WO2015087995A1 - Dérivé cycloalkyle ou hétérocyclyle de pyrazolopyridine - Google Patents

Dérivé cycloalkyle ou hétérocyclyle de pyrazolopyridine Download PDF

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WO2015087995A1
WO2015087995A1 PCT/JP2014/082944 JP2014082944W WO2015087995A1 WO 2015087995 A1 WO2015087995 A1 WO 2015087995A1 JP 2014082944 W JP2014082944 W JP 2014082944W WO 2015087995 A1 WO2015087995 A1 WO 2015087995A1
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group
trifluoromethyl
pyridin
compound
acceptable salt
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PCT/JP2014/082944
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English (en)
Japanese (ja)
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俊雄 金子
雅巳 荒井
小林　英樹
達矢 西
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pyrazolopyridine derivative having a superior lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.
  • LCAT superior 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 a pyrazolopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and completed the present invention.
  • the present invention provides a pyrazolopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.
  • R is a C 6-8 cycloalkyl group, a C 6-8 cycloalkenyl group, or 4-7 which may be substituted with the same or different 1 to 2 substituents selected from the substituent group A.
  • a membered heterocyclyl group (the heteroatom on the heterocyclyl ring is one or two nitrogen atoms);
  • Substituent group A includes a C 1-6 alkyl group, a halogen atom, and an optionally substituted aryl group (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group) , Difluoromethoxy group, 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
  • 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.
  • R is an optionally substituted 4-piperidinyl group
  • at least one of the 2, 3, 5 and 6 positions of the piperidinyl group has a substituent.
  • R is a C 6-8 cycloalkyl group or a C 6-8 cycloalkenyl group, which may be substituted with the same or different one or two substituents selected from Substituent Group A1,
  • Group A1 includes a C 1-6 alkyl group, a halogen atom and 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 difluoro group) Methoxy group, trifluoromethoxy group, cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxy
  • R is a cyclohexyl group substituted by one or two different substituents selected from the substituent group A2, and the substituent group A2 includes a C 1-4 alkyl group, a fluorine atom, chlorine An atom and 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, and a C 1-3 alkoxy group);
  • R is a cyclohexyl group substituted with one or two substituents selected from the same or different substituent group A3, and the substituent group A3 includes a C 1 -C 4 alkyl group, a fluorine atom,
  • R is a cyclohexyl group substituted by 1 to 2 substituents selected from the same or different substituent group A4, and the substituent group A4 includes a C 1 -C 4 alkyl group, a fluorine atom, A chlorine atom and 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 is a 4-phenylcyclohexyl group
  • R is a 4- to 7-membered heterocyclyl group which may be substituted by the same or different 1 to 2 substituents selected from Substituent Group A5 (the number of heteroatoms on the heterocyclyl ring is 1 or 2
  • the substituent group A5 includes a C 1-6 alkyl group and an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring).
  • the hetero atom of is one or two nitrogen atoms, and may further contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, a C 1-6 alkyl group, C 3- 7 cycloalkyl group, a trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 an alkoxycarbonyl Boniru group, a benzyloxycarbonyl group, a di (C 1-6 alkyl) aminocarbonyl Moto ⁇ busy (C 1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino group.) Or a pharmacologically acceptable salt thereof according to (1), (8) R is a substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring.
  • the heteroatom on the ring of the heteroaryl group is one nitrogen atom, A nitrogen atom, an oxygen atom or a sulfur atom may be contained, 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, 4 to 7-membered groups substituted with the same or different groups selected from the group consisting of a cyano group, a C 1-3 alkoxy group, a C 2-4 alkoxycarbonyl group and a benzyloxycarbonyl group.
  • R 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 identical or different 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 A 4- to 7-membered heterocyclyl group (the heteroatom on the heterocycl
  • the heterocyclyl may be further substituted with a methyl group).
  • R 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) 4-7 membered heterocyclyl groups substituted with the same or different 1 or 2 groups, wherein the heteroatom on the ring of the heterocyclyl is a nitrogen atom.
