WO2012173099A1 - Dérivé amino inhibant la lipase endothéliale - Google Patents

Dérivé amino inhibant la lipase endothéliale Download PDF

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Publication number
WO2012173099A1
WO2012173099A1 PCT/JP2012/064954 JP2012064954W WO2012173099A1 WO 2012173099 A1 WO2012173099 A1 WO 2012173099A1 JP 2012064954 W JP2012064954 W JP 2012064954W WO 2012173099 A1 WO2012173099 A1 WO 2012173099A1
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substituted
unsubstituted
halogen
alkyl
cyano
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Japanese (ja)
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直樹 吉川
麻童 中嶋
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P9/10—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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a compound useful for a medicine, which has a vascular endothelial lipase (Endthelial Lipase, hereinafter referred to as EL) inhibitory activity.
  • EL vascular endothelial lipase
  • EL is a Triglyceride Lipase family along with Lipoprotein Lipase (hereinafter referred to as LPL) and Hepatic Lipase (hereinafter referred to as HL), and is involved in the metabolism of HDL cholesterol (hereinafter referred to as HDLc) due to its strong phospholipase activity.
  • LPL Lipoprotein Lipase
  • HL Hepatic Lipase
  • HDLc HDL cholesterol
  • HDLc is considered to exhibit an anti-arteriosclerosis action through an antioxidant action, an anti-inflammatory action, a reverse cholesterol transfer action, and the like, and hypoHDLcemia is recognized as one of the risk factors of CAD. Therefore, an EL inhibitor becomes a CAD therapeutic agent through an increase in HDLc, and an increase in HDLc and a decrease in atherosclerotic lesion sites have been reported in pathological mice that actually knocked out EL (Non-patent Document 2). These findings indicate that EL selective inhibitors are useful as therapeutic agents in dyslipidemia and arteriosclerosis.
  • Patent Documents 1, 2 and 3 disclose various compounds having HL and / or EL inhibitory activity, but none of the oxadiazole derivatives such as the compounds of the present invention are disclosed.
  • Patent Document 4 discloses triglyceride lipase, LPL, HL, pancreatic lipase, and a compound having EL inhibitory activity, but does not disclose an oxadiazole derivative such as the compound of the present invention.
  • Patent Documents 5 to 15 disclose various compounds having EL inhibitory activity, but none of the oxadiazole derivatives such as the compounds of the present invention are disclosed.
  • Patent Document 16 describes a benzothiazole derivative having an elastase inhibitory action. However, none of the benzothiazole derivatives substituted at the 4th or 7th position such as the compounds of the present invention are disclosed.
  • An object of the present invention is to provide an excellent EL inhibitor.
  • R 4 and R 7 are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy or substituted or unsubstituted alkynyloxy, R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted al
  • R 10 and R 11 is hydrogen, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted sulfamoyl or the formula: — ( (C ⁇ O) — (CR 12 R 13 ) nR 14 (wherein R 12 , R 13 , n and R 14 have the same meaning as the above (1)), The compound according to any one of 1) to (4), or a pharmaceutically acceptable salt thereof.
  • X CR 4 - a and, R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy, compounds according to any one of (1) to (7) Or a pharmaceutically acceptable salt thereof.
  • a method for preventing or treating dyslipidemia comprising administering the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof.
  • (20) A method for preventing or treating hyperlipidemia comprising administering the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof.
  • (21) A method for preventing or treating arteriosclerosis comprising administering the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition containing the compound of the present invention can be used for pharmaceuticals, particularly dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, high triglyceride It is very useful as a medicament for the treatment and / or prevention of blood glucose, diabetes, obesity and / or syndrome X.
  • the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL. In addition, it is a compound having utility as a medicine.
  • a point, a point with a small clearance, or a point having a sufficiently long half-life for exhibiting a medicinal effect are included.
  • 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. And 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 hetero atoms in the ring which are optionally selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a group optionally having a bond at any substitutable position which is condensed with the other 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 part of “alkyloxy”, “alkyloxycarbonyl” and “alkylsulfonyl” means the above “alkyl”.
  • the alkenyl part of “alkenyloxy” and “alkenylsulfonyl” means the above “alkenyl”.
  • the alkynyl part of “alkynyloxy” means the above “alkynyl”.
  • the aryl part of “arylsulfonyl” means the above “aryl”.
