and the like. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
  • excipients include lactose, sucrose, D-mannitol, D- Sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light silicic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate, etc. Is mentioned.
  • Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include, for example, starch arsenide, sucrose, gelatin, arabia gum, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxy Propylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • Preferred examples of the disintegrant include, for example, lactose, sucrose, starch, lipoxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light citric anhydride, low-substituted hydroxypropylcellulose and the like.
  • Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizing agent examples include, for example, polyethylene glycol, propylene glycol, D-manni! ⁇ L, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, Examples include sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
  • the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol. , Polybutylpyrrolidone, sodium oxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose Hydrophilic polymers such as cellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate
  • polyvinyl alcohol polybutylpyrrolidone
  • Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
  • buffers such as phosphate, acetate, carbonate, citrate and the like. '
  • the soothing agent include benzyl alcohol and the like.
  • preservative examples include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferred examples of the antioxidant include, for example, sulfite, ascorbate and the like.
  • the coloring agent include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, water-insoluble lakes). Dyes (eg, aluminum salts of the water-soluble edible tar dyes, etc.), and natural dyes (eg, ⁇ -potency rotin, chlorophyll, bengalara, etc.), etc.
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, water-insoluble lakes.
  • Dyes eg, aluminum salts of the water-soluble edible tar dyes, etc.
  • natural dyes eg, ⁇ -potency rotin, chlorophyll, bengalara, etc.
  • the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the dosage form of the pharmaceutical composition include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, Oral preparations such as suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, intranasal preparations, transdermal preparations, Ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), parenteral preparations such as pellets, drops, eye drops, pulmonary preparations (inhalants), etc. Alternatively, it can be safely administered parenterally. In addition, these preparations may be controlled-release preparations
  • the pharmaceutical composition can be produced by a method commonly used in the technical field of formulation, for example, the method described in the Japanese Pharmacopoeia. Hereinafter, the specific production method of the drug product will be described in detail.
  • active ingredients include, for example, excipients (eg, lactose, sucrose, starch, D-mannitol!), Disintegrants (eg, carboxymethylcellulose sodium), binders (eg, For example, add starch arsenide, gum arabic, lipoxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc. or lubricant (eg, talc, magnesium stearate, polyethylene glycol 600, etc.) Then, if necessary, it is produced by coating with a coating base in a manner known per se for the purpose of taste masking, enteric coating or persistence.
  • excipients eg, lactose, sucrose, starch, D-mannitol!
  • Disintegrants eg, carboxymethylcellulose sodium
  • binders eg, For example, add starch arsenide, gum arabic, lipoxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc. or lubricant
  • the coating base examples include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained release film coating base, and the like.
  • sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal acetylaminoacetate; And synthetic polymers such as aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.) and polyvinylpyrrolidone; and polysaccharides such as pullulan.
  • cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose
  • polyvinyl acetal acetylaminoacetate examples include synthetic polymers such as aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.) and polyvinylpyrrolidone; and polysaccharides such as pullulan.
  • Enteric film coating bases include, for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and acetic acid phthalate.
  • Cellulose-based polymers such as llulose; methacrylic acid copolymer L (Eidragit L (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L-1 30 D55 (trade name), Kuchiichi Mufarma Co., Ltd.) And methacrylic acid copolymers S (Eudragit S (trade name), Rohm Pharma Co., Ltd.); and acrylic acid-based polymers; natural products such as shellac.
  • sustained-release film coating base examples include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Oidragit RS (trade name), Rohm Pharma Co., Ltd.), and ethyl acrylate * methyl acrylic Acrynolate-based polymers such as acid-methyl copolymer suspension [Eudragit NE (trade name), Kuchiichi Mufalma Co., Ltd.] and the like.
  • cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Oidragit RS (trade name), Rohm Pharma Co., Ltd.), and ethyl acrylate * methyl acrylic Acrynolate-based polymers such as acid-methyl copolymer suspension [Eudragit NE (trade name), Kuchiichi Mufalma Co., Ltd.] and the like.
  • the above-mentioned coating bases may be used as a mixture of two or more kinds at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.
  • Injectables contain active ingredients as dispersants (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., preservatives (eg, methylparaben, propylparaben, benzyl alcohol) , Chlorobutanol, phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D_mannitol, D-sorbitol, dextrose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) It is manufactured by dissolving, suspending or emulsifying in an oily solvent (eg, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.).
  • an oily solvent eg, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glyco
  • additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.
  • a solubilizing agent eg, sodium salicylate, sodium acetate, etc.
  • a stabilizer eg, human serum albumin, etc.
  • a soothing agent eg, benzyl alcohol, etc.
  • the compound of the present invention has a blood sugar lowering action, a blood lipid lowering action, a blood insulin lowering action, an insulin resistance improving action, an insulin sensitivity enhancing action, and a retinoid-related receptor function regulating activity.
  • the function-modulating activity as used herein means both agonist activity and antagonist activity.
  • retinoid-related receptors are DNA-binding transcription factors that are contained in nuclear receptors and have ligands for signal molecules such as fat-soluble vitamins. These are monomeric receptors and homodimeric receptors. It may be any of a body and a heterodimeric receptor.
  • retinoid O receptor for example, retinoid O receptor (hereinafter sometimes abbreviated as R ⁇ R) a (GenBank Accession No. L14611), ROR jS (GenBank Accession No. L14160), ROR r Ev-erb (GenBank Accession No.M24898), R ev — erb ⁇ (GenBank Accession No. L31785); ERR a (GenBank Accession No. X51416), ERR jS (GenBank Accession No. X51417); Ftz-FI (GenBank Accession No. S65876); Ftz-FI ⁇ (GenBank Accession No. M81385); TI x (GenBank Accession No. S77482); GCNF (GenBank Accession No. U14666).
  • R ⁇ R retinoid O receptor
  • homodimer-type receptors examples include retinoid X receptor (hereinafter sometimes abbreviated as RXR) a (GenBank Accession on No. X52773) RXR / 3 (GenBank Accession No. M84820), RXR r (GenBank Accession No. U38480); C OUP a (GenBank Accession No. X12795), COUP j3 (GenBank Accession No. M64497), COUP r (GenBank Accession No. X12794); TR2 o; (GenBank Accession No. M29960), TR2 3 (GenBank Accession No. L27586); or a homodimer formed by HNF4a (GenBank Accession No. X76930), HNF4r (GenBank Accession No. Z49826), or the like.
