WO2015111545A1 - Dérivé condensé de pyrazole - Google Patents

Dérivé condensé de pyrazole Download PDF

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WO2015111545A1
WO2015111545A1 PCT/JP2015/051241 JP2015051241W WO2015111545A1 WO 2015111545 A1 WO2015111545 A1 WO 2015111545A1 JP 2015051241 W JP2015051241 W JP 2015051241W WO 2015111545 A1 WO2015111545 A1 WO 2015111545A1
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group
compound
acceptable salt
pharmacologically acceptable
trifluoromethyl
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PCT/JP2015/051241
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Japanese (ja)
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小林　英樹
敏雄 斧田
俊雄 金子
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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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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 condensed pyrazole 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.
  • Patent Document 3 As a compound having a pyrazolopyridine skeleton, a compound described in Patent Document 3 is known. Patent Document 3 describes a GSK-3 inhibitory 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 condensed pyrazole 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 condensed pyrazole derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing them.
  • A represents a formula —CH (Y) — wherein Y represents a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl C 1- Represents a 5 alkyl group or a hydroxy C 1-6 alkyl group), a group —CH 2 —CH 2 — or a group —NH—, B represents a hydrogen atom or a hydroxyl group; X represents an oxygen atom or a sulfur atom, and R 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 difluoro group) Methoxy group, trifluoromethoxy group, cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 al
  • 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.
  • B is a hydroxyl group and A is a group represented by the formula —CH (Y) —
  • Y represents a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group or a hydroxy C 1-6. It is an alkyl group.
  • A represents a formula —CH (Y) — (wherein Y represents a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group or a hydroxy C 1-6 alkyl group).
  • a compound represented by (1) or a pharmacologically acceptable salt thereof (3) A is a formula —CH (Y) — (wherein Y is a hydrogen atom, a C 1-3 alkyl group, a fluorine atom, a chlorine atom, a C 1-3 alkoxy group or a hydroxy C 1-3 alkyl group) Or a pharmacologically acceptable salt thereof according to (1), which is a group represented by: (4) The compound or pharmacology thereof according to (1), wherein A is a group represented by the formula —CH (Y) — (wherein Y represents a hydrogen atom, a methyl group or a fluorine atom).
  • R 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 (7), (11) R 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 is a heteroaryl group which may be substituted (the heteroaryl is a 5-membered or 6-membered ring.
  • the heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 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, trifluoro Methoxy 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) one or two groups selected from the group consisting of amino groups, which are the same or different), and any one of (1)
  • the heteroatom on the ring of the heteroaryl group is one nitrogen atom, and 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, (1 or 2 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 Or a pharmacologically acceptable salt thereof according to any one of (1) to (7), (15) R is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consist
  • Or therapeutic agent, (22) A preventive 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 (16) or a pharmacologically acceptable salt thereof.
  • Or therapeutic agent, (23) An LCAT activator comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient, (24) A reversible LCAT activator comprising as an active ingredient the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof, (25) An anti-arteriosclerotic agent comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient, (26) A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof, (27) A method for preventing or treating a disease, comprising administering to a human an effective amount of the compound according
  • Method, (29) For preventing or treating dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof.
  • Method, (30) 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 (16) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused, (31) 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 (16) or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of the disease caused (32) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis, (33) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia, (34) The compound according to any one of (1) to (16) 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 (35) The compound according to any one of (1) to (16) 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 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 “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 “hydroxy C 1-6 alkyl group” is the “C 1-6 alkyl group” substituted with one hydroxyl group, such as a hydroxymethyl group, a 1-hydroxyethyl group. Or a 2-hydroxyethyl group, preferably the above-mentioned “C 1-3 alkyl group” substituted with one hydroxyl group, and more preferably a hydroxymethyl group.
  • 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 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.)
  • 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 1 represents a benzyl group or diphenylmethyl group which may have a substituent on the aromatic ring.
  • This step is a step for producing compound (I) by removing protecting group R 1 of compound (II) in an inert solvent.
  • Examples of the reagent used for removing the protecting group in compound (II) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And a reagent capable of removing the protecting group described in the above, preferably hydrochloric acid or trifluoroacetic acid, more preferably trifluoroacetic acid, and triethylsilane, anisole as additives.
