WO2014175330A1 - Dérivé de 5-oxybenzimidazole et de 5-oxyazabenzimidazole ayant pour effet d'activer l'ampk - Google Patents

Dérivé de 5-oxybenzimidazole et de 5-oxyazabenzimidazole ayant pour effet d'activer l'ampk Download PDF

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WO2014175330A1
WO2014175330A1 PCT/JP2014/061419 JP2014061419W WO2014175330A1 WO 2014175330 A1 WO2014175330 A1 WO 2014175330A1 JP 2014061419 W JP2014061419 W JP 2014061419W WO 2014175330 A1 WO2014175330 A1 WO 2014175330A1
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substituted
unsubstituted
compound
alkyl
heterocyclyl
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PCT/JP2014/061419
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Japanese (ja)
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栄一 児嶋
優 日向
友亮 田村
正彦 藤岡
むつみ 定
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塩野義製薬株式会社
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Priority to JP2015513798A priority Critical patent/JP6372891B2/ja
Publication of WO2014175330A1 publication Critical patent/WO2014175330A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound useful for a medicine having an adenosine monophosphate-activated protein kinase (Adenosine monophosphate-activated protein kinase, hereinafter referred to as AMPK) activating action.
  • AMPK adenosine monophosphate-activated protein kinase
  • AMPK is a serine / threonine kinase that is activated by AMP and has three subunits ⁇ , ⁇ , and ⁇ . Each subunit has multiple isoforms ( ⁇ 1, ⁇ 2, ⁇ 1, ⁇ 2, ⁇ 1, ⁇ 2, and ⁇ 3).
  • AMPK is involved in various physiological functions such as suppression of gluconeogenesis in the liver, inhibition of fatty acid synthesis, glucose uptake in skeletal muscle and enhancement of fatty acid oxidation, as an in vivo energy sensor, and is of interest as a target molecule for antidiabetic drugs Has been. Therefore, the AMPK activator is expected to be effective for the treatment of diabetes as an insulin resistance ameliorating agent having an insulin-independent blood glucose lowering and lipid improving action (Non-patent Document 1).
  • Patent Documents 1 to 20 disclose various compounds having an AMPK activating action, and any of 5-oxobenzimidazole and 5-oxoazabenzimidazole derivatives such as the compound of the present invention is disclosed in any of them. Not disclosed. Reference 7 describes the following compounds, but they are not actually synthesized compounds. Patent Document 21 describes the following compounds as intermediates of compounds useful for diabetes and the like, but does not describe the AMPK activation action. When structure search was performed with SciFinder (online search database), the following compounds were hit, but there was no literature information and the AMPK activation action is unknown.
  • An object of the present invention is to provide an excellent AMPK activator.
  • the present invention relates to the following.
  • Y is a substituted or unsubstituted heterocyclyl, and the substituted or unsubstituted heterocyclyl is (Where R 11 And R 12 Each independently represents hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino, R 14 And R 16 Each independently is a substituted or unsubstituted alkyl, R 13 , R 15 And R 17 Each independently is hal
  • Y is a substituted or unsubstituted heterocyclyl, and the substituted or unsubstituted heterocyclyl is (Where R 11 And R 12 Each independently represents hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino, R 13 Each independently is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted amino, R 13 Each independently is
  • R 4 Is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted
  • R 4 Or a pharmaceutically acceptable salt thereof, wherein is hydrogen.
  • R 2 wherein the substituent is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • R 2 Is substituted alkyl and the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl and substituted or unsubstituted heterocyclyl
  • R 2 Is a substituted alkyl, and the substituted alkyl is (Where R 18 Is halogen, hydroxy, cyano or substituted or unsubstituted alkyl, R 19 Is hydrogen, halogen, hydroxy, cyano or substituted or unsubstituted alkyl, R 20 Is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted
  • a pharmaceutical composition having an adenosine monophosphate-activated protein kinase activating action which comprises a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (17) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to the above (19) which has an action to activate adenosine monophosphate-activated protein kinase.
  • the pharmaceutical composition according to any one of the above (18) to (20) for the treatment and / or prevention of diabetes.
  • a method for preventing or treating diabetes comprising administering the compound according to any one of (1) to (18) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition for parenteral administration containing the compound shown by this, or its pharmaceutically acceptable salt.
  • an insulin secretagogue a fast acting insulin secretagogue, a glucose absorption inhibitor, an insulin resistance improver, a thiazolidine derivative, an insulin preparation, a peptidyl peptidase IV inhibitor , A GLP-1 receptor agonist, a type 1 sodium-dependent glucose transporter inhibitor, or a combination with a type 2 sodium-dependent glucose transporter inhibitor.
  • an insulin secretagogue a fast acting insulin secretagogue, a glucose absorption inhibitor, an insulin sensitizer, a thiazolidine derivative, an insulin preparation, peptidyl peptidase IV
  • R 5 Or a pharmaceutically acceptable salt thereof, wherein is hydrogen.
  • R 4 Is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkynyl
  • R 4 Or a pharmaceutically acceptable salt thereof, wherein is hydrogen.
  • R 2 Wherein the substituent is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • R 2 Is substituted alkyl and the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl and substituted or unsubstituted heterocyclyl
  • a pharmaceutical composition having an adenosine monophosphate-activated protein kinase activating action which comprises a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1A) to (14A) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to the above (16A) which has an adenosine monophosphate activated protein kinase activating action.