  • RXR retinoid X receptor
  • the heterodimeric receptor includes, for example, the above-mentioned retinoid X receptor (R XR o !, RXRj3 or RXR) and retinoid A receptor (hereinafter sometimes abbreviated as RAR) (GenBank Accession No. X06614). ), RAR ⁇ (GenBank Accession No. Y00291), RARa (GenBank Accession No. M24857); Thyroid hormone receptor (hereinafter sometimes abbreviated as TR) (GenBank Accession No. M24748) , TRj3 (GenBank Accession No. M26747); Vitamin D receptor (VDR) (GenBank Accession No.
  • P PAR Peroxisome proliferator-responsive receptor
  • the compounds of the present invention include, among the above-mentioned retinoid-related receptors, retinoid X receptors (RXRa, RXR / 3, RXRr) and peroxisome proliferator-activated receptors (PPARc3 ⁇ 4, PPARi3 (PPAR ⁇ ), PPARr). It has an excellent ligand activity against, and is useful as an agonist, a partial agonist (partial agonist), an antagonist or a partial antagonist (partial antagonist) for these receptors.
  • the compound of the present invention is a heterodimeric receptor formed by a retinoid X receptor and a peroxisome proliferator-responsive receptor (eg, a heterodimeric receptor formed by RXRa and PPAR ⁇ , RXRo ! And PPART have an excellent ligand activity for a peroxisome proliferator-activated receptor in a heterodimeric receptor, etc.).
  • a heterodimeric receptor formed by a retinoid X receptor and a peroxisome proliferator-responsive receptor eg, a heterodimeric receptor formed by RXRa and PPAR ⁇ , RXRo ! And PPART have an excellent ligand activity for a peroxisome proliferator-activated receptor in a heterodimeric receptor, etc.
  • the retinoid-related receptor ligand of the present invention is suitably used as a peroxisome proliferator-activated receptor ligand or a retinoid X receptor ligand.
  • the compound of the present invention is characterized by a peroxisome proliferator-activated receptor (PP)
  • the compound of the present invention can exert a blood glucose lowering effect by suppressing the differentiation of preadipocytes into adipocytes and improving insulin resistance based on the PPARr antagonistic activity.
  • the compound of the present invention is a prophylactic / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, low HDL blood) ⁇ Improvement of insulin resistance; Insulin sensitivity enhancer; Insufficiency of glucose tolerance [I GT (I immediately aired Glucose Tolerance)] Can be used as an inhibitor of the transition from glucose to diabetes.
  • diabetes is defined as a fasting blood glucose level (Dalcose concentration in venous plasma) of 126 mg Zd 1 or more, 75 g transglucose tolerance test (75 g OGTT), and a 2-hour value (glucose concentration in venous plasma). Is 200 mgZd 1 or more, and the blood glucose level (glucose concentration in venous plasma) at any time is 20 OmgZd 1 or more.
  • diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / d1 or more, and a 2-hour glucose glucose load test (75 g glucose concentration in venous plasma). ) Is a state showing SO OmgZd l or more.
  • impaired glucose tolerance refers to a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg Zd1 and a 2-hour value of 75 g translobulin glucose tolerance test (venous plasma Is less than 140 mg / d1 and less than 20 OmgZd1.
  • ADA reported that fasting blood glucose (Dalcos concentration in venous plasma) was ll Omg. / ⁇ 1 or more and less than 1 26 mg / d 1 is called IFG (Impaired Fasting Glucose).
  • the compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Immediate aired Fasting Glucose) and IFG (Impaired Fasting Giycemia) determined by the above-mentioned new criteria. Further, the compound of the present invention can also prevent the progression of diabetes from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Giycemia).
  • the compound of the present invention may be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infectious diseases (eg, respiratory infections, urine Tract infections, digestive organ infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, decreased hearing, cerebrovascular disorders, peripheral blood circulation disorders, etc.), obesity, osteoporosis, cachexia (Eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, cachexia due to infectious cachexia or cachexia due to late immune deficiency syndrome), fatty liver , Hypertension, polycystic ovary syndrome, renal disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end-stage renal disease,
  • the compound of the present invention has a total cholesterol lowering effect and has a plasma anti-atherosclerosis index It can be used as a prophylactic and therapeutic agent for arteriosclerosis (eg, atherosclerosis, etc.) to increase [(HD L cholesterol Z total cholesterol) X 100].
  • arteriosclerosis eg, atherosclerosis, etc.
  • the compound of the present invention may also be used for improving symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis, etc. Can be.
  • the compound of the present invention may be used as a therapeutic agent for slimming and phagocytosis (weight gain in subjects to which slimming or phagocytosis is administered) or a therapeutic agent for obesity, for example, to regulate (enhance or suppress) appetite. it can.
  • the compound of the present invention has a TNF- ⁇ inhibitory effect (an effect of reducing the amount of TNF- ⁇ production in living tissues and an effect of reducing the activity of TNF- ⁇ ), and prevents and treats inflammatory diseases in which TNF_Q! Is involved. Also used as medicine.
  • Such inflammatory diseases include, for example, diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorders, etc.), rheumatoid arthritis, osteoarthritis, osteoarthritis, back pain, gout And inflammation after surgery and trauma, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, gastric mucosal damage (including gastric mucosal damage caused by aspirin).
  • diabetic complications eg, retinopathy, nephropathy, neuropathy, macrovascular disorders, etc.
  • rheumatoid arthritis eg., osteoarthritis, osteoarthritis
  • back pain gout And inflammation after surgery and trauma, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, gastric mucosal damage (including gastric mucosal damage caused by aspirin).
  • the compound of the present invention has an inhibitory effect on apoptosis, and is also used as a preventive / therapeutic agent for diseases associated with promotion of apoptosis.
  • diseases associated with promotion of apoptosis include, for example, viral diseases (eg, AIDS, fulminant hepatitis, etc.), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Retinitis pigmentosa, cerebellar degeneration, etc., spinal dysplasia (eg, aplastic anemia, etc.), ischemic disease (eg, myocardial infarction, stroke, etc.), liver disease (eg, 7-leukor hepatitis, hepatitis B) , Hepatitis C, etc.), joint diseases (eg, osteoarthritis, etc.), atherosclerosis and the like.
