WO2015087996A1 - Imidazopyridine derivative - Google Patents

Imidazopyridine derivative Download PDF

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WO2015087996A1
WO2015087996A1 PCT/JP2014/082945 JP2014082945W WO2015087996A1 WO 2015087996 A1 WO2015087996 A1 WO 2015087996A1 JP 2014082945 W JP2014082945 W JP 2014082945W WO 2015087996 A1 WO2015087996 A1 WO 2015087996A1
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group
trifluoromethyl
acceptable salt
pharmacologically acceptable
compound
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PCT/JP2014/082945
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French (fr)
Japanese (ja)
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敏雄 斧田
俊雄 金子
雅巳 荒井
小林 英樹
直生 寺坂
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第一三共株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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

Definitions

  • the present invention relates to an imidazopyridine derivative having an excellent lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
  • LCAT lecithin cholesterol acetyltransferase
  • cardiovascular diseases for example, heart disease, cerebrovascular disease, kidney disease, etc.
  • hypertension for example, hypertension, dyslipidemia, diabetes, etc.
  • Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively.
  • ⁇ and ⁇ blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates.
  • These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels.
  • mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.
  • a direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.
  • LDL oxidized low density lipoprotein
  • Non-Patent Document 3 An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.
  • HDL high-density lipoprotein
  • Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester.
  • Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.
  • Non-patent Document 6 examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.
  • Patent Document 2 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.
  • the present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that an imidazopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, thereby completing the present invention.
  • the present invention provides an imidazopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing these.
  • R 1 represents an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto ⁇ busy (C 1-6 Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring.
  • the heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom,
  • An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto ⁇ busy (C 1-6 alkyl And the same or different groups selected from the group consisting of amino groups.
  • a group represented by R 2 is a hydrogen atom or a hydroxyl group.
  • R 1 is an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group) , Cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di (C 1-6 alkyl) the same or different 1 to 3 groups selected from the group consisting of amino groups), or the pharmacologically of the compound according to any one of (1) to (3) Acceptable salts, (5) R 1 is a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a trifluoromethyl group, a difluorome
  • R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) Or the pharmacologically acceptable salt thereof according to any one of (1) to (3), (7) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group).
  • R 1 is an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring.
  • the heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Furthermore, it may contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, C 1-6 alkyl group, C 3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, Fluoromethoxy group, cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di is a (C 1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, in any one of (1)
  • the heteroatom on the ring of the heteroaryl group is one nitrogen atom, and one more Or a substituent such as a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group.
  • a substituent such as a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydrogen atom and n is 2.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group)
  • R 2 is a hydrogen atom
  • n is 2, or a pharmacologically acceptable salt thereof according to (1)
  • (23) The compound according to ( 1 ), wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydrogen atom, and n is 2.
  • R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) ), R 2 is a hydroxyl group, and n is 2, the compound according to (1) or a pharmacologically acceptable salt thereof, (25) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group).
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydroxyl group and n is 2.
  • R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group)
  • R 2 is a hydroxyl group
  • n is 2, or a pharmacologically acceptable salt thereof
  • a pharmacologically acceptable salt (29) The compound according to any one of (1) to (28), wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis, or a pharmaceutically acceptable salt thereof, (30) The compound according to any one of (1) to (14), (16), (17) and (19) to (28), wherein the optical rotation is (+), or a pharmacologically acceptable salt thereof Salt, (31) A pharmaceutical composition comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (32) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, (33) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any
  • Or therapeutic agent A prophylactic agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent (37) an LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (38) A reversible LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (39) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient, (40) A method for activating LCAT comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, (41) A method for the prevention or treatment of a disease, comprising administering an effective amount of the compound according to any one of (1) to (30)
  • Method, (43) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • Method, (44) By increasing the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused (46) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (47) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (48) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and (49) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in blood It is an acceptable salt.
  • any isomer of a tautomer is contained in the present compound (I).
  • the compound (I) containing any isomer is referred to as a compound (I).
  • the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms ( C 1-3 alkyl group), more preferably a methyl group.
  • the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.
  • the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded.
  • a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group Alternatively, it may be a butoxy group, preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.
  • the “C 3-7 cycloalkoxy group” is an oxygen atom to which the “C 3-7 cycloalkyl group” is bonded, and includes a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group.
  • Group, a cyclohexyloxy group, or a cycloheptyloxy group preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, more preferably a methoxy group It is.
  • the “C 2-7 alkoxycarbonyl group” is a carbonyl group to which the “C 1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Or a butoxycarbonyl group, preferably a carbonyl group to which the “C 1-3 alkoxy group” is bonded (C 2-4 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. It is.
  • the “di (C 1-6 alkyl group) amino group” is an amino group to which two identical or different “C 1-6 alkyl groups” are bonded. Is a dimethylamino group.
  • the “di (C 1-6 alkyl group) aminocarbonyl group” is a carbonyl group to which the “di (C 1-6 alkyl group) amino group” is bonded. , A dimethylaminocarbonyl group.
  • a heteroaryl group (the heteroaryl is a 5- or 6-membered ring.
  • the hetero atom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 1 nitrogen atom, oxygen atom or sulfur atom may be included.)
  • Nyl group, thiadiazolyl group or thiazolyl group still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or thiadiazolyl group
  • Particularly preferred is a pyridyl group, a pyrimidyl group or a pyrazinyl group.
  • “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates.
  • Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.
  • Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
  • the compound (I) of the present invention has a geometric isomer at the 4-5 position of the imidazopyridine ring, and both cis and trans isomers are included in the present invention unless otherwise specified. For example, by producing both geometric isomers and comparing their instrument data, the respective structure can be determined.
  • the 4-position trifluoromethyl group and the 5-position hydroxyl group are preferably cis.
  • Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.
  • Production method 1 is a method for producing compound (I) of the present invention from compound (II).
  • R and R 2 are as defined above
  • R 3 is a hydrogen atom or a formula —O—R 5
  • R 5 is a hydrogen atom, a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyl group).
  • -Re represents a butyldiphenylsilyl group
  • R 4 represents a methyl group or an ethyl group.
  • This step is a step for producing compound (I) by heating and condensing compound (II) and compound (III) in a solvent inert to the reaction or in the absence of a solvent.
  • Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy Alcohols such as ethanol, diethylene glycol or glycerine; aromatic hydrocarbons such as benzene, toluene or xylene; or these It is
  • the reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.
  • microwaves can be irradiated.
  • the reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.
  • R 5 of the compound (III) is a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group
  • the compound prepared by the above reaction is exemplified by P.I. G. Wuts, T.W. W. Greene, Greene's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. Etc. can be used to remove the hydroxyl-protecting group to produce compound (I).
  • Manufacturing method 2 The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R represents the same meaning as described above, and X represents a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, a methanesulfonyl group or a trifluoromethanesulfonyl group.
  • This step is a step for producing compound (VI) by reacting compound (IV) with compound (V) in an inert solvent using a base.
  • Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably amides or sulfoxides An earth, more preferably, N, is N- dimethylformamide or dimethyl sulfoxide.
  • the base used in this step is preferably an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and more preferably potassium carbonate or cesium carbonate. .
  • the reaction temperature in this step is preferably ⁇ 10 ° C. to 150 ° C., and more preferably 20 ° C. to 120 ° C.
  • the reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 minute to 4 hours.
  • Step 2-2 This step is a step for producing compound (II) by catalytic hydrogenation of compound (VI) in the presence of a metal catalyst in an inert solvent.
  • Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin.
  • An ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; an aromatic hydrocarbon such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Is a mixed solvent of alcohols or ethers and alcohols, more preferably a mixture of ethanol or methanol and tetrahydrofuran. It is a medium.
  • the metal catalyst used in this step may be platinum, palladium-activated carbon, palladium-activated carbon diphenyl sulfide complex or nickel, and is preferably palladium-activated carbon or palladium-activated carbon diphenyl sulfide complex.
  • the hydrogenating agent used in this step can be hydrogen gas or ammonium formate, preferably hydrogen gas.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 5 ° C. to 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 10 hours, and more preferably 20 minutes to 2 hours.
  • Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VIII).
  • R 1 and R 2 are as defined above, Boc represents a tert-butoxycarbonyl group, and n represents 1 or 2.
  • Compound (VIII) can be produced, for example, according to the methods described in Reference Examples 1 and 2, or Reference Examples 9, 10, 11, and 12.
  • Step 4-1 This step is a step for producing compound (Ib) by removing the Boc group in compound (VIII).
  • reagents used for removing Boc in compound (VIII) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably dichloromethane.
  • an alcohol such as methanol or ethanol
  • an ether such as tetrahydrofuran or 1,4-dioxane
  • an alkyl halide such as dichloromethane or chloroform
  • Esters aromatic hydrocarbons such as toluene
  • a mixed solvent thereof more preferably ethers or alkyl halides, and even more preferably dichloromethane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • Step 3-2 This step is a step for producing compound (Ic) by reacting compound (Ib) with an arylating agent or heteroarylating agent.
  • Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably sulfoxides More preferably a dimethyl sulfoxide.
  • halogenated hydrocarbons such as dichloromethane,
  • the base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine.
  • organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.
  • the arylating agent or heteroarylating agent used in this step is a compound having the formula R 1 -F, the formula R 1 -Cl or the formula R 1 -Br, preferably the formula R 1 -F or the formula R 1- Cl-containing compound (R 1 is as defined above).
  • the reaction temperature in this step is preferably 20 ° C to 200 ° C.
  • microwaves can be irradiated.
  • the reaction time in this step is preferably 5 minutes to 120 hours, more preferably 10 minutes to 96 hours.
  • n and R 1 are as defined above.
  • Step 4-1) This step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a ligand and a base in addition to a palladium catalyst.
  • the palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. 2002, 219, p. 131.
  • the solvent used in this step is an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl-methyl ether; or an aromatic hydrocarbon such as benzene, toluene or xylene. , Preferably toluene or dioxane, and more preferably toluene.
  • the palladium catalyst used in this step is preferably palladium (II) acetate or palladium (0) dibenzylideneacetone.
  • the ligand used in this step is preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane, 2, 2′-bis (diphenylphosphanyl) 1,1′-binaphthyl, 2- (dicyclohexylphosphino) biphenyl or 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, more preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine or 2,2′-bis (diphenylphosphanyl) 1,1′-binaphthyl.
  • the base used in this step is preferably sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, and more preferably tert-butoxy sodium.
  • the arylating or heteroarylating agent used in this step is a compound having the formula R 1 -Cl, the formula R 1 -Br or the formula R 1 -I, preferably the formula R 1 -Cl or the formula R 1- Br (R 1 is as defined above).
  • the reaction temperature in this step is preferably 20 ° C. to 150 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 30 minutes to 12 hours, and more preferably 1 hour to 4 hours.
  • this step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
  • This step can be performed under the same conditions as in step 3-2.
  • Step 4-2 the hydroxyl group in compound (IVb) is methanesulfonylated to produce compound (Ic).
  • the solvent used in this step is preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene, or a mixed solvent thereof, more preferably alkyl halides, and still more preferably Is dichloromethane.
  • a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene
  • diethyl ether diisopropyl ether, tetrahydrofuran, dioxane
  • the reagent used in this step is preferably methanesulfonyl chloride or methanesulfonic anhydride, and more preferably methanesulfonyl chloride.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
  • the product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) )
  • the crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration.
  • the isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary.
  • the product of each step can be used in the next step without isolation or purification.
  • Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers can be separated by utilizing differences in physicochemical properties between isomers.
  • a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column.
  • the diastereo mixture can be separated by fractional crystallization or various chromatographies.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
  • Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs.
  • Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents.
  • the additive can be prepared according to a conventional method using additives appropriately selected as necessary.
  • the dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms.
  • the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
  • hexane represents n-hexane
  • THF represents tetrahydrofuran
  • IPA 2-propanol
  • DMF represents N, N′-dimethylformamide
  • DMSO dimethyl sulfoxide
  • the product was purified to obtain the target compound (188 mg, yield: 47%, optically active substance).
  • the reaction solution was cooled to room temperature and then filtered, and the solvent of the filtrate was distilled off under reduced pressure.
  • the reaction solution was cooled to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure.
  • the obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the compound A-1 eluting first (2 g, yield: 42%) and the compound A-2 eluting later (1.77 g, 37%) were obtained respectively.
  • the solvent of the reaction solution was distilled off under reduced pressure, and N, N-diisopropylethylamine (126 ⁇ L, 0.741 mmol) and 2-fluoro-5- (trifluoromethyl) pyridine were added to a solution of the obtained residue in DMSO (1 mL). (44.6 ⁇ L, 0.370 mmol) was added and stirred overnight.
  • Trifluoroacetic acid (3.4 mL, 44.0 mmol) was added to a dichloromethane (20 mL) solution of the compound produced in Reference Example 2 (2.15 g, 5.32 mmol), and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was added dropwise to a mixed solvent of diethyl ether (90 mL) and hexane (20 mL) at 0 ° C. and stirred at room temperature for 3 hours.
  • the resulting solid was collected by filtration to obtain a trifluoroacetate compound (2.36 g).
  • the solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted 3 times with ethyl acetate.
  • the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure.
  • the solvent was distilled off.
  • Example 21 1- ⁇ 1- [2-Cyclopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl ⁇ -7-hydroxy-7- (trifluoromethyl) -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
  • Test Example 1 Measurement of LCAT activity (in vitro) A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 ⁇ specific gravity ⁇ 1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide.
  • the radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.
  • Test Example 2 Measurement of LCAT activity (plasma) Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT.
  • the test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 ⁇ L of each plasma and 45 ⁇ L of PBS. Add the test drug at a concentration to make the total volume 80 ⁇ L. After incubating this mixture at 37 ° C.
  • X represents the logarithm of the concentration of the test drug
  • Y represents the response of the test drug (LCAT activity)
  • Top indicates the maximum value (maximum plateau)
  • Bottom indicates a minimum value (minimum flat area);
  • EC 50 indicates a 50% effective concentration.
  • DTNB Ielman's reagent, final concentration 0.26 mM
  • mercaptoethanol final concentration 2 mM
  • bovine serum albumin 0.6% bovine serum albumin
  • the radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.
  • Test Example 4 Cynomolgus monkey efficacy test
  • the test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) It was dissolved in an aqueous methylcellulose solution and orally administered to cynomolgus monkeys for 1 or 7 days. Blood was collected before and after administration on the first or seventh day of administration to obtain plasma. Plasma cholesterol content was measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile was analyzed by HPLC (column: Lipopropak XL, manufactured by Tosoh Corporation). The contents of HDL cholesterol and non-HDL cholesterol were calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • the increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.
  • Test Example 5 Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
  • HDL cholesterol content plasma cholesterol content ⁇ (HDL cholesterol peak area / sum of each peak)
  • non-HDL cholesterol content plasma cholesterol content ⁇ (peak area of non-HDL cholesterol / sum of each peak)
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease.
  • arteriosclerosis arteriosclerotic heart disease
  • coronary heart disease including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

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Abstract

A compound which has excellent LCAT activation effects, is useful as an active ingredient of a therapeutic or preventive agent for arteriosclerosis, arteriosclerotic cardiovascular disease, coronary heart disease (including heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorder, and angioplastic restenosis), cerebrovascular disease (including cerebral stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complication), dyslipidemia, low HDL cholesterol, high HDL cholesterol, or kidney disease, in particular, of an anti-arteriosclerosis agent, and is represented by a formula [In the formula, n is 1 or 2, and R1 is an aryl group which may be substituted or a heteroaryl group which may be substituted.] or a pharmacologically acceptable salt thereof.