  • Y is a substituted or unsubstituted heterocyclyl, and the substituted or unsubstituted heterocyclyl is (Where R 11 And R 12 Each independently represents hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino, R 14 And R 16 Each independently is a substituted or unsubstituted alkyl, R 13 , R 15 And R 17 Each independently is a substitute
  • Y is a substituted or unsubstituted heterocyclyl, and the substituted or unsubstituted heterocyclyl is (Where R 11 And R 12 Each independently represents hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino, R 13 Each independently is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted amino, R 13 Each independently is
  • R 4 Is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio
  • R 4 Or a pharmaceutically acceptable salt thereof, wherein is hydrogen.
  • R 2 Wherein the substituent is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • R 2 Is substituted alkyl and the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl and substituted or unsubstituted heterocyclyl
  • R 2 Is a substituted alkyl, and the substituted alkyl is (Where R 18 Is halogen, hydroxy or cyano and R 19 Is hydrogen, halogen, hydroxy or cyano and R 20 Is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl; 21 Is hydrogen, halogen, hydroxy or cyano and R 22 Is halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl. Or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition having an adenosine monophosphate-activated protein kinase activating action which comprises a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1B) to (17B) or a pharmaceutically acceptable salt thereof.
  • 21B The pharmaceutical composition according to any one of the above (18B) to (20B), for the treatment and / or prevention of diabetes.
  • (22B) A method for preventing or treating diabetes, comprising administering the compound according to any one of (1B) to (18B) or a pharmaceutically acceptable salt thereof.
  • (23B) The compound according to any one of (1B) to (18B) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of diabetes.
  • the pharmaceutical composition containing the compound of the present invention can be used to treat pharmaceuticals, particularly type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and / or hypertension and It is very useful as a medicine for prevention. In addition, it is a compound having utility as a medicine.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.
  • Alkenyl means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.
  • Alkynyl means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, you may have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.
  • “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.
  • “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl.
  • Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like.
  • Heteroaryl refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
  • the “monocyclic aromatic heterocyclic group” is derived from a 5- to 8-membered aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. Means a group which may have a bond at any substitutable position.
  • the “fused aromatic heterocyclic group” has 1 to 4 5- to 8-membered aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from oxygen, sulfur and nitrogen atoms in the ring. And a group optionally having a bond at any substitutable position, which is condensed with the 5- to 8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.
  • heteroaryl examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl).
  • Imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • triazolyl eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl
  • tetrazolyl eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
  • oxazolyl eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg 3-isoxazolyl, 4-isoxazolyl, -Isoxazolyl
  • thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • thiadiazolyl isothiazolyl (eg 3-isothiazo
  • Heterocyclyl means a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring, or cycloalkane (preferably 5-6 members), benzene ring and / or such ring
  • a non-aromatic heterocyclic group which may have a bond at any substitutable position on a ring condensed with a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring.
  • the “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic. A 5- to 8-membered ring is preferred.
  • Acyl refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, It means substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.
  • alkenylcarbonyl alkenylcarbonyl
  • cycloalkylcarbonyl cycloalkenylcarbonyl
  • arylcarbonyl cycloalkenylcarbonyl
  • heteroarylcarbonyl cyclocyclylcarbonyl
  • alkyl moiety, “alkenyl” moiety, The “cycloalkyl” moiety, “cycloalkenyl” moiety, “aryl” moiety, “heteroaryl” moiety, and “heterocyclyl” moiety are the above “alkyl”, “alkenyl”, “cycloalkyl”, “cycloalkenyl”, respectively. ”,“ Aryl ”,“ heteroaryl ”,“ heterocyclyl ”.
  • alkyl part of “alkyloxy”, “alkylthio” and “alkylsulfonyl” means the above “alkyl”.
  • the aryl part of “aryloxy”, “arylthio” and “arylsulfonyl” means the above “aryl”.
  • the heteroaryl part of “heteroaryloxy”, “heteroarylthio” and “heteroarylsulfonyl” means the above “heteroaryl”.
  • the cycloalkyl part of “cycloalkyloxy”, “cycloalkylthio” and “cycloalkylsulfonyl” means the above “cycloalkyl”.
  • cycloalkenyl part of “cycloalkenyloxy”, “cycloalkenylthio” and “cycloalkenylsulfonyl” means the above “cycloalkenyl”.
  • the heterocyclyl part of “heterocyclyloxy”, “heterocyclylthio” and “heterocyclylsulfonyl” means the above “heterocyclyl”.
  • Substituted or unsubstituted alkenyl include carboxy, carbamoyl, —CON ( CH 3 ) 2.
  • Aryl substituted or unsubstituted cycloalkyl (hydroxy as substituent), substituted or unsubstituted cycloalkenyl (carboxyl as substituted, substituted or unsubstituted alkyl (substituent) As hydroxy, alkyloxy.
  • Substituted or unsubstituted heterocyclyl substituted or unsubstituted acyl (substituent is hydroxy, alkyloxy).
  • Substituted or unsubstituted alkyloxy substituted or unsubstituted alkyloxy (substituent Is halogen, hydroxy, carboxy, aryl, heteroaryl, substituted or unsubstituted heterocyclyl (substituents are halogen, hydroxy), alkyloxy, alkylsulfonyl, substituted or unsubstituted carbamoyl (substituents are , Alkyl.).