  • viral diseases eg, AIDS, fulminant hepatitis, etc.
  • the compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary artery metabolism, and improves cardiovascular complications.
  • the compound of the present invention is also used for secondary prevention of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction).
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptoms, and the like.For example, when orally administered to an adult diabetic patient, the dose is usually about 0.005 to 5 Omg / kg as a single dose.
  • the body weight is preferably 0.01 to 2 mg / kg body weight, more preferably 0.025 to 0.5 mg Zkg body weight, and it is desirable to administer this amount once to three times a day.
  • the compound of the present invention is a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, and an improvement in cachexia. It can be used in combination with drugs such as drugs (hereinafter abbreviated as concomitant drugs). At this time, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at an interval.
  • the concomitant drug may be a low molecular compound, a high molecular protein, a polypeptide, an antibody, or a vaccine.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.
  • the antidiabetic drugs include insulin preparations (eg, animal insulin preparations extracted from the stomach of the mouse and bush; human insulin preparations genetically synthesized using Escherichia coli and yeast; insulin zinc; protamine) Insulin zinc; insulin fragment or derivative (eg, INS-1 etc.), insulin resistance improver (eg, pioglitazone hydrochloride, troglitazone, oral ciglitazone or its maleate, GI-262570, JTT-501) , M Compounds described in CC—555, YM—440, KRP—297, CS—011, FK-614, WO 99/58510 (for example, (E) —4— [4— (5—Methyl-2-phenyl-4 1-oxazolylmethoxy) benzyloxyimino] —4-monophenylbutyric acid), NN—622, AZ—242, BMS—298 585, ON-ichi 5816, LM—4156,
  • Therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolurestat, epalrestat, zenarestat, zovolrestat, minalrestat, fidalestat (SNK-860), CT-112, etc.), neurotrophic factors ( Eg, NGF, NT-3, BDNF, etc., neurotrophic factor production ⁇ secretion enhancer [eg, neurotrophin production ⁇ secretion enhancer described in W ⁇ 01 Z 14372 (eg, Phenyl) —2— (2-methyl-1-midazolyl) -15- (3- (2-methylphenoxy) propyl) oxazole, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors ( For example, ALT 946, pimagedin, pyratoxatin, N-phenacylthiazolidome promide (ALT 766), EXO-226, etc., active oxygen scavengers (eg, thioctic acid,
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, oral pastatin, atorvastatin, fluvastatin, ripantile, seripastatin, itavastatin, ZD-4 522 or their salts (eg, sodium salt, etc.), fibrate-based compounds (eg, bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate, etofibrate, ethofibrate, huetibrate) Nofibrate, gemfibrate gill, nicofibrate, pyrifibrate, ronifibrate, simfibrate, theofibrate, etc., squalene synthase inhibitors (eg, compounds described in W097Z1022, such as N) — [[(3R, 5
  • Antihypertensive agents include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesaltan cilexetil, oral sultan, eprosartan, valsantan, telmisartan, ilbesartan, and evening sosartan) ), Calcium antagonists (eg, manidipine, difludipine, dicardipine, amlodipine, efonidipine, etc.), potassium channel openers (eg, levocromakalim, L_27152, AL0671, NIP-121, etc.), clonidine, etc. .
  • angiotensin converting enzyme inhibitors e.g., captopril, enalapril, delapril, etc.
  • angiotensin II antagonists e.g., candesaltan cilexetil
  • anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, Fenfluramine, phentermine, sibutramine, ampuepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc., lipase inhibitors (eg, orlistat, etc.), 33agonists (eg, CL—316243, SR— 58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc., Peptide anorectics (eg, lebutin, CNTF (Ciliary neurotrophic factor), etc.) And cholecystokinin agonists (eg, lynch tribute, FPL-15849, etc.).
  • central anti-obesity agents eg, dexfenfluramine, Fenfluramine, phentermine, sibutramine,
  • diuretics examples include xanthine derivatives (eg, sodium theobromine salicylate, calcium theopromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochloride) Oral thiazide, penflutide, polythiazide, methiclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefurside) , Indapamide and the like), azosemide, isosorbide, ethacrynic acid, pyrethrinide, bumetanide,
  • chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluoroperacil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin) Etc.), plant-derived anti-cancer agents (eg, vincristine, vindesine, taxol, etc.), cis-bratin, carpoplatin, etopoxide and the like.
  • alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluoroperacil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin Etc.
  • plant-derived anti-cancer agents eg, vincristine, vindesine, taxol, etc.
  • cis-bratin carpoplatin, e
  • immunotherapeutic agents include microbial or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), and gene engineering techniques.
  • Obtained cytokins eg, interferon, interleukin (IL), etc.
  • colony stimulating factors eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • interleukins such as IL-11, IL-2 and IL-12 are preferred.
  • antithrombotic agents examples include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium, etc.), perfurin (eg, perfurin potassium, etc.), antithrombin drugs (eg, argato Roban (aragatroban), etc., thrombolytic drugs (eg, perokinase (urokinase :), thisokinase (tisokinase), alteplase n (alteplase nateplase), monteplase (monteplase), pamitehu, fuse pamiteplase, etc.) Inhibitors (eg, ticlopidine hydrochloride (tic 1 op idi ne hydr och och 10 ri de), syrosazol, ethyl icosapentate, beraprost sodium (beraprost sodium), sarpogrelate hydrochloride (sarpogre
  • agents for improving cachexia include cyclooxygenase inhibitors (eg, indomethacin) [Cancer 1 Research (Cancer Research), Vol. 49, pp. 5935-5939, 1989], progesterone derivatives ( Examples: Megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 2]: 3-225 pages, 1994], carbohydrate steroids (eg, dexamethasone, etc.), metoclobramide Drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improving agents (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, British Journal of Cancer, 68, pp. 314-318, 19993], growth hormone, IGF-1 or TNF- ⁇ , LIF, IL-16, which is a factor that induces cachexia. Antibodies to Oncoscintin M and the like.