  • a compound called a cation scavenger such as thioanisole may be used.
  • 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 alkyl halides, and still 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 alkyl halides, and still more preferably dichloromethane.
  • 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.
  • X is an oxygen atom
  • A is a formula —CH (Y 1 ) — (where Y 1 is a hydrogen atom, a C 1-6 alkyl group, a halogen atom. Or a group represented by C 1-6 alkoxy group) or the compound (IIa) in the case of the group —CH 2 CH 2 — can be produced, for example, by the following method.
  • R and R 1 are as defined above, R 2 is a methyl group or an ethyl group, A 1 is a formula —CH (Y 1 ) — (where Y 1 is a hydrogen atom, C 1 Represents a -6 alkyl group, a halogen atom or a C 1-6 alkoxy group.) Or a group —CH 2 CH 2 —.
  • This step is a step for producing compound (IV) by reacting compound (III) with acetonitrile using a base in an inert solvent.
  • 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; Aliphatic hydrocarbons; or a mixed solvent thereof, preferably ethers, and more preferably tetrahydrofuran.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • Aliphatic hydrocarbons 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.
  • Step 2-2 This step is a step for producing compound (V) having protecting group R 1 by reacting compound (IV) with R 1 —NH—NH 2 or a salt thereof 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, and more preferably ethanol.
  • R 1 —NH—NH 2 used in this step commercially available products or those produced by methods known in the literature can be used. Moreover, what produced the corresponding benzyl halide by making hydrazine monohydrate in alcohols react can also be used.
  • 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 This step is a step for producing compound (IIa) by condensing compound (VI) with compound (VI) 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, 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 200 ° C, preferably 50 ° C to 160 ° C, and 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.
  • microwaves can be irradiated.
  • Production method 3 Compound (IIa) which is an intermediate of the compound of the present invention can also be produced, for example, by the following method.
  • R, R 2 and A 1 are as defined above, and Cbz represents a benzyloxycarbonyl group.
  • Step 3-1 This step is a step for producing compound (X) by reacting compound (IX) with acetonitrile in an inert solvent using a base.
  • This step can be performed in the same manner as step 2-1.
  • Step 3-2 This step is a step for producing compound (XI) by reacting compound (X) with a diphenylmethylhydrazine compound in an inert solvent.
  • This step can be performed in the same manner as step 2-2.
  • Step 3-3 This step is a step for producing compound (XII) by condensing compound (VI) with compound (VI) by heating in a solvent inert to the reaction or in the absence of a solvent.
  • This step can be performed in the same manner as step 2-3.
  • Step 3-4 This step is a step of producing compound (XIII) by removing the Cbz group in compound (XII).
  • reagents used for removing Cbz in compound (XII) 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 are capable of removing Boc, and the like, and are preferably palladium-activated carbon.
  • 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 alcohols, and still more preferably ethanol.
  • 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 alcohols, and still more preferably ethanol.
  • 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 3-5 This step is a step for producing compound (IIa) by reacting compound (XIII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
  • 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, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine.
  • Preferred is diisopropylethylamine or 1,8-diazabicyclo [5.4.0] -7-undecene.
  • the arylating agent or heteroarylating agent used in this step is a compound represented by the formula RF, formula R-Cl or formula R-Br, and preferably the formula RF or formula R-Cl. (R represents the same meaning as described 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.
  • Manufacturing method 4 is a method for producing compound (Ib) from compound (XIV), wherein A is a methylene group, B is a hydrogen atom, and X is an oxygen atom, among compounds (I) of the present invention.
  • R is as defined above.
  • This step is a step for producing compound (Ib) by reacting compound (XIV) with trifluoroacetaldehyde equivalent and meldrum acid 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.
  • Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl acetate or propyl acetate; aromatic carbonization such as benzene, toluene or xylene Or a mixed solvent thereof, preferably an alcohol, a halogenated hydrocarbon, an ester, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably The ethanol, or a mixed solvent of dichloromethane, ethyl acetate and toluene.
  • the trifluoroacetaldehyde equivalent used in this step can be, for example, trifluoroacetaldehyde alkyl hemiacetal or trifluoroacetaldehyde dialkyl acetal, and preferably trifluoroacetaldehyde ethyl hemiacetal.