  • Ants Ruoxy substituted or unsubstituted cycloalkyloxy (hydroxy as a substituent), heterocyclyloxy, alkyloxycarbonyl, alkylsulfonyl, substituted or unsubstituted acyl (substituents are halogen, hydroxy, substitute
  • Substituted or unsubstituted sulfamoyl alkyl is substituted
  • substituted or unsubstituted carbamoyl substituted is hydroxy
  • substituted or unsubstituted alkyl substituted is halogen, hydroxy, cyano
  • substituent include hydroxy, -CH 2 OH.
  • Substituted or unsubstituted heteroaryl (the substituent is alkyl), substituted or unsubstituted heterocyclyl (the substituent is hydroxy, —CH 2 OH.), Alkyloxy, alkylsulfonyl, substituted or Unsubstituted amino (the substituent is alkyl).
  • Substituted or unsubstituted cycloalkyl (substituent is hydroxy, substituted or unsubstituted alkyl (substituent is hydroxy, alkyloxy.)), Substituted or unsubstituted heteroaryl (substituent is , Alkyl.), Substituted or unsubstituted heterocyclyl (the substituent is alkyl), substituted or unsubstituted alkyloxy (the substituent is hydroxy, cycloalkyl, alkyloxy), cycloalkyloxy, -CH 2 CH 2 OH, -CH 2 COOH, -CH 2 CH 2 OCH 3, -CH 2 C (CH 3) 2 OH, -CH 2 CH 2 N (CH 3) 2.
  • alkylcarbonyl arylcarbonyl
  • Cycloalkylcarbonyl cycloalkenylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, formyl, acetyl, isopropylcarbonyl.
  • Substituted or unsubstituted alkylsulfonyl substituted or unsubstituted alkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, such as methanesulfonyl, ethanesulfonyl), Substituted or unsubstituted arylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted cycloalkylsulfonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl,
  • Substituted carbamoyl “substituted sulfamoyl” or “substituted amino”, preferably Substituted or unsubstituted alkyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl.
  • alkylamino means the above “alkyl”.
  • alkenyl part of “alkenyloxy” means the above “alkenyl”.
  • aryl part of “arylalkyl”, “arylamino”, “arylalkylamino”, “arylsulfonylamino”, “aryloxycarbonyl” and “arylsulfinyl” means the above “aryl”.
  • the heteroaryl part of “heteroarylamino”, “heteroarylsulfonylamino”, “heteroarylalkylcarbamoyl”, “heteroaryloxycarbonyl” and “heteroarylsulfinyl” means the above “heteroaryl”.
  • cycloalkyl part of “cycloalkylamino”, “cycloalkylsulfonylamino”, “cycloalkyloxycarbonyl” and “cycloalkylsulfinyl” means the above “cycloalkyl”.
  • the cycloalkenyl part of “cycloalkenylamino”, “cycloalkenylsulfonylamino”, “cycloalkenyloxycarbonyl” and “cycloalkenylsulfinyl” means the above “cycloalkenyl”.
  • heterocyclyl part of “heterocyclylamino”, “heterocyclylsulfonylamino”, “heterocyclyloxycarbonyl” and “heterocyclylsulfinyl” means the above “heterocyclyl”.
  • the following compounds are preferable.
  • Y is substituted or unsubstituted alkyl (unless it is unsubstituted methyl or unsubstituted ethyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Preferred is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl.
  • Y is a substituted or unsubstituted heterocyclyl
  • the substituted or unsubstituted heterocyclyl is preferably Is mentioned. Particularly preferably, Is mentioned.
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.
  • one of R 11 and R 12 is hydroxy and the other is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino It is. More preferably, one of R 11 and R 12 is hydroxy and the other is hydrogen or substituted or unsubstituted alkyl. Particularly preferably, one of R 11 and R 12 is hydroxy and the other is hydrogen.
  • R 14 and R 16 are each independently substituted or unsubstituted alkyl.
  • R 13 , R 15 and R 17 are each independently halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.
  • Each m is independently an integer of 0 to 4. Preferably, it is 0 or 1. More preferably, it is 0.
  • -N is
  • R 1 is hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • R 2 is hydrogen, substituted or unsubstituted alkyl (unless it is unsubstituted methyl or trifluoromethyl), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl Substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, or substituted or unsubstituted carbamoyl.
  • a substituted alkyl from which the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • a substituted alkyl from which the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • One or more selected or substituted or unsubstituted cycloalkenyl.
  • a substituted alkyl (wherein the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl. 1 or more selected from.).
  • R 2 is substituted alkyl
  • the substituted alkyl is preferably Is mentioned.
  • R 18 is halogen, hydroxy, cyano or substituted or unsubstituted alkyl. Preferably, it is halogen.
  • R 19 is hydrogen, halogen, hydroxy, cyano or substituted or unsubstituted alkyl. Preferably, it is halogen.
  • R 20 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or Unsubstituted sulfamoyl or substituted or unsubstituted amino.
  • R 21 is hydrogen, halogen, hydroxy, cyano or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • R 22 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted A sulfamoyl or a substituted or unsubstituted amino.
  • it is a substituted or unsubstituted alkyl.
  • R 23 is hydrogen, halogen, hydroxy, cyano or substituted or unsubstituted alkyl. Preferred is halogen, hydroxy, cyano, or substituted or unsubstituted alkyl. More preferred is halogen.
  • R 24 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or Unsubstituted sulfamoyl or substituted or unsubstituted amino.