  • cyclooxygenase inhibitors eg
  • concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-855, prosaptide, etc.), antidepressants (eg, desipramine, amitriptyline, imipramine, etc.), antiepileptic drugs (eg, lamotrigine, etc.) , Antiarrhythmic drugs (eg, mexiletine, etc.), acetylcholine receptor ligands (eg, ABT-594, etc.), endoselin receptor antagonists (eg, ABT-627, etc.), monoamine uptake inhibitors (eg, Tramadol, etc.), narcotic analgesics (eg, morphine, etc.), GABA receptor agonists (eg, gearbapentin, etc.), ⁇ 2 receptor agonists (eg, clonidine, etc.), topical analgesics
  • nerve regeneration promoters eg, Y-128, VX-855, prosaptide, etc.
  • osteoporosis eg, alfacalcidol, calcitriol, ercatonin, salmon calcitonin, estriol, ibriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate
  • Anti-dementia drugs eg, tacrine, donevezil, rivastigmine, galantamine, etc.
  • therapeutic agents for urinary incontinence and frequent urination eg, flapoxant hydrochloride, oxyptinin hydrochloride, propiverine hydrochloride), etc., midazol
  • the concomitant drug is preferably an insulin preparation, an insulin sensitizer, a dalcosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonyliderea agent) and the like.
  • Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • Preferred combinations when two or more concomitant drugs are used include, for example, the following.
  • Insulin sensitizers insulin preparations and insulin secretion promotion Agent
  • Insulin sensitizers Insulin sensitizers, insulin secretagogues and biguanides
  • Insulin sensitizer biguanide, a-darcosidase
  • the amount of each drug can be reduced within a safe range considering the adverse effects of those drugs.
  • the dose of the insulin sensitizer, insulin secretagogue and biguanide can be reduced from the usual dose. Therefore, the adverse effects that would be caused by these agents can be safely prevented.
  • the dosage of diabetic complications, hyperlipidemia, and antihypertensives can be reduced, thus effectively preventing the adverse effects that would be caused by these agents.
  • Compound (I) can be produced by a method known per se, for example, Method II to Method C shown below, or a method analogous thereto.
  • the raw material compound may be used as a salt.
  • a salt those exemplified as the salt of the compound (I) are used.
  • the compound (1-1) in which W is — W ′ —CH 2 _ (W represents a bond or a divalent hydrocarbon residue having 1 or 19 carbon atoms)
  • W represents a bond or a divalent hydrocarbon residue having 1 or 19 carbon atoms
  • the “divalent hydrocarbon residue having 1 to 19 carbon atoms” represented by W ′ is the “divalent hydrocarbon residue having 1 to 20 carbon atoms” exemplified as W above. Among them, those having 1 to 19 carbon atoms can be mentioned. (Method A)
  • Examples of the leaving group represented by Z include a hydroxy group, a halogen atom, — 0 S 0 2 R 14 (R 14 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms) Represents an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group, or an aralkyl group having 7 to 14 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms.
  • R 14 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms
  • examples of the halogen atom include fluorine, chlorine, bromine and iodine.
  • R 1 4 represented by "alkyl group having 1 to 4 carbon atoms", "Ariru group alkylene Le carbon atoms which may be have 6-1 substituent in group 0 containing 1 to 4 carbon atoms” and "1 carbon atoms
  • alkyl group having 1 to 4 carbon atoms in the ⁇ aralkyl group having 7 to 14 carbon atoms which may be substituted with an alkyl group of 4 '' include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl. , T._butyl, and among them, methyl is preferable.
  • the Ariru group having a carbon number of 6 to 1 0 in the "Ariru group having a carbon number of 6 to 1 0 may be substituted with an alkyl group having a carbon number of 1-4" represented by R 1 4, phenyl, naphthyl can be mentioned Of these, phenyl is preferred.
  • aralkyl group having 7 to 14 carbon atoms in the aralkyl group j having 7 to 14 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms represented by R 14 , benzyl, phenethyl, naphthyl Methyl, especially Benzil Is preferred.
  • compound (II) is reacted with compound (III) to produce compound (1-1).
  • the amount of compound (II) to be used is preferably about 1 to about 3 molar equivalents relative to compound (II).
  • this reaction is carried out by a method known per se, for example, the method described in Synthesis, page 1, (1981), or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophile in a solvent that does not adversely influence the reaction.
  • organic phosphorus compound examples include triphenylphosphine, triptylphosphine, and the like.
  • electrophilic agent examples include getyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperidine and the like.
  • the amount of the organophosphorus compound and the electrophile to be used is preferably about 1 to about 5 molar equivalents relative to compound (II).
  • Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. Amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about 110 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] pentacar 7-ene; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium And alkali metal alkoxides such as ethoxide, potassium t.-butoxide.
  • alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate
  • pyridine triethylamine
  • Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] pentacar 7-ene
  • metal hydrides such as potassium hydride and sodium hydride
  • sodium methoxide sodium And alkali metal alkoxides
  • ethoxide potassium t.-butoxid
  • the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (II).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethyl ether; ketones such as acetone and 2-butanone; Octogenated hydrocarbons such as dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually about 150 to about 150, preferably about -10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (1-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can. ,
  • Compound (II) used as a starting compound in the above-mentioned Method A can be produced according to a method known per se.
  • the compound (II-1) in which W ′ is a bond and Z is a hydroxy group can be produced by the method described in WO 01/38325 or the like, or a method analogous thereto.
  • Compound (III) can be produced according to a method known per se.
  • V is a bond
  • W ′ is a bond or a divalent hydrocarbon residue having 1 to 18 carbon atoms
  • R 2 is In the compound (1-2), which is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • V is a bond
  • W is —W ′ ′ — CH 2 — CH 2 — (W ′ has the same meaning as described above)
  • the compound (1-3) in which R 2 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group is as follows: It is also manufactured by Method B.
  • the “divalent hydrocarbon residue having 1 to 18 carbon atoms” represented by W ′ represents the “divalent hydrocarbon residue having 1 to 20 carbon atoms” exemplified as W above. Among them, those having 1 to 18 carbon atoms are mentioned.
  • R 2 ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and other symbols have the same meanings as described above.