  • the heteroaryl part of “heteroarylsulfonyl” means the above “heteroaryl”.
  • the cycloalkyl part of “cycloalkylsulfonyl” means the above “cycloalkyl”.
  • cycloalkenyl moiety of “cycloalkenylsulfonyl” means the above “cycloalkenyl”.
  • heterocyclyl part of “heterocyclylsulfonyl” means the above “heterocyclyl”.
  • Substituted or unsubstituted alkenyl substituted or unsubstituted alkenyl
  • substituted or unsubstituted alkynyl substituted or unsubstituted alkynyl
  • Substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, eg ethynyl
  • Substituted or unsubstituted aryl substituted or unsubstituted aryl
  • substituted or unsubstituted aryl substituted or unsubstituted aryl
  • substituted or unsubstituted aryl include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl,
  • alkylcarbamoyl eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl
  • alkylsulfonylcarbamoyl Heteroarylalkylcarbamoyl, alkyloxycarbamoyl.
  • Substituted or unsubstituted carbamoyloxy the substituent is alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl
  • Substituted or unsubstituted acyl substituted or unsubstituted acyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl.
  • alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Heterocyclylcarbonyl, formyl, acetyl. Substituted or unsubstituted alkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted cycloalkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstit
  • substituted sulfamoyl or “substituted carbamoyl” is preferably hydroxy, Substituted or unsubstituted alkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted alkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted aryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
  • alkylamino means the above “alkyl”.
  • aryl moiety of “arylthio”, “aryloxy”, “arylalkylamino”, “arylsulfonylamino”, “arylsulfonyl”, “aryloxycarbonyl”, “arylsulfinyl” and “arylalkyloxy” means the above “cycloalkyl”.
  • cycloalkenyl part of “cycloalkenyloxy”, “cycloalkenylthio”, “cycloalkenyloxycarbonyl” and “cycloalkenylsulfinyl” means the above “cycloalkenyl”.
  • the heteroaryl part of means the above “heteroaryl”.
  • heterocyclyl moiety of “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonylamino”, “heterocyclyloxycarbonyl”, “heterocyclylsulfonyl” and “heterocyclylsulfinyl” It means “heterocyclyl”.
  • the following compounds are preferable.
  • CR 4 - a CR 4 - a.
  • R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted Of alkynyloxy.
  • Preferred is hydrogen, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. More preferred is hydrogen or substituted or unsubstituted alkyloxy.
  • R 7 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted Of alkynyloxy.
  • Preferred is hydrogen, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. More preferred is halogen.
  • R 5 and R 6 are each independently 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 or substituted or unsubstituted heterocyclyl.
  • R 6 is preferably substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy, and R 1 and R 2 are taken together Oxo may be formed. Preferably, it is hydrogen.
  • R 3 is a group represented by the formula: — (CR 8 R 9 ) m—NR 10 R 11 .
  • Each R 8 is independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Preferably, it is hydrogen.
  • Each R 9 is independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Preferably, it is hydrogen.
  • M is an integer of 0 to 3, preferably an integer of 0 to 2, and more preferably 1.
  • R 10 and R 11 are each independently hydrogen, 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 alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloal
  • Each R 12 is independently 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, or substituted or unsubstituted alkyloxy, and each R 13 is independently 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 unsubstit
  • R 12 is preferably hydrogen or substituted or unsubstituted alkyl
  • R 13 is preferably hydrogen or substituted or unsubstituted alkyl
  • Rings formed by R 12 and R 13 together with adjacent carbon atoms include 3 to 15 saturated or unsaturated hydrocarbon rings, oxygen atoms, sulfur atoms and / or nitrogen atoms. It means a saturated or unsaturated heterocycle containing 1 to 4 rings in the ring.
  • Non-aromatic rings are preferred, and examples of such rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and oxygen and sulfur atoms.
  • / or a saturated or unsaturated heterocycle containing 1 to 4 nitrogen atoms in the hydrocarbon ring Preferably, the following are mentioned. More preferably, the following are mentioned.
  • N is 0 or 1, preferably 1.
  • R 14 is cyano, 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 acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted alkyloxycarbonyl. Preferably, it is cyano.
  • Examples of preferable combinations of substituents of the compound represented by the formula (I) include the following 1) to 8).