  • halogen hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted A sulfamoyl or a substituted or unsubstituted amino.
  • R 3 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubsti
  • R 4 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubsti
  • R 5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubsti
  • X represents a single bond, —O—, —S—, —NR 6 —, —C ( ⁇ O) —, —C ( ⁇ O) NR 7 —, —NR 8 C ( ⁇ O) —, —NR 9 —.
  • Preferred is a single bond, —O— or —S—. More preferred is —O— or —S—. Particularly preferred is —O—.
  • R 6 is hydrogen or substituted or unsubstituted alkyl.
  • R 7 is hydrogen or substituted or unsubstituted alkyl.
  • R 8 is hydrogen or substituted or unsubstituted alkyl.
  • R 9 is hydrogen or substituted or unsubstituted alkyl.
  • R 10 is hydrogen or substituted or unsubstituted alkyl.
  • Examples of preferable combinations of substituents of the compound represented by the formula (I) include the following 1) to 28).
  • R 1 is hydrogen, A compound in which Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl; 2) R 1 is hydrogen, A compound wherein Y is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; 3) a compound wherein R 1 is hydrogen and Y is an unsubstituted heterocyclyl; 4) a compound wherein R 1 is hydrogen and Z is —N ⁇ ; 5) R 1 is hydrogen, R 2 is substituted alkyl (from which the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
  • Y is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl
  • R 2 is substituted alkyl (from which the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • Y is a substituted or unsubstituted heterocyclyl
  • R 2 is substituted alkyl (from which the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl.
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen or halogen; 15) Y is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;
  • R 2 is substituted alkyl (the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and substituted or unsubstituted heterocyclyl) Or one or more selected from cycloalkenyl), or substituted or unsubstituted cycloalkenyl A compound wherein R 3 is hydrogen or halogen; 24) R 2 is substituted alkyl (the substituent is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycl
  • R 3 is hydrogen or halogen;
  • R 4 is hydrogen, 27)
  • R 1 is hydrogen
  • Y is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen or halogen;
  • R 4 is hydrogen, 28)
  • R 1 is hydrogen
  • Y is a substituted or unsubstituted heterocyclyl
  • R 4 is hydrogen.
  • One or more hydrogen, carbon or other atoms of the compounds of formula (I) and formula (II) of the present invention may be replaced with isotopes of hydrogen, carbon or other atoms.
  • the compound of formula (I) encompasses all radiolabeled forms of the compound of formula (I).
  • Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays.
  • isotopes that can be incorporated into the compounds of formula (I) of the present invention are 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, respectively.
  • radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method involves reacting a tritium gas with a suitably halogen-substituted precursor of a compound of formula (I) in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and strontium salt; metal salts such as beryllium salt, magnesium salt, zinc salt and transition metal salt; ammonium salt ; Aliphatic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; N, N-dibenzylethylenediamine, venetamine Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salt
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Acidic amino acids such as aspartate and glutamate are included.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate,
  • Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate
  • sulfonates such as methanesulfonate, isethionate, benz
  • the compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form solvates (for example, hydrates and the like) and / or crystalline polymorphs.
  • the present invention also encompasses such various solvates and polymorphs.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I), for example.
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is hydrolyzed by a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I) or formula (II), gastric acid, etc.
  • the compound etc. which are converted into the compound shown by Formula (I) or Formula (II) are included.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent.
  • activation means that the compound of the present invention activates the action of AMPK.
  • pharmaceutically acceptable means not prophylactically or therapeutically harmful.
  • the general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the compound represented by the formula (I-1) can be synthesized as follows. (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (A-1) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen, Pro means protecting group, and examples of Pro include benzyl group, benzoyl group, SEM (trimethylsilylethoxymethyl) and the like.
  • Reaction solvents include N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg,
  • N, N-dimethylformamide or ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyllithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides eg, sodium hydride
  • the base is preferably a metal hydride (eg, sodium hydride), metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) or metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t -Butoxide and the like).
  • the reaction may be performed at ⁇ 78 to 100 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula: R 2 —O—H include benzyl alcohol and phenol.
  • the second step is a step for producing a compound represented by the formula (A-3) by reducing a compound represented by the formula (A-2).
  • the solvent described in the first step can be used.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • esters eg, acetic acid
  • nitriles eg, acetonitrile, etc.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • water etc.
  • the reaction may be performed at room temperature to 120 ° C. for 0.5 to 12 hours in the presence of Fe, Pd / C, Sn or the like.
  • an acid may be used, it is not necessary to use it.
  • the acid includes hydrochloric acid, ammonium chloride, and the like.
  • This step can be performed using reaction conditions known as a hydrogenation reaction.
  • the reduction may be performed in the presence of Pd / C.
  • the third step is a step for producing a compound represented by the formula (A-4) by reacting a compound represented by the formula (A-3) with carbonyldiimidazole (CDI).
  • CDI carbonyldiimidazole
  • phosgene, triphosgene or the like may be used instead of carbonyldiimidazole (CDI).
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide, halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles for example, acetonitrile etc.
  • the reaction may be performed at 0 to 100 ° C. for 0.5 to 24 hours.
  • the compound represented by the formula (A-4) is reacted with a halogenating agent to produce the compound represented by the formula (A-5).
  • a reaction solvent the solvent described in the first step can be used, but it may not be used.
