WO2008084873A1 - Dérivé oxime - Google Patents

Dérivé oxime Download PDF

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Publication number
WO2008084873A1
WO2008084873A1 PCT/JP2008/050467 JP2008050467W WO2008084873A1 WO 2008084873 A1 WO2008084873 A1 WO 2008084873A1 JP 2008050467 W JP2008050467 W JP 2008050467W WO 2008084873 A1 WO2008084873 A1 WO 2008084873A1
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Prior art keywords
substituted
unsubstituted
compound
alkyl
acceptable salt
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PCT/JP2008/050467
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Japanese (ja)
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Kazutoshi Sugawara
Naoto Kawabata
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Mitsubishi Tanabe Pharma Corporation
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Publication of WO2008084873A1 publication Critical patent/WO2008084873A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P3/04—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
    • A61P3/08—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel oxime derivative having an excellent darcokinase activating action and useful as a medicine.
  • GK Darcokinase
  • GK is one of the four hexokinases found in mammals. Hexokinase catalyzes the conversion of glucose to dulcose-6-phosphate, the first step in glucose metabolism. GK is mainly localized in liver parenchymal cells and knee ⁇ cells, and plays an important role in glucose homeostasis throughout the body as a rate-limiting enzyme for glucose metabolism in these cells. The forms of the enzyme in liver parenchymal cells and knee ⁇ cells are functionally identical due to differences in the sequences of 15 amino acids at the end due to differences in splicing. G 3 hexo other than ⁇ ?
  • Non-Patent Document 1 G ⁇ ⁇ ⁇ gene-disrupted mice die soon after birth (Non-patent document 2) Both normal and diabetic mice overexpressing GK are wild-type animals. Lower blood sugar (Non-Patent Document 3).
  • Type II young-onset diabetes of the type II (MODY—2: maturity-onset diabetes of the young type II)
  • MO DY-2 maturity-onset diabetes of the young type II
  • a decrease in GK activity in MO DY-2 is thought to cause an increase in blood glucose (Non-patent Document 4).
  • families with GK mutations that increase enzyme activity have been found, and such people exhibit hypoglycemia (Non-patent Document 5). Therefore, GK functions as a glucose sensor in humans and is considered to play an important role in maintaining glucose homeostasis. Since the compound that activates GK activates the GK sensor system, it can be expected to have an insulin secretion promoting action in 3 cells, a glucose uptake enhancing action in the liver, and a liver release inhibiting action. The compound is believed to be useful, for example, in the treatment of type II diabetes.
  • VMH feeding hypothalamus
  • VMH Approximately 20% of neurons in VMH are called glucose responsive neurons and have traditionally been thought to play an important role in controlling body weight. Intrarat administration of the glucose analog, darcosamine, causes overeating of the rat, resulting in suppression of glucose metabolism. From electrophysiological experiments, the glucose responsive neuron in V MH is stimulated when glucose increases from 5 to 2 O mM, and its activity is blocked by dalcosamine or the like (Non-patent Document 6). The mechanism of glucose sensor of V HM is considered to be the same as that of the knee] 3 cells. Thus, GK activators have the potential to improve obesity and correct hyperglycemia, one of the main problems in type I diabetes.
  • the compound having GK activation action is used as a therapeutic agent and / or a therapeutic agent for diabetes or chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease or arteriosclerosis, and obesity.
  • a preventive agent Useful as a preventive agent.
  • Examples of compounds having GK activating activity include pyridinecarboxylic acid derivatives (Patent Document 1), 2-pyridinecarboxamide derivatives (Patent Document 2), heteroaryl rubamoylbenzene derivatives (Patent Document 3), heteroaryl derivatives ( Patent Document 4), Substituted Alicyclic Methyl Propylacetamide Derivative (Patent Document 5), 5 Monosubstituted Pyrazine or Pyridine Derivative (Patent Document 6), Substituted (Thiazole-2-yl) Amide or Sulfonamide Derivative (Patent Document 7), substituted phenylacetamide derivatives (Patent Document 8) or amide derivatives (Patent Document 9). Further, compounds having an oxime structure are described in Patent Documents 10 to 13 and Non-Patent Documents 7 to 9.
  • Patent Document 1 WO 05/044801
  • Patent Document 2 WO 04/081001
  • Patent Document 3 WO 04/076420
  • Patent Document 4 WO 04/063194
  • Patent Document 5 WO 04/063179
  • Patent Document 6 WO 04/052869
  • Patent Document 7 WO 04/050645
  • Patent Document 8 WOO 3/095438
  • Patent Document 9 WO 03/055482
  • Patent Document 10 WO05Z023761
  • Patent Document 1 WOO 1/012189
  • Patent Document 12 WO00 / 026202
  • Patent Document 13 WO 96-no 023763
  • Non-patent document 1 American Journal Physiology, 247 (3Pt2), 1984, p.527-536
  • Non-patent document 2 Cell, 83, 1995, p.69-78
  • Non-patent literature 3 Proceedings of the National Academy of Sciences of the USA, 93, 1996, p.7225-7230
  • Non-Patent Document 4 Nature Genetics, 356, 1992, p. 721-722
  • Non-Patent Document 5 New England Journal of Medicine, 338, 1998 'p. 226-230
  • Non-Patent Document 6 Diabetes, 48 (9), 1999, p. 1763-72
  • Non-Patent Document 7 Bulletin des Societes Chimiques Beiges, 103 (5-6), 1994, p. 213-18
  • Non-Patent Document 8 Bulletin of the Chemical Society of Japan, 66 (8), 1993, p. 2335-8
  • Non-Patent Document 9 Pharmazie, 43 (8), 1988,. 535-6 Disclosure of the Invention
  • An object of the present invention is to provide a novel compound having an excellent action of darcokinase activity useful as an active ingredient of a drug for prevention and Z or treatment of diseases associated with darcokinase such as diabetes, diabetic complications or obesity. Is to provide. As a result of intensive studies on the problems of the present invention, it was found that an oxime derivative represented by the following formula has an excellent darcokinase activating action, and the present invention was completed.
  • the present invention includes the following specific embodiments.
  • ring A represents aryl or heteroaryl.
  • Q represents cycloalkyl, a heterocyclic group, alkyl or alkenyl.
  • Ring T represents a heteroaryl or hetero ring group.
  • R 1 is a hydrogen atom, a halogen atom, cycloalkylsulfonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, substituted or unsubstituted tetrazolyl, — COR 10 or one CR 12 (OH) R 1 . Represents.
  • R 2 represents one COR 11 or one CR 13 (OH) R 11 .
  • R 10 represents an alkyl, cycloalkyl, heteroaryl or heterocyclic group.
  • R 11 represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroaryl or a heterocyclic group.
  • R 12 represents a hydrogen atom or alkyl.
  • R 13 represents a hydrogen atom or alkyl.
  • R 3 and R 4 are independently a hydrogen atom, alkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, alkoxyalkoxy, substituted or unsubstituted cycloalkyl, cyano, substituted or unsubstituted aryl, substituted Alternatively, it represents unsubstituted rubamoyl, hydroxy, alkanoyl, alkylthio, alkoxycarbonyl, substituted or unsubstituted aryloxy, halogen atom, oxo, or substituted or unsubstituted arylcarbonyloxy.
  • R 5 is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminominosulfonyl, substituted or unsubstituted alkylthio, cyan, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted Or unsubstituted cycloalkyl, alkoxycarbonyl, alkenyl, alkylsulfonyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyl, substituted or unsubstituted heterocyclic carbonyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclic group, substituted or un
  • R 6 represents a hydrogen atom, substituted or unsubstituted alkyl, halogen atom or carboxy.
  • Ring T is thiazolyl, thiazo-orthopyridinyl, pyridyl, pyradiel, benzothiazolyl, quinolyl, thiadiazolyl, pyrazolyl, thiazolopyrazinole, thiazo-orthopyrimidinyl, hexahexanothiazolyl or dihydrovirazopyridinyl (1) or (2)
  • Ring T is thiazolyl, thiazo-orthopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, thiadiazolyl, thiazolovirazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl, or dihydrazolazopyridinyl (1) or (2 ) The described oxime derivative or a pharmaceutically acceptable salt thereof.