Description

イミダゾピリジン誘導体Imidazopyridine derivatives
 本発明は、優れたレシチンコレステロールアセチルトランスフェラーゼ(以下、LCATという)活性化作用(好適には、可逆的なLCAT活性化作用)を有するイミダゾピリジン誘導体又はその薬理上許容される塩に関する。 The present invention relates to an imidazopyridine derivative having an excellent lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
 先進文明国では、高血圧症、脂質異常症、糖尿病などにより引き起こされる循環器疾患(例えば、心疾患、脳血管疾患、腎疾患等)が、大きな問題になっている。これら高血圧症、脂質異常症及び高血糖症の治療には、それぞれ抗高血圧薬、抗脂質異常薬及び抗糖尿病薬が用いられている。臨床では、抗高血圧薬として、α及びβ遮断薬、利尿剤、カルシウム拮抗剤、ACE阻害剤、及び、A-II拮抗剤等が、抗脂質異常薬として、HMG-CoA還元酵素阻害剤、陰イオン交換樹脂、ニコチン酸誘導体、プロブコール、及び、フィブラート類等が、抗糖尿病薬として、インシュリン、スルホニル尿素類、メトフォルミン、グリタゾン類、及び、DPP4阻害剤等が用いられている。これらの薬剤は、血圧及び血中の脂質又は血糖レベルの調節に寄与している。しかし、心疾患、脳血管疾患及び腎疾患による死亡率は、これらの医薬の使用によっても、大きく改善されてはおらず、より優れたこれらの疾患の治療薬の開発が望まれている。 In advanced civilized countries, cardiovascular diseases (for example, heart disease, cerebrovascular disease, kidney disease, etc.) caused by hypertension, dyslipidemia, diabetes, etc. are a major problem. Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively. Clinically, α and β blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels. However, mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.
 循環器疾患の直接の危険因子は、動脈壁の肥厚を伴う動脈硬化であり、その肥厚の原因は、酸化低密度リポ蛋白(以下、LDLという)コレステロールの動脈壁中のマクロファージなどへの蓄積によるプラークの形成である(非特許文献1及び2)。このプラークは血液の流れを阻害し、血栓の生成を促進する。 A direct risk factor for cardiovascular disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is due to accumulation of oxidized low density lipoprotein (hereinafter referred to as LDL) cholesterol in macrophages in the arterial wall. It is the formation of plaque (Non-Patent Documents 1 and 2). This plaque inhibits blood flow and promotes thrombus formation.
 血清リポ蛋白の濃度は、脂質異常症、動脈硬化症等の疾患と関連することが、多くの疫学的調査の結果より示されている(例えば、非特許文献3)。血中のLDLコレステロールの濃度の増加、及び、高比重リポ蛋白(以下、HDLという)コレステロールの濃度の減少は、いずれも冠状動脈性疾患の危険因子である。 The results of many epidemiological studies show that the serum lipoprotein concentration is associated with diseases such as dyslipidemia and arteriosclerosis (for example, Non-Patent Document 3). An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.
 末梢組織のコレステロールは、HDLにより引き抜かれ、HDL上でLCATによりエステル化されてコレステリルエステルとなる。LCAT活性の亢進は、マクロファージ中からのコレステロールの引き抜きを促進させる(例えば、非特許文献4及び5)。したがって、LCAT活性を亢進する薬剤は、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用であると考えられる。 Peripheral tissue cholesterol is extracted by HDL and esterified by LCAT on HDL to become cholesteryl ester. Increased LCAT activity promotes the withdrawal of cholesterol from macrophages (for example, Non-Patent Documents 4 and 5). Therefore, it is considered that a drug that enhances LCAT activity is useful as a medicament for treating or preventing diseases such as dyslipidemia and arteriosclerosis.
 LCAT活性を亢進する薬剤は、ペプチド化合物(たとえば、非特許文献6)や、低分子としては、例えば、特許文献1に記載の化合物が知られている。 Examples of known drugs that enhance LCAT activity include peptide compounds (for example, Non-patent Document 6) and, as small molecules, for example, compounds described in Patent Document 1.
 ピラゾロピリジン骨格を有する化合物としては、特許文献2に記載の化合物が知られている。特許文献2には抗LPA受容体作用が記載されているが、LCAT活性化作用は記載されていない。 As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.
WO2008/002591号パンフレットWO2008 / 002591 pamphlet WO2012/028243号パンフレットWO2012 / 028243 pamphlet
 現在知られているLCAT活性化作用を有する化合物は、安全性及び有効性の面で満足できるものではなく、安全性及び有効性に優れたLCAT活性化剤が切望されていた。 Currently known compounds having an LCAT activating action are not satisfactory in terms of safety and effectiveness, and LCAT activators having excellent safety and effectiveness have been desired.
 本発明者らは、優れたLCAT活性化作用を有し、マクロファージより直接的にコレステロールの引き抜きを促進させることによる新しい抗動脈硬化薬の獲得を目指して種々の合成検討を行った。その結果、特定の構造を有するイミダゾピリジン誘導体又はその薬理上許容される塩が、優れたLCAT活性化作用を有することを見出し、本発明を完成した。 The present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that an imidazopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, thereby completing the present invention.
 本発明は、優れたLCAT活性化作用(好適には、可逆的なLCAT活性化作用)を有するイミダゾピリジン誘導体又はその薬理上許容される塩及びこれらを含有する医薬を提供する。 The present invention provides an imidazopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing these.
 すなわち、本発明は、
(1)式
That is, the present invention
(1) Formula
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
[式中、Rは、式(X) [Wherein, R represents the formula (X)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
{式中、nは、1又は2の整数であり、
は、置換されてよいアリール基(当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1乃至3個の基である。)、又は、
置換されてよいヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1又は2個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である。}で表される基であり、
は、水素原子又は水酸基である。]で表される化合物又はその薬理上許容される塩、
(2)nが1である、(1)に記載の化合物又はその薬理上許容される塩、
(3)nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(4)Rが、置換されてよいアリール基(当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1乃至3個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(5)Rが、置換されたアリール基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基及びC1-3アルコキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(6)Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(7)Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(8)Rが、置換されてよいヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1又は2個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(9)Rが、置換されたヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-3アルキル基、C3-6シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1つに記載の化合物又はその薬理上許容される塩、
(10)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(11)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(12)Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基である、(1)~(3)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(13)Rが、水素原子である、(1)~(12)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(14)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 6-{4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-イル}-4-(トリフルオロメチル)ピリジン-3-カルボニトリル、
 7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
 7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピロリジン-3-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、(13)に記載の化合物又はその薬理上許容される塩、
(15)(+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 (+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 (+)-7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
 (+)-7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
 (+)-1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、(13)に記載の化合物又はその薬理上許容される塩、
(16)Rが、水酸基である、(1)~(12)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(17)6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
 6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、(16)に記載の化合物又はその薬理上許容される塩、
(18)(+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
 (+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、(16)に記載の化合物又はその薬理上許容される塩、
(19)Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(20)Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(21)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(22)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(23)Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基であり、Rが、水素原子であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(24)Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(25)Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(26)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(27)Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(28)Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基であり、Rが、水酸基であり、nが2である、(1)に記載の化合物又はその薬理上許容される塩、
(29)イミダゾピリジン環の4位のトリフルオロメチル基と5位の水酸基がcisである、(1)~(28)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(30)旋光度が(+)である、(1)~(14)、(16)、(17)及び(19)~(28)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(31)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物、
(32)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患、脳血管疾患、末梢血管疾患、脂質異常症、低HDLコレステロール血症、高LDLコレステロール血症、又は、腎疾患の予防若しくは治療のための医薬組成物、
(33)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症の予防剤若しくは治療剤、
(34)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、脂質異常症の予防剤若しくは治療剤、
(35)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のLDLコレステロールの濃度の増加により引き起こされる疾患の予防剤若しくは治療剤、
(36)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のHDLコレステロールの濃度の減少により引き起こされる疾患の予防剤若しくは治療剤、
(37)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、LCAT活性化剤、
(38)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、可逆的LCAT活性化剤、
(39)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、抗動脈硬化剤、
(40)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、LCAT活性化方法、
(41)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、疾患の予防若しくは治療のための方法、
(42)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、動脈硬化症の予防若しくは治療のための方法、
(43)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、脂質異常症の予防若しくは治療のための方法、
(44)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のLDLコレステロールの濃度の増加により引き起こされる疾患の予防若しくは治療のための方法、
(45)(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のHDLコレステロールの濃度の減少により引き起こされる疾患の予防若しくは治療のための方法、
(46)動脈硬化症の治療又は予防のための方法における使用のための、(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(47)脂質異常症の治療又は予防のための方法における使用のための、(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(48)血中のLDLコレステロールの濃度の増加により引き起こされる疾患の治療又は予防のための方法における使用のための、(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩、及び、
(49)血中のHDLコレステロールの濃度の減少により引き起こされる疾患の治療又は予防のための方法における使用のための、(1)~(30)のいずれか1項に記載の化合物又はその薬理上許容される塩である。
{Wherein n is an integer of 1 or 2,
R 1 represents an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or
An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 alkyl And the same or different groups selected from the group consisting of amino groups. }, A group represented by
R 2 is a hydrogen atom or a hydroxyl group. Or a pharmacologically acceptable salt thereof,
(2) The compound or pharmacologically acceptable salt thereof according to (1), wherein n is 1.
(3) The compound according to (1) or a pharmacologically acceptable salt thereof, wherein n is 2.
(4) R 1 is an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group) , Cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di (C 1-6 alkyl) the same or different 1 to 3 groups selected from the group consisting of amino groups), or the pharmacologically of the compound according to any one of (1) to (3) Acceptable salts,
(5) R 1 is a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, or a C 1 group) Or a pharmacologically acceptable compound thereof according to any one of (1) to (3), which are the same or different 1 or 2 groups selected from the group consisting of -3 alkoxy groups). salt,
(6) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) Or the pharmacologically acceptable salt thereof according to any one of (1) to (3),
(7) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). A compound or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
(8) R 1 is an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring. The heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Furthermore, it may contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, C 1-6 alkyl group, C 3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, Fluoromethoxy group, cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di is a (C 1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, in any one of (1) to (3) Compound or a pharmacologically acceptable salt thereof of the mounting,
(9) R 1 is a substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and one more Or a substituent such as a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group. , A cyano group, a C 1-3 alkoxy group, a C 2-4 alkoxycarbonyl group and a benzyloxycarbonyl group, the same or different one or two groups.) The compound according to any one of (3) or a pharmacologically acceptable salt thereof,
(10) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
(11) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different selected one or two groups), or the pharmacologically acceptable salt thereof according to any one of (1) to (3),
(12) The compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group salt,
(13) The compound according to any one of (1) to (12), wherein R 2 is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(14) 7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro -5H-imidazo [4,5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine- 1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile,
7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4 , 5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one and
7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,6,7-tetrahydro-5H- The compound or pharmacologically acceptable salt thereof according to (13), selected from the group consisting of imidazo [4,5-b] pyridin-5-one,
(15) (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 , 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H -Imidazo [4,5-b] pyridin-5-one and
(+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro A compound according to (13) or a pharmacologically acceptable salt thereof selected from the group consisting of -5H-imidazo [4,5-b] pyridin-5-one,
(16) The compound according to any one of (1) to (12), wherein R 2 is a hydroxyl group, or a pharmacologically acceptable salt thereof,
(17) 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- The compound or a pharmaceutically acceptable salt thereof according to (16), selected from the group consisting of 5H-imidazo [4,5-b] pyridin-5-one,
(18) (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4 , 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
(+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 The compound or a pharmaceutically acceptable salt thereof according to (16), selected from the group consisting of 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(19) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group, and a cyano group) ), R 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof according to (1),
(20) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R 2 is a hydrogen atom and n is 2.
(21) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydrogen atom and n is 2.
(22) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different 1 or 2 groups selected), R 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof according to (1),
(23) The compound according to ( 1 ), wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydrogen atom, and n is 2. Its pharmacologically acceptable salts,
(24) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) ), R 2 is a hydroxyl group, and n is 2, the compound according to (1) or a pharmacologically acceptable salt thereof,
(25) R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R 2 is a hydroxyl group and n is 2.
(26) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R 2 is a hydroxyl group and n is 2.
(27) R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different selected 1 or 2 groups), R 2 is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof,
(28) The compound according to ( 1 ), wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydroxyl group, and n is 2. A pharmacologically acceptable salt,
(29) The compound according to any one of (1) to (28), wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis, or a pharmaceutically acceptable salt thereof,
(30) The compound according to any one of (1) to (14), (16), (17) and (19) to (28), wherein the optical rotation is (+), or a pharmacologically acceptable salt thereof Salt,
(31) A pharmaceutical composition comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(32) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease,
(33) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(34) A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(35) A preventive agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(36) A prophylactic agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(37) an LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(38) A reversible LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(39) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(40) A method for activating LCAT comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof,
(41) A method for the prevention or treatment of a disease, comprising administering an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof to a human,
(42) For prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Method,
(43) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Method,
(44) By increasing the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(45) By reducing the concentration of HDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(46) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis,
(47) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia,
(48) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and
(49) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in blood It is an acceptable salt.
 以下に、本発明の化合物(I)における置換基の定義を説明する。 Hereinafter, the definition of the substituent in the compound (I) of the present invention will be described.
 本願では、特に断りのない限り、互変異性体(アミド-イミド酸)のいずれの異性体も本願化合物(I)に含有され、本願では、便宜上、いずれの異性体を含む化合物(I)をも、式(I)で表される構造式、及び、それに対応する化学名で表す。 In the present application, unless otherwise specified, any isomer of a tautomer (amide-imidic acid) is contained in the present compound (I). In the present application, for convenience, the compound (I) containing any isomer is referred to as a compound (I). Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.
 本発明の化合物(I)において、「アリール基」は、例えば、フェニル基又はナフチル基であり、好適には、フェニル基である。 In the compound (I) of the present invention, the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
 本発明の化合物(I)において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又はヨウ素原子であり、好適には、フッ素原子又は塩素原子であり、より好適には、塩素原子である。 In the compound (I) of the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom. .
 本発明の化合物(I)において、「C1-6アルキル基」は、炭素数1~6個の直鎖又は分枝鎖飽和炭化水素基であり、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec-ブチル基、tert-ブチル基、イソブチル基、ペンチル基又はヘキシル基であり得、好適には、炭素数1~3個の直鎖又は分枝鎖飽和炭化水素基(C1-3アルキル基)であり、より好適には、メチル基である。 In the compound (I) of the present invention, the “C 1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms ( C 1-3 alkyl group), more preferably a methyl group.
 本発明の化合物(I)において、「C3-7シクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基のような炭素数3~7個の環状飽和炭化水素基であり、好適には、炭素数3~6個の環状飽和炭化水素基(C3-6シクロアルキル基)であり、より好適には、シクロプロピル基である。 In the compound (I) of the present invention, the “C 3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.
 本発明の化合物(I)において、「C1-6アルコキシ基」は、前記「C1-6アルキル基」が結合した酸素原子であり、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基又はブトキシ基であり得、好適には、前記「C1-3アルキル基」が結合した酸素原子(C1-3アルコキシ基)であり、より好適には、メトキシ基である。 In the compound (I) of the present invention, the “C 1-6 alkoxy group” is an oxygen atom to which the “C 1-6 alkyl group” is bonded. For example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group Alternatively, it may be a butoxy group, preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, and more preferably a methoxy group.
 本発明の化合物(I)において、「C3-7シクロアルコキシ基」は、前記「C3-7シクロアルキル基」が結合した酸素原子であり、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基又はシクロヘプチルオキシ基であり得、好適には、前記「C1-3アルキル基」が結合した酸素原子(C1-3アルコキシ基)であり、より好適には、メトキシ基である。 In the compound (I) of the present invention, the “C 3-7 cycloalkoxy group” is an oxygen atom to which the “C 3-7 cycloalkyl group” is bonded, and includes a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group. Group, a cyclohexyloxy group, or a cycloheptyloxy group, preferably an oxygen atom (C 1-3 alkoxy group) to which the “C 1-3 alkyl group” is bonded, more preferably a methoxy group It is.
 本発明の化合物(I)において、「C2-7アルコキシカルボニル基」は、前記「C1-6アルコキシ基」が結合したカルボニル基であり、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基又はブトキシカルボニル基であり得、好適には、前記「C1-3アルコキシ基」が結合したカルボニル基(C2-4アルコキシカルボニル基)であり、より好適には、メトキシカルボニル基又はエトキシカルボニル基である。 In the compound (I) of the present invention, the “C 2-7 alkoxycarbonyl group” is a carbonyl group to which the “C 1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Or a butoxycarbonyl group, preferably a carbonyl group to which the “C 1-3 alkoxy group” is bonded (C 2-4 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. It is.
 本発明の化合物(I)において、「ジ(C1-6アルキル基)アミノ基」は、同一又は異なった2個の前記「C1-6アルキル基」が結合したアミノ基であり、好適には、ジメチルアミノ基である。 In the compound (I) of the present invention, the “di (C 1-6 alkyl group) amino group” is an amino group to which two identical or different “C 1-6 alkyl groups” are bonded. Is a dimethylamino group.
 本発明の化合物(I)において、「ジ(C1-6アルキル基)アミノカルボニル基」は、前記「ジ(C1-6アルキル基)アミノ基」が結合したカルボニル基であり、好適には、ジメチルアミノカルボニル基である。 In the compound (I) of the present invention, the “di (C 1-6 alkyl group) aminocarbonyl group” is a carbonyl group to which the “di (C 1-6 alkyl group) amino group” is bonded. , A dimethylaminocarbonyl group.