  • X CR 4 a and, R 7 is halogen,
  • X CR 4 a and, R 7 is halogen, R 6 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R 1 and R 2 are hydrogen, m is 1 or 2, and one of R 10 and R 11 is hydrogen, A compound wherein the other of R 10 and R 11 is
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium labeled compound represented by the formula (I) can be prepared, for example, by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • 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 An aliphatic amine salt such as a trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltols Examples include quaternary am
  • 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 compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • 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).
  • 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 compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, 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 a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • 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 reacting with a condensing agent.
  • inhibitor means that the compound of the present invention suppresses the action of EL.
  • 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) can be synthesized as follows. Wherein each symbol is as defined above, and the compound represented by the formula (E-1) may be a known compound or a compound derived from a known compound by a conventional method. “Ak” means alkyl having 1 to 3 carbon atoms, and “Hal” means halogen.)
  • First Step This is a step for producing a compound represented by the formula (E-2) by halogenating a compound represented by the formula (E-1).
  • 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.
  • N, N-dimethylformamide or alcohols eg, methanol, ethanol, t-butanol, etc.
  • the reaction may be performed at 0 to 50 ° C. for 0.5 to 12 hours.
  • the halogenating agent include NBS.
  • Second Step In the step of reacting a compound represented by the formula (E-2) with a compound represented by the formula: (CHR 1 R 2 —CO) 2 O to produce a compound represented by the formula (E-3) is there.
  • the reaction solvent 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 Methyl, ethyl acetate, etc.
  • a base may be used if necessary.
  • 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, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • sodium hydrogen carbonate organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) or pyridine
  • organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • pyridine e.g, acetic anhydride.
  • the solvent the solvent described in the first step can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles eg, acetonitrile, etc.
  • metal hydride eg, sodium hydride, etc.
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • sodium bicarbonate metal sodium, metal amide, organic amine (eg, triethylamine, diisopropyl) Ethylamine, DBU, 2,6-lutidine, etc.) or pyridine
  • metal amide e.g, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • organic amine eg, triethylamine, diisopropyl
  • Ethylamine e.g, DBU, 2,6-lutidine, etc.
  • pyridine e.g, pyridine
  • Lawson reagent, P 2 S 5 or the like may be used as a reagent.
  • the fourth step is a step for producing a compound represented by the formula (E-5) by reacting a compound represented by the formula (E-4) with a compound represented by the formula: (ak-O) 2 CO.
  • the reaction solvent the solvent described in the first step can be used.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, etc.
  • the base the base described in the second step can be used.
  • metal amide or alkyl lithium n-BuLi, sec-BuLi, tert-BuLi
  • the reaction may be performed at ⁇ 78 to 30 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula: (ak-O) 2 CO include diethyl carbonate.
  • Fifth step is a step of producing a compound represented by the formula (E-6) by reacting a compound represented by the formula (E-5) with hydrazine.
  • the reaction solvent the solvent described in the first step can be used.
  • N, N-dimethylformamide, alcohols (eg, methanol, ethanol, t-butanol, etc.) or N-methyl-2-pyrrolidone may be used.
  • the reaction may be carried out at a temperature at which the solvent used is refluxed for 0.5 to 12 hours. When the reaction is performed using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • the compound represented by the formula (E-6) is reacted with the compound represented by the formula: HOOC-R 3 to produce a compound represented by the formula (E-7).
  • This step can be performed using reaction conditions known as a condensation reaction between a carboxylic acid and an amine.
  • reaction conditions known as a condensation reaction between a carboxylic acid and an amine for example, N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSCD), or the like can be used as a condensing agent.
  • 1-hydroxybenzotriazole HOBt
  • 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine HOOBt
  • N-hydroxysuccinimide HSu
  • the reaction solvent the solvent described in the first step can be used.
  • anhydrous dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone may be used.
  • the reaction may be carried out at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 24 hours. When the reaction is performed using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Examples of the compound represented by the formula: HOOC-R 3 include 3-tert-butoxy-3-oxopropanoic acid, 4-tert-butoxy-4-oxobutanoic acid or 2- (tert-butoxycarbonylamino) acetic acid. .
  • the seventh step is a step for producing a compound represented by the formula (E-8) by dehydrating a compound represented by the formula (E-7).
  • the solvent 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 Methyl, ethyl acetate, etc.