  • Ring T is thiazolyl, thiazopyridinyl, pyrajur, thiadiazolyl, thiazopyrazuril or thiazolopyrimidyl (1) or (2) the oxime derivative or pharmacologically acceptable Get salt.
  • R 11 is methyl, 3-main Tokishipuropiru or cyclopropyl (1) - (1 2) Okishimu derivative or a pharmaceutically acceptable 3 ⁇ 4 according to any one of.
  • R 5 is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted heterocyclic sulfonyl, nitro , Substituted or unsubstituted cycloalkyl, alkoxycarbonyl, alkenyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or non-substituted
  • the oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16), which is substituted alkynyl, substituted or unsubstituted heterocyclicoxy, alkanol, or substituted or unsubstituted
  • R 5 is a hydrogen atom, halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted rubermoyl, substituted or unsubstituted amino, substituted or unsubstituted
  • R 5 is a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkyl
  • the oxime derivative or a pharmacologically acceptable salt thereof according to any one of (16) to (16).
  • substituted alkyl in R 5 is a substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted rubermoyl, hydroxyl, trialkyl. Silyloxy, alkylthio, alkylsulfonyl, substituted or unsubstituted heterocyclicoxy, heteroaryl, substituted or unsubstituted hydroxyimino, halogen atom, carboxy, alkoxyl or alkanoyloxy (1) to (21) Or an pharmacologically acceptable salt thereof.
  • R 5 The substituent of “substituted alkoxy” in R 5 is optionally substituted with 1 or 2 groups selected from alkyl, alkoxycarbonyl and optionally substituted with amino, alkoxycarbonyl, mono or dialkyl.
  • Good power An oxime derivative described in any one of (1) to (16) and (2 3), or a pharmacology thereof, which is a heterocyclic group optionally substituted by ruberamoyl, carboxyl, hydroxy, oxo, trialkylsilyloxy or alkoxy Acceptable salt.
  • a medicament comprising the oxime derivative described in any one of (1) to (26) or a pharmacologically acceptable salt thereof.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
  • Alkyl as a ( “alkylthio”, the same.
  • alkylthio the same.
  • Preferred examples include linear or branched alkyl, and specific examples include methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, hexyl and the like.
  • c 2 - 6 preferably include a straight-chain or branched Kusaria Rukeeru of c 2 _ 4, specifically Bulle, propenyl, isopropenyl, Buteyu Honoré, Penteeru, Hexenyl and the like can be mentioned.
  • alkynyl for example, C 2 - 6, preferably C 2 - 4 straight or branched Kusaria Rukieru are mentioned in, include Asechireniru, Purobyuru, butynyl, pentynyl, Kishuru like to have specifically .
  • Alkoxy includes, for example d-6, preferably include ⁇ 4 linear or branched Kusaria alkoxy, specifically main butoxy, ethoxy, propoxy, Isopurobo alkoxy, butoxy, t one butoxy, Penchiruokishi, Hexyloxy and the like can be mentioned.
  • the "Arukanoiru”, for example, C 2 _ 7, preferably include a straight-chain or branched Zhen Arukanoiru of C 2 _ 5, specifically Asechiru, propionyl, butyryl, pen Tanoiru and the like.
  • Cycloalkyl for example C 3 _ 8, preferably C 3 - 6 cycloalkyl Le of the like, specifically, cyclopropyl, cyclobutyl, consequent opening pentyl, heptyl is to shea hexyl or consequent opening to click port Can be mentioned.
  • aryl include 6 to 14 membered, preferably 6 to: L 0 membered monocyclic, bicyclic or tricyclic aromatic hydrocarbons, such as phenyl, naphthyl, Examples thereof include phenanthryl and anthryl, and particularly preferred is phenol.
  • Heteroaryl refers to 4- to 10-membered, preferably 5- to 9-membered, in which 1 to 3 carbon atoms are replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen atoms.
  • monocyclic or bicyclic aromatic hydrocarbons such as ceryl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyragel, quinolyl, benzothiazolyl, thiazolo Pyridinyl, thiazolovirazinyl, thiazolopyrimidinyl and the like.
  • heterocyclic group 1 to 3 carbon atoms are independently substituted with a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, 4 to 10 members, preferably 4 ⁇ 9-membered monocyclic or bicyclic non-aromatic hydrocarbons, such as oxetani ⁇ /, azetidyl, pyrrolidinyl, tetrahydrofl ⁇ /, dioxolaninore, piperidininore, piperajunole, homopipe Raju / Le, Tetrahydrobila / Le, Thiashi Chlohexinore, Monoreforinole, Thiomonolefolinole, Cyclohexanothiazolinole, Dihydrothiazolopyridinyl, Tetrahydrothiazolopyridinyl and the like.
  • a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • 4 to 10 members preferably 4
  • halogen atom “alkyl”, “alkyl”, “alkynyl”, “alkoxy”, “alk force mail”, “cycloalkyl”, “aryl”, “heteroaryl”, “heterocyclic group”
  • cycloalkyl “aryl”, “heteroaryl”, “heterocyclic group”
  • the “aryl” in ring A is preferably phenyl.
  • heteroaryl in ring A is preferably cenyl or pyridyl, particularly preferably pyridyl.
  • substitution position of R 2 is preferably the 4-position.
  • cycloalkyl in Q includes, for example, a 5 to 6-membered monocyclic cycloalkyl, and specifically, sucral pentyl, sucral hexyl and the like, and particularly sucral pentyl is preferable.
  • heterocyclic group for example, a 4- to 6-membered monocyclic group optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • Heterocyclic groups are exemplified, and specific examples include oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydroviral, tetrahydrothiobilael, thiaxoxyhexyl and the like, with tetrahydrofuryl being particularly preferred.
  • heteroaryl in ring T is, for example, a 5- to 9-membered monocyclic ring optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom
  • Bicyclic heteroaryls include thiazolyl, pi Examples include lazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl / le, thiazo oral pyridinyl, thiazolopyrazuril, thiazolopyrimidel, quinolyl and the like.
  • thiazolyl, thiadiazolyl, pyridyl, pyragel, benzothiazolyl, thiazolopyridyl, thiazolopyridyl, and thiazolopyrimidinyl are preferred, more preferably thiazolyl, thiadiazolyl, pyrazinyl, thiazolopyridinyl, thiazobirazinyl, Zolopyridinyl, more particularly thiazolyl is preferred.
  • heterocyclic group in ring T is, for example, a 5- to 9-membered single atom optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • cycloalkyl in R 1 0 and R 1 1 is for example, an 3-4-membered cycloalkyl, specifically cyclopropyl, Shikuropuchiru like, in particular cyclopropyl are preferred.
  • heterocyclic group in R 1 Q and R 11 , for example, it may optionally have 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom 5 to 9-membered monocyclic and bicyclic heterocyclic groups are mentioned, preferably 5 to 7-membered monocyclic heterocyclic groups, such as azetidinyl, pyrrolidiel, tetrahydrofuryl, piperidinyl, Piperazorenole, morpholinole, thiomorpholinyl, oxazepidinyl and perhydrodiazepier are preferred.
  • the “aryl” in R 3 and R 4 is preferably phenyl.
  • the “heteroaryl” in R 3 and R 4 may have 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • a cyclic or bicyclic heteroaryl, preferably a 5- to 6-membered monocyclic heteroaryl optionally having 1 to 3 nitrogen atoms Specifically, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl and the like are preferable, and pyrimidinyl is particularly preferable.
  • heterocyclic group examples include a 5- to 6-membered monocyclic hetero ring group, and specifically include pyrrolidinyl, tetrahydrofuryl, dioxolanyl, piperidinyl, thiacyclohexyl and the like. Can be mentioned.
  • the “cycloalkyl” in R 3 and R 4 is preferably a 3- to 6-membered monocyclic cycloalkyl, specifically, cyclopropyl or cyclopentyl.
  • heterocyclic group examples include a 4- to 6-membered monocyclic heterocyclic group, and specifically, azetiduyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and the like are preferable.
  • a preferable substituent of “substituted tetrazolyl” in R 1 includes alkyl.
  • Preferred substituents for “substituted alkyl” in R 1 1 are alkoxycarbonyl, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl selected from 1 Or a group of 2), substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfoel, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydrobiranyl, Dihydro-3H-isoindolyl) (substituents: oxo, dioxo) and the like.