  • R 2 As “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R 2 ', it includes those exemplified for the aforementioned R 2.
  • compound (1-2) is produced by reacting compound (IV) with a phosphonium salt.
  • the reaction between compound (IV) and the phosphonium salt is carried out in a conventional manner in the presence of a base in a solvent that does not adversely influence the reaction.
  • the phosphonium salt include, for example, a compound represented by the formula: R 2 'C3 ⁇ 4P (C 6 H 5 ) 3 Za
  • Za represents a halogen atom.
  • examples of the halogen atom represented by Za include chlorine, bromine, and iodine.
  • the phosphonium salt can be produced according to a method known per se.
  • the amount of the phosphonium salt to be used is generally about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (IV).
  • Examples of the base include alkali metal salts such as sodium hydroxide, hydroxylated lime, carbonated lime, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine, N, N, -dimethylaniline; hydrogenation Metal hydrides such as sodium and potassium hydride; and alkali metal alkoxides such as sodium ethoxide, sodium methoxide and potassium t-butoxide.
  • alkali metal salts such as sodium hydroxide, hydroxylated lime, carbonated lime, sodium carbonate and sodium hydrogen carbonate
  • amines such as pyridine, triethylamine, N, N, -dimethylaniline
  • hydrogenation Metal hydrides such as sodium and potassium hydride
  • alkali metal alkoxides such as sodium ethoxide, sodium methoxide and potassium t-butoxide.
  • the amount of the base to be used is preferably about 1 to about 5 mol equivalent relative to compound (IV).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, and dimethoxetane; alcohols such as methanol, ethanol, and propanol; Amides such as dimethylformamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and the like. Can be These solvents may be used in a mixture at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as dioxane, tetrahydrofuran, and dimethoxetane
  • alcohols such as methanol, ethanol, and propanol
  • Amides such as
  • the reaction temperature is usually about 150 ° C to about 150 ° C, preferably about -10 ° C to about 100 ° C.
  • the reaction time is, for example, about 0.5 to about 30 hours.
  • the compound (I-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • the compound (1-2) was isolated without isolating the compound (1-2). As it is, it may be used as a raw material in the next step 2.
  • compound (1-3) is produced by subjecting compound (1-2) to a reduction reaction.
  • This reaction is carried out in a conventional manner under a hydrogen atmosphere or in the presence of a hydrogen source such as formic acid and a metal catalyst in a solvent that does not adversely influence the reaction.
  • a hydrogen source such as formic acid and a metal catalyst in a solvent that does not adversely influence the reaction.
  • metal catalyst examples include transition metal catalysts such as palladium-carbon, palladium black, platinum oxide, Raney nickel, Wilkinson catalyst and the like.
  • the amount of the transition metal catalyst to be used is preferably about 0.01 to about 10 molar equivalents relative to compound (1-2).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide; alcohols such as methanol, ethanol and isopropanol. These solvents may be used in a mixture at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and ethyl ether
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • Amides such as N, N-dimethylformamide
  • alcohols such as methanol, ethanol and isopropanol.
  • the reaction temperature is usually about -50 to about 150 ° C, preferably about 110 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (1-3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • V is a bond
  • W is - W '
  • -CH CH-
  • R 2 gar PO (OR 8) OR 9
  • V is a bond
  • W is —W, '— CH 2 —CH 2 — (W' Is as defined above)
  • the compound (1-5) wherein R 2 is —P ⁇ (OR 8 ) (OR 9 ) (R 8 and R 9 are as defined above) is It is also manufactured by the method.
  • compound (1-4) is produced by reacting compound (IV) with an organic phosphorus reagent.
  • This reaction is carried out according to a conventional method, in the presence of a base, in a solvent that does not adversely influence the reaction.
  • organic phosphorus reagent examples include tetramethyl methylenediphosphonate, tetraethyl methylenediphosphonate, and tetraisopropyl methylenediphosphonate.
  • the amount of the organophosphorus reagent to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] indene 7-ene; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium Alkoxides such as ethoxide and potassium t.-butoxide.
  • alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate
  • pyridine triethylamine
  • Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] indene 7-ene
  • metal hydrides such as potassium hydride and sodium hydride
  • sodium methoxide sodium Alkoxides
  • ethoxide and potassium t.-butoxide sodium methoxide
  • the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (IV).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethyl ether; halogenation such as chloroform and dichloromethane. Hydrocarbons; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and ethyl ether
  • halogenation such as chloroform and dichloromethane.
  • Hydrocarbons Hydrocarbons
  • amides such as N, N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about -10 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (I-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • reaction mixture containing compound (1-4) may be used as it is as a starting material in the next step 2.
  • compound (1-5) is produced by subjecting compound (1-4) to a reduction reaction.
  • This reaction is carried out, for example, in the same manner as in Step 2 of the above-mentioned Method B.
  • the compound (1-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • Compound (IV) used as a starting compound in the above-mentioned Method B and Method C can be produced according to a method known per se.
  • the compound (IV-1) in which W ′ is a bond can be produced by the method described in WO 01/38325 or a method analogous thereto.
  • the compound (IV-2) in which W ′ ′ is a divalent hydrocarbon residue having 1 to 18 carbon atoms in the general formula (IV) may be produced, for example, according to the following Method D. Can be.
  • compound (IV-2) is produced by subjecting compound (V-1) to an oxidation reaction.
  • This reaction is carried out according to a conventional method in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
  • oxidizing agent examples include metal oxidizing agents such as manganese dioxide, pyridinium chromate, pyridinium dichromate, and ruthenium oxide.
  • the amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound (V-1).
  • Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. Is mentioned. These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about -10 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours. .
  • Compound (IV-2) can be prepared by adding sulfur trioxide pyridine complex or compound (V-1) to compound (V-1) in a mixed solvent of halogenated hydrocarbons such as chloroform and dichloromethane and dimethyl sulfoxide, or in dimethyl sulfoxide. It can also be produced by reacting a reaction reagent such as oxalyl chloride and an organic base such as triethylamine and N-methylmorpholine.
  • the amount of the reaction reagent to be used is preferably about 1 to about 10 molar equivalents relative to compound (V-1).
  • the amount of the organic base to be used is preferably about 1 to about 10 molar equivalents relative to compound (V-1).