  • T 3 P propylphosphonic anhydride
  • Burgess reagent TsCl and organic amine
  • MsCl and organic amine MsCl and organic amine
  • PPh 3 and CBr 4 PPh 3 and C 2 Cl 6 and the like
  • the reaction may be carried out at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 24 hours.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • the solvent the solvent described in the first step can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in Step 2 can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.)
  • the reaction may be performed for 0.5 to 12 hours at a temperature at which the solvent to be refluxed.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Examples of the compound represented by the formula: R 6 —B (OH) 2 include phenylboronic acid.
  • the compound represented by the formula (E-5) can also be synthesized by the following method. (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (E-9) may be a known compound or a compound derived from a known compound by a conventional method. “Ak” means alkyl having 1 to 3 carbon atoms, and “Hal” means halogen.)
  • Ninth step is a step of producing a compound represented by the formula (E-5) by reacting a compound represented by the formula (E-9) with a compound represented by the formula: CHR 1 R 2 -COO-ak. .
  • the solvent the solvent described in the first step can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in the second step can be used.
  • metal sodium or metal amide may be used.
  • the reaction may be performed at ⁇ 78 to 30 ° C. for 0.5 to 12 hours.
  • Examples of the compound represented by the formula: CHR 1 R 2 —COO-ak include butyl acetate, ethyl acetate, and methyl acetate.
  • the compound represented by the formula (E-14) can be synthesized as follows. (In the formula, each symbol is as defined above. “Hal” means halogen, “PG” means a protecting group. Examples of PG include a benzoyl group and a t-butoxycarbonyl group.)
  • Tenth step is a step of reacting a compound represented by the formula (E-6) with a compound represented by the formula (E-10) to produce a compound represented by the formula (E-11). What is necessary is just to perform like the said 6th process.
  • Eleventh step is a step of producing a compound represented by the formula (E-12) by dehydrating a compound represented by the formula (E-11). What is necessary is just to carry out similarly to the said 7th process.
  • Twelfth Step A compound represented by the formula (E-12) is reacted with a compound represented by the formula: R 6 —B (OH) 2 in the presence of a palladium catalyst to produce a compound represented by the formula (E-13). It is a process to do. What is necessary is just to perform like the said 8th process.
  • the thirteenth step is a step for producing a compound represented by the formula (E-14) by deprotecting the compound represented by the formula (E-13).
  • the reaction solvent 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 Methyl, ethyl acetate, etc.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like.
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • R 10 and R 11 By reacting the compound represented by the formula (E-14) with an acid chloride in the presence of a base, one or both of R 10 and R 11 can be converted to the formula: — (C ⁇ O) — (CR 12 R 13 ) A compound represented by the formula (I) which is a group represented by nR 14 can be produced.
  • R 10 and R 11 By reacting the compound represented by the formula (E-14) with a sulfonyl chloride in the presence of a base, either or both of R 10 and R 11 are substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted.
  • the above is an example, and other compounds represented by the formula (I) can also be produced by conducting chemical reactions known in the field of organic chemistry using the compound represented by the formula (E-14) as a raw material. it can.
  • 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 excellent EL inhibitory activity. Therefore, it can be used for the treatment or prevention of diseases involving EL, particularly diseases such as dyslipidemia, hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and / or syndrome X. . In particular, it is useful in the treatment or prevention of hyperlipidemia, arteriosclerosis and dyslipidemia.
  • the compound used in the present invention can be administered orally or parenterally.
  • the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form.
  • the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • the preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
  • the dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.
  • Triethylamine (0.98 ml, 7.10 mmol) and compound (I-1-2) (620 mg, 1.42 mmol) were added at ⁇ 10 ° C. and the mixture was stirred for 2 hours.
  • the reaction was returned to room temperature, extracted with 1N hydrochloric acid and ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography to obtain Compound (I-1-3) (545 mg, 74%) as a solid.
  • Boc represents a tert-butoxycarbonyl group.
  • examples of Z include ⁇ CR 7 — or ⁇ N—.
  • examples of R 7 include hydrogen, fluorine, chloro, methyl, ethyl, cyano, trifluoromethyl, methoxy, and ethoxy.
  • examples of R 4 include hydrogen, fluorine, chloro, methyl, cyano, trifluoromethyl, methoxy, and ethoxy.
  • examples of R 5 include the following substituents.