  • alkoxy, cycloalkynole preferably cycl
  • Preferred substituents for “substituted cycloalkyl” in R 11 include hydroxy; alkyl; oxo; alkanol; hydroxyalkyl; forceful rubamoyl optionally substituted with mono- or dialkyl; heteroaryl; Or an aminosulfonyl optionally substituted with dialkyl; an amino optionally substituted with mono- or alkyl; alkylsulfonyl; alkoxy; alkoxyalkyl.
  • hydroxy; alkyl; forceful rubamoyl optionally substituted with mono or dialkyl; oxo; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.
  • Preferred substituents for “substituted heteroaryl” in R 11 include: hydroxy; alkyl; alkanoyl; hydroxyalkyl; force rubamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl Aminosulfonyl which may be substituted; amino optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; forceful rubamoyl optionally substituted with mono- or dialkyl; alkoxy; alkoxyalkyl are more preferable, and alkyl is particularly preferable.
  • Preferable substituents for the “substituted heterocycle” in R 3 and R 4 include alkoxyl, oxo, alkyl, alkanoyl and the like, and oxo and alkyl are particularly preferable.
  • Preferred substituents for “substituted heteroaryl” in R 3 and R 4 include alkyl; an amino optionally substituted with mono- or dialkyl. Of these, alkyl is more preferred.
  • Preferred substituents for “substituted cycloalkyl” in R 3 and R 4 include benzoinoreoxy, oxo, hydroxy, and alkanoyl. Of these, oxo and hydroxy are more preferred.
  • Preferred substituents for the “substituted aryl” in R 3 and R 4 include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and particularly preferred are cyan and halogen atoms.
  • substituents of “substituent rubermoyl” in R 3 and R 4 include alkyl.
  • “Preferable substituents of substituted aryloxy j in R 3 and R 4 include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and particularly preferred are cyan and halogen atoms.
  • substituents of “substituted aryl carbooxy” in R 3 and R 4 include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and the like.
  • Preferred substituents for “substituted alkoxy” in R 5 include substituted or unsubstituted amino (substituent: 1 or 2 groups selected from alkyl and alkoxycarbonyl); alkoxycarbonyl; optionally substituted with mono or dialkyl May include rubamoyl, ruboxyl, hydroxy, substituted or unsubstituted heterocyclic group (substituent: oxo), trialkylsilyloxy, and alkoxy.
  • Amino optionally substituted with mono or dialkyl as appropriate; strong rubamoyl optionally substituted with mono or dialkyl; hydroxy is more preferred, especially amino optionally substituted with mono or dialkyl; hydroxy is preferred .
  • a preferable substituent of “substituted aminosulfonyl” in R 5 includes alkyl. Therefore, the substituent is monoalkyl or dialkyl, preferably dialkyl.
  • Preferred substituents for “substituted alkylthio” in R 5 include amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; halogen atom; hydroxy; carboxyl; optionally substituted with mono or dialkyl. Rubamoyl which may be included; alkoxycarbonyl. Of these, amino optionally substituted with mono or dialkyl as appropriate; alkoxycarbonylamino; hydroxy; rubamoyl optionally substituted with mono or dialkyl is more preferable, and dialkyl strength rubamoyl is particularly preferable.
  • a preferable substituent of “substituted heterosulfoyl” in R 5 includes alkyl.
  • substituents of “substituted cycloalkyl” in R 5 include amino optionally substituted with mono or dialkyl.
  • a preferable substituent of “substituted cycloalkyloxy” in R 5 includes amino optionally substituted with mono or dialkyl.
  • substituents for “substituent rubermoyl” in R 5 include substituted or unsubstituted alkyl (substituent: hydroxyl; cycloalkyl; heterocyclic group; amino optionally substituted with mono- or dialkyl; heteroaryl; 1 or 2 groups selected from the group consisting of cycloalkyl and heteroaryl. Of these, substituted or unsubstituted alkyl (substituent: hydroxy, heterocyclic group, dialkylamino) And 1 or 2 groups selected from heteroaryl), cycloalkyl is more preferred.
  • a preferable substituent of “substituted heteroarylthio” in R 5 includes alkyl.
  • substituents of “substituted amino” in R 5 include alkyl, substituted or unsubstituted aminoalkyl (substituent: 1 or 2 groups selected from alkyl, alkanol), alkanoyl, hydroxyalkyl, alkoxy force Lupoel. Of these, alkyl, and therefore monoalkyl or dialkyl is more preferable, and dialkyl is particularly preferable.
  • Preferred substituents for “substituted heteroaryl” for R 5 include alkyl.
  • Preferred substituents for “substituted alkynyl” in R 5 include hydroxy, optionally an amino optionally substituted with mono- or dialkyl. Of these, hydroxy and dialkylamino are more preferred.
  • substituents of “substituted heterocyclic carbonyl” in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, and alkanoyl. Of these, hydroxy, alkyl, and hydroxyalkyl are more preferable.
  • Preferred substituents for “substituted heterooxy” in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, alkyl and oxo are more preferred.
  • substituents of the “substituted heterocyclic group” in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl and alkanoyl. Of these, oxo is more preferred.
  • Preferred substituents for “substituted heterocycle” in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, and alkylol. Of these, alkyl and alkanol are more preferred.
  • Preferred substituents for the “substituted alkyl” in R 5 include a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted rubamoyl, a hydroxy, a trialkylsilyloxy, Examples thereof include substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclicoxy, heteroaryl, substituted or unsubstituted hydroxyimino, and halogen atom, and more preferably substituted or unsubstituted heterocyclic group, substituted or unsubstituted.
  • substituted or unsubstituted alkoxy hydroxy, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclicoxy, substituted or unsubstituted hydroxyimino, halogen atom, more preferably substituted or unsubstituted Substituted heterocyclic group, substituted or non-substituted Conversion alkoxy, heterocycle Okishi to substituted or unsubstituted, particularly preferably a substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy, more particularly preferably terrorist ring group to a substituted or unsubstituted.
  • Preferred substituents of the substituted heterocyclic group which is the substituent of “substituted alkyl” in R 5 include alkyl; oxo; alkoxy alkanol; alkanol; alkoxy; anolecaninoreamino; Tri (halogeno) alkanoylamino; honoreminoreamino; alkoxy group lupoelamino; hydroxy; alkyl alkylcarbonyl; tri (halogeno) alkyl; alkoxycarbonyl; formyl; optionally substituted with mono or dialkyl Amino, optionally substituted with mono- or dialkyl as appropriate; alkylsulfol; heteroaryl; alkoxycarbonylalkyl; alkanoloxyalkanoyl; alkoxycarbocarbonyl; Is an aminoalkanoyl optionally substituted with a alkyl; substituted or unsubstituted rubermoyl (substituent: 1 or
  • Preferred substituents of the substituted amino which is a substituent of “substituted alkyl” in R 5 are alkyl; carbamoylalkyl optionally substituted with mono- or dialkyl; substituted or unsubstituted aminoalkyl (substituent: alkyl, alkyl 1 or 2 groups selected from force-neils); alkoxyalkyl; hydroxyalkynole; alkoxyalkanol; heteroaryl; heteroarylalkyl It is done.
  • alkyl alkyl; rubamoyl alkyl optionally substituted with mono or dialkyl; aminoalkynole optionally substituted with mono or dialkyl; alkoxyalkyl; heteroaryl is more preferable, and alkyl is particularly preferable. Les.
  • substituents of substituted alkoxy which is a substituent of “substituted alkyl” in R 5 include hydroxy and alkoxy.
  • substituents of the substituent ruberamoyl which is a substituent of “substituted alkyl” in R 5 include alkyl and alkoxy.
  • substituents of substituted heterocyclic oxy which is a substituent of “substituted alkyl” in R 5 , include alkanoyl, alkyl, formyl, cycloalkylcarboyl, alkoxyalkanoyl, and alkylsulfoyl. Of these, aralkyl and alkyl are more preferred, and alkanol is particularly preferred.
  • a preferred substituent of the substituted hydroxyimino which is the substituent of “substituted alkyl” in R 5 includes alkoxycarbonyl.