  • triethylamine and molecular sieves 4A may be used as additives.
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 20 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 30 minutes to 24 hours, and more preferably 1 hour to 6 hours.
  • Production method 5 is a method for producing compound (Ib) from compound (XV), wherein A is a methylene group, B is a hydrogen atom, and X is an oxygen atom, among compounds (I) of the present invention.
  • R represents the same meaning as described above, and Boc represents a tert-butoxycarbonyl group.
  • Step 5-1 This step is a step for producing compound (XVI) by reacting compound (XV) with trifluoroacetaldehyde equivalent and meldrum acid in an inert solvent.
  • This step can be performed in the same manner as step 4.
  • Step 5-2 This step is a step of producing compound (XVII) by removing the Boc group in compound (XVI).
  • reagents used for removing Boc in compound (XVI) 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 are capable of removing Boc, and the like, and are preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.
  • 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 alkyl halides, and still 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 alkyl halides, and still more preferably dichloromethane.
  • 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 5-3 This step is a step for producing compound (Ib) by reacting compound (XVII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
  • This step can be performed in the same manner as step 3-5.
  • A is the formula —CH (Y) — (wherein Y is as defined above) and B is a hydrogen atom.
  • the compound represented by the formula (IId) can be produced, for example, by the following method.
  • R and Y are as defined above, and Y 1 represents a hydroxy C 1-6 alkyl group.
  • Step 6-1 This step is a step for producing a compound (XIX) by reacting the compound (XVIII) with a trifluoroacetaldehyde equivalent and Meldrum's acid in an inert solvent.
  • This step can be performed in the same manner as step 4.
  • Step 6-2 This step is a step for producing compound (IIc) by reacting compound (XIX) with a nucleophile in the presence of a base in an inert solvent.
  • 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, potassium hydride, sodium carbonate, potassium carbonate or cesium carbonate; or sodium tert-butoxide, potassium tert-butoxide, n-butyl It can be an organometallic base such as lithium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium 2,2,6,6-tetramethylpiperidide, preferably organic A metal base, and more preferably lithium diisopropylamide.
  • an organometallic base such as lithium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium 2,2,6,6-tetramethylpiperidide, preferably organic A metal base, and more preferably lithium diisopropylamide.
  • the nucleophile used in this step is preferably an alkylating agent such as methyl iodide, dimethyl sulfate or dimethyl carbonate; a halogenating agent such as N-fluorobenzenesulfonimide; or methyl chlorocarbonate or An alkyl chlorocarbonate such as ethyl chlorocarbonate, more preferably methyl iodide, N-fluorobenzenesulfonimide or ethyl chlorocarbonate.
  • an alkylating agent such as methyl iodide, dimethyl sulfate or dimethyl carbonate
  • a halogenating agent such as N-fluorobenzenesulfonimide
  • methyl chlorocarbonate or An alkyl chlorocarbonate such as ethyl chlorocarbonate, more preferably methyl iodide, N-fluorobenzenesulfonimide or ethyl chlorocarbonate.
  • the reaction temperature in this step is preferably ⁇ 100 ° C. to 100 ° C., and more preferably ⁇ 78 ° C. to 30 ° C.
  • the reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 hours to 5 hours.
  • Step 6-3 This step is a step for producing compound (IId) by reducing compound (IIc) when Y is a C 1-6 alkoxycarbonyl C 1-5 alkyl group in an inert solvent.
  • 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, alcohols such as tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethyl Amides such as phosphorotriamide; ketones such as acetone; or like dichloromethane, dichloroethane or chloroform Alkyl halides are exemplified such, preferably an alcohol, more preferably methanol
  • Examples of the reagent used in this step include lithium borohydride, sodium borohydride, lithium aluminum hydride, and the like, and preferably sodium borohydride.
  • the reaction temperature in this step is preferably ⁇ 30 ° C. to 50 ° C., and more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 5 minutes to 5 hours, and more preferably 30 minutes to 2 hours.
  • a compound represented by the formula (IIe) in which A is a methylene group and B is a hydrogen atom can be produced, for example, by the following method.