  • the halogenating agent include phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, thionyl chloride, sulfuryl chloride, or dichlorotriphenylphosphorane. Particularly preferred is phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
  • the reaction may be performed at 0 to 120 ° C. for 0.5 to 24 hours.
  • Fifth step is a step of producing a compound represented by the formula (A-6) from a compound represented by the formula (A-5).
  • the reaction solvent the solvent described in the first step can be used.
  • the solvent described in the first step can be used.
  • N, N-dimethylformamide, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) Or nitriles (for example, acetonitrile etc.) etc. are mentioned.
  • the base the base described in the first step can be used.
  • the base is preferably a metal hydride (eg, sodium hydride), metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t). -Butoxide, etc.) or organic amines (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.).
  • the reaction may be performed at 0 to 100 ° C. for 0.5 to 12 hours.
  • the compound represented by the formula: H—O—Y include phenol, methanol, ethanol and the like.
  • the reaction solvent the solvent described in the first step can be used.
  • N-dimethylformamide, dimethyl sulfoxide, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (eg, acetonitrile, etc.) and the like can be mentioned.
  • the base described in the first step can be used.
  • metal hydride eg, sodium hydride, etc.
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • metal amide organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2, 6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • a metal hydride eg, sodium hydride
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • the reaction may be performed at 0 to 100 ° C. for 0.5 to 12 hours. (When Hal is bromine or iodine) It can be performed using reaction conditions known as the Ullmann reaction.
  • the reaction solvent the solvent described in the first step can be used.
  • N-dimethylformamide, dimethyl sulfoxide, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (eg, acetonitrile, etc.) and the like can be mentioned.
  • the base the base described in the first step can be used.
  • metal hydride eg, sodium hydride
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • metal amide organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2, 6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • copper iodide may be used as the catalyst.
  • the reaction may be performed at room temperature to 100 ° C. for 0.5 to 12 hours.
  • the seventh step is a step for producing a compound represented by the formula (I-1) by deprotecting the compound represented by the formula (A-7).
  • the reaction solvent the solvent described in the first step can be used.
  • N-dimethylformamide, halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • esters Eg, methyl acetate, ethyl acetate, etc.
  • nitriles eg, acetonitrile, etc.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • the reaction may be performed at 0 to 100 ° C. for 0.5 to 24 hours in the presence of hydrochloric acid, TFA (trifluoroacetic acid), TBAF (t
  • the compound in which R 1 is substituted or unsubstituted alkyl is, for example, an alkylation reaction using a compound represented by formula (I-1) using sodium hydride and an alkyl halide. Can be synthesized.
  • a compound in which X is —O—, —S— or —NR 6 — can be synthesized as follows. (In the formula, each symbol has the same meaning as above. “Hal” represents halogen, and Pro represents a protecting group. Examples of Pro include benzyl group, benzoyl group, SEM (trimethylsilylethoxymethyl)).
  • the eighth step is a step for producing a compound represented by the formula (A-8) by reacting a compound represented by the formula (A-6) with a compound represented by the formula: H-XY.
  • X is —O—
  • examples of the compound represented by the formula: H—O—Y include phenol, methanol, ethanol and the like.
  • X is —S—
  • examples of the compound represented by the formula: HSY are methanethiol or ethanethiol.
  • X is —NR 6 —
  • examples of the compound represented by the formula: H—NR 6 —Y include methylamine and ethylamine. What is necessary is just to perform reaction similarly to the said 6th process.
  • the ninth step is a step for producing a compound represented by the formula (II-1) by deprotecting the compound represented by the formula (A-8). What is necessary is just to perform reaction similarly to the said 7th process.
  • the compound in which R 1 is substituted or unsubstituted alkyl is, for example, an alkylation reaction using a compound represented by formula (II-1) using sodium hydride and an alkyl halide. Can be synthesized.
  • the compound represented by the formula (A-7) can also be synthesized by the following method.
  • each symbol has the same meaning as described above, and the compound represented by the formula (A-1) may be a known compound or a compound derived from a known compound by a conventional method.
  • “Hal” means halogen
  • Pro means protecting group
  • examples of Pro include benzyl group, benzoyl group, SEM (trimethylsilylethoxymethyl) and the like.
  • Tenth step is a step of producing a compound represented by the formula (A-9) by reducing a compound represented by the formula (A-1). What is necessary is just to perform reaction similarly to the said 2nd process.
  • Eleventh step is a step of producing a compound represented by the formula (A-10) by reacting a compound represented by the formula (A-9) with a compound represented by the formula: (akO) 3 CH.
  • the reaction solvent the solvent described in the first step can be used.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • an acid may be used, it is not necessary to use it.
  • the acid is preferably hydrochloric acid, NH 3 SO 3 or the like.
  • the reaction may be performed at room temperature to 150 ° C. for 0.5 to 12 hours.
  • Examples of the compound represented by the formula: (akO) 3 CH include (MeO) 3 CH, (EtO) 3 CH, and the like.
  • Twelfth step is a step of producing a compound represented by the formula (A-11) from a compound represented by the formula (A-10). What is necessary is just to perform reaction similarly to the said 5th process.
  • a thirteenth step is a step of reacting a compound represented by the formula (A-11) with a compound represented by the formula: Pro-OH to produce a compound represented by the formula (A-12).
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide or ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in the first step can be used.
  • the base is preferably a metal hydride (eg, sodium hydride), metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) or metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t -Butoxide and the like).