  • the heterocyclic group of the “substituted or unsubstituted heterocyclic group” which is the substituent of “substituted alkyl” in R 5 is, for example, 1 to 3 independently selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Examples include a 5- to 9-membered monocyclic or bicyclic heterocyclic group which may have a telo atom as appropriate, and preferably have a nitrogen atom of 1 to 3 as appropriate.
  • a monocyclic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinole, monoreforinole, thiomonoreforinole, penolehydridozepinyl, octahydropyro mouth [1,2_a] piperazinyl and the like.
  • piperazil and morpholinyl are more preferable, and piperazinyl is particularly preferable.
  • heterocyclic group of “substituted or unsubstituted heterocyclicoxy” which is a substituent of “substituted alkyl” in R 5 is independently selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom.
  • substituent of “substituted alkyl” in R 5 is independently selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom.
  • a 4- to 6-membered monocyclic heterocyclic group optionally having 1 to 3 nitrogen atoms, specifically azetidiel, pyrrolidinyl, piperidinyl, Piperazonole, morpholyl, thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo [1,2-a] piperazyl and the like.
  • piperidinyl is preferable.
  • preferred compounds are as follows: ring A is fur; nyl, ring T is 2-thiazolyl or 2-thiazolopyridyl, R 1 is a hydrogen atom, and R 2 is cyclopropylcarboxyl. -R, Al or Alkyl, and R 3 and R 4 are both hydrogen atoms, and R 5 is appropriately selected from alkyl, oxo, alkanoyl and alkoxyalkanoyl, and hydroxyalkyl 1 And a compound that is piperazinyl-substituted alkyl optionally substituted with ⁇ 3 substituents.
  • ring A as a ring
  • ring T as 2-thiazolopyridyl
  • R 1 as a hydrogen atom
  • R 2 as cyclopropylcarbonyl
  • R 3 and R 4 are both hydrogen atoms
  • R 5 is substituted with 1 or 2 alkyl optionally substituted with amino, alkoxy, 1 or 2 alkyl optionally substituted with amino
  • a compound that is an alkylamino substituted with an amino optionally substituted with 1 or 2 alkyl is an alkylamino substituted with an amino optionally substituted with 1 or 2 alkyl.
  • the compound [I] of the present invention can be a mixture of stereoisomers, or pure or substantially pure It includes each stereoisomer in a nifty form.
  • the compound of the present invention has one or more asymmetric centers at any carbon atom, the compound [I] may exist in an enantiomer or diastereomer or a mixture thereof.
  • the compound of the present invention includes an isomer or a mixture thereof.
  • Examples of the pharmacologically acceptable salt of compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, and queen. And organic acid salts such as acid salts, methanesulfonate, benzenesulfonate, tosylate, and maleate.
  • the salt when it has a substituent such as carboxyl, the salt includes, for example, a base such as an alkali metal salt such as a sodium salt or an alkaline salt or an alkaline metal salt such as a calcium salt. Of the salt.
  • the pharmacologically acceptable salt of the compound [I] of the present invention includes an inner salt, and the compound [I] and the salt thereof can be in the form of a solvate such as a hydrate thereof.
  • the compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition containing a therapeutically effective amount of the present compound and a pharmaceutically acceptable carrier.
  • Pharmacologically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth or polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit or Glycine), lubricant (magnesium stearate, talc, polyethylene glycol or silica), disintegrating agent (potato starch) and wetting agent (sodium lauryl sulfate).
  • binders saccharic, gelatin, sorbit, tragacanth or polyvinylpyrrolidone
  • excipients lactose, sucrose, corn starch, potassium phosphate, sorbit or Glycine
  • lubricant magnesium stearate, talc, polyethylene glycol or silica
  • disintegrating agent potato starch
  • wetting agent sodium lauryl sulfate
  • the compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used in an appropriate pharmaceutical preparation.
  • Suitable pharmaceutical preparations for this purpose include, for example, solid preparations such as tablets, granules, capsules or powders, or liquid, suspension or emulsion forms.
  • Suitable pharmaceutical preparations for parenteral administration include suppositories, or injectable solutions or infusion preparations using distilled water for injection, physiological saline or aqueous buducose, or inhalants.
  • the compound [I] of the present invention a pharmacologically acceptable salt thereof or a pharmaceutical preparation thereof can be used in combination with one or more other drugs selected from antidiabetic drugs and antihyperglycemic drugs.
  • the term “combination” includes the concept of administration together with these other drugs at the same time or separately at an arbitrary interval, and administration together with these other drugs as a single pharmaceutical preparation. There are cases.
  • Such other drugs include snorephoninoreurea (eg, daliprid, glimepiride, dalipiride, glipizide, chlorpropamide, gliclazide, glyoxepide, acetohexamide, daliborneuride, tolptamide, tolazamide , Carpamide, darikidon, darifexamide, fenptamide, tolcyclamide, etc., biguanide (eg, methonoremine, phenphonolemin, bufonoremin, etc.), gnore gon'antagonist (eg, peptide or non-peptide) Glucagon 'antagonists), dalcosidase inhibitors (eg, acarporte, miglitol, etc.), insulin sensitizers (eg, troglitazone, rosiglitazone, pioglitazone), anti-obesity agents (eg, sibutramine) Oruris
  • the dose of the compound [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight or pathological condition, but is usually about 0.01 to about 100 mg / kg per day. Yes, preferably from about 0.1 to about lOra g Z kg.
  • the compound [I] of the present invention can be produced by the following method.
  • Z 1 is a halogen atom, hydroxy or alkoxy
  • Z 2 is a hydrogen atom or alkyl
  • Z 3 is hydroxy, a halogen atom or aryl sulfonyloxy, alkylsulfonyloxy
  • Z 4 is halogen Atom, dialkoxyboryl, dihydroxyboryl or trialkylstannyl
  • lithium z 5 is a hydrogen atom, halogen atom, dialkoxyboryl, dihydroxypolyl or trialkylstanyl, lithium, and the other symbols are as described above. Have the same meaning.
  • reaction for producing compound [VI] (Z 2 is alkyl) from compound [VII] (Z 5 is a hydrogen atom) and compound [VIII] (Z 1 is a halogen atom, Z 2 is alkyl) It can be carried out under so-called Friedel-Crafts reaction conditions.
  • this reaction can be carried out in the presence of a suitable acid (such as aluminum chloride) in a suitable solvent (such as black mouth form, methylene chloride, nitromethane).
  • Compound [VI] (Z 2 is alkyl) can also be a compound [VII] (Z 5 is Jiarukoki Shiboriru, dihydric de port Kishiborinore or trialkyl stannyl) with the compound [VIII] (Z 1 is a halogen atom, Z 2 is alkyl )
  • a suitable solvent for example, dichlorobis (trifurphosphine) paradium, tetrakis (Triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichloro [1,1, _bis (diphenylphosphino) phenolacene] palladium, etc.
  • a metal catalyst for example, dichlorobis (trifurphosphine) paradium, tetrakis (Triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichloro [1,1, _bis (dipheny
  • compound [VI] (Z 2 is alkyl) can also be combined with compound [VII] (Z 5 is lithium) and compound [VIII] (Z 1 is alkoxy, Z 2 is alkyl) with a suitable solvent (THF, Dioxane, DMF, toluene, 1,2-dimethoxetane, etc., or a mixture thereof), and this step can be preferably carried out at -78 ° C to 200 ° C. .
  • a suitable solvent THF, Dioxane, DMF, toluene, 1,2-dimethoxetane, etc., or a mixture thereof
  • compound [VII] (Z 5 is a halogen atom
  • compound [VI] (Z 2 is alkyl) is used in an appropriate solvent (THF, jetyl ether, toluene, 1,2-dimethoxetane, etc.) or a mixture thereof), suitable alkyl lithium (n- butyl lithium, sec- butyl lithium, t chromatography Bed butyllithium, etc.) using a compound [VII] (Z 5 is a halogen atom) the compound [VII] (Z 5 Can be prepared by reacting with compound [VIII] (Z 1 is alkoxy, Z 2 is alkyl) in the same manner as described above.
  • the oxime produced in the cis form or a mixture of the cis form and the trans form can be converted into the desired trans form by treatment with an acid (trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc.).
  • the oxime produced by the reaction described below can also be converted to the desired trans form by treating in the same manner as described above.