  • the reaction temperature is usually from about 150 to about 150 ° (preferably, from about 110 to about 100 ° C.
  • the reaction time is generally about 0.5 to about 20 hours.
  • the compound (IV-2) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (V-1) used as a starting compound in the above-mentioned Method D can be produced according to a method known per se.
  • compound (V-1) in which W ′ ′ is a bond can be produced by the method described in W ⁇ 01 / 383325 or a method analogous thereto.
  • compounds wherein Z is a hydro alkoxy group (I I-2), and Z is a halogen atom or - OS_ ⁇ 2 1 ⁇ 4 (R 1 4 is Compound ( ⁇ -3) having the same meaning as described above can be produced, for example, according to the following Method E.
  • Z ' is a halogen atom or a OS0 2 R 14 (R 14 is as defined above), and other symbols are as defined above. ]
  • compound (VI) is reacted with compound (VII) to produce compound (VIII).
  • This reaction is carried out, for example, in the same manner as in the above-mentioned Method A.
  • the compound (VIII) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • reaction mixture containing the compound (VIII) may be used as it is as a raw material in the next step 2 without isolating the compound ( ⁇ ).
  • Compound (VI) and compound (VII) can be produced according to a method known per se.
  • Compound (VI) can be produced, for example, by the method described in EP-A 710659, EP-A 629624 (Japanese Patent Application Laid-Open No. 7-53555), WO 98/03505, or a method analogous thereto.
  • compound (VIII) is subjected to a reduction reaction to produce compound (II-2).
  • This reaction is carried out according to a conventional method, in the presence of a reducing agent, in a solvent that does not adversely influence the reaction.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like.
  • the amount of the reducing agent to be used is preferably about 0.5 to about 10 molar equivalents relative to compound (VIII).
  • solvents that do not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; and hydrocarbons such as tetrahydrofuran, dioxane, and getyl ether. Ters; alcohols such as water, methanol, ethanol, and isopropanol; These solvents may be used in a mixture at an appropriate ratio.
  • the reaction temperature is usually about 150 to about 150 ° C, preferably about -10 to about 100.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (II-12) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. it can.
  • reaction mixture containing the compound (II-12) may be used as it is as a raw material in the next step 3 without isolating the compound (II-12).
  • compound (II-13) is produced by reacting compound (II-12) with a halogenating agent or a sulfonylating agent.
  • halogenating agent for example, hydrochloric acid, thionyl chloride, phosphorus tribromide or the like is used.
  • Z ′ is a halogen atom (eg, chlorine or bromine) is obtained.
  • the amount of the halogenating agent to be used is generally about 1-about 10 mol equivalent relative to compound (II-2).
  • This reaction is carried out in a solvent such as aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and getyl ether.
  • a solvent such as aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and getyl ether.
  • a solvent such as aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and getyl ether.
  • the sulfonylating agent for example, methanesulfonyl chloride, chloride benzenesulfonic Ruhoniru, p- toluenesulfonyl chloride and the like are used, in this case, Z 'gar OS0 2 R 14 (R 14 is as defined above) (for example, methanesulfonate Compound (II-3) is obtained, which is dioxy, P-toluenesulfonyl chloride).
  • the amount of the sulfonylating agent to be used is generally about 1 to about 10 molar equivalents relative to compound ( ⁇ -2).
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • octacyclic hydrocarbons such as dichloromethane and chloroform
  • ethers such as tetrahydrofuran, dioxane, and getyl ether
  • the reaction is carried out in a solvent such as esters in the presence of a base at about 120 to about 100 ° C. for about 0.5 to about 24 hours.
  • the base include amines such as triethylamine and N-methylmorpholine; metal salts such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.
  • the amount of the base to be used is generally about 1 to about 10 molar equivalents relative to compound (II-2).
  • the compound (II-3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • a protecting group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as needed after the reaction.
  • the protecting group of the Amino group include those exemplified for the aforementioned R 5.
  • Examples of the protecting group for the carbonyl group include C 6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C 7 _ ⁇ aralkyl (eg, benzyl, etc.), phenyl, trityl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethyl-phenylalanine silyl, tert - butyldimethylsilyl, tert - butyl Jefferies chill silyl, etc.), C 2 one 6 an alkenyl (e.g., 1-Ariru) and the like.
  • These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 6 -alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • 6 -alkoxy eg, methoxy, ethoxy, propoxy, etc.
  • Examples of the hydroxyl-protecting group include those exemplified as the aforementioned R 4 .
  • the protecting group of Karuponiru group for example, cyclic Asetaru (e.g., 1, 3-Jiokisan), acyclic Asetaru (eg, etc. di C i _ 6 alkyl ⁇ Se tar), and the like.
  • protective groups can be removed by a method known per se, for example, Protective Groups in Organic Synthesis. in Organic Synthes is), published by John Wiley and Sons (1980).
  • acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiolrubamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (eg, trimethylsilyl chloride, trimethylsilylpromide) Etc.), a reduction method, etc. are used.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotamers, these are also contained as compound (I) and are synthesized by known synthesis methods and separation methods. Each can be obtained as a single item.
  • the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I).
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the racemic final product according to a conventional method.
  • optical resolution method a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used.
  • Racemic and optically active compounds eg, (+) monomandelic acid, (_) monomandelic acid, (+)-tartaric acid, (-1) monotartaric acid, (+) — 1-phenethylamine, (-1)- 1-phenethylamine, cinchonine, (1) cinchonidine, brucine, etc.
  • Racemic and optically active compounds eg, (+) monomandelic acid, (_) monomandelic acid, (+)-tartaric acid, (-1) monotartaric acid, (+) — 1-phenethylamine, (-1)- 1-phenethylamine, cinchonine, (1) cinchonidine, brucine, etc.
  • a method in which a racemate or a salt thereof is applied to a chiral column for separation of optical isomers is applied to a chiral column for separation of optical isomers.
  • a mixture of optical isomers is added to a chiral column such as E NAN TIO- ⁇ VM (] Soichi Co., Ltd. or Daicel CHI RAL series, and water, various buffer solutions (eg, Acid buffer), organic solvents (eg, ethanol, methanol, isopropanol, Acetonitrile, trifluoroacetic acid, getylamine, etc.) are developed alone or as a mixture to separate optical isomers.