  • the reaction may be performed at ⁇ 78 to 100 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula: Pro-OH include 4-methoxybenzyl alcohol.
  • the reaction solvent the solvent described in the first step can be used.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • the base the base described in the first step can be used.
  • Preferable examples include metal hydrides (eg, sodium hydride) or metal amides (eg, lithium hexamethyldisilazide), alkyllithiums (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • the reaction may be performed at ⁇ 78 to 50 ° C. for 0.5 to 24 hours.
  • the halogenating agent I 2 , Br 2 , NIS (N-iodosuccinimide), NBS (N-bromosuccinimide) or NCS (N-chlorosuccinimide) may be used.
  • Fifteenth step is a step of producing a compound represented by the formula (A-14) by reacting a compound represented by the formula (A-13) with a compound represented by the formula: H—O—Y. What is necessary is just to perform reaction similarly to the said 6th process.
  • Sixteenth step is a step of producing a compound represented by the formula (I-15) by deprotecting the compound represented by the formula (A-14).
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide, halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) or ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) Etc. can be used.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, and trifluoroacetic acid.
  • the reaction may be performed at ⁇ 78 to 100 ° C. for 0.5 to 24 hours.
  • the seventeenth step is a step for producing a compound represented by the formula (A-7) by reacting a compound represented by the formula (A-15) with a compound represented by the formula: R 2 —OH. It can be carried out using reaction conditions known as Mitsunobu reaction.
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide or ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the reaction may be performed at ⁇ 78 to 100 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula: R 2 —OH include cyclopentanol.
  • the compound represented by the formula (A-7) is synthesized from the compound represented by the formula (A-15) by an alkylation reaction using the compound represented by the formula: R 2 -Hal. You can also.
  • “Hal” means halogen.
  • the compound represented by the formula (II-2) can be synthesized as follows. (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (A-16) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen.)
  • the eighteenth step is a step for producing a compound represented by the formula (A-17) by reacting a compound represented by the formula (A-16) with thiocarbonyldiimidazole or carbon disulfide (CS 2 ).
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide, halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane and the like), nitriles (eg, acetonitrile and the like), water and the like can be mentioned.
  • carbon disulfide (CS 2 ) it is preferable to use a base.
  • the base described in the first step can be used.
  • Preferable examples include metal hydrides (eg, sodium hydride) and metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide).
  • the reaction may be performed at room temperature to 150 ° C. for 0.5 to 12 hours.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • a nineteenth step is a step for producing a compound represented by the formula (II-2) by reacting a compound represented by the formula (A-17) with a compound represented by the formula: Hal-Y.
  • the reaction solvent the solvent described in the first step can be used.
  • the solvent described in the first step can be used.
  • the base the base described in the first step can be used.
  • metal hydride eg, sodium hydride, etc.
  • metal hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
  • metal carbonate eg, sodium carbonate
  • the reaction may be performed at 0 to 150 ° C. for 0.5 to 12 hours.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • the various substituents of the compound of the present invention are (1) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry (2) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry II (3) RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYLIC COMPOUNDS etc.
  • the compound of the present invention has an excellent AMPK activation action. Therefore, it can be used for the treatment or prevention of diseases involving AMPK, particularly diseases such as type 1 diabetes, type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and / or hypertension. In particular, it is useful in the treatment or prevention of type 2 diabetes, hyperglycemia, metabolic syndrome and obesity.
  • parenteral administration When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • Oral administration is in accordance with conventional methods, such as solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, syrups, (Limonade, alcohol, aromatic water, extract, decoction, tincture, etc.) and the like may be prepared and administered.
  • the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • Parenteral administration includes injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, ointments Any of the commonly used dosage forms such as plasters, jelly preparations, cream preparations, patches, poultices, external powders, suppositories, etc. can be suitably administered.
  • the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type and the like.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
  • the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • parenteral administration although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound of the present invention is an insulin secretagogue (for example, a sulfonylurea (SU) drug), a fast-acting insulin secretagogue (for example, a phenylalanine derivative) for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • an insulin secretagogue for example, a sulfonylurea (SU) drug
  • a fast-acting insulin secretagogue for example, a phenylalanine derivative
  • Drugs glucose absorption inhibitors (for example, ⁇ -glucosidase inhibitors ( ⁇ GI drugs)), insulin sensitizers (for example, biguanide drugs (BG drugs), thiazolidine derivatives (TZD drugs)), insulin preparations, peptidyl peptidases IV (DPP-IV) inhibitors, GLP-1 receptor agonists, type 1 sodium-dependent glucose transporter (SGLT1) inhibitors, type 2 sodium-dependent glucose transporter (SGLT2) inhibitors, etc. (Abbreviated) and the like.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • 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, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • Iron powder (3.29 g, 59 mmol) and ammonium chloride (0.063 g, 1.179 mmol) were added to a mixed solution of Compound 2 (3.3 g, 11.8 mmol) in ethanol (45 mL) and water (12 mL) at 110 ° C. Stir for hours.
  • the reaction solution was filtered through celite, the filtrate was concentrated, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 3.
  • the following reaction was performed without purification.
  • CDI (0.848 g, 5.23 mmol) was added to a DMF (10 mL) solution of the crude product of Compound 3 (1.0g, 4.02 mmol), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was collected by filtration to obtain Compound 4 (0.633 g, 2.3 mmol, 57%) as a white solid.