  • the heterocyclyl further comprises a methyl group Or a pharmacologically acceptable salt thereof according to (1), wherein (11) A 4- to 7-membered heterocyclyl group in which R is substituted with a substituted pyridyl group or pyrazinyl group (the substituent is a trifluoromethyl group) (the heteroatom on the heterocyclyl ring is 1 Or a pharmacologically acceptable salt thereof, wherein the heterocyclyl may be further substituted with a methyl group), (12) 4-hydroxy-3- (4-phenylcyclohexyl) -4- (trifluoromethyl) -1,4,5,7-tetrahydro-6H-pyrazolo [3,4-b] pyridin-6-one, 4-hydroxy-4- (trifluoromethyl) -3- ⁇ 1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl ⁇ -1,4,5,7-tetrahydro-6H- Pyr
  • Or therapeutic agent (19) 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 (13) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent (20) an LCAT activator comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient, (21) A reversible LCAT activator comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient, (22) An anti-arteriosclerotic agent comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient, (23) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof, (24) A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according to
  • Method, (26) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof.
  • Method, (27) 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 (13) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused (28) 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 (13) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused (29) The compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (30) The compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (31) The compound according to any one of (1) to (13) 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 (32) The compound according to any one of (1) to (13) 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.
  • Compound (I) of the present invention is a compound represented by formula (I) or a tautomer thereof.
  • the compound (I) containing any tautomer is represented by the structural formula of the formula (I) and the corresponding chemical name.
  • any isomer of the other tautomer (amide-imidic acid) of the compound (I) of the present invention is contained in the present compound (I).
  • the compound (I ) Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.
  • the “C 6-8 cycloalkyl group” is a cyclic saturated hydrocarbon group having 6 to 8 carbon atoms such as cyclohexyl group, cycloheptyl group or cyclooctyl group, Is a cyclohexyl group.
  • the “C 6-8 cycloalkenyl group” is a cyclic hydrocarbon group having 6 to 8 carbon atoms having a double bond, such as a cyclohexenyl group, a cycloheptenyl group or a cyclooctenyl group. Yes, preferably a cyclohexenyl group.
  • the “4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is 1 or 2 nitrogen atoms)” means, for example, an azetidinyl group, a pyrrolidinyl group, a pyrazolidinyl group , An imidazolidinyl group, a piperidinyl group, a tetrahydropyrazinyl group, a tetrahydropyrimidinyl group, a tetrahydropyridazinyl group, a hexahydroazepinyl group, or a tetrahydroimidazo [1,2-a] pyridinyl group, and preferably A 4- to 7-membered heterocyclyl group (the heteroatom on the heterocyclyl ring is one nitrogen atom), and more preferably an azetidinyl group, a pyrrolidinyl group, or
  • 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 “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 “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl 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.
  • 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.)
  • alkylsulfonyl group, thiadiazolyl or thiazolyl group even more preferably, pyridyl group, pyrimidyl group, a pyrazinyl group or a pyridazinyl group, particularly preferably a pyridyl 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.
  • 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 is as defined above, and R 1 represents a methyl group or an ethyl group.
  • Compound (II) includes compound (IIx) which is a tautomer.
  • compound (II) includes all isomers of tautomers. That is, the compound (II) includes all of the compound (II), the compound (IIx), and a mixture of the compound (II) and the compound (IIx) in an arbitrary ratio.
  • the compound represented by the compound name of compound (II) includes all of compound (II), compound (IIx), and a mixture of compound (II) and compound (IIx) in an arbitrary ratio.
  • This step is a step for producing compound (I) by condensing compound (III) with compound (II) by heating 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 , Tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2 Alcohols such as methoxyethanol, diethylene glycol or glycerol; aromatic hydrocarbons such as benzene, toluene or xylene; or It is a
  • 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.
  • 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.
  • Manufacturing method 2 The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R is as defined above, R 2 is an alkoxy group or a chlorine atom, Ra is one or more amino groups (the amino group is a primary or secondary amino group, A cyclic amino group) or a group having an unsaturated bond and converted to R by Step 2-3.
  • This step is a step of producing compound (V) by reacting compound (IV) with acetonitrile using a base in an inert solvent when R 2 is an alkoxy group.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably sodium hydride or n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • this step is a step of producing compound (V) by reacting compound (IV) with cyanoacetic acid using a base in an inert solvent when R 2 is a chlorine atom. is there.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene, or xylene; hexane Or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide or n-butyllithium. It can be an organometallic base, more preferably n-butyllithium.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 0 ° C., and more preferably ⁇ 78 ° C. to ⁇ 40 ° C.