  • examples of R 6 include the following substituents.
  • examples of R 11 include the following substituents.
  • the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL.
  • the selectivity was examined by the following test.
  • Test Example 2 Evaluation method using mouse very low density lipoprotein (VLDL) for inhibiting mouse HL 20 mM Tris-HCl buffer (pH 7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM), An inhibitor dissolved in DMSO was added to a reaction solution composed of human VLDL (0.5 mg / ml) so as to be 5% DMSO, and then HL enzyme was added (10 ⁇ l in total amount). After reacting at 37 ° C.
  • VLDL very low density lipoprotein
  • free fatty acid (NEFA) produced from VLDL by HL was measured with a commercially available assay kit, and the amount of NEFA was used as an enzyme activity index.
  • enzyme activity when no inhibitor was included as a control value the inhibition rate relative to the control value at each concentration of the inhibitor was calculated, and the 50% inhibitory concentration (IC50 value) of the inhibitor was determined from the inhibition curve.
  • Test Examples 1, 2, and 3 are shown below. As a result of Test Examples 1, 2, and 3, it was confirmed that the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL.
  • Test Example 4 Pharmacological test of HDL-elevating action C57BL / 6J mice aged 8 to 25 weeks were divided into groups of 5 to 20 mice, and a test compound (20-200 mg / kg / day) was orally administered. The control group was orally administered with a 0.5% aqueous methylcellulose solution (10 mL / kg). Blood was collected from the tail vein 24 hours before, 3 days or 6 days after the start of administration, and serum HDL cholesterol concentration was measured using Cholestest N HDL (Daiichi Chemical Co., Ltd.). At the time of grouping, the animals were distributed so that the average values of body weight and serum HDL cholesterol level were almost equal among the test groups. The effect of the test compound was determined by a significant difference test of serum HDL cholesterol level after administration between the control group and the administration group.
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of a compound by a metabolic reaction. ) was debenzylated with the CYP3A4 enzyme, and the reaction for producing a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) was performed as an index.
  • 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 ( ⁇ ).
  • Test Example 6 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), Tolbutamide methyl-hydroxylation (CYP2C9), Mephenytoin 4'-hydroxylation (CYP2C19), Dextromethorphan O-demethylation (CYP2D6), Terfenadine hydroxylation (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the test compound was evaluated.
  • reaction conditions were 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.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Test Example 7 FAT test 20 mL of Salmonella typhimurium TA98 strain, TA100 strain that has been cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) for 10 hours at 37 ° C. Incubate before shaking.
  • TA98 strain 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 110 mL of exposure Add to medium (Biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: MicroF buffer solution containing 8 mg / mL), TA100 strain is added to 120 mL of Exposure medium against 3.16 mL bacterial solution, and test bacterial solution To prepare.
  • Micro F buffer solution K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH
  • Test substance DMSO solution (maximum dose 50mg / 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, TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution, and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution, 12 ⁇ L each and test bacterial solution 588 ⁇ L (under metabolic activation conditions, 498 ⁇ L test bacterial solution and S9 mix 90 ⁇ L) and incubate at 37 ° C for 90 minutes with shaking.
  • Test Example 9 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.
  • Human liver microsome 0.5mg0.5protein / mL containing 0.2 mL buffer solution (50mmol / L tris-HCl pH7.4, 150mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1mmol / L NADPH 37
  • the reaction was carried out at 0 ° C. for 0 minutes or 30 minutes (oxidative reaction).
  • 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.
  • Test example 10 For the purpose of risk assessment of ECG QT interval prolongation, HEK293 cells expressing human ether-a-go-go related gene (hERG) channel are used to play an important role in ventricular repolarization process The effect on the delayed rectifier K + current (I Kr ) is studied. Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of -80 mV by whole cell patch clamp method, +40 mV depolarization stimulation was applied for 2 seconds and then -50 Record the I Kr evoked when mV repolarization stimulus is applied for 2 seconds.
  • PatchXpress 7000A Axon Instruments Inc.
  • the absolute value of the maximum tail current is 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.
  • the inhibition rate for the maximum tail current before application of the test substance is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the test substance on I Kr is evaluated.