  • reaction of a compound Z 3 is hydroxy [V] can be carried out in a suitable solvent (THF, methylene chloride, etc.) in, triphenyl phosphinite down the presence,
  • a suitable solvent THF, methylene chloride, etc.
  • triphenyl phosphinite down the presence,
  • an activator jetylazodicarboxylate, diisopropylazodicarboxylate, etc.
  • cyanomethyltri_n-butylphosphorane in the absence of triphenylphosphine (so-called Mitsunobu reaction).
  • reaction with the compound [V] wherein Z 3 is a halogen atom, arylsulfonyloxy or alkylsulfonyloxy is carried out by using an appropriate solvent (acetone, ethanol, THF, dimethylsulfoxide, DMF, dioxane, N , N-dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof) in the presence of a base such as potassium carbonate, potassium t-butoxide, sodium hydride, cesium carbonate.
  • an appropriate solvent acetone, ethanol, THF, dimethylsulfoxide, DMF, dioxane, N , N-dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof
  • a base such as potassium carbonate, potassium t-butoxide, sodium hydride, cesium carbonate.
  • the product thus obtained can be obtained by any conventional method for hydrolyzing an alkoxy carbonate to carboxyl, for example, a suitable solvent (alcohol solvent such as methanol or ethanol, THF, dioxane, water, etc., or a mixed solvent thereof) in, hydroxide Ihirichiumu, sodium hydroxide, and treated with potassium carbonate or the like by hydrolyzing Z 2 group, the compound [II] (Z 2 can be converted to a hydrogen atom).
  • a suitable solvent alcohol solvent such as methanol or ethanol, THF, dioxane, water, etc., or a mixed solvent thereof
  • the solvent water, methanol, isopropanol, ethanol, methylene chloride, THF, dioxane, DMF, dimethylacetamide, black mouth form and the like can be suitably used as a single or mixed solvent.
  • This reaction preferably proceeds at _78 ° C to 100 ° (more preferably from -25 ° C to 25 ° C.)
  • a base an inorganic base such as carbonated lithium, sodium carbonate, sodium hydrogen carbonate, or triethylamine, Organic bases such as diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine, etc. are added.
  • N-hydroxysuccinimide 3-hydroxy 3,4-Dihydr Draw 4-Oxo 1, 2, 3 Addition of benzotriazolone, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. to promote the progress of this reaction Can do.
  • Conversion to the acid chloride is thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, or tetra It can be suitably carried out by using triphenylphosphine in the presence of carbon chloride, and conversion to a mixed acid anhydride can be carried out using diphenylphosphoryl chloride, jetylphosphorus didate, methanesulfoalkoxide, This can be carried out by using ethyl formate, isobutyl formate, etc. in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • the solvent methylene chloride, black-form, THF, DMF and the like can be suitably used as single or mixed solvents.
  • This reaction preferably proceeds at ⁇ 78 ° C. to 100 ° C., more preferably _25 ° C. to 25 ° C.
  • the reaction between the acid chloride or mixed acid anhydride thus obtained and compound [III] involves the presence of a base such as pyridine, tritylamine, N, N-dimethylaminopyridine, disopropylethylamine, etc.
  • a base such as pyridine, tritylamine, N, N-dimethylaminopyridine, disopropylethylamine, etc.
  • methylene chloride, black form, THF, DMF, etc. are used as a single or mixed solvent. It can be used suitably.
  • Conversion of compound [VI] (Z 2 is alkyl) to compound [VI '] (Z 2 is a hydrogen atom) can be accomplished by any conventional method for reducing ketones to alcohols, such as suitable solvents (water, methanol, ethanol).
  • suitable solvents water, methanol, ethanol.
  • a reducing agent such as zinc borohydride, sodium triacetoxyborohydride, sodium borohydride, etc.
  • a suitable solvent methanol, ethanol, THF, dioxane, water, etc. or a mixed solvent thereof.
  • reaction between compound [VI '] (Z 2 is a hydrogen atom) and compound [III] is the same as the reaction in (4) above. Can be applied. Conversion of compound [X '] to compound [X] can be accomplished by any conventional method for oxidizing alcohols to ketones, for example, in an appropriate solvent (dimethylsulfoxide, chloroform, methylene chloride, etc.), an activator such as oxalyl chloride, etc.
  • Oxidizing agent activated manganese dioxide, sulfur trioxide monopyridine complex, 1-hydroxy-1) in the presence or absence of potassium or base (triethylamine etc.) by dimethyl sulfoxide oxidation (Swern oxidation) using , 2—Benzodoxol _ 3 (1 H) —On 1 1-oxide, 1, 1, 1—Triacetoxy 1, 1—Dihydr draw 1, 2—Benzo-doxolol 1 3 (1 H) 1 on, black It can be carried out by using pyridinium chromate, pyridinium dichromate, etc.).
  • reaction between compound [VI] and compound [XI] is carried out by using O-substituted hydroxylamine or a salt thereof as a substitute for hydroxylamine in the reaction (2) above.
  • the reaction can be carried out in the same manner as in the above reaction (2) by using ruxylamine, cycloalkyloxyamine, heterocyclic oxyamine, benzyloxyamine and the like.
  • This reaction can also be carried out in the presence of triphenylphosphine by using carbon tetrachloride, carbon tetrabromide, N-prosuccinic acid imide, N-mouth succinic acid imide, iodine, or the like.
  • Metal catalysts eg, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichloro [1, 1, monobis (diphenyl phosphino) phenolic] (E.g. palladium). wear.
  • This reaction suitably proceeds under an inert gas stream such as argon at room temperature to 200 ° C or under microwave irradiation.
  • Compound [I] can be further converted by the following method.
  • a compound containing sulfiel (SO) or sulfonyl (so 2 ) on R 1 ! ⁇ 6 converts the corresponding sulfido compound into a sulfinyl or sulfonyl compound.
  • SO sulfiel
  • sulfonyl so 2
  • R 1 ! ⁇ 6 converts the corresponding sulfido compound into a sulfinyl or sulfonyl compound.
  • an oxidizing agent in an appropriate solvent (methylene chloride, chloroform, THF, methanol, water or a mixed solvent thereof).
  • peroxy acids such as hydrogen peroxide, m-chlorobenzoic acid, peracetic acid, and oxone (registered trademark) ("Peroxyhydrogensulfuric acid lithium / disulfuric acid lithium / hydrogensulfuric acid hydrogenum mixture” DuPont And the like.
  • the reaction can be preferably carried out at ⁇ 78 ° C. to 100 ° C.
  • R 11 and R 12 are substituents of the substituted amino group described herein, or R 11 and R 12 are combined with the nitrogen atom of the amino group to form an oxygen atom.
  • a heterocyclic group having 1 to 3 heteroatoms independently selected from a sulfur atom and a nitrogen atom, wherein the heterocyclic group may be substituted
  • this compound means "substituted or unsubstituted amine", and the group after removing a hydrogen atom from this substituted or unsubstituted amine is "substituted or unsubstituted amine”.
  • This reaction can be carried out by any conventional method of reductive amination.
  • this reaction is By using a reducing agent (sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) at -78 ° C-100 ° C It can implement suitably.
  • the nitrogen atom on R 1 ! ⁇ 6 is substituted or unsubstituted alkanoyl such as alkanoyl, cyclyl alkylcarbonyl, alkoxyalkanoyl, alkanoyloxycanol, etc.
  • alkanoyl such as alkanoyl, cyclyl alkylcarbonyl, alkoxyalkanoyl, alkanoyloxycanol, etc.
  • a compound that is simply substituted with a substituted or unsubstituted alkyl group is also a compound in which the corresponding nitrogen atom is unsubstituted (eg R 5 is piperazinylmethyl, piperazinylcarbonyl or pipera). It can also be produced by alkanoylation of a compound such as dinylsulfonyl.
  • the alkanoylation can be produced by using any conventional method of amide formation that is usually used for peptide synthesis and the like.
  • the alkanoylation can be carried out using a base (triethylamine, pyridine, etc.) in a suitable solvent (methylene chloride, TI-IF, DMF, N, N-dimethylacetamide, chloroform or a mixed solvent thereof).
  • a base triethylamine, pyridine, etc.
  • a suitable solvent methylene chloride, TI-IF, DMF, N, N-dimethylacetamide, chloroform or a mixed solvent thereof.