  • the reaction time in this step is preferably 5 minutes to 3 hours, and more preferably 15 minutes to 2 hours.
  • Compound (IV) which is a starting material for this step may be a commercially available product, or can be produced by esterification or acid chlorideation of a known benzoic acid compound by a conventional method.
  • Step 2-2 This step is a step for producing compound (II) by reacting compound (V) with a hydrazine compound 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.
  • Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably alcohols, more preferably ethanol.
  • the hydrazine compound used in this step is anhydrous hydrazine, hydrazine monohydrate, hydrazine hydrochloride, hydrazine acetate, hydrazine sulfate, hydrazine nitrate, hydrazine hydrobromide, hydrazine oxalate, or hydrazine phosphate.
  • Preferred is hydrazine monohydrate or hydrazine acetate.
  • the reaction temperature in this step is preferably 20 ° C. to 120 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 10 minutes to 24 hours, and more preferably 1 hour to 5 hours.
  • Step 2-3 (I)
  • the compound (VI) is subjected to Buchwald-Hartwig reaction using a palladium catalyst in an inert solvent in the presence of a ligand and a base in addition to the palladium catalyst.
  • compound (IV) is produced by reacting with an arylating agent or heteroarylating agent.
  • 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. And preferably toluene or dioxane, 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 b —Cl, the formula R b —Br or the formula R b —I, preferably the formula R b —Cl or the formula R b 1 -Br 2
  • R b 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) , 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 Moto ⁇ busy (C 1-6 alkyl) is the same or different 1 to 3 groups selected from the group consisting of amino group.), or may be substituted
  • the heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further includes one nitrogen atom, oxygen atom or sulfur atom.
  • the substituents are halogen atom, C 1-6 alkyl, C 3-7 cycloalkyl group, a trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-6 alkoxy group , 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) group consisting of amino group 1 or 2 groups selected from the same or different.
  • 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.
  • 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 ethers such as tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, Amides such as N-methyl-2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably nitriles It is sulfoxides, more preferably, acetonitrile, dimethyl sulfoxide.
  • the base used in this step is organic such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine, or 2,6-lutidine. It can be a base and is preferably triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.
  • the arylating or heteroarylating agent used in this step is a compound having the formula RF, formula R—Cl or formula R—Br, preferably having the formula RF or formula R—Cl.
  • a compound (R 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.
  • Solvents used in this step include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , Tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate And preferably alcohols, more preferably methanol or ethanol.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dim
  • Examples of the catalyst used in this step include platinum oxide, palladium-carbon, or palladium hydroxide, and platinum oxide is preferable.
  • acetic acid As an additive for accelerating the reaction used in this step, acetic acid, hydrochloric acid, or sulfuric acid can be mentioned, and hydrochloric acid is preferable.
  • the reaction temperature in this step is preferably 10 ° C. to 50 ° C., and more preferably 20 ° C. to 40 ° C.
  • the reaction time in this step is preferably 5 hours to 10 days, more preferably 10 hours to 7 days.
  • Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VII).
  • R b is as defined above, Boc represents a tert-butoxycarbonyl group, and R C represents a 4- to 7-membered nitrogen-containing cyclyl group. However, when R C is may 4-piperidinyl group which is substituted, at least one of 2, 3, 5 and 6 of the piperidinyl group having a substituent.
  • Compound (VII) can be produced, for example, according to the method described in Reference Example 8, 12, 13, 14, 22, 23, or 29.
  • Step 3-1 This step is a step of producing compound (Ib) by removing the Boc group in compound (VII).
  • reagents used for removing Boc in compound (VII) 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 such as toluene; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably 1,4- Dioxane.
  • 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 such as toluene
  • aromatic hydrocarbons such as toluene
  • a mixed solvent thereof more preferably ethers or alkyl halides, and even more preferably 1,4- Dioxane.
  • the reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably hydrochloric 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.
  • This step can be performed under the same conditions as in step 2-3 (ii).
  • Boc, R b , and R C are as defined above.
  • Step 4-1 This step is a step of producing compound (IIb) by removing the Boc group in compound (IIa).
  • This step can be performed under the same conditions as in step 3-1.
  • Step 4-2 This step is a step of producing compound (IIc) by reacting compound (IIb) with an arylating agent or heteroarylating agent.