  • Test Example 11 Powder solubility test An appropriate amount of specimen is placed in a suitable container, JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution (pH 6.8 phosphoric acid) Add 500 mL of water to 500 mL of salt buffer), and add 20 ⁇ L each of 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (add water to 1.08 g of TCA to make 100 mL). When dissolving after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C for 1 hour. Filter, add 100 ⁇ L of methanol to 100 ⁇ L of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. Quantify using HPLC with the absolute calibration curve method.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Test Example 13 Fluctuation Ames Test 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium (Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460mg
  • Tablets are manufactured using the following ingredients: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide (fume) 10 Stearic acid 5 665mg total The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • Aerosol solution is prepared containing the following ingredients: weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00
  • the active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to ⁇ 30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
  • a tablet containing 60 mg of active ingredient is prepared as follows: Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows: Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • a suppository containing 225 mg of active ingredient is prepared as follows: Active ingredient 225mg Saturated fatty acid glyceride 2000mg Total 2225mg The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
  • a suspension containing 50 mg of active ingredient is prepared as follows: Active ingredient 50mg Sodium carboxymethylcellulose 50mg Syrup 1.25ml Benzoic acid solution 0.10ml Fragrance q. v. Dye q. v. 5ml in total with purified water The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add a sufficient amount of water to the required volume.
  • the intravenous formulation is manufactured as follows: Active ingredient 100mg Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • the compound according to the present invention exhibits an EL inhibitory action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for dyslipidemia, a therapeutic agent for hyperlipidemia, and a therapeutic agent for arteriosclerosis.

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Abstract

Composé représenté par la formule ou sel pharmacologiquement acceptable de celui-ci. (Dans la formule, X représente =CR4- ou =N-; Y représente -CR5= ou -N=; Z représente =CR7- ou =N-; R4 et R7 représentent un atome d'hydrogène, des atomes d'halogènes, ou autres; R5 et R6 représentent un atome d'hydrogène, des hétéroaryles, ou autres; R1 et R2 représentent un atome d'hydrogène, des atomes d'halogènes, ou autres; et R3 représente -(CR8R9)m-NR10R11 (où m représente un entier de 0 à 3 et R8, R9, R10, et R11 représentent un atome d'hydrogène, des alkyles, ou autres)).
PCT/JP2012/064954 2011-06-14 2012-06-12 Dérivé amino inhibant la lipase endothéliale Ceased WO2012173099A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011513A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale de type benzothiazole contenant un sulfonyle
WO2014011461A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Dérivés de benzothiazole substitués par amide ou urée en tant qu'inhibiteurs de lipase endothéliale
WO2014015088A1 (fr) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale à base de benzothiazole liés à une amine, l'urée ou un sulfone amide
WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale
WO2016159082A1 (fr) * 2015-03-30 2016-10-06 塩野義製薬株式会社 Dérivé à cycle condensé à 9 chaînons

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WO2014011461A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Dérivés de benzothiazole substitués par amide ou urée en tant qu'inhibiteurs de lipase endothéliale
US8680090B2 (en) 2012-07-09 2014-03-25 Bristol-Myers Squibb Company Sulfonyl containing benzothiazole inhibitors of endothelial lipase
US9139578B2 (en) 2012-07-09 2015-09-22 Bristol-Myers Squibb Company Amide or urea containing benzothiazole inhibitors of endothelial lipase
WO2014015088A1 (fr) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale à base de benzothiazole liés à une amine, l'urée ou un sulfone amide
US8987314B2 (en) 2012-07-19 2015-03-24 Bristol-Myers Squibb Company Amide, urea or sulfone amide linked benzothiazole inhibitors of endothelial lipase
WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale
US10173991B2 (en) 2014-01-07 2019-01-08 Bristol-Myers Squibb Company Sulfone amide linked benzothiazole inhibitors of endothelial lipase
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WO2016159082A1 (fr) * 2015-03-30 2016-10-06 塩野義製薬株式会社 Dérivé à cycle condensé à 9 chaînons
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RU2702637C2 (ru) * 2015-03-30 2019-10-09 Сионоги Энд Ко., Лтд. Производные бензимидазола или имидазопиридина, полезные для лечения или профилактики болезней, ассоциированных с асс2
AU2016240715B2 (en) * 2015-03-30 2020-10-08 Shionogi & Co., Ltd. 9-membered fused ring derivative
CN107428700B (zh) * 2015-03-30 2021-08-03 盐野义制药株式会社 9元稠环衍生物
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