  • an acid chloride, an acid anhydride or an ester in the presence or absence at -78 ° C to 100 ° C.
  • This reaction can also be carried out, for example, in a suitable solvent in the presence or absence of a condensing agent.
  • water, methanol, isopropanol, ethanol, salt methylene chloride, THF, DMF, N, N-dimethylacetamide, chloroform, etc. can be preferably used as a single or mixed solvent. it can. Genuine The reaction preferably proceeds at -78 ° C to 100 ° C, more preferably at -25 ° C to 25 ° C.
  • a substituted or unsubstituted aminocarbon on R 1 ! ⁇ 6 that is, a compound having a substituted or unsubstituted rubamoyl group is replaced with a compound whose corresponding site is force loxy.
  • it can be produced by reacting with an unsubstituted amine. This reaction can be carried out in the same manner as in the above reaction (C).
  • a compound in which R 5 or R 6 has a substituted or unsubstituted alkoxymethyl or a substituted or unsubstituted heteroarylmethyl may be any compound in which the corresponding site is hydroxymethyl.
  • This condensation reaction is carried out in the absence of a solvent or in an appropriate solvent (THF, dioxane, methylene chloride, chlorophonolem, tonoleene, benzene, etc.), in the presence of an acid (p-tonoleensenophonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.).
  • THF dioxane
  • methylene chloride methylene chloride
  • chlorophonolem tonoleene
  • tonoleene benzene, etc.
  • an acid p-tonoleensenophonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.
  • it can be suitably carried out in the absence of -78 ° C to 200 ° C, more preferably 25 ° C to 100 ° C.
  • a compound having hydroxymethyl on 1 ⁇ to 16 can reduce a compound having a corresponding site of formyl by any conventional method for reducing formyl to alcohol.
  • this reaction is Reducing agent (sodium borohydride, sodium triacetoxyborohydride, diporane, diisoptylaluminum hydride, lithium aluminum hydride, etc.) in appropriate solvents (methanol, ethanol, methylene chloride, black mouth form, dioxane, THF, etc.) ) At ⁇ 78 ° C. to 100 ° C.
  • Reducing agent sodium borohydride, sodium triacetoxyborohydride, diporane, diisoptylaluminum hydride, lithium aluminum hydride, etc.
  • solvents methanol, ethanol, methylene chloride, black mouth form, dioxane, THF, etc.
  • a compound having a carboxyl on ⁇ to 6 can be produced by oxidizing a compound in which the corresponding site is formyl by any conventional method of acidifying formyl to carboxyl.
  • the oxidation can be carried out, for example, in an appropriate solvent (DMF, dimethyl sulfoxide, acetone, t-ptanol, water, methylene chloride, black mouth form, etc.), an oxidizing agent (sodium chlorite, potassium permanganate, pyridinium dichromate). Etc.) at ⁇ 78 ° C. to 100 ° C.
  • a compound having alkoxycarbonyl on R i R 6 is also a compound in which the corresponding site is carboxyl by any conventional method for esterifying carboxyl to alkoxycarbonyl. It can also be produced by esterification.
  • esterification for example, acid (sulfuric acid, hydrochloric acid, P- toluenesulfonic acid) in a suitable solvent (methanol, ethanol, isopropanol, t-butanol, etc.) is more preferable at -78 ° C to 200 ° C. Can be preferably carried out by using at 0 ° C to 100 ° C.
  • esterification can also be carried out by reacting a carboxyl compound with an acid halide using a halogenating agent (oxalyl chloride, thionyl chloride, etc.) in an appropriate solvent (methylene chloride, chloroform, THF, dioxane, etc.). After conversion to an intermediate, it can also be carried out by using an alkenol (methanol, ethanol, isopropanol, etc.) at _78 ° C to 200 ° C.
  • a halogenating agent oxalyl chloride, thionyl chloride, etc.
  • an appropriate solvent methylene chloride, chloroform, THF, dioxane, etc.
  • the hydrolysis is In a suitable solvent (alcohol solvent such as methanol or ethanol or dioxane, THF, water or a mixed solvent thereof), base (sodium hydroxide, potassium hydroxide, potassium carbonate, lithium hydroxide, etc.) is -78 ° C ⁇ It can be suitably carried out by using at 200 ° C, more preferably from 0 ° C to 100 ° C.
  • hydrolysis is also preferably performed by using an acid (sulfuric acid, hydrochloric acid, etc.) at -78 ° C to 200 ° C in an appropriate solvent (THF, dioxane, acetic acid, water, etc. or a mixed solvent thereof). It can also be implemented.
  • a compound having hydroxymethyl on R 1 ! ⁇ 6 can be produced by using any conventional method for the reduction reaction of ester or carboxylic acid to alcohol. .
  • the corresponding carboxyl or alkoxycarbonyl is reduced to a reducing agent (sodium borohydride, diborane, dioxane, etc.) at -78 ° C to 200 ° C in an appropriate solvent (methylene chloride, black mouth form, THF, etc.) It can be preferably carried out by treating with aluminum lithium hydride, diisoptyl aluminum hydride, etc.).
  • a compound having a carboxyl on ⁇ 1 to! ⁇ 6 can be produced by using a conventional method for oxidizing a primary alcohol to a carboxylic acid.
  • a compound in which the corresponding site is hydroxymethyl in an appropriate solvent methylene chloride, acetone, chloroform, DMF, etc.
  • an oxidizing agent 3 Chromium oxide, pyridinium dichromate, etc. 8050467
  • Compound having an amino on-scale 6 can be prepared by using any conventional method of reduction to Amin nitro.
  • a compound with a corresponding nitro compound as a metal catalyst (palladium) in a suitable solvent methanol, ethanol, DMF, THF, dioxane, etc.
  • a hydrogen atmosphere at _78 ° C to 200 ° C. Carbon, platinum dioxide, etc.
  • this step can also be performed at -78 ° C to 200 ° C in an appropriate solvent (alcohol solvents such as methanol and ethanol, or methylene chloride, chloroform, THF, dioxane, acetic acid, water, etc., or a mixed solvent thereof). More preferably, it can be suitably carried out by using a reducing agent (such as stannous chloride, iron, zinc, etc.) at 0 ° C to 100 ° C.
  • a reducing agent such as stannous chloride, iron, zinc, etc.
  • a compound having halogenosulfonyl on 1 ⁇ to 16 is obtained by reacting a compound in which the corresponding site is an amino group under the so-called S and mayer reaction conditions. It can be produced by halogenosulfuration via a salt. Formation of the diazonium salt can be achieved by, for example, using an appropriate acid (hydrochloric acid, sulfuric acid, etc.) and Z or an additive (cupric chloride, etc.) in an appropriate solvent (water, methylene chloride, chloroform, THF, or a mixed solvent thereof). ) In the presence or absence of -78 ° C.
  • halogenosulfonylation can be carried out by adding a sulfonating agent (sulfur dioxide, sodium bisulfite, etc.) to the obtained reaction solution at -78 ° C to 200 ° C.
  • a sulfonating agent sulfur dioxide, sodium bisulfite, etc.
  • a compound having a substituted or unsubstituted aminosulfonyl on 1 ⁇ to 16 also reacts a compound having a corresponding site of halogenosulfonyl with a substituted or unsubstituted amine. J? Can also be manufactured. This reaction is carried out in the presence of a base group (pyridine, triethylamine, sodium hydroxide, sodium carbonate, etc.) in an appropriate solvent (methylene chloride, chloroform, THF, dioxane, water, etc.). It can be suitably carried out at -78 ° C to 200 ° C in the presence or absence.
  • a base group pyridine, triethylamine, sodium hydroxide, sodium carbonate, etc.
  • an appropriate solvent methylene chloride, chloroform, THF, dioxane, water, etc.
  • a compound having a substituted or unsubstituted alkanoylamino on ⁇ to 6 can also be produced by alkanoylating a compound in which the corresponding site is amino.
  • the alkanoich can be carried out in the same manner as the reaction (C) above. Further, the alkanoylation can be carried out with a compound in which the corresponding site is a secondary amine or a primary amine.
  • R among the objective compound [I], R 1 ⁇ : alkylsulfonyl El ⁇ Mino on R 6, Te lower reel sulfo El amino, substituted sulfo, such as heterocyclic Suruhoniruamino to - compounds with Rua amino or It can also be produced by sulfonylating a compound in which the corresponding site is an amino.