  • Phenol (0.75 g, 7.97 mmol) and tBuOK (0.766 g, 7.97 mmol) were added to the DMF (15 mL) solution, and the mixture was stirred at 100 ° C. for 1 hour.
  • Compound 1 1.5 g, 7.25 mmol was added to the solution, and the mixture was further stirred at 100 ° C. for 1 hour.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Compound 17 was produced according to the method described in the pamphlet of International Publication No. WO2012 / 033149. To a solution of compound 17 (10.0 g, 31.4 mmol) and compound 18 (5.85 mL, 47.1 mmol) in toluene (300 mL), BINAP (3.91 g, 6.28 mmol), Pd 2 (dba) 3 (2.88 g, 3.14 mmol) And NaOt-Bu (6.04 g, 62.8 mmol) were sequentially added at room temperature, followed by stirring at 100 ° C. for 1 hour.
  • Trifluoroacetic acid (31.8 mL, 413 mmol) was added to a solution of compound 22 (6.36 g, 9.38 mmol) in dichloromethane (31.8 mL), and the mixture was stirred at 0 ° C. for 20 minutes. Under ice-cooling, the reaction solution was quenched with a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain compound 23 (4.46 g, 7.99 mmol, 85%) as a white solid.
  • Trifluoroacetic acid 400 ⁇ L was added to a methylene chloride (400 ⁇ L) solution of compound 28 (40 mg, 0.061 mmol), and the mixture was stirred at room temperature for 6.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain compound (I-3-3) (15.5 mg, 0.037 mmol, 62%) as a white solid.
  • TMEDA (11.4 ml, 75.0 mmol) and NCS (4.57 g, 34.2 mmol) were added to a solution of compound 35 (9.72 g, 22.8 mmol) in THF (97 ml) at -78 ° C, and 1.0M LHMDS at -78 ° C. / THF (75.0 ml, 75.0 mmol) was added dropwise over 20 minutes and the mixture was stirred for 10 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure.
  • Triethylamine (2.13 mL, 15.4 mmol) and methanesulfonyl chloride (0.778 mL, 9.98 mmol) were added to a solution of compound 21 (2.00 g, 7.68 mmol) in dichloromethane (20 mL) under ice-cooling, and the mixture was stirred for 1 hour.
  • the reaction solution was quenched with water and extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 43 (2.30 g, 6.79 mmol, 89%) as a colorless liquid.
  • Compound 54 was synthesized according to US Publication No. 2012/238751.
  • N-iodosuccinimide (2.32 g, 10.29 mmol) was added to a solution of compound 54 (1.76 g, 9.36 mmol) in acetic acid (20 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, quenched with saturated multilayered water, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain Compound 55 (3.0 g) as a crude product.
  • Triethyl orthoformate (1.187 ml, 7.13 mmol) was added to a solution of compound 56 (1.35 g, 4.75 mmol) in ethanol (10 ml), and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was washed with ethyl acetate and hexane to obtain Compound 57 (0.95 g, 3.23 mmol, 68%) as a gray solid.
  • Compound 57; 1H-NMR (CDCl3) ⁇ : 3.83 (s, 3H), 6.99 (d, J 7.0 Hz, 1H), 7.83 (s, 1H).
  • Tributylethynyltin (1.9 ml, 6.63 mmol) was added to a solution of compound 57 (650) mg, 2.211 mmol) and tetrakis (triphenylphosphine) palladium (0) (255 mg, 0.221 mmol) in dioxane (5 ml). Stir at 4 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product (0.6 g) containing Compound 58.
  • reaction mixture was quenched with water, warmed to room temperature, and extracted with ethyl acetate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 63 (240 mg, 0.707 mmol, 44%) as a white solid.
  • X includes —O—.
  • examples of Y include the following substituents.
  • examples of Z include —CH ⁇ or —N ⁇ .
  • R 1 it includes H is.
  • examples of R 2 include the following substituents.
  • examples of R 3 include H, F, and Cl.
  • R 4 it includes H is.
  • AMP-activated protein kinase (AMPK) activator 50 mM HEPES-NaOH buffer (pH 7.0), 100 mM NaCl, 10 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate (V), 1 mM ethylene glycol-bis (2 aminoethyl ether)
  • EGTA N, N, N ', N'-tetraacetic acid
  • EGTA 5
  • the reaction solution was applied to a measuring device Caliper Science LabChip EZ Reader II which detects fluorescence using a difference in mobility due to a charge difference.
  • the instrument was set to -1.5 PSI for pressure, -2250 V for upstream voltage, -400 V for downstream voltage, 40 seconds for post-sample buffer ship time, 120 seconds for final delay, and Product First for peak order. .
  • the conversion rate was calculated from the peak heights of the obtained substrate and product, and the concentration dependency curve was plotted plotting the rate of increase in activity relative to the control at each concentration of the compound, with the conversion rate when no compound was included as a control. .
  • the compound concentration showing 150% with respect to the control (100%) was defined as the EC150 value, and the maximum activity increase rate within the measurement range was defined as Emax.
  • the expression strain was cultured in TB medium, 0.5 mM IPTG was induced, and the cells were collected after culturing at 25 ° C. for 3 hours. After sonication, the supernatant was recovered and applied to a Histrap FF column (GE) and a RESOUECE Q column (GE) to prepare 12.5 mg of a purified sample containing three types of subunits from a 1.8 L culture solution.