 本発明の化合物(I)において、「ヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1又は2個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよい。)」は、例えば、ピリジル基、ピラジニル基、ピリミジル基、ピリダジニル基、オキサゾリル基、チアゾリル基、イソキサゾリル基、イソチアゾリル基、ピロール基、ピラゾリル基、イミダゾリル基、トリアゾリル基又はチアジアゾリル基であり得、好適には、5員又は6員ヘテロアリール基(当該ヘテロアリール環上の複素原子は、1個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよい。)であり、より好適には、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基又はチアゾリル基であり、更により好適には、ピリジル基、ピリミジル基、ピラジニル基又はピリダジニル基であり、更により好適には、ピリジル基、ピリミジル基、ピラジニル基又はチアジアゾリル基であり、特に好適には、ピリジル基、ピリミジル基又はピラジニル基である。 In the compound (I) of the present invention, “a heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The hetero atom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 1 nitrogen atom, oxygen atom or sulfur atom may be included.) "Means, for example, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl Group, imidazolyl group, triazolyl group or thiadiazolyl group, preferably a 5- or 6-membered heteroaryl group (the heteroatom on the heteroaryl ring is one nitrogen atom, and one nitrogen atom) More preferably a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyrida group. Nyl group, thiadiazolyl group or thiazolyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or thiadiazolyl group Particularly preferred is a pyridyl group, a pyrimidyl group or a pyrazinyl group.
 本発明の化合物(I)は、塩基性基を有するため、薬理上許容される酸との酸付加塩とすることができる。本発明において「その薬理上許容される塩」としては、例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等のハロゲン化水素酸塩;硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩;メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩等の低級アルカンスルホン酸塩;ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のアリールスルホン酸塩;酢酸、リンゴ酸、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩;及びオルニチン酸塩、グルタミン酸塩、アスパラギン酸塩等のアミノ酸塩を挙げることができる。 Since the compound (I) of the present invention has a basic group, it can be converted into an acid addition salt with a pharmacologically acceptable acid. In the present invention, “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates. Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.
 本発明の化合物(I)又はその薬理上許容される塩は、大気中に放置されることにより水分を吸収し、水和物になる場合があり、そのような水和物も本発明に包含される。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
 本発明の化合物(I)又はその薬理上許容される塩は、溶媒中に放置されることにより、溶媒から取り出して溶媒和物になる場合があり、そのような溶媒和物も本発明に包含される。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.
 本発明の化合物(I)には、分子内の不斉中心に基づく光学異性体が存在する。特に断りのない限り、本発明の化合物においては、これらの異性体及びこれらの異性体の混合物が全て単一の式、すなわち一般式(I)で示されている。従って、本発明はこれらの異性体及びこれらの異性体の混合物をも全て含むものとする。 Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
 本発明化合物(I)は、イミダゾピリジン環の4-5位において、幾何異性体が存在し、特に断りのない限り、シス体及びトランス体の両方が本発明に含まれる。例えば、両方の幾何異性体を製造し、それらの機器データを比較することにより、それぞれの構造を決定することができる。本発明において、4位のトリフルオロメチル基と5位の水酸基がcisであることが好ましい。 The compound (I) of the present invention has a geometric isomer at the 4-5 position of the imidazopyridine ring, and both cis and trans isomers are included in the present invention unless otherwise specified. For example, by producing both geometric isomers and comparing their instrument data, the respective structure can be determined. In the present invention, the 4-position trifluoromethyl group and the 5-position hydroxyl group are preferably cis.
 本発明の化合物(I)は、化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素(H)、トリチウム(H)、ヨウ素-125(125I)、又は炭素-14(14C)等が挙げられる。また、前記化合物は、例えば、トリチウム(H)、ヨウ素-125(125I)、又は炭素-14(14C)等の放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. In addition, the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
 本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、優れたLCAT活性化作用を有し、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患(心不全、心筋梗塞、狭心症、心虚血、心血管障害及び血管形成性再狭窄を含む)、脳血管疾患(脳卒中及び脳梗塞を含む)、末梢血管疾患(糖尿病血管合併症を含む)、脂質異常症、低HDLコレステロール血症、高LDLコレステロール血症、又は、腎疾患の治療剤又は予防剤、特に、抗動脈硬化剤の有効成分として有用である。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activating action, and is arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (heart failure). , Including myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), lipid abnormalities It is useful as an active ingredient of a therapeutic or prophylactic agent for renal disease, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease, particularly an anti-arteriosclerotic agent.
本発明の試験例1及び2におけるLCAT活性化の50%効果濃度(EC50)を求めるため用量反応曲線Dose response curve for determining 50% effective concentration (EC 50 ) of LCAT activation in Test Examples 1 and 2 of the present invention
 以下に、本発明の化合物(I)及び本発明の化合物(I)の製造に使用する原料化合物の代表的な製造方法について説明するが、本発明はこれらの方法に限定されるものではない。 Hereinafter, typical methods for producing the compound (I) of the present invention and the starting compound used for the production of the compound (I) of the present invention will be described, but the present invention is not limited to these methods.
 製造法1
 製造法1は、化合物(II)から本発明の化合物(I)を製造する方法である。
Manufacturing method 1
Production method 1 is a method for producing compound (I) of the present invention from compound (II).
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
 式中、R及びRは前記と同意義を示し、Rは水素原子又は式-O-R(Rは、水素原子、メチル基、トリエチルシリル基、tert-ブチルジメチルシリル基又はtert-ブチルジフェニルシリル基を示す。)を示し、Rはメチル基又はエチル基を示す。 In the formula, R and R 2 are as defined above, R 3 is a hydrogen atom or a formula —O—R 5 (R 5 is a hydrogen atom, a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyl group). -Represents a butyldiphenylsilyl group), and R 4 represents a methyl group or an ethyl group.
 (工程1)
 本工程は、化合物(II)及び化合物(III)を、反応に不活性な溶媒中又は溶媒の非存在下、加熱して縮合させることにより、化合物(I)を製造する工程である。
(Process 1)
This step is a step for producing compound (I) by heating and condensing compound (II) and compound (III) in a solvent inert to the reaction or in the absence of a solvent.
 本工程に用いられる溶媒としては、酢酸、ギ酸、シュウ酸、メタンスルホン酸、p-トルエンスルホン酸、カンファースルホン酸、トリフルオロ酢酸若しくはトリフルオロメタンスルホン酸のような有機酸類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチルメチルエーテルのようなエーテル類;メタノール、エタノール、n-プロパノール、イソプロパノール、n-ブタノール、イソブタノール、tert-ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、2-メトキシエタノール、ジエチレングリコール若しくはグリセリンのようなアルコール類;ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類;又は、これらの混合溶媒であり得、好適には、エタノール及び酢酸の混合溶媒である。 Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy Alcohols such as ethanol, diethylene glycol or glycerine; aromatic hydrocarbons such as benzene, toluene or xylene; or these It is a mixed solvent, preferably a mixed solvent of ethanol and acetic acid.
 本工程の反応温度は、通常、40℃乃至150℃であり、好適には、50℃乃至130℃であり、より好適には、60℃乃至溶媒の還流温度である。 The reaction temperature in this step is usually 40 ° C. to 150 ° C., preferably 50 ° C. to 130 ° C., more preferably 60 ° C. to the reflux temperature of the solvent.
 本工程の反応を促進するために、反応液を加熱する他に、マイクロ波を照射することもできる。 In order to promote the reaction in this step, in addition to heating the reaction solution, microwaves can be irradiated.
 本工程の反応時間は、通常、5分間乃至72時間であり、好適には、15分間乃至24時間であり、より好適には、30分間乃至3時間である。 The reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.
 化合物(III)のRが、メチル基、トリエチルシリル基、tert-ブチルジメチルシリル基又はtert-ブチルジフェニルシリル基の場合、上記反応により製造した化合物を、例えば、P.G.Wuts,T.W.Greene,Greene’s Protective Groups in Organic Synthesis.Third Edition,2006年,John Wiley & Sons,Inc.などに記載されている方法を用いて、水酸基の保護基を除去し、化合物(I)を製造することができる。 When R 5 of the compound (III) is a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, the compound prepared by the above reaction is exemplified by P.I. G. Wuts, T.W. W. Greene, Greene's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. Etc. can be used to remove the hydroxyl-protecting group to produce compound (I).
 製造法2
 本発明の化合物の中間体(II)は、例えば次の方法で製造することができる。
Manufacturing method 2
The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
 式中、Rは前記と同意義を示し、Xは塩素原子、臭素原子、ヨウ素原子、p-トルエンスルホニル基、メタンスルホニル基又はトリフルオロメタンスルホニル基を示す。 In the formula, R represents the same meaning as described above, and X represents a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, a methanesulfonyl group or a trifluoromethanesulfonyl group.
 (工程2-1)
 本工程は、化合物(IV)を、不活性溶媒中、塩基を用いて化合物(V)と反応させることにより、化合物(VI)を製造する工程である。
(Process 2-1)
This step is a step for producing compound (VI) by reacting compound (IV) with compound (V) in an inert solvent using a base.
 本工程に用いられる溶媒は、ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン、クロロベンゼン若しくはジクロロベンゼンのようなハロゲン化炭化水素類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチルメチルエーテルのようなエーテル類;ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類;アセトニトリル若しくはプロピオニトリルのようなニトリル類;ホルムアミド、N,N-ジメチルホルムアミド、ジメチルアセトアミド、N-メチル-2-ピロリドン若しくはヘキサメチルホスホロトリアミドのようのアミド類;又は、ジメチルスルホキシドのようなスルホキシド類;であり得、好適には、アミド類又はスルホキシド類であり、より好適には、N,N-ジメチルホルムアミド又はジメチルスルホキシドである。 Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably amides or sulfoxides An earth, more preferably, N, is N- dimethylformamide or dimethyl sulfoxide.
 本工程に用いられる塩基としては、好適には、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウムのような無機塩基であり得、より好適には、炭酸カリウム又は炭酸セシウムである。 The base used in this step is preferably an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and more preferably potassium carbonate or cesium carbonate. .
 本工程の反応温度は、好適には、-10℃乃至150℃であり、より好適には、20℃乃至120℃である。 The reaction temperature in this step is preferably −10 ° C. to 150 ° C., and more preferably 20 ° C. to 120 ° C.
 本工程の反応時間は、好適には、30分間乃至10時間であり、より好適には、1分間乃至4時間である。 The reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 minute to 4 hours.
 (工程2-2)
 本工程は、化合物(VI)を、不活性溶媒中、金属触媒存在下、接触水素化することにより、化合物(II)を製造する工程である。
(Step 2-2)
This step is a step for producing compound (II) by catalytic hydrogenation of compound (VI) in the presence of a metal catalyst in an inert solvent.
 本工程に用いられる溶媒は、メタノール、エタノール、n-プロパノール、イソプロパノール、n-ブタノール、イソブタノール、tert-ブタノール、イソアミルアルコール、オクタノール、シクロヘキサノール、2-メトキシエタノール、ジエチレングリコール若しくはグリセリンのようなアルコール類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチルメチルエーテルのようなエーテル類;ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類;又は、これらの混合溶媒であり得、好適には、アルコール類若しくはエーテル類とアルコール類との混合溶媒であり、より好適には、エタノール若しくはメタノールとテトラヒドロフランとの混合溶媒である。 Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin. An ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; an aromatic hydrocarbon such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Is a mixed solvent of alcohols or ethers and alcohols, more preferably a mixture of ethanol or methanol and tetrahydrofuran. It is a medium.
 本工程に用いられる金属触媒は、白金、パラジウム-活性炭素、パラジウム-活性炭素ジフェニルスルフィド複合体又はニッケルなどであり得、好適にはパラジウム-活性炭素又はパラジウム-活性炭素ジフェニルスルフィド複合体である。 The metal catalyst used in this step may be platinum, palladium-activated carbon, palladium-activated carbon diphenyl sulfide complex or nickel, and is preferably palladium-activated carbon or palladium-activated carbon diphenyl sulfide complex.
 本工程に用いられる水素化剤は、水素ガス若しくはギ酸アンモニウムであり得、好適には水素ガスである。 The hydrogenating agent used in this step can be hydrogen gas or ammonium formate, preferably hydrogen gas.
 本工程の反応温度は、好適には、0℃乃至100℃であり、より好適には、5℃乃至40℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 5 ° C. to 40 ° C.
 本工程の反応時間は、好適には、5分間乃至10時間であり、より好適には、20分間乃至2時間である。 The reaction time in this step is preferably 5 minutes to 10 hours, and more preferably 20 minutes to 2 hours.
 製造法3
 製造法3は、化合物(VIII)から、本発明の化合物(Ib)及び(Ic)を製造する方法である。
Production method 3
Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VIII).
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
 式中、R及びRは前記と同意義を示し、Bocはtert-ブトキシカルボニル基を示し、nは1又は2を示す。 In the formula, R 1 and R 2 are as defined above, Boc represents a tert-butoxycarbonyl group, and n represents 1 or 2.
 化合物(VIII)は、例えば参考例1及び2、又は、参考例9、10、11及び12に記載の方法に準じて製造することができる。 Compound (VIII) can be produced, for example, according to the methods described in Reference Examples 1 and 2, or Reference Examples 9, 10, 11, and 12.
 (工程4-1)
 本工程は、化合物(VIII)におけるBoc基を除去することにより、化合物(Ib)を製造する工程である。
(Step 4-1)
This step is a step for producing compound (Ib) by removing the Boc group in compound (VIII).
 化合物(VIII)におけるBocの除去に使用される試薬としては、例えば、P.G.Wuts,T.W.Greene,Greene’s Protective Groups in Organic Synthesis.Third Edition,2006年,John Wiley & Sons,Inc.などに記載されているBocの除去が可能な試薬などが挙げられる。 Examples of reagents used for removing Boc in compound (VIII) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.
 本工程に用いられる溶媒は、好適には、メタノール若しくはエタノールのようなアルコール類;テトラヒドロフラン若しくは1,4-ジオキサンのようなエーテル類;ジクロロメタン若しくはクロロホルムのようなハロゲン化アルキル類;酢酸エチルのようなエステル類;トルエンのような芳香族炭化水素類;又はこれらの混合溶媒であり、より好適には、エーテル類又はハロゲン化アルキル類であり、更により好適には、ジクロロメタンである。 The solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably dichloromethane.
 本工程に用いられる試薬は、好適には、塩酸又はトリフルオロ酢酸であり、より好適には、トリフルオロ酢酸である。 The reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
 本工程の反応温度は、好適には、0℃乃至100℃であり、より好適には、0℃乃至50℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.
 本工程の反応時間は、好適には、5分間乃至24時間であり、より好適には、10分間から6時間である。 The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
 (工程3-2)
 本工程は、化合物(Ib)を、アリール化剤若しくはヘテロアリール化剤と反応させることにより、化合物(Ic)を製造する工程である。
(Step 3-2)
This step is a step for producing compound (Ic) by reacting compound (Ib) with an arylating agent or heteroarylating agent.
 本工程に用いられる溶媒は、ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン、クロロベンゼン若しくはジクロロベンゼンのようなハロゲン化炭化水素類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチルメチルエーテルのようなエーテル類;ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類;アセトニトリル若しくはプロピオニトリルのようなニトリル類;ホルムアミド、N,N-ジメチルホルムアミド、ジメチルアセトアミド、N-メチル-2-ピロリドン若しくはヘキサメチルホスホロトリアミドのようのアミド類;又は、ジメチルスルホキシドのようなスルホキシド類;であり得、好適には、スルホキシド類であり、より好適には、ジメチルスルホキシドである。 Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably sulfoxides More preferably a dimethyl sulfoxide.
 本工程に用いられる塩基は、トリエチルアミン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン、N-メチルモルホリン、ピリジン、ジメチルアミノピリジン若しくは2,6-ルチジンなどの有機塩基であり得、好適には、トリエチルアミン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン、ピリジン又はジメチルアミノピリジンである。 The base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine. Preferred are triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.
 本工程に用いられるアリール化剤若しくはヘテロアリール化剤は、式R-F、式R-Cl又は式R-Brを有する化合物であり、好適には、式R-F又は式R-Clを有する化合物である(Rは前記と同意義を示す。)。 The arylating agent or heteroarylating agent used in this step is a compound having the formula R 1 -F, the formula R 1 -Cl or the formula R 1 -Br, preferably the formula R 1 -F or the formula R 1- Cl-containing compound (R 1 is as defined above).
 本工程の反応温度は、好適には、20℃乃至200℃である。 The reaction temperature in this step is preferably 20 ° C to 200 ° C.
 本工程の反応を促進するために、反応液を加熱する他に、マイクロ波を照射することもできる。 In order to promote the reaction in this step, in addition to heating the reaction solution, microwaves can be irradiated.
 本工程の反応時間は、好適には、5分間乃至120時間であり、より好適には10分間乃至96時間である。 The reaction time in this step is preferably 5 minutes to 120 hours, more preferably 10 minutes to 96 hours.
 製造法4
 本発明の化合物の中間体(IV)のうち、式(IVc)で表される化合物は、例えば次の方法で製造することができる。
Manufacturing method 4
Of the intermediate (IV) of the compound of the present invention, the compound represented by the formula (IVc) can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
 式中、n、Rは前記と同意義を示す。 In the formula, n and R 1 are as defined above.
 (工程4-1)
 (i)本工程は、化合物(IVa)を、パラジウム触媒の他にリガンド及び塩基存在下、アリール化剤若しくはヘテロアリール化剤と反応させることにより、化合物(IVb)を製造する工程である。
(Step 4-1)
(I) This step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a ligand and a base in addition to a palladium catalyst.
 本工程で使用されるパラジウム触媒、リガンド、塩基ならびに反応条件は、通常ブッフバルト・ハートウィッグ反応に使用される試薬および条件であれば特に限定されないが、例えば、A.R.Muci,S.L.Buchwald,Top.Curr.Chem.2002年,219巻,p.131などに記載されている。 The palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. 2002, 219, p. 131.
 本工程に用いられる溶媒は、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチル-メチルエーテルのようなエーテル類;又は、ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類であり、好適には、トルエンまたはジオキサンであり、より好適には、トルエンである。 The solvent used in this step is an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl-methyl ether; or an aromatic hydrocarbon such as benzene, toluene or xylene. , Preferably toluene or dioxane, and more preferably toluene.
 本工程に用いられるパラジウム触媒は、好適には、酢酸パラジウム(II)又はパラジウム(0)ジベンジリデンアセトンである。 The palladium catalyst used in this step is preferably palladium (II) acetate or palladium (0) dibenzylideneacetone.
 本工程で用いられるリガンドは、好適には、2-(ジ-tert-ブチルホスフィノ)ビフェニル、トリ-tert-ブチルホスフィン、トリシクロヘキシルホスフィン、1,3-ビス(ジフェニルホスフィノ)プロパン、2,2’-ビス(ジフェニルホスファニル)1,1’-ビナフチル、2-(ジシクロヘキシルホスフィノ)ビフェニル又は2-ジシクロヘキシルホスフィノ-2’-(N,N-ジメチルアミノ)ビフェニルであり、より好適には、2-(ジ-tert-ブチルホスフィノ)ビフェニル、トリ-tert-ブチルホスフィン又は2,2’-ビス(ジフェニルホスファニル)1,1’-ビナフチルである。 The ligand used in this step is preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane, 2, 2′-bis (diphenylphosphanyl) 1,1′-binaphthyl, 2- (dicyclohexylphosphino) biphenyl or 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, more preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine or 2,2′-bis (diphenylphosphanyl) 1,1′-binaphthyl.
 本工程で用いられる塩基は、好適には、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、tert-ブトキシナトリウム又はtert-ブトキシカリウムであり、より好適には、tert-ブトキシナトリウムである。 The base used in this step is preferably sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, and more preferably tert-butoxy sodium.
 本工程に用いられるアリール化剤若しくはヘテロアリール化剤は、式R-Cl、式R-Br又は式R-Iを有する化合物であり、好適には、式R-Cl又は式R-Brを有するである(Rは前記と同意義を示す。)。 The arylating or heteroarylating agent used in this step is a compound having the formula R 1 -Cl, the formula R 1 -Br or the formula R 1 -I, preferably the formula R 1 -Cl or the formula R 1- Br (R 1 is as defined above).
 本工程の反応温度は、好適には20℃乃至150℃であり、より好適には、50℃乃至溶媒の還流温度である。 The reaction temperature in this step is preferably 20 ° C. to 150 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
 本工程の反応時間は、好適には、30分間乃至12時間であり、より好適には、1時間乃至4時間である。 The reaction time in this step is preferably 30 minutes to 12 hours, and more preferably 1 hour to 4 hours.
 (ii)或いは、本工程は、化合物(IVa)を、不活性溶媒中、塩基存在下、アリール化剤若しくはヘテロアリール化剤と反応させることにより、化合物(IVb)を製造する工程である。 (Ii) Alternatively, this step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
 本工程は、工程3-2と同様の条件で行うことができる。 This step can be performed under the same conditions as in step 3-2.
 (工程4-2)化合物(IVb)における水酸基をメタンスルホニル化することにより、化合物(Ic)を製造する工程である。 (Step 4-2) In this step, the hydroxyl group in compound (IVb) is methanesulfonylated to produce compound (Ic).
 本工程に用いられる溶媒は、好適には、ジクロロメタン、クロロホルム、四塩化炭素、1,2-ジクロロエタン、クロロベンゼン若しくはジクロロベンゼンのようなハロゲン化炭化水素類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン若しくはtert-ブチルメチルエーテルのようなエーテル類;ベンゼン、トルエン若しくはキシレンのような芳香族炭化水素類又はこれらの混合溶媒であり、より好適には、ハロゲン化アルキル類であり、更により好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene, or a mixed solvent thereof, more preferably alkyl halides, and still more preferably Is dichloromethane.
 本工程に用いられる試薬は、好適には、メタンスルホニルクロリド又は無水メタンスルホン酸であり、より好適には、メタンスルホニルクロリドである。 The reagent used in this step is preferably methanesulfonyl chloride or methanesulfonic anhydride, and more preferably methanesulfonyl chloride.
 本工程の反応温度は、好適には、0℃乃至100℃であり、より好適には、0℃乃至30℃である。 The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.
 本工程の反応時間は、好適には、5分間乃至24時間であり、より好適には、10分間から6時間である。 The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.
 上記各工程の生成物は、遊離化合物又はその塩として、反応終了後、必要に応じて、常法、例えば、(1)反応液をそのまま濃縮する方法、(2)触媒等の不溶物をろ過により除去し、ろ液を濃縮する方法、(3)反応液に水及び水と混和しない溶媒(例えば、ジクロロエタン、ジエチルエーテル、酢酸エチル、トルエン等)を加え、生成物を抽出する方法、(4)結晶化した又は沈殿した生成物をろ取する方法等により、反応混合物から単離することができる。単離された生成物は、必要に応じて、常法、例えば、再結晶、再沈殿、各種クロマトグラフィー等により、精製することができる。又は、各工程の生成物は、単離又は精製することなく次の工程に用いることもできる。 The product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) ) The crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration. The isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary. Alternatively, the product of each step can be used in the next step without isolation or purification.
 本発明の化合物(I)は、遊離化合物、その薬理上許容される塩、水和物、又は溶媒和物の物質として単離され、精製される。本発明の化合物(I)の薬理上許容される塩は、常法の造塩反応に付すことにより、製造することができる。単離、精製は、抽出、濃縮、留去、結晶化、ろ過、再結晶、又は各種クロマトグラフィー等の通常の化学操作を適用して行われる。 Compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate, or solvate thereof. The pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
 各種の異性体は、異性体間の物理化学的性質の差を利用して分離することができる。例えば、ラセミ混合物は、光学活性な塩基若しくは酸とのジアステレオマー塩に導く分別結晶化又はキラルカラムを用いたクロマトグラフィー等により、光学的に純粋な異性体に導くことができる。又、ジアステレオ混合物は、分別結晶化又は各種クロマトグラフィー等により分離できる。又、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Various isomers can be separated by utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column. Further, the diastereo mixture can be separated by fractional crystallization or various chromatographies. An optically active compound can also be produced by using an appropriate optically active raw material.
 本発明の一般式(I)を有する化合物又はその薬理上許容される塩の投与形態としては、例えば、錠剤、顆粒剤、散剤、カプセル剤若しくはシロップ剤等による経口投与、又は注射剤若しくは坐剤等による非経口投与を挙げることができ、全身的又は局所的に投与することができる。 Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
 本発明の一般式(I)を有する化合物又はその薬理上許容される塩の経口用の医薬の形態としては、錠剤、丸剤、顆粒剤、散剤、カプセル剤、液剤、懸濁剤、乳剤、シロップ剤、又はエリキシル剤等が挙げられる。非経口用の医薬の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、又は坐剤等が挙げられる。これらの形態の医薬は、賦形剤、結合剤、希釈剤、安定化剤、防腐剤、着色剤、溶解補助剤、懸濁化剤、緩衝剤、又は湿潤化剤等の薬学的に許容される添加剤から、必要に応じて適宜選択した添加剤を用いて、常法に従って調製することができる。 Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs. Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, and suppositories. These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents. The additive can be prepared according to a conventional method using additives appropriately selected as necessary.
 本発明の一般式(I)を有する化合物又はその薬理上許容される塩の投与する際の投与量は、その投与される者(温血動物、例えばヒト)の症状、体重、年齢、投与方法等により異なる。例えば、経口投与の場合には、1回当たり、下限として0.01mg/kg体重(好ましくは、0.03mg/kg体重)、上限として、300mg/kg体重(好ましくは、100mg/kg体重)を、1日当たり1乃至数回、症状に応じて投与することが望ましい。また、静脈内投与の場合には、1回当たり、下限として0.01mg/kg体重(好ましくは、0.03mg/kg体重)、上限として、300mg/kg体重(好ましくは、100mg/kg体重)を1日あたり1乃至数回、症状に応じて投与することが望ましい。 The dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc. For example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms. In the case of intravenous administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
 