  • R and Boc are as defined above.
  • Step 7-1 This step is a step of producing compound (XXI) by reacting compound (XX) with a diphenylmethylhydrazine compound in an inert solvent.
  • This step can be performed in the same manner as step 2-2.
  • Step 7-2 This step is a step for producing compound (XXII) by reacting compound (XXI) with a trifluoroacetaldehyde equivalent and Meldrum's acid in an inert solvent.
  • This step can be performed in the same manner as step 4.
  • Step 7-3 This step is a step of producing compound (XXIII) by removing the Boc group in compound (XXII).
  • This step can be performed in the same manner as step 5-2.
  • Step 7-4 This step is a step for producing compound (IIe) by reacting compound (XXIII) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.
  • This step can be performed in the same manner as step 3-5.
  • Production method 8 is a method for producing compound (Ie) of compound (I) of the present invention wherein A is a group —NH— and B is a hydroxyl group from compound (XVIII).
  • R is as defined above.
  • Step 8-1 This step is a step for producing compound (XXIV) by reacting compound (XVIII) with N, N-dimethylformamide dimethyl acetal in the absence of a solvent.
  • the reaction temperature in this step is preferably 0 ° C. to 200 ° C., more preferably 20 ° C. to the reflux temperature of N, N-dimethylformamide dimethyl acetal.
  • the reaction time in this step is preferably 1 hour to 10 hours, and more preferably 2 hours to 5 hours.
  • Step 8-2 This step is a step of producing compound (XXV) by reacting compound (XXIV) with trifluoroacetic anhydride in the presence of a base 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.
  • Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof Obtained, preferably halogenated hydrocarbons, more preferably 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, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine.
  • Preferred is 1,8-diazabicyclo [5.4.0] -7-undecene.
  • the reaction temperature in this step is preferably ⁇ 20 ° C. to 100 ° C., more preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is preferably 10 hours to 2 days, and more preferably 15 hours to 1 day.
  • Step 8-3 This step is a step of producing compound (XXVI) by removing the diphenylmethyl group of compound (XXV) in an inert solvent.
  • This step can be performed in the same manner as step 1.
  • Step 8-4 This step is a step for producing a compound (XXVI) by converting the imidoformamide group of the compound (XXVI) into an amino group in the presence of a base in an inert solvent.
  • Solvents used in this step are ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert Alcohols such as butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerol; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Aromatic hydrocarbons such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Ether such a alcohols, or a mixture of these solvents, more
  • the base used in this step can be sodium hydroxide, potassium hydroxide or an aqueous solution thereof, and preferably an aqueous sodium hydroxide solution.
  • the reaction temperature in this step is preferably 0 ° C. to 120 ° C., more preferably 20 ° C. to the reflux temperature of the solvent.
  • the reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 hour to 2 hours.
  • Step 8-5 This step is a step for producing compound (Id) by reacting compound (XXVII) with potassium cyanate in an inert solvent.
  • the solvent used in this step is water; 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- Alcohols such as methoxyethanol, diethylene glycol or glycerine; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane
  • the reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 10 ° C. to 30 ° C.
  • the reaction time in this step is preferably 3 hours to 15 hours, and more preferably 5 hours to 10 hours.
  • A, B and R are as defined above.
  • This step is a step of producing compound (IIf) from compound (XXVIII) 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 mixed solvent thereof. More preferred are ethers or aromatic hydrocarbons, and still more preferred is 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.
  • 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.
  • the 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 performed 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 dosage form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration such as tablets, granules, powders, capsules or syrups; Parenteral administration by an agent, etc. can be mentioned, and it can administer 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 or 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 additives 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 represents dimethyl sulfoxide
  • DBU Represents 1,8-diazabicyclo [5.4.0] -7-undecene.
  • N-Butyllithium (2.69 M hexane solution, 18.0 mL, 48.4 mmol) was added dropwise to a solution of anhydrous acetonitrile (3.0 mL, 57.3 mmol) in anhydrous THF (50 mL) at ⁇ 78 ° C., and then at the same temperature.