  • the sulfonylation is carried out in a suitable solvent (water, THF, methylene chloride, black mouth form, etc.) in the presence or absence of a base (triethylamine, diisopropyl pyrethylamine, pV gin, etc.) at -78 ° C to Can be performed at 200 ° C.
  • a suitable solvent water, THF, methylene chloride, black mouth form, etc.
  • a base triethylamine, diisopropyl pyrethylamine, pV gin, etc.
  • the sulfoleation can be carried out with a compound in which the corresponding site is a secondary amine and also a primary amine.
  • this reaction can be carried out in the same manner as the above reaction (K) with a compound having a corresponding oxo.
  • compounds having oxo on 1 ⁇ to 16 can be produced by using any conventional method for converting a secondary alcohol to a ketone.
  • this reaction can be carried out using dimethyl sulfoxide oxidation (Swern oxidation) using an activating agent such as oxalyl chloride in an appropriate solvent (dimethyl sulfoxide, black mouth form, methylene chloride, etc.), or a base (triethyla
  • an activating agent such as oxalyl chloride in an appropriate solvent (dimethyl sulfoxide, black mouth form, methylene chloride, etc.), or a base (triethyla
  • oxidants activated manganese dioxide, sulfur trioxide mono-pyridine complex, 1-hydroxy 1,2-benzobenzoxo 1 3 (1 H) 1 on 1 1 oxide 1, 1, 1-triacetoxy 1,1-dihydr draw 1,2-benzodoxol-3 (1 H) 1-on, pyridinium dichromate, pyridinium dichromate,
  • a compound having a secondary alcohol on 6 can be produced by using any conventional method for converting a compound having formyl to a secondary alcohol.
  • this reaction can be carried out in a suitable solvent (THF, toluene, jetyl ether, etc.) at -78 ° C to 100 ° C with the corresponding formyl compound and metal reagent (alkylmagnesium halide, alkyllithium, Dialkyl dumbbell etc.) can be preferably used.
  • a compound having unsubstituted rubamoyl on 1 to! ⁇ 6 is produced by using any conventional method for converting a cyano group to an unsubstituted rubamoyl group. can do.
  • a compound having the corresponding cyano is converted into a base (sodium hydroxide, water, water) at ⁇ 20 ° C. to 100 ° C. in an appropriate solvent (water, methanol, ethanol, isopropanol, etc., or a mixed solvent thereof). It can be suitably carried out by treatment with oxidizing power, such as oxidizing power, or power, t-butoxide.
  • a compound having a tertiary alcohol on ⁇ to 6 can be produced, for example, by reacting a compound having a corresponding oxo under the above-mentioned conditions (U).
  • the production of a compound having an optically active secondary alcohol on 6 can be carried out by any conventional method for dividing the secondary alcohol compound by enzymatic transesterification. It can be implemented by using.
  • the preparation can be carried out in a suitable solvent (t-butyl methyl ether, hexane, diisopropyl ether, THF, jetyl ether, water, etc.) at -78 ° C to 100 ° C at the corresponding racemic second.
  • the treatment can be suitably carried out by treating the secondary alcohol with an acyl donor (such as bulacetic acid) in the presence of an enzyme (such as lipase PS).
  • (Z) Of the target compound [I],! The production of a compound having alkyl on ⁇ 1 to! ⁇ 6 can be carried out by using a so-called catalytic hydrogenation method.
  • this compound can be obtained by converting a compound having the corresponding alkenyl into a metal catalyst in a suitable solvent (methanol, ethanol, DMF, THF, acetic acid or the like or a mixed solvent thereof) at 0 ° C to 200 ° C in a hydrogen atmosphere. By treating with (palladium carbon, platinum dioxide, etc.), it can be suitably produced.
  • a compound having 1,2-diol on 1 ⁇ to 16 can be produced by, for example, using a suitable solvent (water, acetone, THF, acetonitrile, ethyl acetate, etc. or a mixture thereof)
  • a suitable solvent water, acetone, THF, acetonitrile, ethyl acetate, etc. or a mixture thereof
  • the corresponding alkenyl-containing compound is oxidant (osmium tetroxide, ruthenium tetroxide, sodium periodate 7
  • the production of a compound having a halogen atom on ⁇ ⁇ 6 can be carried out by using any conventional method for halogenating alcohols.
  • the corresponding alcohol is treated with carbon tetrafluoride in the presence of triphenylphosphine in an appropriate solvent (methylene chloride, black mouth form, etc.) at 0 ° C to 100 ° C. It can implement suitably.
  • Lucio are halogenated Ariru the thiols body It can be carried out by using any conventional method of coupling with halogenated heteroaryl, aryltriflate or heteroaryltriflate. For example, this production is carried out in the presence or absence of a base (triethylamine, disopropylamine, etc.) in an appropriate solvent (dioxane, toluene, THF, 1,2-dimethoxetane, etc.
  • a base triethylamine, disopropylamine, etc.
  • solvent dioxane, toluene, THF, 1,2-dimethoxetane, etc.
  • a compound having a corresponding haloaryl with a thiol (hydroxyalkylthiol, dialkylaminoalkylthiol, etc.) in the presence of a metal catalyst (tetrakis (triphenylphosphine) palladium, etc.) at C to 200 ° C.
  • a metal catalyst tetrakis (triphenylphosphine) palladium, etc.
  • the production of compounds having mono- or di-substituted alkylamino on R 1 ! ⁇ 6 can be carried out by using, for example, an appropriate solvent (methanol, ethanol, dioxane, toluene, THF, 1, 2-dimethoxetane, etc.)
  • an appropriate solvent methanol, ethanol, dioxane, toluene, THF, 1, 2-dimethoxetane, etc.
  • a base triethylamine, disopropylamine, etc.
  • the corresponding haloalkyl-containing compound is mono- or di-substituted. It can be preferably carried out by treatment with an alkylamine (dimethylamine, jetylamine, methylamine, etc.).
  • a compound having dimethylamino is a compound having a corresponding haloalkyl at 0 ° C to 200 ° C in an appropriate solvent (eg, methanol, ethanol, dioxane, toluene, THF, 1,2-dimethoxetane).
  • an appropriate solvent eg, methanol, ethanol, dioxane, toluene, THF, 1,2-dimethoxetane.
  • - bird Methylsilyl
  • the production of a compound having alkynyl on RR 2 , R 5 or R 6 can be carried out by using halogenated aryl, halogenated heteroaryl, aryl triflate or heteroaryl triflate and alkyne. It can be carried out by using any conventional method of so-called bacterial head coupling reaction with the compound having the above-mentioned compounds.
  • this production is carried out in the presence of a base (such as triethylamine or diisopropylamine) and / or a copper salt (such as cuprous iodide) in a suitable solvent (such as dioxane, toluene, THF, 1,2-dimethoxetane).
  • a base such as triethylamine or diisopropylamine
  • a copper salt such as cuprous iodide
  • a suitable solvent such as dioxane, toluene, THF, 1,2-dimethoxetane.
  • a metal catalyst tetrakis (triphenylphosphine) palladium, etc.
  • alkyne propargyl alcohol, N, N-dimethylpropargylamine
  • a compound having tetrazolyl on scales 1 to! ⁇ 6 can be produced by using any conventional method for converting a cyano group into a tetrazolyl group.
  • this production can be carried out in a suitable solvent (methanol, ethanol, DMF, dioxane, toluene, TI-IF, 1,2-dimethoxetane, etc.), salt (triethylamine, diisopropylamine, etc.) or salt (triethylamine).
  • a suitable solvent methanol, ethanol, DMF, dioxane, toluene, TI-IF, 1,2-dimethoxetane, etc.
  • salt triethylamine, diisopropylamine, etc.
  • salt triethylamine
  • mine hydrochloride, etc. In the presence or absence, the corresponding cyano-containing compound is treated with metal azide (sodium azide, triptyltin
  • the production of compounds with O-alkoxy carbonyl oximine on 1 ⁇ to 16 can be carried out using suitable solvents (DMF, dioxane, toluene, THF, 1, 2-dimethoxetane, etc.) or in the absence of a base, in the presence or absence of a base (pyridine, triethylamine, etc.) or at 0 ° C to 200 ° C, the corresponding hydroxyimine compound can be converted to an alkyl carbonate. Treated with ethyl ether etc.) It can implement suitably.