 以下、実施例、試験例及び製剤例を挙げて本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。以下の実施例において、ヘキサンは、n-ヘキサンを示し、THFはテトラヒドロフランを示し、IPAは2-プロパノールを示し、DMFはN,N’-ジメチルホルムアミドを示し、DMSOはジメチルスルホキシドを示す。

EXAMPLES Hereinafter, although an Example, a test example, and a formulation example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these. In the following examples, hexane represents n-hexane, THF represents tetrahydrofuran, IPA represents 2-propanol, DMF represents N, N′-dimethylformamide, and DMSO represents dimethyl sulfoxide.
 (参考例1)4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル Reference Example 1 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] Piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
 4-(4-ニトロ-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(WO2005/92864号パンフレットに記載された化合物、210mg、0.709mmol)及び10%パラジウム-活性炭素(100mg)のエタノール(5mL)懸濁液を水素雰囲気下、3.5時間撹拌した。セライトろ過後、減圧下、溶媒を留去して得られた残渣のエタノール(3mL)及び酢酸(1mL)混合溶液に、トリフルオロアセト酢酸エチル(313μL、2.13mmol)を加え、80℃で80分間攪拌した。減圧下、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=88/12-0/100(グラジェント)]で精製し、標記化合物(220mg、収率:77%)を得た。 Tert-Butyl 4- (4-nitro-1H-imidazol-1-yl) piperidine-1-carboxylate (compound described in WO 2005/92864, 210 mg, 0.709 mmol) and 10% palladium-activated carbon ( A suspension of 100 mg) in ethanol (5 mL) was stirred under a hydrogen atmosphere for 3.5 hours. After filtration through Celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (3 mL) and acetic acid (1 mL) of the residue obtained by distilling off the solvent under reduced pressure. Stir for minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 100 (gradient)] to give the title compound (220 mg, yield). : 77%).
 1H-NMR (500Hz, DMSO-D6) δ: 10.30 (1H, s), 7.81 (1H, s), 7.21 (1H, s), 4.42 (1H, m), 4.19-4.01 (2H, m), 3.07 (1H, d, J=17Hz), 2.93-2.65 (2H, m), 2.77 (1H, d, J=17Hz), 2.10-2.00 (1H, m), 1.94 (1H, m), 1.88-1.79 (1H, m), 1.65 (1H, m), 1.42 (9H, s)。 1 H-NMR (500Hz, DMSO-D 6 ) δ: 10.30 (1H, s), 7.81 (1H, s), 7.21 (1H, s), 4.42 (1H, m), 4.19-4.01 (2H, m) , 3.07 (1H, d, J = 17Hz), 2.93-2.65 (2H, m), 2.77 (1H, d, J = 17Hz), 2.10-2.00 (1H, m), 1.94 (1H, m), 1.88- 1.79 (1H, m), 1.65 (1H, m), 1.42 (9H, s).
 (参考例2) (Reference example 2)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
 参考例1にて製造された4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル(400mg、0.989mmol)の酢酸エチル-メタノール(1/1)(4mL)混合溶液を中性シリカゲルに吸着させ、減圧下、溶媒を留去して得られた粉末を、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=93/7、流速:12mL/分]で3回に分けて精製し、目的化合物(188mg、収率:47%、光学活性体)を得た。 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 -Il] piperidine-1-carboxylate tert-butyl (400 mg, 0.989 mmol) in ethyl acetate-methanol (1/1) (4 mL) was adsorbed on neutral silica gel, and the solvent was distilled off under reduced pressure. The powder obtained in this manner was divided into 3 portions by flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 93/7, flow rate: 12 mL / min]. The product was purified to obtain the target compound (188 mg, yield: 47%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=80/20、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate 1.0 mL / min].
 光学純度99%以上(保持時間:5.0分)。 Optical purity 99% or more (retention time: 5.0 minutes).
 (参考例3)1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-オール (Reference Example 3) 1- (5-Isopropoxypyridin-2-yl) piperidin-4-ol
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
 2-ブロモ-5-イソプロポキシピリジン(3.25g、15.0mmol)及び4-ヒドロキシピペリジン(1.98g、19.6mmol)、のトルエン(50mL)溶液に、tert-ブトキシナトリウム(3.18g、33.1mmol)、トリス(ジベンジリデンアセトン)二パラジウム(0)(689mg、0.752mmol)及び2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(468mg、0.752mmol)を加え、窒素雰囲気下、80℃で1時間攪拌した。反応液を室温まで冷却した後にろ過し、減圧下にて、ろ液の溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=95/5-0/100(グラジェント)]で精製して、標記化合物(2.67g、収率:75%)を得た。 To a solution of 2-bromo-5-isopropoxypyridine (3.25 g, 15.0 mmol) and 4-hydroxypiperidine (1.98 g, 19.6 mmol) in toluene (50 mL) was added tert-butoxy sodium (3.18 g, 33.1 mmol), tris (dibenzylideneacetone) dipalladium (0) (689 mg, 0.752 mmol) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (468 mg, 0.752 mmol). In addition, the mixture was stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-0 / 100 (gradient)] to give the title compound (2.67 g, yield: 75%). It was.
 1H-NMR (400MHz, CDCl3) δ: 7.91 (1H, d, J=3Hz), 7.13 (1H, dd, J=9Hz, 3Hz), 6.65 (1H, d, J=9Hz), 4.42-4.31 (1H, m), 3.98-3.84 (3H, m), 3.10-3.01 (2H, m), 2.03-1.94 (2H, m), 1.67-1.53 (2H, m), 1.48 (1H, d, J=4Hz), 1.30 (6H, d, J=6Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.91 (1H, d, J = 3Hz), 7.13 (1H, dd, J = 9Hz, 3Hz), 6.65 (1H, d, J = 9Hz), 4.42-4.31 (1H, m), 3.98-3.84 (3H, m), 3.10-3.01 (2H, m), 2.03-1.94 (2H, m), 1.67-1.53 (2H, m), 1.48 (1H, d, J = 4Hz), 1.30 (6H, d, J = 6Hz).
 (参考例4)1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-1H-イミダゾール-4-アミン (Reference Example 4) 1- {1- (5-Isopropoxypyridin-2-yl) piperidin-4-yl} -1H-imidazol-4-amine
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
 参考例3にて製造された1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-オール及びトリエチルアミン(2.63mL、19.0mmol)のジクロロメタン(30mL)溶液に、0℃にて、塩化メタンスルホニル(1.28mL、16.4mmol)を加え、室温で30分間攪拌した。反応液に氷水を加え、分液し、有機相を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣を酢酸エチル、ヘキサンで順次洗浄して、合成中間体Bを得た。 To a solution of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol and triethylamine (2.63 mL, 19.0 mmol) prepared in Reference Example 3 in dichloromethane (30 mL) at 0 ° C., Methanesulfonyl chloride (1.28 mL, 16.4 mmol) was added and stirred at room temperature for 30 minutes. Ice water was added to the reaction solution and the phases were separated, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed successively with ethyl acetate and hexane to obtain a synthetic intermediate B.
 4-ニトロ-1H-イミダゾール(651mg、5.76mmol)及び上記操作にて得られた合成中間体BのDMF(20mL)溶液に、炭酸セシウム(2.25g、6.91mmol)を加え、120℃にて3時間攪拌した。反応液を酢酸エチルで希釈し、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=50/50-0/100(グラジェント)]で精製して、標記化合物(0.76g、収率:36%)を得た。 To a solution of 4-nitro-1H-imidazole (651 mg, 5.76 mmol) and the synthetic intermediate B obtained by the above operation in DMF (20 mL), cesium carbonate (2.25 g, 6.91 mmol) was added, and 120 ° C. For 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to give the title compound (0.76 g, yield: 36%). It was.
 1H-NMR (400MHz, CDCl3) δ: 7.94 (1H, d, J=3Hz), 7.83 (1H, d, J=2Hz), 7.54 (1H, d, J=2Hz), 7.18 (1H, dd, J=9Hz, 3Hz), 6.71 (1H, d, J=9Hz), 4.47-4.30 (3H, m), 4.28-4.17 (1H, m), 3.00-2.90 (2H, m), 2.29-2.20 (2H, m), 2.09-1.97 (2H, m), 1.32 (6H, d, J=6Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 7.94 (1H, d, J = 3Hz), 7.83 (1H, d, J = 2Hz), 7.54 (1H, d, J = 2Hz), 7.18 (1H, dd , J = 9Hz, 3Hz), 6.71 (1H, d, J = 9Hz), 4.47-4.30 (3H, m), 4.28-4.17 (1H, m), 3.00-2.90 (2H, m), 2.29-2.20 ( 2H, m), 2.09-1.97 (2H, m), 1.32 (6H, d, J = 6Hz).
 (参考例5)1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-オール (Reference Example 5) 1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-ol
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
 5-クロロ-2-(トリフルオロメチル)ピリミジン(1.71g、9.37mmol)及び4-ヒドロキシピペリジン(1.20g、11.9 mmol)のDMSO(10mL)溶液に、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(2.90mL、19.4mmol)を加え、80℃にて4時間攪拌した。反応液に水を加え、酢酸エチルで3回抽出し、減圧下にて、得られた有機相の溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=70/30-0/1000(グラジェント)]で精製して、標記化合物(1.95g、収率:84%)を得た。 To a solution of 5-chloro-2- (trifluoromethyl) pyrimidine (1.71 g, 9.37 mmol) and 4-hydroxypiperidine (1.20 g, 11.9 mmol) in DMSO (10 mL) was added 1,8-diazabicyclo [ 5.4.0] -7-undecene (2.90 mL, 19.4 mmol) was added and stirred at 80 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the solvent of the obtained organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-0 / 1000 (gradient)] to give the title compound (1.95 g, yield: 84%). It was.
 1H-NMR (400MHz, CDCl3) δ: 8.42 (2H, s), 4.06-3.96 (1H, m), 3.74-3.66 (2H, m), 3.26-3.17 (2H, m), 2.08-2.00 (2H, m), 1.77-1.67 (2H, m), 1.56-1.53 (1H, m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.42 (2H, s), 4.06-3.96 (1H, m), 3.74-3.66 (2H, m), 3.26-3.17 (2H, m), 2.08-2.00 ( 2H, m), 1.77-1.67 (2H, m), 1.56-1.53 (1H, m).
 (参考例6)1-{1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-イル}-1H-イミダゾール-4-アミン (Reference Example 6) 1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1H-imidazol-4-amine
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
 1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-オールの代わりに、参考例5にて製造された1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-オール(1.92g、7.77mmol)を用いて、参考例4と同様に反応を行い、標記化合物(1.07g、収率:43%)を得た。 Instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol, 1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4- 4 prepared in Reference Example 5 was used. The reaction was carried out in the same manner as in Reference Example 4 using all (1.92 g, 7.77 mmol) to obtain the title compound (1.07 g, yield: 43%).
 1H-NMR (400MHz, DMSO-d6) δ: 8.70 (2H, s), 8.60 (1H, s), 8.00 (1H, s), 4.57-4.47 (1H, m), 4.22 (2H, d, J=14Hz), 3.08 (2H, t, J=12Hz), 2.14-1.96 (4H, m)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 8.70 (2H, s), 8.60 (1H, s), 8.00 (1H, s), 4.57-4.47 (1H, m), 4.22 (2H, d, J = 14Hz), 3.08 (2H, t, J = 12Hz), 2.14-1.96 (4H, m).
 (参考例7)1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-オール Reference Example 7 1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-ol
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
 2-ブロモ-5-イソプロポキシピリジンの代わりに、2-ブロモ-5-(ジフルオロメトキシ)ピリジン(J.Med.Chem.、2010年、第53巻、第8421-8439頁に記載された化合物、2.85g、12.7mmol)を用いて、参考例3と同様に反応を行い、標記化合物(2.11g、収率:68%)を得た。 Instead of 2-bromo-5-isopropoxypyridine, 2-bromo-5- (difluoromethoxy) pyridine (compound described in J. Med. Chem., 2010, 53, 8421-8439, 2.85 g, 12.7 mmol) was used in the same manner as in Reference Example 3 to obtain the title compound (2.11 g, yield: 68%).
 1H-NMR (400MHz, CDCl3) δ: 8.05 (1H, d, J=3Hz), 7.30 (1H, dd, J=9Hz, 3Hz), 6.65 (1H, d, J=9Hz), 6.39 (1H, t, J=74Hz), 4.06-3.98 (2H, m), 3.97-3.88 (1H, m), 3.21-3.11 (2H, m), 2.02-1.93 (2H, m), 1.64-1.51 (3H, m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.05 (1H, d, J = 3Hz), 7.30 (1H, dd, J = 9Hz, 3Hz), 6.65 (1H, d, J = 9Hz), 6.39 (1H , t, J = 74Hz), 4.06-3.98 (2H, m), 3.97-3.88 (1H, m), 3.21-3.11 (2H, m), 2.02-1.93 (2H, m), 1.64-1.51 (3H, m).
 (参考例8)1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-1H-イミダゾール-4-アミン (Reference Example 8) 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -1H-imidazol-4-amine
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
 1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-オールの代わりに、参考例7にて製造された1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-オール(1.91g、7.82mmol)を用いて、参考例4と同様に反応を行い、標記化合物(447mg、収率:25%)を得た。 1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-ol prepared in Reference Example 7 instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol (1.91 g, 7.82 mmol) was used in the same manner as in Reference Example 4 to obtain the title compound (447 mg, yield: 25%).
 1H-NMR (400MHz, CDCl3) δ: 8.09 (1H, d, J=3Hz), 7.83 (1H, d, J=2Hz), 7.54 (1H, d, J=2Hz), 7.37 (1H, dd, J=9Hz, 3Hz), 6.71 (1H, d, J=9Hz), 6.43 (1H, t, J=74Hz), 4.52-4.43 (2H, m), 4.33-4.22 (1H, m), 3.06-2.95 (2H, m), 2.29-2.20 (2H, m), 2.05-1.92 (2H, m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 8.09 (1H, d, J = 3Hz), 7.83 (1H, d, J = 2Hz), 7.54 (1H, d, J = 2Hz), 7.37 (1H, dd , J = 9Hz, 3Hz), 6.71 (1H, d, J = 9Hz), 6.43 (1H, t, J = 74Hz), 4.52-4.43 (2H, m), 4.33-4.22 (1H, m), 3.06- 2.95 (2H, m), 2.29-2.20 (2H, m), 2.05-1.92 (2H, m).
 (参考例9)3-(4-ニトロ-1H-イミダゾール-1-イル)ピロリジン-1-カルボン酸tert-ブチル (Reference Example 9) tert-butyl 3- (4-nitro-1H-imidazol-1-yl) pyrrolidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
 1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-オールの代わりに、3-ヒドロキシピロリジン-1-カルボン酸tert-ブチル(13.0g、69.4mmol)を用いて、参考例4と同様に反応を行い、標記化合物(7.54g、収率:77%)を得た。 Reference Example 4 was carried out using tert-butyl 3-hydroxypyrrolidine-1-carboxylate (13.0 g, 69.4 mmol) instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol. To give the title compound (7.54 g, yield: 77%).
 1H-NMR (400MHz, DMSO-d6) δ: 7.81 (1H, d, J=2Hz), 7.51 (1H, d, J=2Hz), 4.84-4.79 (1H, m), 3.91 (1H, dd, J=12Hz, 6Hz), 3.76-3.63 (3H, m), 2.57-2.48 (1H, m), 2.28-2.20 (1H, m), 1.49 (9H, s)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: 7.81 (1H, d, J = 2Hz), 7.51 (1H, d, J = 2Hz), 4.84-4.79 (1H, m), 3.91 (1H, dd , J = 12Hz, 6Hz), 3.76-3.63 (3H, m), 2.57-2.48 (1H, m), 2.28-2.20 (1H, m), 1.49 (9H, s).
 (参考例10)化合物A-1、及び、化合物A-2 (Reference Example 10) Compound A-1 and Compound A-2
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
及び、 as well as,
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
 参考例9にて製造された3-(4-ニトロ-1H-イミダゾール-1-イル)ピロリジン-1-カルボン酸tert-ブチル(3.17g、12.6mmol)及び10%パラジウム-活性炭素(550mg)のメタノール(110mL)懸濁液を、水素雰囲気下、3時間攪拌した。セライトろ過後、減圧下にて、溶媒を留去して得られた残渣のエタノール(45mL)溶液に、酢酸(15mL)及び4,4,4-トリフルオロアセト酢酸エチル(5.1mL、35mmol)を加え、80℃にて2.5時間攪拌した。反応液を室温まで冷却した後、減圧下にて、反応液の溶媒を留去し、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、分液した。得られた有機相を無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[展開溶媒:(i)ヘキサン/酢酸エチル=25/75-0/100(グラジェント)、(ii)酢酸エチル/メタノール=100/0-97/3(グラジェント)]で精製し、先に溶出する化合物A-1(2g、収率:42%)、及び、後に溶出する化合物A-2(1.77g、37%)をそれぞれ得た。 Tert-butyl 3- (4-nitro-1H-imidazol-1-yl) pyrrolidine-1-carboxylate (3.17 g, 12.6 mmol) and 10% palladium-activated carbon (550 mg) prepared in Reference Example 9 ) In methanol (110 mL) was stirred under a hydrogen atmosphere for 3 hours. After filtration through celite, the solvent was distilled off under reduced pressure, and a solution of the resulting residue in ethanol (45 mL) was added to acetic acid (15 mL) and ethyl 4,4,4-trifluoroacetoacetate (5.1 mL, 35 mmol) And stirred at 80 ° C. for 2.5 hours. The reaction solution was cooled to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [developing solvent: (i) hexane / ethyl acetate = 25 / 75-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-97 / 3 (gradient). The compound A-1 eluting first (2 g, yield: 42%) and the compound A-2 eluting later (1.77 g, 37%) were obtained respectively.
 化合物A-1:
 1H-NMR (400MHz, DMSO-d6) δ: 10.36 (1H, s), 7.73-7.71 (1H, m), 7.32 (1H, s), 5.07-4.94 (1H, m), 3.79-3.69 (1H, m), 3.61-3.54 (1H, m), 3.42-3.27 (2H, m), 3.11 (1H, d, J=17Hz), 2.77 (1H, d, J=17Hz), 2.37-2.28 (2H, m), 1.41-1.39 (9H, m)。
Compound A-1:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.36 (1H, s), 7.73-7.71 (1H, m), 7.32 (1H, s), 5.07-4.94 (1H, m), 3.79-3.69 ( 1H, m), 3.61-3.54 (1H, m), 3.42-3.27 (2H, m), 3.11 (1H, d, J = 17Hz), 2.77 (1H, d, J = 17Hz), 2.37-2.28 (2H , m), 1.41-1.39 (9H, m).
 化合物A-2:
 1H-NMR (400MHz, DMSO-d6) δ: 10.37 (1H, s), 7.63 (1H, s), 7.33 (1H, s), 5.09-5.04 (1H, m), 3.71-3.66 (1H, m), 3.49-3.31 (3H, m), 3.09 (1H, d, J=17Hz), 2.78 (1H, d, J=17Hz), 2.39-2.13 (2H, m), 1.42-1.41 (9H, m)。
Compound A-2:
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.37 (1H, s), 7.63 (1H, s), 7.33 (1H, s), 5.09-5.04 (1H, m), 3.71-3.66 (1H, m), 3.49-3.31 (3H, m), 3.09 (1H, d, J = 17Hz), 2.78 (1H, d, J = 17Hz), 2.39-2.13 (2H, m), 1.42-1.41 (9H, m ).
 (参考例11) (Reference Example 11)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
 参考例10にて製造された化合物A-1(2.72g、6.97mmol)の酢酸エチル溶液をシリカゲルに吸着させ、減圧下にて、溶媒を留去して得られた粉末をフラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=90/10、流速:12mL/分]で精製し、目的化合物(1.19g、収率:43%、光学活性体)を得た。 The ethyl acetate solution of compound A-1 (2.72 g, 6.97 mmol) produced in Reference Example 10 was adsorbed on silica gel, and the solvent was distilled off under reduced pressure. Column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min], and purified by the target compound (1.19 g, yield: 43%). Optically active substance) was obtained.
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:4.6分)。 Optical purity 99% or more (retention time: 4.6 minutes).
 (参考例12) (Reference Example 12)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
 参考例10にて製造された化合物A-2(2.49g、6.38mmol)の酢酸エチル、及び、メタノール混合溶液をシリカゲルに吸着させ、減圧下にて、溶媒を留去して得られた粉末をフラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=95/5、流速:12mL/分]で精製し、目的化合物(820mg、収率:33%、光学活性体)を得た。 Obtained by adsorbing a mixed solution of compound A-2 (2.49 g, 6.38 mmol) prepared in Reference Example 10 in ethyl acetate and methanol onto silica gel, and distilling off the solvent under reduced pressure. The powder was purified by flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 95/5, flow rate: 12 mL / min], and the target compound (820 mg, yield). : 33%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:4.2分)。 Optical purity 99% or more (retention time: 4.2 minutes).
 (実施例1)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 1 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
 参考例1にて製造された4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル(100mg、0.247mmol)のジクロロメタン(1mL)懸濁液に、トリフルオロ酢酸(1mL)を0℃で加え、室温下、1時間撹拌した。減圧下、反応液の溶媒を留去して、得られた残渣のDMSO(1mL)溶液にN,N-ジイソプロピルエチルアミン(126μL、0.741mmol)及び2-フルオロ-5-(トリフルオロメチル)ピリジン(44.6μL、0.370mmol)を加え、一晩攪拌した。反応液をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=88/12-0/10(グラジェント)]で精製し、減圧下、溶媒を留去して得られた残渣を酢酸エチルに溶解し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=88/12-0/10(グラジェント)]で精製し、標記化合物(53.5mg、収率:48%)を得た。 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 To a suspension of tert-butyl-yl] piperidine-1-carboxylate (100 mg, 0.247 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and N, N-diisopropylethylamine (126 μL, 0.741 mmol) and 2-fluoro-5- (trifluoromethyl) pyridine were added to a solution of the obtained residue in DMSO (1 mL). (44.6 μL, 0.370 mmol) was added and stirred overnight. The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 10 (gradient)], and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 10 (gradient)] to give the title compound (53.5 mg, yield: 48%). .
 1H-NMR (500Hz, DMSO-d6) δ: 10.31 (1H, s), 8.45-8.38 (1H, m), 7.80 (1H, dd, J=10Hz 3Hz), 7.79 (1H, s), 7.25 (1H, s), 7.03 (1H, d, J=10Hz), 4.71-4.55 (3H, m), 3.09 (1H, d, J=17Hz), 2.97 (2H, m), 2.79 (1H, d, J=17Hz), 2.21-2.12 (1H, m), 2.04 (1H, m), 1.98-1.90 (1H, m), 1.74 (1H, m);
 MS (ESI) m/z: 450 (M+H)+
1 H-NMR (500Hz, DMSO-d 6 ) δ: 10.31 (1H, s), 8.45-8.38 (1H, m), 7.80 (1H, dd, J = 10Hz 3Hz), 7.79 (1H, s), 7.25 (1H, s), 7.03 (1H, d, J = 10Hz), 4.71-4.55 (3H, m), 3.09 (1H, d, J = 17Hz), 2.97 (2H, m), 2.79 (1H, d, J = 17Hz), 2.21-2.12 (1H, m), 2.04 (1H, m), 1.98-1.90 (1H, m), 1.74 (1H, m);
MS (ESI) m / z: 450 (M + H) <+> .
 (実施例2)(+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 2 (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
 実施例1にて製造された7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(480mg、1.07mmol)の酢酸エチル-メタノール(1/1)(8mL)混合溶液を中性シリカゲルに吸着させ、減圧下、溶媒を留去して得られた粉末を、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=80/20、流速:12mL/分]で精製し、標記化合物(233mg、収率:49%、光学活性体)を得た。 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 prepared in Example 1 A mixed solution of 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (480 mg, 1.07 mmol) in ethyl acetate-methanol (1/1) (8 mL) was adsorbed on neutral silica gel. The powder obtained by distilling off the solvent under reduced pressure was obtained by flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 12 mL. / Min] to obtain the title compound (233 mg, yield: 49%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=80/20、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate 1.0 mL / min].
 光学純度99%以上(保持時間:7.6分);
 [α]D 25 = +31°(DMF, c=0.970)。
Optical purity 99% or more (retention time: 7.6 minutes);
[α] D 25 = + 31 ° (DMF, c = 0.970).
 (実施例3)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 3 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
 参考例1にて製造された4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル(647mg、1.60mmol)のジクロロメタン(6mL)懸濁液に、トリフルオロ酢酸(6mL)を0℃で加え、室温下、1時間撹拌した。反応液をジエチルエーテルに滴下し、生じた沈殿をろ取して、固体(813mg)を得た。 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 To a suspension of tert-butyl-yl] piperidine-1-carboxylate (647 mg, 1.60 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to diethyl ether, and the resulting precipitate was collected by filtration to obtain a solid (813 mg).
 上記操作にて得られた固体の一部(100mg)のDMSO(1mL)溶液に、N,N-ジイソプロピルエチルアミン(203μL、1.20mmol)及び2-クロロ-5-(トリフルオロメチル)ピラジン(44.3μL、0.359mmol)を加え、3時間攪拌した。反応液を酢酸エチルで希釈し、水で2回、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下、溶媒を留去した。得られた残渣にジクロロメタンを加え、生じた固体をろ取し、標記化合物(73.0mg、収率:67%)を得た。 To a solution of a part (100 mg) of the solid obtained in the above operation in DMSO (1 mL), N, N-diisopropylethylamine (203 μL, 1.20 mmol) and 2-chloro-5- (trifluoromethyl) pyrazine (44 3 μL, 0.359 mmol) was added and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane was added to the resulting residue, and the resulting solid was collected by filtration to obtain the title compound (73.0 mg, yield: 67%).
 1H-NMR (500Hz, DMSO-d6) δ: 10.31 (1H, s), 8.53-8.49 (2H, m), 7.79 (1H, s), 7.26 (1H, s), 4.77-4.59 (3H, m), 3.14-3.02 (2H, m), 3.09 (1H, d, J=17Hz), 2.79 (1H, d, J=17Hz), 2.25-2.03 (2H, m), 2.01-1.92 (1H, m), 1.86-1.75 (1H, m);
 MS (ESI) m/z: 451 (M+H)+
1 H-NMR (500Hz, DMSO-d 6 ) δ: 10.31 (1H, s), 8.53-8.49 (2H, m), 7.79 (1H, s), 7.26 (1H, s), 4.77-4.59 (3H, m), 3.14-3.02 (2H, m), 3.09 (1H, d, J = 17Hz), 2.79 (1H, d, J = 17Hz), 2.25-2.03 (2H, m), 2.01-1.92 (1H, m ), 1.86-1.75 (1H, m);