  • GE Histrap FF column
  • AMP-activated protein kinase (AMPK) activator Test Example 2 Since human AMPK ⁇ 2 ⁇ 2 ⁇ 1 prepared in E. coli is not phosphorylated and exhibits no activity, phosphorylation was performed as a pretreatment.
  • a compound dissolved in DMSO was added to the phosphorylated enzyme solution so as to have a concentration of 1% DMSO, and allowed to stand for 10 minutes.
  • 50 mM HEPES-NaOH buffer (pH 7.0) 100 mM NaCl, 10 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate (V), 1 mM ethylene glycol-bis (2 aminoethyl) Ether) -N, N, N ', N'-tetraacetic acid (EGTA), 5 mM ⁇ -glycerophosphate disodium, 2 mM dithiothreitol, 0.4 mM ATP, 3 ⁇ M FL-Peptide 7 (Caliper Life Sciences) An equal volume of a substrate solution consisting of 10 ⁇ l in total was added.
  • reaction solution was applied to a measuring device Caliper Science LabChip EZ Reader II which detects fluorescence using a difference in mobility due to a charge difference.
  • the instrument was set to -1.5 PSI for pressure, -2250 V for upstream voltage, -400 V for downstream voltage, 40 seconds for post-sample buffer ship time, 120 seconds for final delay, and Product First for peak order. .
  • the conversion rate was calculated from the peak heights of the obtained substrate and product, and the concentration dependency curve was plotted plotting the rate of increase in activity relative to the control at each concentration of the compound, with the conversion rate when no compound was included as a control. .
  • the compound concentration showing 150% with respect to the control (100%) was defined as the EC150 value, and the maximum activity increase rate within the measurement range was defined as Emax.
  • the compound of the present invention has an excellent activating effect on AMPK ⁇ 1 trimer and / or AMPK ⁇ 2 trimer.
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of compounds by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (7-BFC) as the CYP3A4 enzyme using E. coli-expressed CYP3A4 as the enzyme. The reaction was debenzylated as described above to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC).
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ M or more was designated as (+), and the case where it was 3 ⁇ M or less was designated as ( ⁇ ).
  • CYP inhibition test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin (CYP1A2) as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), Metabolites are generated using tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) as indices. The extent to which the amount was inhibited by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6) , 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration, 1, 5, 10, 20 ⁇ mol / L (4 point).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was analyzed with a fluorescent multilabel counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • Metabolic stability test Using commercially available pooled human liver microsomes, the target compound was reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • test compound in the centrifugal supernatant was quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction was calculated with the amount of the compound at 0 minute reaction as 100%.
  • the hydrolysis reaction was performed in the absence of NADPH, the glucuronic acid conjugation reaction was performed in the presence of 5 mM UDP-glucuronic acid instead of NADPH, and the same operation was performed thereafter.
  • hERG test Delayed rectification K that plays an important role in ventricular repolarization process using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of risk assessment of ECG QT interval prolongation
  • + current I Kr
  • a fully automatic patch clamp system PatchXpress 7000A, Axon Instruments Inc.
  • a +40 mV depolarization stimulus is applied for 2 seconds and then -50 I Kr evoked when mV repolarization stimulus was applied for 2 seconds was recorded.
  • the absolute value of the maximum tail current was measured from the obtained I Kr using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the influence of the test substance on I Kr was evaluated.
  • Powder solubility test Put an appropriate amount of specimen in a suitable container, JP-1 solution (2.0 g sodium chloride, 7.0 mL hydrochloric acid to 1000 mL), JP-2 solution (pH 6.8 phosphate buffer 500 mL) 500 mL of water was added to the solution, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (water was added to 1.08 g of TCA to make 100 mL) was added 200 ⁇ L at a time. When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • Formulation examples are shown below.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 3 Granules
  • the compound of the present invention, lactose and calcium stearate are mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed, granulated, and tableted to obtain an orally disintegrating tablet.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
  • Formulation Example 9 Ointment
  • the compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.
  • the compound according to the present invention exhibits an AMPK activation action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for type 1 diabetes, type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and hypertension.

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Abstract

La présente invention concerne un composé pouvant être utilisé en tant qu'activateur de l'AMPK. L'invention concerne, donc, un composé représenté par la formule (dans la formule, Y représente un groupe alkyle substitué ou non substitué) (à l'exclusion d'un groupe méthyle non substitué ou d'un groupe éthyle non substitué), un groupe alcényle substitué ou non substitué, un groupe alcynyle substitué ou non substitué, un groupe aryle substitué ou non substitué, etc., Z représente -CR5= ou -N=, R1 représente un atome d'hydrogène ou un groupe alkyle substitué ou non substitué, R2 représente un atome d'hydrogène ou un groupe alkyle substitué ou non substitué (à l'exception d'un groupe trifluorométhyle ou méthyle non substitué), un groupe alcényle substitué ou non substitué, un groupe alcynyle substitué ou non substitué, etc., R3, R4 et R5 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe hydroxyle, cyano, nitro, carboxy, un groupe alkyle substitué ou non substitué, un groupe alcényle substitué ou non substitué, un groupe alcynyle substitué ou non substitué, etc.) ou un sel pharmaceutiquement acceptable dudit composé.
PCT/JP2014/061419 2013-04-24 2014-04-23 Dérivé de 5-oxybenzimidazole et de 5-oxyazabenzimidazole ayant pour effet d'activer l'ampk WO2014175330A1 (fr)

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US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
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