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • a racemic mixture is formed into a mixture of diastereomers by a chemical reaction with an optically active reagent, which is converted into a single substance through ordinary separation means (eg, fractional recrystallization, chromatographic method, etc.), and then subjected to hydrolysis.
  • a method of obtaining an optical isomer by separating an optically active reagent site by a chemical treatment such as a reaction.
  • compound (I) when compound (I) has hydroxy or 1,2-amino in the molecule, the compound and an optically active organic acid (for example, MTPA [0; -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]), (1) -menthoxyacetic acid, etc.) to give a diastereomer of an ester form or an amide form, respectively.
  • an optically active organic acid for example, MTPA [0; -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]
  • (1) -menthoxyacetic acid, etc. when the compound (I) has a carboxylic acid group, the compound and an optically active amine or an alcohol reagent are subjected to a condensation reaction to obtain an amide or ester diastereomer, respectively.
  • the separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.
  • the room temperature indicates a temperature of 1 to 30 ° C.
  • compound A is 5- [4- [2- (5-methyl-2-phenyl-1-4-oxazolyl) ethoxy] benzyl] -2,4-monothiazolidinedione, and [3 ⁇ 4] —compound A is Compound A labeled with 3 ⁇ 4 is shown.
  • the compound A is a compound that binds to P PART and activates P PARTer.
  • sequence numbers in the sequence listing in the present specification indicate the following sequences.
  • [SEQ ID NO: 1] 3 shows the nucleotide sequence of primer XRA-U used in Reference Example 1a.
  • FIG 3 shows the nucleotide sequence of primer PAG-U used in Reference Example 3a.
  • Example 3 shows the nucleotide sequence of primer PAG-L used in Reference Example 3a.
  • the binding inhibitory activity of the test compound was calculated as a percentage, with the measured value of addition of only 20 nM [] -Compound A being 100%, and the measurement value of simultaneous addition of 20 nM [3 ⁇ 4] Compound A and ⁇ ⁇ ⁇ Compound A being 0%. did. Furthermore, the compound concentration and percentage value were analyzed using PRISM3.0 (Graphpad) to determine the IC 5 of the test compound. Values were calculated. The results are shown in [Table 1]. [Table 1] Test compound I c 50
  • the compounds of the present invention have excellent PPARa binding activity.
  • the cells transfected in Reference Example 2 were collected, suspended in a DMEM medium (Nikken Biomedical Research Institute) containing 0.1% BSA (containing no fatty acid) (Wako Pure Chemical Industries), and then placed in a 96-well white plate (C 8.8xl0 3 cells were seeded at 601 in each well of Ichining Co., Ltd.). Subsequently, to each well, test compound 201 and compound A at final concentration ⁇
  • the compounds of the present invention have excellent PPARr-RXRa hetero: body antagonist activity.
  • Reference example la (cloning of the human RXR gene)
  • kidney cDNA manufactured by Toyobo, trade name QUICK-Clone cDNA
  • type III reported by Mangelsdorf, DJ, et al. (Nature, 1990, 1991, 345 (6272), 224-2)
  • XRA-L 5'-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3 '(SEQ ID NO: 2)
  • the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo).
  • 1 O XLA PCR Buffer 2 ⁇ , 2.5 mM d NTP solution 3 (i l 2. M each of 2.5 M primer solution and 10 l of sterile distilled water were mixed to form a lower layer mixture.
  • One Ampli Wax PCR Gem 100 (manufactured by Takara Shuzo) was added to the lower mixture, and the mixture was treated at 70 for 5 minutes and on ice for 5 minutes.
  • the upper mixture was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set on a thermocycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 15 seconds at 95 ° C. and 2 minutes at 68 ° C. was repeated 35 times, followed by treatment with 72 for 8 minutes.
  • a DNA fragment containing the PPAR-responsive element (PPRE) of acetyl-CoA oxidase was prepared using the following 5'-terminal phosphorylated synthetic DNA.
  • PPRE-U 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3 '(SEQ ID NO: 3)
  • PPRE-L 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3 '(SEQ ID NO: 4)
  • TK promoter-1 Minimum 'promoter
  • TK-U 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3 '(SEQ ID NO: 5)
  • T-L 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3 '(SEQ ID NO: 6)
  • the PCR reaction was performed by the Hot Start method using pliWax PCR Gem 100 (Takara Shuzo).
  • 2.5X each of 10XLA PCR Buffer 2 2.5 mM dNTP solution 3 12.5 M primer solution and 10 ⁇ ⁇ of sterile distilled water were mixed to form a lower layer mixed solution.
  • 1 xl, 10 XL A PCR Buffer 3 fi 2.5 mM dNTP solution l 1, TaKaRa LA Taq DNA olymerase (Takara Shuzo) 0.5 UL 24.5 ⁇ ⁇ of sterile distilled water was mixed to obtain an upper layer mixed solution.
  • One Ampli Wax PCR Gem 100 (manufactured by Takara Shuzo) was added to the above lower mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper mixture was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set in a thermal cycler (PerkinElmer, USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes.
  • the obtained PCR product was subjected to agarose gel (1%) electrophoresis, After the 140 b DNA fragment containing the DNA fragment was recovered from the gel, it was introduced into pT7 Blue-T vector (Takara Shuzo).
  • the fragment containing the TK promoter obtained by digesting this plasmid with the restriction enzymes Bglll and Ncol was ligated to the Bglll-Ncol fragment of the plasmid pGL3-Basic vector [Promega, USA] to form the plasmid P.
  • GL3-TK was prepared.
  • Plasmid pGL3-4ERPP-TK was prepared by ligating the obtained 4.9 kb Nhel-Xhol fragment of plasmid PGL3-TK with the Nhel-Xhol fragment 200b of plasmid pBSS-PPRE4.
  • This plasmid GL3-4ERPP-TK was digested with BamHI (Takara Shuzo) and blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo) to obtain a DNA fragment.
  • pGFP-C1 (manufactured by Toyobo) was digested with Bsu36I (NEB), and then blunt-ended by treatment with T4 DNA polymerase (manufactured by Takara Shuzo) to obtain a 1.6 kb DNA fragment.