MS (ESI) m / z: 451 (M + H) <+> .
 (実施例4)(+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 4 (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
 実施例3にて製造された7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(420mg、0.933mmol)の酢酸エチル-メタノール(1/1)(16mL)混合溶液を中性シリカゲルに吸着させ、減圧下、溶媒を留去して得られた粉末を、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=80/20、流速:12mL/分]で6回に分けて精製し、標記化合物(141mg、収率:22%、光学活性体)を得た。 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4, prepared in Example 3 A mixed solution of 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (420 mg, 0.933 mmol) in ethyl acetate-methanol (1/1) (16 mL) was adsorbed onto neutral silica gel. The powder obtained by distilling off the solvent under reduced pressure was obtained by flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 12 mL. / Min] to give the title compound (141 mg, yield: 22%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate 1.0 mL / min].
 光学純度99%以上(保持時間:5.6分);
 [α]D 25 = +38°(DMF, c=1.01)。
Optical purity 99% or more (retention time: 5.6 minutes);
[α] D 25 = + 38 ° (DMF, c = 1.01).
 (実施例5)1-{1-[3-クロロ-5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 5 1- {1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
 2-クロロ-5-(トリフルオロメチル)ピラジンの代わりに、3-クロロ-2-フルオロ-5-(トリフルオロメチル)ピリジン(46.9μL、0.359mmol)を用いて、実施例3と同様に反応を行い、標記化合物(72.0mg、収率:62%)を得た。 Similar to Example 3 using 3-chloro-2-fluoro-5- (trifluoromethyl) pyridine (46.9 μL, 0.359 mmol) instead of 2-chloro-5- (trifluoromethyl) pyrazine The title compound (72.0 mg, yield: 62%) was obtained.
 1H-NMR (500Hz, DMSO-d6) δ: 10.31 (1H, s), 8.59-8.56 (1H, m), 8.21 (1H, d, J=2Hz), 7.83 (1H, s), 7.25 (1H, s), 4.55 (1H, m), 4.27-4.13 (2H, m), 3.09 (1H, d, J=17Hz), 2.98 (2H, m), 2.78 (1H, d, J=17Hz), 2.27-2.15 (2H, m), 2.03-1.87 (2H, m);
 MS (ESI) m/z: 484 (M+H)+
1 H-NMR (500Hz, DMSO-d 6 ) δ: 10.31 (1H, s), 8.59-8.56 (1H, m), 8.21 (1H, d, J = 2Hz), 7.83 (1H, s), 7.25 ( 1H, s), 4.55 (1H, m), 4.27-4.13 (2H, m), 3.09 (1H, d, J = 17Hz), 2.98 (2H, m), 2.78 (1H, d, J = 17Hz), 2.27-2.15 (2H, m), 2.03-1.87 (2H, m);
MS (ESI) m / z: 484 (M + H) <+> .
 (実施例6)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)-1,3,4-チアジアゾール-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 6 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] piperidin-4-yl}- 1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
 2-クロロ-5-(トリフルオロメチル)ピラジンの代わりに、2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾール(75mg、0.398mmol)を用いて、実施例3と同様に反応を行い、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:酢酸エチル/メタノール=100/0-80/20]で精製して、標記化合物(78mg、収率:68%)を得た。 Example 2 with 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole (75 mg, 0.398 mmol) instead of 2-chloro-5- (trifluoromethyl) pyrazine and The reaction was carried out in the same manner, and the resulting residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20] to give the title compound (78 mg, yield: 68%). It was.
 1H-NMR (400MHz, DMSO-d6) δ: 10.34 (1H, s), 7.84 (1H, s), 7.29 (1H, s), 4.65-4.55 (1H, m), 4.15-4.03 (2H, m), 3.48-3.35 (2H, m), 3.09 (1H, d, J=16Hz), 2.78 (1H, d, J=16Hz), 2.27-2.15 (1H, m), 2.02-1.90 (3H, m);
 MS (ESI) m/z: 457 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.34 (1H, s), 7.84 (1H, s), 7.29 (1H, s), 4.65-4.55 (1H, m), 4.15-4.03 (2H, m), 3.48-3.35 (2H, m), 3.09 (1H, d, J = 16Hz), 2.78 (1H, d, J = 16Hz), 2.27-2.15 (1H, m), 2.02-1.90 (3H, m );
MS (ESI) m / z: 457 (M + H) + .
 (実施例7)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[4-(トリフルオロメチル)-1,3-チアゾール-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 7 7-Hydroxy-7- (trifluoromethyl) -1- {1- [4- (trifluoromethyl) -1,3-thiazol-2-yl] piperidin-4-yl} -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
 2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾールの代わりに、2-クロロ-4-(トリフルオロメチル)-1,3-チアゾール(108mg、0.578mmol)を用いて、実施例6と同様に反応を行い、標記化合物(43mg、収率:26%)を得た。 Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 2-chloro-4- (trifluoromethyl) -1,3-thiazole (108 mg, 0.578 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (43 mg, yield: 26%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.33 (1H, s), 7.84 (1H, s), 7.55 (1H, s), 7.28 (1H, s), 4.60-4.50 (1H, m), 4.11-4.00 (2H, m), 3.29-3.05 (3H, m), 2.78 (1H, d, J=16Hz), 2.21-2.10 (2H, m), 2.00-1.82 (2H, m);
 MS (ESI) m/z: 456 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.33 (1H, s), 7.84 (1H, s), 7.55 (1H, s), 7.28 (1H, s), 4.60-4.50 (1H, m) , 4.11-4.00 (2H, m), 3.29-3.05 (3H, m), 2.78 (1H, d, J = 16Hz), 2.21-2.10 (2H, m), 2.00-1.82 (2H, m);
MS (ESI) m / z: 456 (M + H) <+> .
 (実施例8)7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 8 7-Hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
 2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾールの代わりに、4-クロロ-2-イソプロピル-6-(トリフルオロメチル)ピリミジン(138mg、0.614mmol)を用いて、実施例6と同様に反応を行い、標記化合物(129mg、収率:71%)を得た。 Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 4-chloro-2-isopropyl-6- (trifluoromethyl) pyrimidine (138 mg, 0.614 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (129 mg, yield: 71%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.32 (1H, s), 7.81 (1H, s), 7.27 (1H, s), 7.16 (1H, s), 4.66-4.55 (1H, m), 3.37-2.88 (6H, m), 2.79 (1H, d, J=17Hz), 2.22-1.70 (4H, m), 1.23 (6H, d, J=7Hz);
 MS (ESI) m/z: 493 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.32 (1H, s), 7.81 (1H, s), 7.27 (1H, s), 7.16 (1H, s), 4.66-4.55 (1H, m) , 3.37-2.88 (6H, m), 2.79 (1H, d, J = 17Hz), 2.22-1.70 (4H, m), 1.23 (6H, d, J = 7Hz);
MS (ESI) m / z: 493 (M + H) <+> .
 (実施例9)(+)-7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 9 (+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
 参考例2にて製造された化合物(2.15g、5.32mmol)のジクロロメタン(20mL)溶液に、トリフルオロ酢酸(3.4mL、44.0mmol)を加え、室温にて3時間攪拌した。反応液を、ジエチルエーテル(90mL)及びヘキサン(20mL)の混合溶媒に0℃で滴下し、室温にて3時間攪拌した。生じた固体をろ取して、トリフルオロ酢酸塩化合物(2.36g)を得た。 Trifluoroacetic acid (3.4 mL, 44.0 mmol) was added to a dichloromethane (20 mL) solution of the compound produced in Reference Example 2 (2.15 g, 5.32 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was added dropwise to a mixed solvent of diethyl ether (90 mL) and hexane (20 mL) at 0 ° C. and stirred at room temperature for 3 hours. The resulting solid was collected by filtration to obtain a trifluoroacetate compound (2.36 g).
 得られたトリフルオロ酢酸塩化合物(220mg)及び4-クロロ-2-イソプロピル-6-(トリフルオロメチル)ピリミジン(WO2010/134478号パンフレットに記載された化合物、180mg、0.801mmol)のDMSO(3.0mL)溶液に、N,N-ジイソプロピルエチルアミン(0.25mL、1.50mmol)を加え、室温にて18時間攪拌した。反応液に水を加え、酢酸エチルで3回抽出し、減圧下にて、得られた有機相の溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=50/50-0/100]で精製して、標記化合物(205mg、収率:79%、光学活性体)を得た。 The obtained trifluoroacetate compound (220 mg) and 4-chloro-2-isopropyl-6- (trifluoromethyl) pyrimidine (compound described in WO2010 / 134478, 180 mg, 0.801 mmol) in DMSO (3 0.0 mL) solution was added N, N-diisopropylethylamine (0.25 mL, 1.50 mmol) and stirred at room temperature for 18 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the solvent of the obtained organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100] to give the title compound (205 mg, yield: 79%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate 1.0 mL / min].
 光学純度99%以上(保持時間:4.6分);
 [α]D 25 = +32°(DMF, c=0.996)。
Optical purity 99% or more (retention time: 4.6 minutes);
[α] D 25 = + 32 ° (DMF, c = 0.996).
 (実施例10)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[6-(トリフルオロメチル)ピリダジン-3-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 10 7-Hydroxy-7- (trifluoromethyl) -1- {1- [6- (trifluoromethyl) pyridazin-3-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
 2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾールの代わりに、3-クロロ-6-(トリフルオロメチル)ピリダジン(48.0mg、0.263mmol)を用いて、実施例6と同様に反応を行い、標記化合物(12mg、収率:11%)を得た。 Using 3-chloro-6- (trifluoromethyl) pyridazine (48.0 mg, 0.263 mmol) instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole The reaction was carried out in the same manner as in 6 to obtain the title compound (12 mg, yield: 11%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.33 (1H, s), 7.83 (1H, d, J=10Hz), 7.80 (1H, s), 7.49 (1H, d, J=10Hz), 7.28 (1H, s), 4.79-4.58 (3H, m), 3.15-3.01 (3H, m), 2.79 (1H, d, J=17Hz), 2.23-2.03 (2H, m), 2.01-1.93 (1H, m), 1.86-1.74 (1H, m);
 MS (ESI) m/z: 451 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.33 (1H, s), 7.83 (1H, d, J = 10Hz), 7.80 (1H, s), 7.49 (1H, d, J = 10Hz), 7.28 (1H, s), 4.79-4.58 (3H, m), 3.15-3.01 (3H, m), 2.79 (1H, d, J = 17Hz), 2.23-2.03 (2H, m), 2.01-1.93 (1H , m), 1.86-1.74 (1H, m);
MS (ESI) m / z: 451 (M + H) <+> .
 (実施例11)6-{4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-イル}-4-(トリフルオロメチル)ピリジン-3-カルボニトリル Example 11 6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 -Yl] piperidin-1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
 2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾールの代わりに、6-クロロ-4-(トリフルオロメチル)ピリジン-3-カルボニトリル(57.0mg、0.276mmol)を用いて、実施例6と同様に反応を行い、標記化合物(46mg、収率:39%)を得た。 Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 6-chloro-4- (trifluoromethyl) pyridine-3-carbonitrile (57.0 mg, 0.276 mmol) was used. And the reaction was carried out in the same manner as in Example 6 to obtain the title compound (46 mg, yield: 39%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.33 (1H, s), 8.73 (1H, s), 7.79 (1H, s), 7.36 (1H, s), 7.28 (1H, s), 4.96-4.56 (3H, m), 3.20-3.04 (3H, m), 2.79 (1H, d, J=17Hz), 2.23-2.14 (1H, m), 2.14-2.00 (1H, m), 2.00-1.92 (1H, m), 1.84-1.71 (1H, m);
 MS (ESI) m/z: 475 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.33 (1H, s), 8.73 (1H, s), 7.79 (1H, s), 7.36 (1H, s), 7.28 (1H, s), 4.96 -4.56 (3H, m), 3.20-3.04 (3H, m), 2.79 (1H, d, J = 17Hz), 2.23-2.14 (1H, m), 2.14-2.00 (1H, m), 2.00-1.92 ( 1H, m), 1.84-1.71 (1H, m);
MS (ESI) m / z: 475 (M + H) <+> .
 (実施例12)7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 12 7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro- 5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
 参考例4にて製造された1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-1H-イミダゾール-4-アミン(0.76g、2.3mmol)及び10%パラジウム-活性炭素(0.25g)のメタノール(20mL)及びTHF(10mL)の懸濁液に、酢酸(パスツールピペット3滴)を加え、水素雰囲気下、1時間撹拌した。セライトろ過後、減圧下、溶媒を留去して得られた残渣のエタノール(9mL)及び酢酸(3mL)混合溶液に、トリフルオロアセト酢酸エチル(313μL、2.13mmol)を加え、80℃で1.5時間攪拌した。減圧下、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=50/50-0/100(グラジェント)]で精製し、標記化合物(546mg、収率:49%)を得た。 1- {1- (5-Isopropoxypyridin-2-yl) piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 4 (0.76 g, 2.3 mmol) and 10% Acetic acid (3 drops of Pasteur pipette) was added to a suspension of palladium-activated carbon (0.25 g) in methanol (20 mL) and THF (10 mL), and the mixture was stirred under a hydrogen atmosphere for 1 hr. After filtration through Celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (9 mL) and acetic acid (3 mL) of the residue obtained by evaporating the solvent under reduced pressure. Stir for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to give the title compound (546 mg, yield). : 49%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.32 (1H, s), 7.84 (1H, d, J=3Hz), 7.79 (1H, s), 7.26 (1H, dd, J=9Hz, 3Hz), 7.23 (1H, s), 6.85 (1H, d, J=9Hz), 4.53-4.27 (4H, m), 3.09 (1H, d, J=16Hz), 2.81-2.66 (3H, m), 2.18-2.00 (2H, m), 1.96-1.88 (1H, m), 1.84-1.72 (1H, m), 1.23 (6H, d, J=6Hz);
 MS (ESI) m/z: 440 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.32 (1H, s), 7.84 (1H, d, J = 3Hz), 7.79 (1H, s), 7.26 (1H, dd, J = 9Hz, 3Hz ), 7.23 (1H, s), 6.85 (1H, d, J = 9Hz), 4.53-4.27 (4H, m), 3.09 (1H, d, J = 16Hz), 2.81-2.66 (3H, m), 2.18 -2.00 (2H, m), 1.96-1.88 (1H, m), 1.84-1.72 (1H, m), 1.23 (6H, d, J = 6Hz);
MS (ESI) m / z: 440 (M + H) <+> .
 (実施例13)(+)-7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 13 (+)-7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
 実施例12にて製造された7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(506mg、1.15mmol)の酢酸エチル-メタノール(1/1)(5mL)混合溶液を中性シリカゲルに吸着させ、減圧下、溶媒を留去して得られた粉末を、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=90/10、流速:12mL/分]で3回に分けて精製し、標記化合物(240mg、収率:47%、光学活性体)を得た。 7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7 prepared in Example 12 -A mixed solution of tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (506 mg, 1.15 mmol) in ethyl acetate-methanol (1/1) (5 mL) was adsorbed onto neutral silica gel, The powder obtained by distilling off the solvent was flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min] In three steps, the title compound (240 mg, yield: 47%, optically active substance) was obtained.
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=80/20、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate 1.0 mL / min].
 光学純度99%以上(保持時間:7.8分);
 [α]D 25 = +17°(DMF, c=0.890)。
Optical purity 99% or more (retention time: 7.8 minutes);
[α] D 25 = + 17 ° (DMF, c = 0.890).
 (実施例14)7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 14 7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
 参考例6にて製造された1-{1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-イル}-1H-イミダゾール-4-アミン(1.07g、3.13mmol)及び10%パラジウム-活性炭素(640mg)のメタノール(15mL)及びTHF(5mL)の懸濁液を、水素雰囲気下、6時間撹拌した。セライトろ過後、減圧下、溶媒を留去して得られた残渣のエタノール(30mL)及び酢酸(10mL)混合溶液に、トリフルオロアセト酢酸エチル(1.50g、8.15mmol)を加え、80℃で4時間攪拌した。減圧下にて、溶媒を留去し、酢酸エチル及び飽和重曹水を加え、酢酸エチルで3回抽出し、得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=40/60-0/100(グラジェント)]で精製して、標記化合物(342mg、収率:28%)を得た。 1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 6 (1.07 g, 3.13 mmol) And a suspension of 10% palladium-activated carbon (640 mg) in methanol (15 mL) and THF (5 mL) was stirred under a hydrogen atmosphere for 6 hours. After filtration through Celite, ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a mixed solution of ethanol (30 mL) and acetic acid (10 mL) of the residue obtained by distilling off the solvent under reduced pressure, and 80 ° C. For 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted 3 times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 40 / 60-0 / 100 (gradient)] to give the title compound (342 mg, yield: 28%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.33 (1H, s), 8.68 (2H, s), 7.83 (1H, s), 7.26 (1H, s), 4.62-4.52 (1H, m), 4.22 (2H, t, J=16Hz), 3.13-2.97 (3H, m), 2.79 (1H, d, J=17Hz), 2.22-2.10 (2H, m), 1.97-1.81 (2H, m);
 MS (ESI) m/z: 451 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.33 (1H, s), 8.68 (2H, s), 7.83 (1H, s), 7.26 (1H, s), 4.62-4.52 (1H, m) , 4.22 (2H, t, J = 16Hz), 3.13-2.97 (3H, m), 2.79 (1H, d, J = 17Hz), 2.22-2.10 (2H, m), 1.97-1.81 (2H, m);
MS (ESI) m / z: 451 (M + H) <+> .
 (実施例15)1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 15 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
 参考例8にて製造された1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-1H-イミダゾール-4-アミン(447mg、1.32mmol)及び10%パラジウム-活性炭素(0.15g)のメタノール(10mL)及びTHF(10mL)の懸濁液に、酢酸(パスツールピペット3滴)を加え、水素雰囲気下、1時間撹拌した。セライトろ過後、減圧下、溶媒を留去して得られた残渣のエタノール(9mL)及び酢酸(3mL)混合溶液に、トリフルオロアセト酢酸エチル(313μL、2.13mmol)を加え、80℃で2時間攪拌した。減圧下、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:(i)ヘキサン/酢酸エチル=50/50-0/100(グラジェント)、(ii)酢酸エチル/メタノール=100/0-90/10(グラジェント)]で精製し、更に、シリカゲルカラムクロマトグラフィー[NH-シリカゲル、溶出溶媒:酢酸エチル/メタノール=100/0-90/10(グラジェント)]で精製して、標記化合物(195mg、収率:33%)を得た。 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 8 (447 mg, 1.32 mmol) and 10% Acetic acid (3 drops of Pasteur pipette) was added to a suspension of palladium-activated carbon (0.15 g) in methanol (10 mL) and THF (10 mL), and the mixture was stirred under a hydrogen atmosphere for 1 hour. After filtration through celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (9 mL) and acetic acid (3 mL) of the residue obtained by distilling off the solvent under reduced pressure. Stir for hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 50 / 50-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)], and further purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)]. To give the title compound (195 mg, yield: 33%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.31 (1H, s), 8.02 (1H, d, J=3Hz), 7.78 (1H, s), 7.45 (1H, dd, J=9Hz, 3Hz), 7.24 (1H, s), 7.06 (1H, t, J=74Hz), 6.95 (1H, d, J=9Hz), 4.58-4.38 (3H, m), 3.09 (1H, d, J=17Hz), 2.92-2.74 (3H, m), 2.19-1.97 (2H, m), 1.97-1.88 (1H, m), 1.82-1.69 (1H, m);
 MS (ESI) m/z: 448 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.31 (1H, s), 8.02 (1H, d, J = 3Hz), 7.78 (1H, s), 7.45 (1H, dd, J = 9Hz, 3Hz ), 7.24 (1H, s), 7.06 (1H, t, J = 74Hz), 6.95 (1H, d, J = 9Hz), 4.58-4.38 (3H, m), 3.09 (1H, d, J = 17Hz) , 2.92-2.74 (3H, m), 2.19-1.97 (2H, m), 1.97-1.88 (1H, m), 1.82-1.69 (1H, m);
MS (ESI) m / z: 448 (M + H) <+> .
 (実施例16)(+)-1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 16 (+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
 実施例15にて製造された1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(190mg、0.425mmol)をIPA(4mL)及びメタノール(30mL)に溶解し、減圧下、結晶が析出するまで濃縮した。得られた残渣にメタノール(4mL)を加え、加温した溶液を中性シリカゲルに吸着させ、減圧下、溶媒を留去して得られた粉末を、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=85/15、流速:12mL/分]で3回に分けて精製し、更に、フラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=85/15、流速:12mL/分]で精製して、標記化合物(79.5mg、収率:42%、光学活性体)を得た。 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6 prepared in Example 15 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (190 mg, 0.425 mmol) is dissolved in IPA (4 mL) and methanol (30 mL) and concentrated under reduced pressure until crystals precipitate. did. Methanol (4 mL) was added to the resulting residue, the heated solution was adsorbed on neutral silica gel, the solvent was distilled off under reduced pressure, and the resulting powder was obtained by flash LC [column: Chiralflash IA (30 mm i. x. x100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 85/15, flow rate: 12 mL / min] to obtain the title compound (79.5 mg, yield: 42%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=50/50、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50/50, flow rate 1.0 mL / min].
 光学純度98%以上(保持時間:4.9分);
 [α]D 25 = +22°(DMF, c=0.943)。
Optical purity 98% or more (retention time: 4.9 minutes);
[α] D 25 = + 22 ° (DMF, c = 0.943).
 (実施例17) (Example 17)
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
 4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチルの代わりに、参考例11にて製造された化合物を用いて、実施例3に記載された方法と同様に反応を行い、目的化合物(109mg、収率:83%、光学活性体)を得た。 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine-1-carvone The reaction was conducted in the same manner as in the method described in Example 3 using the compound prepared in Reference Example 11 instead of tert-butyl acid, and the target compound (109 mg, yield: 83%, optically active substance) )
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:6.4分)
 1H-NMR (400MHz, DMSO-d6) δ: 10.39 (1H, s), 8.51 (1H, s), 8.12 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 5.26-5.23 (1H, m), 4.07-4.02 (1H, m), 3.96-3.90 (1H, m), 3.74-3.68 (2H, m), 3.12 (1H, d, J=17Hz), 2.80 (1H, d, J=17Hz), 2.58-2.46 (2H, m);
 MS (ESI) m/z: 437 (M+H)+
Optical purity 99% or more (retention time: 6.4 minutes)
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.39 (1H, s), 8.51 (1H, s), 8.12 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 5.26 -5.23 (1H, m), 4.07-4.02 (1H, m), 3.96-3.90 (1H, m), 3.74-3.68 (2H, m), 3.12 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.58-2.46 (2H, m);
MS (ESI) m / z: 437 (M + H) + .
 (実施例18) (Example 18)
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
 2-クロロ-5-(トリフルオロメチル)ピラジンの代わりに、2-フルオロ-5-(トリフルオロメチル)ピリジンを用いて、実施例17に記載された方法と同様に反応を行い、目的化合物(99mg、収率:75%、光学活性体)を得た。 The reaction was conducted in the same manner as described in Example 17 using 2-fluoro-5- (trifluoromethyl) pyridine in place of 2-chloro-5- (trifluoromethyl) pyrazine, and the target compound ( 99 mg, yield: 75%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:5.4分)
 1H-NMR (400MHz, DMSO-d6) δ: 10.38 (1H, s), 8.41 (1H, brs), 7.82 (1H, dd, J=9Hz, 2Hz), 7.72 (1H, s), 7.38 (1H, s), 6.62 (1H, d, J=9Hz), 5.52-5.16 (1H, m), 4.00-3.95 (1H, m), 3.87-3.80 (1H, m), 3.65-3.56 (2H, m), 3.45 (1H, brs), 3.12 (1H, d, J=16Hz), 2.79 (1H, d, J=16Hz), 2.55-2.45 (1H, m);
 MS (ESI) m/z: 436 (M+H)+
Optical purity 99% or more (Retention time: 5.4 minutes)
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.38 (1H, s), 8.41 (1H, brs), 7.82 (1H, dd, J = 9Hz, 2Hz), 7.72 (1H, s), 7.38 ( 1H, s), 6.62 (1H, d, J = 9Hz), 5.52-5.16 (1H, m), 4.00-3.95 (1H, m), 3.87-3.80 (1H, m), 3.65-3.56 (2H, m ), 3.45 (1H, brs), 3.12 (1H, d, J = 16Hz), 2.79 (1H, d, J = 16Hz), 2.55-2.45 (1H, m);
MS (ESI) m / z: 436 (M + H) <+> .
 (実施例19) (Example 19)
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
 4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチルの代わりに、参考例12にて製造された化合物を用いて、実施例3に記載された方法と同様に反応を行い、目的化合物(89mg、収率:66%、光学活性体)を得た。 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine-1-carvone The reaction was conducted in the same manner as in the method described in Example 3 using the compound prepared in Reference Example 12 instead of tert-butyl acid, and the target compound (89 mg, yield: 66%, optically active substance) )
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:6.7分)
 1H-NMR (400MHz, DMSO-d6) δ: 10.39 (1H, s), 8.53 (1H, s), 8.17 (1H, brs), 7.67 (1H, s), 7.38 (1H, s), 5.32-5.26 (1H, m), 4.04-3.99 (1H, m), 3.88-3.68 (3H, m), 3.13 (1H, d, J=17Hz), 2.80 (1H, d, J=17Hz), 2.58-2.30 (2H, m);