  • This step can be performed under the same conditions as in step 3-2.
  • R d represents a 4- to 7-membered azacyclyl group having a cyclic amino group (an azacyclyl group is a heterocyclyl group, and a hetero atom forming the ring is a nitrogen atom).
  • Step 5-1 This step is a step for producing compound (IX) by condensing compound (VIII) and cyanoacetic acid or cyanoacetic acid ester in a solvent inert to the reaction or in the absence of a solvent.
  • compound (IX) can be produced by using a condensing agent and reaction conditions that are usually used in an amidation reaction.
  • the solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; Aromatic hydrocarbons; or a mixed solvent thereof, more preferably alcohols or ethers, and still more preferably ethanol or toluene.
  • an alcohol such as methanol or ethanol
  • an ether such as tetrahydrofuran or 1,4-dioxane
  • Aromatic hydrocarbons or a mixed solvent thereof, more preferably alcohols or ethers, and still more preferably ethanol or toluene.
  • the cyanoacetate used in this step is preferably ethyl cyanoacetate.
  • the reaction temperature in this step is preferably 0 ° C to 120 ° C, more preferably 20 ° C to 100 ° C.
  • the reaction time in this step is preferably 1 to 24 hours, and more preferably 5 to 20 hours.
  • Step 5-2 This step is a step of producing compound (X) from compound (IX) using a thiocarbonylating reagent.
  • 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 aromatic hydrocarbon such as toluene; or a mixture thereof. It is a solvent, more preferably ethers or aromatic hydrocarbons, and still more preferably tetrahydrofuran.
  • the thiocarbonylating reagent used in this step is a compound having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as hydrogen sulfide or Lawesson's reagent, preferably Lawesson. It is a reagent.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to 60 ° C.
  • the reaction time in this step is preferably 1 hour to 10 hours, and more preferably 3 hours to 7 hours.
  • Step 5-3 This step is a step for producing compound (IId) by reacting compound (X) with a hydrazine compound in an inert solvent.
  • This step can be performed under the same conditions as in step 2-2.
  • 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
  • DMF represents N, N′-dimethylformamide
  • DMSO represents dimethyl sulfoxide
  • IPA represents 2-propanol
  • DBU represents 1,8-diazabicyclo [5.4.0] undec-7-ene.
  • N-Butyllithium (2.66M hexane solution, 10.4 mL, 27.7 mmol) was added dropwise to a solution of anhydrous acetonitrile (1.45 mL, 27.7 mmol) in anhydrous THF (80 mL) at ⁇ 78 ° C., and then at the same temperature. After stirring for 10 minutes, a solution of methyl 4-phenylcyclohexanecarboxylate (1.01 g, 4.76 mmol) prepared in Reference Example 1 in anhydrous THF (20 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 30 minutes. did.
  • the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • 3-Phenylcyclohexanecarboxylic acid can be produced by a method described in WO2011 / 147772 using a racemic mixture of 3-phenylcyclohexanone instead of (R) -3-phenylcyclohexanone.
  • the aminopyrazole intermediate obtained in the above procedure was used in place of tert-butyl 3- (5-amino-1H-pyrazol-3-yl) azetidine-1-carboxylate.
  • the reaction is performed in the same manner as in the method, and the compound eluting first (hereinafter referred to as Compound A-1) (1.40 g, yield: 8%) and the compound eluting later (hereinafter referred to as Compound A-2) ) (1.16 g, yield: 7%).
  • a synthetic intermediate was obtained.
  • the aminopyrazole intermediate obtained in the above procedure was used in place of tert-butyl 3- (5-amino-1H-pyrazol-3-yl) azetidine-1-carboxylate.
  • the reaction was carried out in the same manner as in the above method to obtain a compound eluting first (hereinafter referred to as compound B-1) (5.8 g, yield: 14%) and a compound eluting later (6.0 g). .
  • the obtained solid was suspended in ethyl acetate, stirred at 60 ° C., and collected by filtration.
  • the suspension was further suspended in ethanol, stirred at 60 ° C., and collected by filtration to obtain the title compound (614 mg, yield: 67%).
  • Compound 30-1 Optical purity 99% or more (retention time: 4.5 minutes); Compound 30-2: Optical purity 99% or more (retention time: 8.4 minutes).