  • ERPP-TK neo was constructed.
  • the human PPARa gene was cloned using a heart cDNA (manufactured by Toyobo, trade name: QUICK-Clone cDNA) as type III, reported by Greene et al. [Gene Expr.;, 1995, 4 (4-5) Volume, 281
  • PAG-L 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA C GTC-3 '(SEQ ID NO:
  • the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gera 100 (Takara Shuzo).
  • 10XLA PCR Buffer 21 A 2.5 mM dNTP solution 31 and a 1.5 M primer solution 2.51 each and sterile distilled water 10 ⁇ were mixed to form a lower layer mixed solution.
  • human heart cDNA (1 ng / ml) was used as type 1 in 11 and 10 XLA PGR Buffer 3 ⁇ , 2.5 mM (1 ⁇ [cho? Solution 1 ⁇ 1, TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0.5 24.5 ill of sterile distilled water was mixed to obtain an upper layer mixed solution.
  • One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the lower mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
  • the upper mixture was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set on a thermal cycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 15 seconds at 95 ° C and 2 minutes at 68 was repeated 35 times, followed by treatment at 72 ° C for 8 minutes.
  • a DMEM medium (Nikken Institute of Biomedical Sciences) containing 10% FCS treated with activated carbon (Sigma) was added, and the cells were further cultured at 37 ° C. and 5% CO 2 . Twenty-four hours later, the cells were replaced with 50 ml of MEM medium containing FCS treated with activated charcoal (Nikken Institute of Biomedical Research), and further cultured at 37 ° C. and 5% CO 2 . After 48 hours, the transfected cells were collected and washed with TEG buffer (10 mM Tris-HCl (pH 7.2), 50 mM EDTA, 10% glycerol).
  • TEG buffer 10 mM Tris-HCl (pH 7.2), 50 mM EDTA, 10% glycerol).
  • Cells are 1 ml TEGM buffer (10 mM Tris-HCl (pH 7.2), 1 mM EDTA, 10% glycerol, 7 l / 100 ml jS-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 2 tablets / lOOml Protease inhibitor Cocktail tablets (Boehringer Mannheim))
  • the cells were frozen in liquid nitrogen and thawed on ice for cell lysis.
  • the extract was centrifuged at 228,000 xg at 4 ° C for 20 min to remove cell debris, and the supernatant was stored at -80 ° C until use.
  • reaction mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, and concentrated.
  • a mixture of the obtained residue, trimethyl orthobutyrate (0.54 g), methanesulfonic acid (0.02 g) and 1,4-dioxane (50 mL) was stirred with litre for 1 hour.
  • the reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
  • the compound of the present invention is excellent in blood glucose lowering action, blood lipid lowering action, blood insulin lowering action, insulin resistance improving action, insulin sensitivity enhancing action and retinoid-related receptor function regulating activity, for example, diabetes (eg, type 1) Prevention and treatment of diabetes mellitus, type 2 diabetes, gestational diabetes mellitus, etc .; prevention of hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypo-HDLemia, postprandial hyperlipidemia, etc.) Insulin sensitizer; Insulin sensitivity enhancer; Prevention of impaired glucose tolerance [IGT (Impaired Glucose Tolerance)]. It can be used as a therapeutic agent and an inhibitor of the transition from impaired glucose tolerance to diabetes.
  • diabetes eg, type 1
  • hyperlipidemia eg, hypertriglyceridemia, hypercholesterolemia, hypo-HDLemia, postprandial hyperlipidemia, etc.
  • Insulin sensitizer Insulin sensitivity enhancer
  • IIGT Impaired

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Abstract

La présente invention concerne des composés correspondant à la formule générale (I) dans laquelle: R1 est un groupe hydrocarboné éventuellement substitué ou un groupe hétérocyclique éventuellement substitué; X et Y sont indépendamment une valence libre ou analogue; Q est un radical hydrocarboné bivalent ayant 1 à 20 atomes de carbone; A est un cycle aromatique qui peut en outre porter un à trois substituants; n est un nombre entier de 1 à 8; B est un hétérocycle azoté à 5 chaînons qui peut en outre porter un à trois substituants; W est un radical hydrocarboné bivalent ayant 1 à 20 atomes de carbone; V est une valence libre ou analogue; et R2 est un groupe hétérocyclique éventuellement substitué ou analogue. L'invention concerne également les sels desdits composés. Les composés de l'invention sont utiles en tant que médicaments pour la prévention ou le traitement du diabète et analogue.
PCT/JP2002/006107 2001-06-20 2002-06-19 Derives heterocycliques a 5 chainons WO2003000685A1 (fr)

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7327326B2 (en) 2002-04-24 2008-02-05 Mineral Lassen Llc Wireless communication device having conductive elements antenna
US7368578B2 (en) 2002-09-10 2008-05-06 Takeda Pharmaceutical Company Limited Five-membered heterocyclic compounds
KR100850969B1 (ko) * 2007-01-10 2008-08-12 한국화학연구원 신규한 1-[1-(3,4-디알콕시페닐)-알킬]-1ｈ-피라졸 화합물,이의 제조방법 및 이를 포함하는 약제학적 조성물
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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EP0905133A1 (fr) * 1997-09-26 1999-03-31 Kowa Co. Ltd. Dérivés de tétrazole en tant qu'antagonistes de LTD4 et de H1
WO2001038325A1 (fr) * 1999-11-10 2001-05-31 Takeda Chemical Industries, Ltd. Composes heterocycliques n a 5 elements a activite hypoglycemique et hypolipidemique
WO2001045700A1 (fr) * 1999-12-21 2001-06-28 Smithkline Beecham Corporation Antagonistes des recepteurs de l'urotensine ii

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7327326B2 (en) 2002-04-24 2008-02-05 Mineral Lassen Llc Wireless communication device having conductive elements antenna
US7368578B2 (en) 2002-09-10 2008-05-06 Takeda Pharmaceutical Company Limited Five-membered heterocyclic compounds
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
KR100850969B1 (ko) * 2007-01-10 2008-08-12 한국화학연구원 신규한 1-[1-(3,4-디알콕시페닐)-알킬]-1ｈ-피라졸 화합물,이의 제조방법 및 이를 포함하는 약제학적 조성물
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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