 MS (ESI) m/z: 437 (M+H)+
Optical purity 99% or more (retention time: 6.7 minutes)
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.39 (1H, s), 8.53 (1H, s), 8.17 (1H, brs), 7.67 (1H, s), 7.38 (1H, s), 5.32 -5.26 (1H, m), 4.04-3.99 (1H, m), 3.88-3.68 (3H, m), 3.13 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.58- 2.30 (2H, m);
MS (ESI) m / z: 437 (M + H) + .
 (実施例20) (Example 20)
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
 2-クロロ-5-(トリフルオロメチル)ピラジンの代わりに、2-フルオロ-5-(トリフルオロメチル)ピリジンを用いて、実施例19に記載された方法と同様に反応を行い、目的化合物(99mg、収率:75%、光学活性体)を得た。 The reaction was conducted in the same manner as described in Example 19 using 2-fluoro-5- (trifluoromethyl) pyridine in place of 2-chloro-5- (trifluoromethyl) pyrazine, and the target compound ( 99 mg, yield: 75%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/IPA=70/30、流速:1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].
 光学純度99%以上(保持時間:5.6分)
 1H-NMR (400MHz, DMSO-d6) δ: 10.39 (1H, s), 8.43 (1H, brs), 7.83 (1H, d, J=9Hz, 2Hz), 7.62 (1H, s), 7.38 (1H, s), 6.68 (1H, d, J=9Hz), 5.29-5.23 (1H, m), 3.96-3.92 (1H, m), 3.79-3.53 (3H, m), 3.13 (1H, d, J=17Hz), 2.80 (1H, d, J=17Hz), 2.56-2.29 (2H, m);
 MS (ESI) m/z: 436 (M+H)+
Optical purity 99% or more (retention time: 5.6 minutes)
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.39 (1H, s), 8.43 (1H, brs), 7.83 (1H, d, J = 9Hz, 2Hz), 7.62 (1H, s), 7.38 ( 1H, s), 6.68 (1H, d, J = 9Hz), 5.29-5.23 (1H, m), 3.96-3.92 (1H, m), 3.79-3.53 (3H, m), 3.13 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.56-2.29 (2H, m);
MS (ESI) m / z: 436 (M + H) <+> .
 (実施例21)1-{1-[2-シクロプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 21 1- {1- [2-Cyclopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
 2-クロロ-5-(トリフルオロメチル)-1,3,4-チアジアゾールの代わりに、4-クロロ-2-シクロプロピル-6-(トリフルオロメチル)ピリミジン(95mg、0.427mmol)を用いて、実施例6と同様に反応を行い、標記化合物(71mg、収率:58%)を得た。 Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 4-chloro-2-cyclopropyl-6- (trifluoromethyl) pyrimidine (95 mg, 0.427 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (71 mg, yield: 58%).
 1H-NMR (400MHz, DMSO-d6) δ: 10.28 (1H, s), 7.75 (1H, s), 7.23 (1H, s), 7.06 (1H, s), 4.63-4.35 (1H, m), 3.07-2.87 (3H, m), 2.74 (1H, d, J=16Hz), 2.13-1.66 (7H, m), 0.97-0.89 (4H, m);
 MS (ESI) m/z: 491 (M+H)+
1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.28 (1H, s), 7.75 (1H, s), 7.23 (1H, s), 7.06 (1H, s), 4.63-4.35 (1H, m) , 3.07-2.87 (3H, m), 2.74 (1H, d, J = 16Hz), 2.13-1.66 (7H, m), 0.97-0.89 (4H, m);
MS (ESI) m / z: 491 (M + H) <+> .
 (参考例15)
 水素化ナトリウム(63%、5.13g、135mmol)のトルエン(80mL)懸濁液に、室温で2-トリエチルシリルオキシ酢酸エチル(文献J.Org.Chem.、2008年、第73巻、第6268-6278頁に記載された化合物、18.4g、84.1mmol)、及び、エタノール(0.148mL、2.52mmol)のトルエン(40mL)溶液を加え、続いて、トリフルオロ酢酸エチル(15.07mL、126.2mmol)のトルエン(20mL)溶液を加え、5分間攪拌した後、80℃にて30分間攪拌した。反応液に氷冷下、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥し、減圧下にて、溶媒を留去して、油状粗生成物(23.6g)を得た。
(Reference Example 15)
To a suspension of sodium hydride (63%, 5.13 g, 135 mmol) in toluene (80 mL) at room temperature, ethyl 2-triethylsilyloxyacetate (reference J. Org. Chem., 2008, Vol. 73, No. 6268). -A compound described on page 6278, 18.4 g, 84.1 mmol) and a solution of ethanol (0.148 mL, 2.52 mmol) in toluene (40 mL) were added followed by ethyl trifluoroacetate (15.07 mL). , 126.2 mmol) in toluene (20 mL) was added and stirred for 5 minutes, followed by stirring at 80 ° C. for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. An oily crude product (23.6 g) was obtained.
 (参考例16)4-[6,7-ジヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル Reference Example 16 4- [6,7-dihydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1- Yl] piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
 4-(4-ニトロ-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(WO2005/92864号パンフレットに記載された化合物、6.2g、21mmol)、及び、10%パラジウム-活性炭素(1g)のメタノール(180mL)懸濁液を水素雰囲気下、5.5時間攪拌した。セライトろ過後、減圧下、溶媒を留去して得られた残渣にジエチルエーテルを加えて生じた粉末をろ別し、さらに減圧下、ろ液の溶媒を留去して、合成中間体(5.4g)を得た。 Tert-Butyl 4- (4-nitro-1H-imidazol-1-yl) piperidine-1-carboxylate (compound described in WO 2005/92864, 6.2 g, 21 mmol) and 10% palladium-activity A suspension of carbon (1 g) in methanol (180 mL) was stirred under a hydrogen atmosphere for 5.5 hours. After filtration through Celite, the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the resulting powder was filtered off. The filtrate was further evaporated under reduced pressure to give a synthetic intermediate (5 .4 g) was obtained.
 上記操作にて得られた合成中間体の一部(2g)、及び、参考例15にて製造された油状粗生成物の一部(7.1g)のエタノール(30mL)、及び、酢酸(10mL)の混合溶液を、80℃にて5.5時間攪拌した。反応液を室温まで冷却した後に、酢酸エチル、及び、飽和炭酸水素ナトリウム水溶液を加え分液し、有機層を無水硫酸マグネシウムにて乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ジクロロメタン/メタノール=100/0-85/15]で精製し、さらに、シリカゲルカラムクロマトグラフィー[溶出溶媒:(i)ヘキサン/酢酸エチル=25/75-0/100(グラジェント)、(ii)酢酸エチル/メタノール=97/3(グラジェント)]で精製し、さらに、シリカゲルカラムクロマトグラフィー[NH-シリカゲル、溶出溶媒:酢酸エチル/メタノール=100/0-95/5(グラジェント)]で精製して、標記化合物(280mg、収率:8.9%)を得た。 A part (2 g) of the synthetic intermediate obtained by the above operation and a part (7.1 g) of the oily crude product produced in Reference Example 15 in ethanol (30 mL) and acetic acid (10 mL) ) Was stirred at 80 ° C. for 5.5 hours. After cooling the reaction solution to room temperature, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane / methanol = 100 / 0-85 / 15], and further silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 25/75. −0/100 (gradient), (ii) ethyl acetate / methanol = 97/3 (gradient)], and further silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5 (gradient)] to give the title compound (280 mg, yield: 8.9%).
 1H-NMR (DMSO-d6) δ: 10.38 (1H, s), 7.81 (1H, s), 7.31 (1H, s), 5.80 (1H, d, J=4Hz), 4.52-4.41 (2H, m), 4.21-3.99 (2H, m), 2.92-2.61 (2H, m), 2.12-2.03 (1H, m), 2.01-1.88 (1H, m), 1.86-1.78 (1H, m), 1.69-1.54 (1H, m), 1.42 (9H, s)。 1 H-NMR (DMSO-d 6 ) δ: 10.38 (1H, s), 7.81 (1H, s), 7.31 (1H, s), 5.80 (1H, d, J = 4Hz), 4.52-4.41 (2H, m), 4.21-3.99 (2H, m), 2.92-2.61 (2H, m), 2.12-2.03 (1H, m), 2.01-1.88 (1H, m), 1.86-1.78 (1H, m), 1.69- 1.54 (1H, m), 1.42 (9H, s).
 (実施例22)6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 22 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
 参考例16にて製造された4-[6,7-ジヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-カルボン酸tert-ブチル(0.265g、0.630mmol)のジクロロメタン(3mL)懸濁液に、室温にて、トリフルオロ酢酸(0.50mL、6.5mmol)を加え1時間攪拌した。反応液にジエチルエーテルを加え粉末化し、溶媒をデカンテーションにより除去して、合成中間体を得た。 4- [6,7-Dihydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine prepared in Reference Example 16 To a suspension of tert-butyl-1-yl] piperidine-1-carboxylate (0.265 g, 0.630 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was further stirred for 1 hour. Diethyl ether was added to the reaction solution to form a powder, and the solvent was removed by decantation to obtain a synthetic intermediate.
 上記操作にて得られた合成中間体のDMSO(3mL)溶液に、2-フルオロ-5-(トリフルオロメチル)ピラジン(0.142mL、1.26mmol)、及び、N,N-ジイソプロピルエチルアミン(0.429mL、2.52mmol)を加え、室温にて1時間攪拌した後、そのまま終夜放置した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒:ヘキサン/酢酸エチル=50:50-0/100(グラジェント)]で精製して、標記化合物(0.28g、収率:95%)を得た。 To a DMSO (3 mL) solution of the synthetic intermediate obtained by the above operation, 2-fluoro-5- (trifluoromethyl) pyrazine (0.142 mL, 1.26 mmol) and N, N-diisopropylethylamine (0 .429 mL, 2.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then left overnight. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50: 50-0 / 100 (gradient)] to give the title compound (0.28 g, yield: 95%). It was.
 1H-NMR (DMSO-d6) δ: 10.39 (1H, s), 8.52-8.50 (2H, m), 7.79 (1H, s), 7.36 (1H, s), 5.83 (1H, d, J=4Hz), 4.76-4.60 (3H, m), 4.51-4.46 (1H, m), 3.14-2.99 (2H, m), 2.24-2.16 (1H, m), 2.15-2.03 (1H, m), 1.97-1.90 (1H, m), 1.84-1.70 (1H, m);
 MS (ESI) m/z: 467 (M+H)+
1 H-NMR (DMSO-d 6 ) δ: 10.39 (1H, s), 8.52-8.50 (2H, m), 7.79 (1H, s), 7.36 (1H, s), 5.83 (1H, d, J = 4Hz), 4.76-4.60 (3H, m), 4.51-4.46 (1H, m), 3.14-2.99 (2H, m), 2.24-2.16 (1H, m), 2.15-2.03 (1H, m), 1.97- 1.90 (1H, m), 1.84-1.70 (1H, m);
MS (ESI) m / z: 467 (M + H) <+> .
 (実施例23)(+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 23 (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1 , 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
 実施例22にて製造された6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(0.28g、0.60mmol)の酢酸エチル、及び、メタノール混合溶液をシリカゲルに吸着させ、減圧下にて、溶媒を留去し、得られた粉末をフラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/エタノール=70/30、流速:12mL/分]で精製して、標記化合物(107mg、収率:38%、光学活性体)を得た。 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1, prepared in Example 22 A mixed solution of 4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (0.28 g, 0.60 mmol) in ethyl acetate and methanol was adsorbed onto silica gel, The solvent was distilled off, and the resulting powder was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 70/30, flow rate: 12 mL / min] To obtain the title compound (107 mg, yield: 38%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/エタノール=50/50、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 50/50, flow rate 1.0 mL / min].
 光学純度99%(保持時間:10.6分);
 [α]D 25 = +48°(DMF, c=1.00)。
Optical purity 99% (retention time: 10.6 minutes);
[α] D 25 = + 48 ° (DMF, c = 1.00).
 (実施例24)6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 24 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
 2-フルオロ-5-(トリフルオロメチル)ピラジンの代わりに、2-フルオロ-5-(トリフルオロメチル)ピリジン(0.13mL、1.1mmol)を用いて、実施例22に記載された方法と同様に反応を行い、標記化合物(0.22g、収率:86%)を得た。 Using the method described in Example 22 using 2-fluoro-5- (trifluoromethyl) pyridine (0.13 mL, 1.1 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyrazine. The reaction was conducted in the same manner to obtain the title compound (0.22 g, yield: 86%).
 1H-NMR (DMSO-d6) δ: 10.38 (1H, s), 8.41 (1H, d, J=3Hz), 7.80 (1H, dd, J=9Hz, 3Hz), 7.78 (1H, s), 7.34 (1H, s), 7.03 (1H, d, J=9Hz), 5.80 (1H, d, J=4Hz), 4.70-4.56 (3H, m), 4.51-4.47 (1H, m), 3.04-2.89 (2H, m), 2.22-2.14 (1H, m), 2.10-1.98 (1H, m), 1.96-1.88 (1H, m), 1.77-1.64 (1H, m);
 MS (ESI) m/z: 466 (M+H)+
1 H-NMR (DMSO-d 6 ) δ: 10.38 (1H, s), 8.41 (1H, d, J = 3Hz), 7.80 (1H, dd, J = 9Hz, 3Hz), 7.78 (1H, s), 7.34 (1H, s), 7.03 (1H, d, J = 9Hz), 5.80 (1H, d, J = 4Hz), 4.70-4.56 (3H, m), 4.51-4.47 (1H, m), 3.04-2.89 (2H, m), 2.22-2.14 (1H, m), 2.10-1.98 (1H, m), 1.96-1.88 (1H, m), 1.77-1.64 (1H, m);
MS (ESI) m / z: 466 (M + H) <+> .
 (実施例25)(+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン Example 25 (+)-6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1 , 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
 実施例24にて製造された6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン(0.22g、0.47mmol)の酢酸エチル(2mL)、及び、メタノール(1mL)混合溶液をシリカゲル(3g)に吸着させ、減圧下にて、溶媒を留去し、得られた粉末をフラッシュLC[カラム:Chiralflash IA(30mm i.d.x100mm);ダイセル社製、溶出溶媒:ヘキサン/エタノール=80/20、流速:12mL/分]で精製して、標記化合物(96mg、収率:44%、光学活性体)を得た。 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1, prepared in Example 24 A mixed solution of 4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (0.22 g, 0.47 mmol) in ethyl acetate (2 mL) and methanol (1 mL) was added to silica gel ( 3g), the solvent was distilled off under reduced pressure, and the obtained powder was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 80 / 20, flow rate: 12 mL / min] to obtain the title compound (96 mg, yield: 44%, optically active substance).
 光学純度はHPLC[カラム:Chiralpak IA(4.6mm i.d.x250mm);ダイセル社製、溶出溶媒:ヘキサン/エタノール=50/50、流速1.0mL/分]を用いて測定した。 Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 50/50, flow rate 1.0 mL / min].
 光学純度99%(保持時間:8.3分);
 [α]D 25 = +45°(DMF, c=0.958)。
Optical purity 99% (retention time: 8.3 minutes);
[α] D 25 = + 45 ° (DMF, c = 0.958).
 (試験例1)LCAT活性の測定(in vitro)
 密度勾配遠心分離を行い、健常人の血漿よりHDL3からなる画分(1.125<比重<1.210g/mL)を得た。得られた画分をリン酸緩衝生理食塩水(pH7.4)で透析して、LCATの酵素源及びアクセプターとして使用した。被検薬はジメチルスルホキシドに溶解して調製した。1mg/mLのHDL3を含むリン酸緩衝生理食塩水(pH7.4)に、DTNB(イールマン試薬、最終濃度0.5mM)、メルカプトエタノール(最終濃度12.5mM)、及び0.6%牛血清アルブミンを含む[14C]コレステロールを加え、さらにこれに各種濃度の被検薬を加え全量を80μLとした。この混合物を37℃で約16時間インキュベートした後、ヘキサンとイソプロパノールの混合液(混合比=3:2)を加え反応を停止した。攪拌後ヘキサン層を採取し、これを濃縮乾固した。これにクロロホルム溶液(濃度10mg/mL)を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテルおよび酢酸エチルの混合液(混合比=85:15:2)で展開した。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーBAS-2500(富士フィルム社製)で測定した。被検薬を加えない試料についても同様に処理、測定した。下記の式を用いて、被検薬を加えない場合と比較し、LCAT活性化のEC50値を算出した。その結果を表1に示す。
(Test Example 1) Measurement of LCAT activity (in vitro)
A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 <specific gravity <1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide. Phosphate buffered saline (pH 7.4) containing 1 mg / mL HDL3, DTNB (Ielman reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin [ 14 C] cholesterol containing, and various concentrations of test drug were added to make the total volume 80 μL. After this mixture was incubated at 37 ° C. for about 16 hours, a mixture of hexane and isopropanol (mixing ratio = 3: 2) was added to stop the reaction. After stirring, the hexane layer was collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) was added thereto, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC 50 values of LCAT activation. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-M000048
Figure JPOXMLDOC01-appb-M000048
 式中、Xは、被検薬の濃度の対数を示し、
 Yは、被検薬の応答性(LCAT活性)を示し、
 Topは、最大値(最大平坦域)を示し、
 Bottomは、最小値(最小平坦域)を示し、
 EC50は、50%有効濃度を示す。
In the formula, X represents the logarithm of the concentration of the test drug,
Y represents the response of the test drug (LCAT activity),
Top indicates the maximum value (maximum plateau),
“Bottom” indicates a minimum value (minimum flat area);
EC 50 indicates a 50% effective concentration.
 表1
――――――――――――――――――――――――――――――
試験化合物               EC50(μM)
――――――――――――――――――――――――――――――
実施例1の化合物            0.13
実施例2の化合物            0.069
実施例3の化合物            0.092
実施例4の化合物            0.049
実施例5の化合物            0.69
実施例6の化合物            0.46
実施例7の化合物            0.71
実施例8の化合物            0.054
実施例9の化合物            0.048
実施例10の化合物           0.46
実施例11の化合物           0.12
実施例12の化合物           0.39
実施例13の化合物           0.26
実施例14の化合物           0.14
実施例15の化合物           0.27
実施例16の化合物           0.21
実施例17の化合物           1.44
実施例18の化合物           0.52
実施例19の化合物           0.39
実施例20の化合物           0.14
実施例21の化合物           0.14
実施例22の化合物           0.034
実施例23の化合物           0.015
実施例24の化合物           0.065
実施例25の化合物           0.026
――――――――――――――――――――――――――――――。
Table 1
――――――――――――――――――――――――――――――
Test compound EC 50 (μM)
――――――――――――――――――――――――――――――
Compound of Example 1 0.13
Compound of Example 2 0.069
Compound of Example 3 0.092
Compound of Example 4 0.049
Compound of Example 5 0.69
Compound of Example 6 0.46
Compound of Example 7 0.71
Compound of Example 8 0.054
Compound of Example 9 0.048
Compound of Example 10 0.46
Compound of Example 11 0.12
Compound of Example 12 0.39
Compound of Example 13 0.26
Compound of Example 14 0.14
Example 15 Compound 0.27
Compound of Example 16 0.21
Compound of Example 17 1.44
Compound of Example 18 0.52
Compound of Example 19 0.39
Compound of Example 20 0.14
Compound of Example 21 0.14
Compound of Example 22 0.034
Compound of Example 23 0.015
Compound of Example 24 0.065
Compound of Example 25 0.026
――――――――――――――――――――――――――――――
 以上より、本発明化合物は、優れたLCAT活性化作用を有し、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用である。 As described above, the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.
 (試験例2)LCAT活性の測定(血漿)
 ヒト、カニクイサル又はヒトLCATトランスジェニックマウスの血漿を、LCATの酵素源及びアクセプターとして使用する。被検薬はジメチルスルホキシドに溶解して調製する。各血漿5μLとPBS45μLに、DTNB(イールマン試薬、最終濃度0.5mM)、メルカプトエタノール(最終濃度12.5mM)、及び0.6%牛血清アルブミンを含む[14C]コレステロールを加え、さらにこれに各種濃度の被検薬を加え全量を80μLとする。この混合物を37℃で約16時間インキュベートした後、ヘキサン及びイソプロパノールの混合液(混合比=3:2)を加え反応を停止する。水を加え攪拌後ヘキサン層を採取し、これを濃縮乾固する。これにクロロホルム溶液(濃度10mg/mL)を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテル及び酢酸エチルの混合液(混合比=85:15:2)で展開する。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーBAS-2500(富士フィルム社製)で測定する。被検薬を加えない試料についても同様に処理、測定する。下記の式を用いて、被検薬を加えない場合と比較し、LCAT活性化のEC50値を算出する。
(Test Example 2) Measurement of LCAT activity (plasma)
Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT. The test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 μL of each plasma and 45 μL of PBS. Add the test drug at a concentration to make the total volume 80 μL. After incubating this mixture at 37 ° C. for about 16 hours, the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). The same processing and measurement is performed for the sample to which the test drug is not added. Using the following formula, the EC 50 value of LCAT activation is calculated in comparison with the case where no test drug is added.
Figure JPOXMLDOC01-appb-M000049
Figure JPOXMLDOC01-appb-M000049
 式中、Xは、被検薬の濃度の対数を示し、
 Yは、被検薬の応答性(LCAT活性)を示し、
 Topは、最大値(最大平坦域)を示し、
 Bottomは、最小値(最小平坦域)を示し、
 EC50は、50%有効濃度を示す。
In the formula, X represents the logarithm of the concentration of the test drug,
Y represents the response of the test drug (LCAT activity),
Top indicates the maximum value (maximum plateau),
“Bottom” indicates a minimum value (minimum flat area);
EC 50 indicates a 50% effective concentration.
 (試験例3)LCAT活性の測定(Ex vivo)
 被検薬を投与したカニクイサル又はヒトLCATトランスジェニックマウスの血漿中のLCAT活性を測定する。各血漿25μLに、DTNB(イールマン試薬、最終濃度0.26mM)、メルカプトエタノール(最終濃度2mM)、及び0.6%牛血清アルブミンを含む[14C]コレステロールを加え、全量を40μLとする。この混合物を37℃で1時間インキュベートした後、ヘキサン及びイソプロパノールの混合液(混合比=3:2)を加え反応を停止する。水を加え攪拌後ヘキサン層を採取し、これを濃縮乾固する。これにクロロホルム溶液(濃度10mg/mL)を加え、シリカゲル薄層板にスポットし、ヘキサン、ジエチルエーテル及び酢酸エチルの混合液(混合比=85:15:2)で展開する。コレステロールオレエートに相当する部分の放射能活性をイメージングアナライザーBAS-2500(富士フィルム社製)で測定する。投与前のLCAT活性と比較し、各時点でのLCAT活性化の変化率を算出する。
(Test Example 3) Measurement of LCAT activity (Ex vivo)
LCAT activity in plasma of cynomolgus monkeys or human LCAT transgenic mice administered with the test drug is measured. [25C] Each plasma is added with [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.26 mM), mercaptoethanol (final concentration 2 mM), and 0.6% bovine serum albumin to a total volume of 40 μL. This mixture is incubated at 37 ° C. for 1 hour, and then the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.
 (試験例4)カニクイサル薬効試験
 被検薬をpropylene glycol(Sigma-Aldrich)-Tween 80(Sigma-Aldrich)混合溶液[4/1(v/v)]又は、0.5%(w/v)メチルセルロース水溶液に溶解し、カニクイサルに、1又は7日間経口投与した。投与1又は7日間目の投与前及び投与後の血液を採取し、血漿を得た。血漿中コレステロール含有量は、市販の測定キット(コレステロール-Eワコー、和光純薬)を用いて測定した。リポタンパク質プロファイルを、HPLC(カラム:LipopropakXL、東ソー製)によって分析した。HDLコレステロール、及び、non-HDLコレステロールの含有量は、以下の計算式にしたがって算出した。
(Test Example 4) Cynomolgus monkey efficacy test The test drug was propylene glycol (Sigma-Aldrich) -Tween 80 (Sigma-Aldrich) mixed solution [4/1 (v / v)] or 0.5% (w / v) It was dissolved in an aqueous methylcellulose solution and orally administered to cynomolgus monkeys for 1 or 7 days. Blood was collected before and after administration on the first or seventh day of administration to obtain plasma. Plasma cholesterol content was measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile was analyzed by HPLC (column: Lipopropak XL, manufactured by Tosoh Corporation). The contents of HDL cholesterol and non-HDL cholesterol were calculated according to the following calculation formula.
 HDLコレステロール含有量=血漿中コレステロール含有量×(HDLコレステロールのピーク面積/各ピークの和)
 non-HDLコレステロール含有量=血漿中コレステロール含有量×(non-HDLコレステロールのピーク面積/各ピークの和)
 投与前に比べて10mg/kg1回投与後のHDLの上昇率(%)を、投与前及び投与後24時間のAUCから求め、その結果を表2に示す。
HDL cholesterol content = plasma cholesterol content × (HDL cholesterol peak area / sum of each peak)
non-HDL cholesterol content = plasma cholesterol content × (peak area of non-HDL cholesterol / sum of each peak)
The increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration was determined from AUC before administration and 24 hours after administration, and the results are shown in Table 2.
 表2
――――――――――――――――――――――――――――――
試験化合物            1回投与後のHDLの上昇率
――――――――――――――――――――――――――――――
実施例2の化合物             897
実施例4の化合物            1093
実施例23の化合物            521
――――――――――――――――――――――――――――――。
Table 2
――――――――――――――――――――――――――――――
Test compound Increased HDL after a single dose -------------
Compound of Example 2 897
Compound 1093 of Example 4
Compound 521 of Example 23
――――――――――――――――――――――――――――――
 (試験例5)ヒトLCATトランスジェニックマウス薬効試験
 被検薬をpropylene glycol-Tween 80混合溶液[4/1(v/v)]又は、0.5%(w/v)メチルセルロース水溶液に溶解し、ヒトLCATトランスジェニックマウスに、1、4又は7日間経口投与する。投与1、4又は7日間目の投与前及び投与後の血液を採取し、血漿を得る。血漿中コレステロール含有量は、市販の測定キット(コレステロール-Eワコー、和光純薬)を用いて測定する。リポタンパク質プロファイルを、HPLC(カラム:LipopropakXL、東ソー製)によって分析する。HDLコレステロール、及び、non-HDLコレステロールの含有量は、以下の計算式にしたがって算出する。
(Test Example 5) Human LCAT transgenic mouse drug efficacy test The test drug was dissolved in polypropylene glycol-Tween 80 mixed solution [4/1 (v / v)] or 0.5% (w / v) methylcellulose aqueous solution, Human LCAT transgenic mice are orally administered for 1, 4 or 7 days. Blood is collected before and after administration on the first, fourth or seventh day of administration to obtain plasma. The cholesterol content in plasma is measured using a commercially available measurement kit (cholesterol-E Wako, Wako Pure Chemical Industries). The lipoprotein profile is analyzed by HPLC (column: Lipopropak XL, Tosoh). The content of HDL cholesterol and non-HDL cholesterol is calculated according to the following calculation formula.
 HDLコレステロール含有量=血漿中コレステロール含有量×(HDLコレステロールのピーク面積/各ピークの和)
 non-HDLコレステロール含有量=血漿中コレステロール含有量×(non-HDLコレステロールのピーク面積/各ピークの和)
 以上のように、本発明の化合物は、優れたLCAT活性化作用を示し、脂質異常症及び動脈硬化症等の疾患の治療若しくは予防のための医薬として有用である。