  • Compound 31-1 Optical purity 99% or more (retention time: 10.4 minutes); Compound 31-2: Optical purity 99% or more (retention time: 15.8 minutes).
  • Trifluoroacetic acid (1.5 mL) was added to a dichloromethane (5 mL) solution of the compound (450 mg, 1.15 mmol) produced in Reference Example 13 at 0 ° C., and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was added dropwise to a mixed solvent of hexane (40 mL) and diethyl ether (150 mL) at 0 ° C., and the resulting solid was collected by filtration to obtain a synthetic intermediate.
  • 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.
  • Example 1 Table 1 ⁇ Test compound EC 50 ( ⁇ M) ⁇ Compound of Example 1 0.37 Compound of Example 2 0.26 Compound of Example 3 0.37 Compound of Example 4 1.10 Compound of Example 5 0.76 Compound of Example 6 0.14 Compound of Example 7 0.59 Compound of Example 8 0.75 Compound of Example 9 0.39 Compound of Example 10 1.76 Compound 11-1 of Example 11 0.33 Compound 11-2 of Example 11 0.30 Compound of Example 12 0.26 Compound 13-1 of Example 13 0.34 Compound 13-2 of Example 13 0.045 Compound 14-1 of Example 14 0.70 Compound 14-2 of Example 14 0.082 Compound of Example 15 0.028 Compound of Example 16 0.29 Compound of Example 17 0.050 Compound of Example 18 0.078 Compound of Example 19 0.23 Compound of Example 20 0.90 Compound of Example 21 0.21 Compound 22-1 of Example 22 0.43 Compound 22-2 of Example 22 0.66 Compound of Example 23 0.53 Compound of Example 24 0.25 Compound of Example 25 0.44 Compound of Example 26 0.22 Example 27 Compound 0.78
  • 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

L'invention concerne un composé qui présente d'excellents effets d'activation de la LCAT, qui est utile comme principe actif d'un agent thérapeutique ou préventif contre l'artériosclérose, une maladie cardio-vasculaire artérioscléreuse, une maladie coronarienne (comprenant une insuffisance cardiaque, un infarctus du myocarde, une angine de poitrine, une ischémie cardiaque, un trouble cardio-vasculaire et une resténose après angioplastie), une maladie cérébrovasculaire (comprenant un accident vasculaire cérébral et un infarctus cérébral), une maladie vasculaire périphérique (comprenant une complication vasculaire diabétique), une dyslipidémie, un taux de cholestérol HDL bas, un taux de cholestérol HDL élevé ou une maladie rénale, en particulier d'un agent antiartérioscléreux et est représenté par la formule (I) (I) [Dans la formule, R représente un groupe C6-C8-cycloalkyle, un groupe C6-C8-cycloalcényle ou un groupe hétérocyclyle de 4 à 7 chaînons, qui peut être substitué] ou un sel pharmacologiquement acceptable correspondant.
PCT/JP2014/082944 2013-12-13 2014-12-12 Dérivé cycloalkyle ou hétérocyclyle de pyrazolopyridine WO2015087995A1 (fr)

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WO2016199877A1 (fr) * 2015-06-11 2016-12-15 第一三共株式会社 Cristal de dérivé de 5-hydroxy-4-(trifluorométhyl)pyrazolopyridine
US10189810B2 (en) 2014-09-17 2019-01-29 Verseon Corporation Pyrazolyl-substituted pyridone compounds as serine protease inhibitors
AU2016224974B2 (en) * 2015-02-27 2019-09-26 Verseon Corporation Substituted pyrazole compounds as serine protease inhibitors

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WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

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WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

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US10189810B2 (en) 2014-09-17 2019-01-29 Verseon Corporation Pyrazolyl-substituted pyridone compounds as serine protease inhibitors
AU2016224974B2 (en) * 2015-02-27 2019-09-26 Verseon Corporation Substituted pyrazole compounds as serine protease inhibitors
US10532995B2 (en) 2015-02-27 2020-01-14 Verseon Corporation Substituted pyrazole compounds as serine protease inhibitors
WO2016199877A1 (fr) * 2015-06-11 2016-12-15 第一三共株式会社 Cristal de dérivé de 5-hydroxy-4-(trifluorométhyl)pyrazolopyridine
US10138240B2 (en) 2015-06-11 2018-11-27 Daiichi Sankyo Company, Limited Crystal of 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative

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