  • HH Of the target compound [I], the production of a compound having aryl or heteroaryl on RR 2 , R 5 or R 6 uses any conventional method of so-called Still coupling or Suzuki force coupling reaction. Can be implemented.
  • a base triethylamine, disopropylamine, sodium tertbutoxide, sodium carbonate, cesium carbonate, in a suitable solvent (dioxane, toluene, THF, 1,2-dimethoxetane etc. or a mixed solvent thereof)
  • a suitable solvent dioxane, toluene, THF, 1,2-dimethoxetane etc. or a mixed solvent thereof
  • potassium phosphate etc. 0.
  • metal catalysts eg dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) paradium
  • tris dibenzylideneaceton
  • the corresponding haloaryl-containing compounds are araryltrialkyltin, heteroarrenoretanoloxytin, arenorezig droxyborane, heteroaryldihydroxyborane, aryl It can be suitably carried out by treating with catechol borane, heteroaryl catechol borane and the like.
  • the present compound [I] can also be used in the above steps (A) to (II) for compound [II] to compound [XIII] at an appropriate stage in each step of (1) to (13). It can also be synthesized by appropriately carrying out any reaction.
  • Experimental example
  • reaction solution 25 raM MgCl 2, 25 mM KC1, 1 mM DTT, 5 mM NADP (Roche), 16. 64 / ig / raL G6PDH ( yeast Roche 737-232 grade II) and 2. 8 ⁇ g / ml
  • a 25 mM HEPES buffer (pH 7.4) containing GST-GK was prepared.
  • the evaluation compound dissolved in DMSO was added to the reaction solution so that the final concentration was 0.001 to 100 ⁇ (5% DMSO).
  • glucose final concentration 5 mM
  • ATP final concentration 5 mM
  • the reaction temperature was 30 ° C, and the production of NADPH was monitored by the change in absorbance at 340 nm.
  • the increase in absorbance for 15 minutes from the start of the reaction was measured, and the value corrected for blank was taken as GK activity (mOD / min).
  • the EC 50 value was calculated from the GK activity value at each concentration of the evaluation compound.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent darcokinase activating action, diseases involving dalcokinase such as diabetes, particularly type II diabetes, or retinopathy, kidney It is useful for the prevention or treatment of chronic diabetic complications such as symptom, neurosis, ischemic heart disease or arteriosclerosis, and obesity.
  • APCI is the atmospheric pressure chemical ionization mass 67
  • E S I electrospray ionization mass spectrum.
  • DMF represents N, N-dimethylformamide
  • THF represents tetrahydrofuran.
  • the reaction mixture was cooled, diluted with ethyl acetate, filtered through Celite to remove insoluble materials, and the insoluble materials were washed with ethyl acetate.
  • the combined eluate was washed 3 times with 1 N hydrochloric acid, and extracted with a saturated aqueous sodium hydrogen carbonate solution into the organic layer. Wash the aqueous layer 3 times with ethyl acetate, then add 1 N hydrochloric acid to the aqueous layer! H 2 to 3 and extracted 3 times with ethyl acetate.
  • the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure.
  • Example 4 and 5 The corresponding starting materials were treated in the same manner as in Example 3 to obtain the compounds of Examples 4 and 5 above.
  • the title compound was obtained by using 3-mercapto-4-monomethyl-1,4H-1,2,4-triazole in the same manner as in Reference Example 19.
  • 2-Amino _ 5 Bromopyrazine 2.61 g (15.0 ⁇ ol), t-Puttynorecarbamate 2.11 g (18.0 mmol), Copper iodide (I) 290 mg (1.50 mmol),, ⁇ '-Dimethylolethylene
  • a mixture of 260 mg (3.00 mmol) of diamine, 4.15 g (30.0 mmol) of potassium carbonate and 80 ml of dioxane was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The extract was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • a novel compound having an excellent darcokinase activating action useful as an active ingredient of a medicament for the prevention and Z or treatment of dalcokinase-related diseases such as diabetes, diabetic complications or obesity.

Abstract

Cette invention concerne un dérivé oxime représenté par la formule ci-dessous ou l'un de ses sels acceptables sur le plan pharmacologique, qui est un nouveau composé possédant un excellent effet d'activation de la glucokinase et qui est donc utile en tant que principe actif d'un agent pharmaceutique destiné à la prévention et/ou au traitement d'une maladie associée à la glucokinase telle que le diabète, une complication diabétique ou l'obésité. Le cycle A représente un groupe aryle ou un groupe hétéroaryle ; Q représente un groupe cycloalkyle, un groupe hétérocyclique ou analogues ; le cycle T représente un groupe hétéroaryle ou un groupe hétérocyclique ; R1 représente un atome d'hydrogène ou analogues ; R2 représente -COR11 ou -CR13(OH)R11 ; R11 représente un groupe alkyle substitué ou non substitué, un groupe cycloalkyle substitué ou non substitué ou analogues ; R13 représente un atome d'hydrogène ou un groupe alkyle ; R3 et R4 représentent indépendamment un atome d'hydrogène, un groupe alcoxy ou analogues ; R5 représente un groupe alcoxy substitué ou non substitué, un groupe alkyle substitué ou non substitué ou analogues ; et R6 représente un atome d'hydrogène ou analogues.
PCT/JP2008/050467 2007-01-10 2008-01-09 Dérivé oxime WO2008084873A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011093423A1 (fr) * 2010-01-29 2011-08-04 田辺三菱製薬株式会社 Procédé d'obtention de dérivé d'acide (e)-hydroxyiminophénylacétique
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8497274B2 (en) 2008-12-02 2013-07-30 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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JP2001199971A (ja) * 1999-11-10 2001-07-24 Takeda Chem Ind Ltd アルコキシイミノアルカン酸誘導体
JP2002528537A (ja) * 1998-10-30 2002-09-03 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー ２−アミノ−チアゾール誘導体類、それらの製造方法および抗癌剤としてのそれらの使用
JP2003507329A (ja) * 1999-08-12 2003-02-25 フアルマシア・イタリア・エツセ・ピー・アー ３（５）−アミノ−ピラゾール誘導体、それらの製造方法および抗腫瘍薬としてのそれらの使用
WO2004072066A1 (fr) * 2003-02-11 2004-08-26 Prosidion Limited Composes d'amide a substitution tri(cyclo), activateurs de la glucokinase
WO2005023761A2 (fr) * 2003-09-11 2005-03-17 Kemia, Inc. Inhibiteurs des cytokines
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JPH11500713A (ja) * 1995-01-30 1999-01-19 バイエル・アクチエンゲゼルシヤフト アルコキシイミノ酢酸アミド
JP2002528537A (ja) * 1998-10-30 2002-09-03 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー ２−アミノ−チアゾール誘導体類、それらの製造方法および抗癌剤としてのそれらの使用
JP2003507329A (ja) * 1999-08-12 2003-02-25 フアルマシア・イタリア・エツセ・ピー・アー ３（５）−アミノ−ピラゾール誘導体、それらの製造方法および抗腫瘍薬としてのそれらの使用
JP2001199971A (ja) * 1999-11-10 2001-07-24 Takeda Chem Ind Ltd アルコキシイミノアルカン酸誘導体
WO2004072066A1 (fr) * 2003-02-11 2004-08-26 Prosidion Limited Composes d'amide a substitution tri(cyclo), activateurs de la glucokinase
WO2005023761A2 (fr) * 2003-09-11 2005-03-17 Kemia, Inc. Inhibiteurs des cytokines
WO2007007886A1 (fr) * 2005-07-11 2007-01-18 Mitsubishi Tanabe Pharma Corporation Derive d'oxime et ses preparations

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8497274B2 (en) 2008-12-02 2013-07-30 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CN102712582A (zh) * 2010-01-29 2012-10-03 田边三菱制药株式会社 (e)-羟基亚氨基苯基乙酸衍生物的制备方法
WO2011093423A1 (fr) * 2010-01-29 2011-08-04 田辺三菱製薬株式会社 Procédé d'obtention de dérivé d'acide (e)-hydroxyiminophénylacétique
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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