 (製剤例1)ハ-ドカプセル剤
 標準二分式ハ-ドゼラチンカプセルの各々に、100mgの粉末状の実施例1の化合物、150mgのラクト-ス、50mgのセルロ-ス及び6mgのステアリン酸マグネシウムを充填することにより、単位カプセルを製造し、洗浄後、乾燥する。
HDL cholesterol content = plasma cholesterol content × (HDL cholesterol peak area / sum of each peak)
non-HDL cholesterol content = plasma cholesterol content × (peak area of non-HDL cholesterol / sum of each peak)
As described above, the compound of the present invention exhibits an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.

Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
 (製剤例2)ソフトカプセル剤
 消化性油状物、例えば、大豆油、綿実油又はオリ-ブ油中に入れた、実施例2の化合物の混合物を調製し、正置換ポンプでゼラチン中に注入して、100mgの活性成分を含有するソフトカプセルを得、洗浄後、乾燥する。
Formulation Example 2 Soft Capsules A mixture of the compound of Example 2 in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into gelatin with a positive displacement pump, Soft capsules containing 100 mg of active ingredient are obtained, washed and dried.
 (製剤例3)錠剤
 常法に従って、100mgの実施例3の化合物、0.2mgのコロイド性二酸化珪素、5mgのステアリン酸マグネシウム、275mgの微結晶性セルロ-ス、11mgのデンプン及び98.8mgのラクト-スを用いて製造する。
Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
 なお、所望により、剤皮を塗布する。 In addition, if desired, apply a coating.
 (製剤例4)懸濁剤
 5mL中に、100mgの微粉化した実施例4の化合物、100mgのナトリウムカルボキシメチルセルロ-ス、5mgの安息香酸ナトリウム、1.0gのソルビト-ル溶液(日本薬局方)及び0.025mLのバニリンを含有するように製造する。
(Formulation example 4) Suspension agent In 5 mL, 100 mg of the compound of Example 4 finely divided, 100 mg sodium carboxymethyl cellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia ) And 0.025 mL of vanillin.
 (製剤例5)注射剤 1.5重量%の実施例6の化合物を、10重量%のプロピレングリコール中で撹拌し、次いで、注射用水で一定容量に調整した後、滅菌して注射剤とする。 (Formulation Example 5) Injection: 1.5% by weight of the compound of Example 6 is stirred in 10% by weight of propylene glycol, adjusted to a certain volume with water for injection, and then sterilized to give an injection. .
 本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、優れたLCAT活性化作用を有し、特に、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患(急性冠症候群、心不全、心筋梗塞、狭心症、心虚血、心血管障害及び血管形成性再狭窄を含む)、脳血管疾患(脳卒中及び脳梗塞を含む)、末梢血管疾患(末梢動脈疾患、糖尿病血管合併症を含む)、脂質異常症、LCAT欠損症、低HDLコレステロール血症、高LDLコレステロール血症、糖尿病、高血圧症、メタボリックシンドローム、アルツハイマー病、角膜混濁、又は、腎疾患の治療剤又は予防剤、特に、抗動脈硬化剤の有効成分として有用である。
 
The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease. (Including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

Claims (49)

  1.  式
    Figure JPOXMLDOC01-appb-C000001

    [式中、Rは、式(X)
    Figure JPOXMLDOC01-appb-C000002

    {式中、nは、1又は2の整数であり、
    は、置換されてよいアリール基(当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1乃至3個の基である。)、又は、
    置換されてよいヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1又は2個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である。}で表される基であり、
    は、水素原子又は水酸基である。]で表される化合物又はその薬理上許容される塩。
    formula
    Figure JPOXMLDOC01-appb-C000001

    [Wherein, R represents the formula (X)
    Figure JPOXMLDOC01-appb-C000002

    {Wherein n is an integer of 1 or 2,
    R 1 represents an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or
    An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 alkyl And the same or different groups selected from the group consisting of amino groups. }, A group represented by
    R 2 is a hydrogen atom or a hydroxyl group. Or a pharmacologically acceptable salt thereof.
  2.  nが1である、請求項1に記載の化合物又はその薬理上許容される塩。 The compound according to claim 1, wherein n is 1, or a pharmacologically acceptable salt thereof.
  3.  nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 2. The compound according to claim 1, wherein n is 2, or a pharmacologically acceptable salt thereof.
  4.  Rが、置換されてよいアリール基(当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1乃至3個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the alkyl group is the same or different 1 to 3 groups selected from the group consisting of amino groups.
  5.  Rが、置換されたアリール基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基及びC1-3アルコキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 represents a substituted aryl group (the substituent includes a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, and a C 1-3 alkoxy group). The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, which is the same or different 1 or 2 groups selected from the group consisting of groups.
  6.  Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof.
  7.  Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). Item 4. The compound according to any one of Items 1 to 3, or a pharmacologically acceptable salt thereof.
  8.  Rが、置換されてよいヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1又は2個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-6アルキル基、C3-7シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-6アルコキシ基、C3-7シクロアルコキシ基、フェニル基、C2-7アルコキシカルボニル基、ベンジルオキシカルボニル基、ジ(C1-6アルキル)アミノカルボニル基及びジ(C1-6アルキル)アミノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is an optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Or a substituent such as a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group. , Cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di (C 6alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, of according to any one of claims 1 to 3 Object or a pharmaceutically acceptable salt thereof.
  9.  Rが、置換されたヘテロアリール基(当該ヘテロアリールは5員又は6員環である。当該ヘテロアリール基の環上の複素原子は、1個の窒素原子であり、更に1個の窒素原子、酸素原子又は硫黄原子を含んでもよく、当該置換基は、ハロゲン原子、C1-3アルキル基、C3-6シクロアルキル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and further one nitrogen atom May contain an oxygen atom or a sulfur atom, and the substituent is a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group. Or the same or different groups selected from the group consisting of a C 1-3 alkoxy group, a C 2-4 alkoxycarbonyl group, and a benzyloxycarbonyl group. Or a pharmacologically acceptable salt thereof.
  10.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof.
  11.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound is a different one or two groups.
  12.  Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基である、請求項1~3のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group.
  13.  Rが、水素原子である、請求項1~12のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12, wherein R 2 is a hydrogen atom.
  14.  7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     6-{4-[7-ヒドロキシ-5-オキソ-7-(トリフルオロメチル)-4,5,6,7-テトラヒドロ-1H-イミダゾ[4,5-b]ピリジン-1-イル]ピペリジン-1-イル}-4-(トリフルオロメチル)ピリジン-3-カルボニトリル、
     7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[2-(トリフルオロメチル)ピリミジン-5-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
     7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピロリジン-3-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、請求項13に記載の化合物又はその薬理上許容される塩。
    7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
    7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
    7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
    6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine- 1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile,
    7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4 , 5-b] pyridin-5-one,
    7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
    1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one and
    7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,6,7-tetrahydro-5H- 14. The compound according to claim 13 or a pharmacologically acceptable salt thereof selected from the group consisting of imidazo [4,5-b] pyridin-5-one.
  15.  (+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     (+)-7-ヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     (+)-7-ヒドロキシ-1-{1-[2-イソプロピル-6-(トリフルオロメチル)ピリミジン-4-イル]ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、
     (+)-7-ヒドロキシ-1-{1-(5-イソプロポキシピリジン-2-イル)ピペリジン-4-イル}-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
     (+)-1-{1-[5-(ジフルオロメトキシ)ピリジン-2-イル]ピペリジン-4-イル}-7-ヒドロキシ-7-(トリフルオロメチル)-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、請求項13に記載の化合物又はその薬理上許容される塩。
    (+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
    (+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
    (+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
    (+)-7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H -Imidazo [4,5-b] pyridin-5-one and
    (+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro 14. The compound according to claim 13 or a pharmacologically acceptable salt thereof selected from the group consisting of -5H-imidazo [4,5-b] pyridin-5-one.
  16.  Rが、水酸基である、請求項1~12のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12, wherein R 2 is a hydroxyl group.
  17.  6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
     6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、請求項16に記載の化合物又はその薬理上許容される塩。
    6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- 5H-imidazo [4,5-b] pyridin-5-one, and
    6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- The compound or pharmacologically acceptable salt thereof according to claim 16, selected from the group consisting of 5H-imidazo [4,5-b] pyridin-5-one.
  18.  (+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピラジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オン、及び、
     (+)-6,7-ジヒドロキシ-7-(トリフルオロメチル)-1-{1-[5-(トリフルオロメチル)ピリジン-2-イル]ピペリジン-4-イル}-1,4,6,7-テトラヒドロ-5H-イミダゾ[4,5-b]ピリジン-5-オンからなる群から選ばれる、請求項16に記載の化合物又はその薬理上許容される塩。
    (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
    (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 The compound or pharmacologically acceptable salt thereof according to claim 16, selected from the group consisting of 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one.
  19.  Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydrogen atom and n is 2.
  20.  Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group), and R The compound according to claim 1, wherein 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof.
  21.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydrogen atom, and n is 2.
  22.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水素原子であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different one or two groups.), R 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof.
  23.  Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基であり、Rが、水素原子であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 The compound according to claim 1 , wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydrogen atom, and n is 2. Acceptable salt.
  24.  Rが、置換されたフェニル基(当該置換基は、塩素原子、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R 2 is a hydroxyl group and n is 2.
  25.  Rが、置換されたフェニル基(当該置換基は、ジフルオロメトキシ基、トリフルオロメトキシ基及びシアノ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group), and R The compound according to claim 1, wherein 2 is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof.
  26.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、チアジアゾリル基若しくはチアゾリル基(当該置換基は、塩素原子、フッ素原子、C1-3アルキル基、シクロプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基、シアノ基、C1-3アルコキシ基、C2-4アルコキシカルボニル基及びベンジルオキシカルボニル基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydroxyl group and n is 2.
  27.  Rが、置換された、ピリジル基、ピリミジル基、ピラジニル基若しくはピリダジニル基(当該置換基は、イソプロピル基、トリフルオロメチル基、ジフルオロメトキシ基、シアノ基及びイソプロポキシ基からなる群から選ばれる同一又は異なった1又は2個の基である。)であり、Rが、水酸基であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different one or two groups.), R 2 is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof.
  28.  Rが、トリフルオロメチル基で置換された、ピリジル基、ピリミジル基若しくはピラジニル基であり、Rが、水酸基であり、nが2である、請求項1に記載の化合物又はその薬理上許容される塩。 The compound according to claim 1 , wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydroxyl group, and n is 2. Salt.
  29.  イミダゾピリジン環の4位のトリフルオロメチル基と5位の水酸基がcisである、請求項1~28のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 28 or a pharmacologically acceptable salt thereof, wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis.
  30.  旋光度が(+)である、請求項1~14、16、17及び19~28のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 14, 16, 17, and 19 to 28, wherein the optical rotation is (+).
  31.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  32.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症、動脈硬化性心疾患、冠状動脈性心疾患、脳血管疾患、末梢血管疾患、脂質異常症、低HDLコレステロール血症、高LDLコレステロール血症、又は、腎疾患の予防若しくは治療のための医薬組成物。 An arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral, comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient A pharmaceutical composition for the prevention or treatment of vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease.
  33.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、動脈硬化症の予防剤若しくは治療剤。 A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
  34.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、脂質異常症の予防剤若しくは治療剤。 A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
  35.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のLDLコレステロールの濃度の増加により引き起こされる疾患の予防剤若しくは治療剤。 A preventive or therapeutic agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  36.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血中のHDLコレステロールの濃度の減少により引き起こされる疾患の予防剤若しくは治療剤。 A preventive or therapeutic agent for a disease caused by a decrease in blood HDL cholesterol concentration, comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  37.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、LCAT活性化剤。 An LCAT activator comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
  38.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、可逆的LCAT活性化剤。 A reversible LCAT activator comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
  39.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、抗動脈硬化剤。 An anti-arteriosclerotic agent comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
  40.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、LCAT活性化方法。 A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  41.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、疾患の予防若しくは治療のための方法。 A method for preventing or treating a disease, comprising administering an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof to a human.
  42.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、動脈硬化症の予防若しくは治療のための方法。 A method for the prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  43.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、脂質異常症の予防若しくは治療のための方法。 A method for the prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
  44.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のLDLコレステロールの濃度の増加により引き起こされる疾患の予防若しくは治療のための方法。 Prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof. Or a method for treatment.
  45.  請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩の有効量を、ヒトに投与することからなる、血中のHDLコレステロールの濃度の減少により引き起こされる疾患の予防若しくは治療のための方法。 Prevention of a disease caused by a decrease in the concentration of HDL cholesterol in the blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof. Or a method for treatment.
  46.  動脈硬化症の治療又は予防のための方法における使用のための、請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis.
  47.  脂質異常症の治療又は予防のための方法における使用のための、請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for the treatment or prevention of dyslipidemia.
  48.  血中のLDLコレステロールの濃度の増加により引き起こされる疾患の治療又は予防のための方法における使用のための、請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for the treatment or prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood.
  49.  血中のHDLコレステロールの濃度の減少により引き起こされる疾患の治療又は予防のための方法における使用のための、請求項1~30のいずれか1項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30, for use in a method for the treatment or prevention of a disease caused by a decrease in the concentration of HDL cholesterol in blood.
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