  • N ′-[1- (diphenylmethyl) -3- ⁇ 1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl ⁇ -1H-pyrazol-5 prepared in Reference Example 12 -Yl] -N, N-dimethylimidoformamide (1.18 g, 2.22 mmol) in dichloromethane (12 mL) at 0 ° C. with DBU (0.69 mL, 4.6 mmol) and trifluoroacetic anhydride ( 0.62 mL, 4.5 mmol) was added, and the mixture was stirred at room temperature for 15 hours.
  • reaction solution was evaporated, extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium bicarbonate, 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, The solvent was distilled off under.
  • Triethylsilane (110 ⁇ L, 0.691 mmol) and trifluoroacetic acid (600 ⁇ L) were added at 0 ° C. to a solution of the compound produced in Reference Example 8 (81.7 mg, 0.127 mmol) in dichloromethane (3.0 mL), Stir at room temperature for 2 hours.
  • the reaction solution was diluted with ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the compound eluting first (hereinafter referred to as compound 7-1). ) (170 mg, yield: 49%) and a compound that elutes later (hereinafter referred to as compound 7-2) (172 mg, yield: 49%) were obtained.
  • Example 8 4- (trifluoromethyl) -3- ⁇ 1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl ⁇ -1,4,5,7-tetrahydro-6H -Pyrazolo [3,4-b] pyridin-6-one
  • Trifluoroacetic acid (10 mL) was added to a dichloromethane (3 mL) solution of the compound produced in Reference Example 16 (1.35 g, 3.48 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, poured into diethyl ether (150 mL), and the resulting solid was collected by filtration to obtain a synthetic intermediate (1.43 g).
  • Trifluoroacetic acid (10 mL) was added to a dichloromethane (3 mL) solution of the compound produced in Reference Example 16 (1.35 g, 3.48 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, poured into diethyl ether (150 mL), and the resulting solid was collected by filtration to obtain a synthetic intermediate (1.43 g).
  • Example 12 The procedure described in Example 12 was followed using 6-chloro-4-methylpyridine-3-carbonitrile (55 mg, 0.36 mmol) instead of 6-chloro-2-methylpyridine-3-carbonitrile. The reaction was performed in the same manner to obtain the title compound (78 mg, yield: 79%).
  • 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) Dissolve in aqueous methylcellulose and administer orally to cynomolgus monkeys for 1 or 7 days. Blood is collected before and after administration on the 1st or 7th 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)
  • the increase rate (%) of HDL after a single administration of 10 mg / kg as compared to before administration is determined from AUC before administration and 24 hours after administration.
  • 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)
  • 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 représenté par la formule (I) [dans laquelle A représente un groupe -CH(Y)-, un groupe -CH2-CH2- ou un groupe -NH- ; B représente un atome d'hydrogène ou un groupe hydroxy ; X représente un atome d'oxygène ou un atome de soufre ; et R représente un groupe aryle qui peut être substitué ou un groupe hétéroaryle qui peut être substitué] ou un sel pharmacologiquement acceptable correspondant, qui présente une excellente activité d'activation de la LCAT et qui est utile comme principe actif pour un agent thérapeutique ou prophylactique pour l'artériosclérose, les maladies cardiaques artérioscléreuses, les coronaropathies (comprenant l'insuffisance cardiaque, l'infarctus du myocarde, l'angine de poitrine, l'ischémie cardiaque, les troubles cardio-vasculaires et la resténose post-angioplastie), des maladies cérébrovasculaires (comprenant l'accident vasculaire cérébral et l'infarctus cérébral), des maladies vasculaires périphériques (comprenant des complications vasculaires associées au diabète), la dyslipidémie, la cholestérolémie basse des HDL, la cholestérolémie élevée des LDL ou les maladies rénales, en particulier comme principe actif pour un agent antiartérioscléreux.
PCT/JP2015/051241 2014-01-21 2015-01-19 Dérivé condensé de pyrazole WO2015111545A1 (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

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JP2007516170A (ja) * 2003-06-27 2007-06-21 ファイザー・プロダクツ・インク ＧＳＫ−３阻害剤としてのピラゾロ［３，４−ｂ］ピリジン−６−オン
WO2008002591A2 (fr) * 2006-06-26 2008-01-03 Amgen Inc Procédés de traitement de l'athérosclérose
JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

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JP2007516170A (ja) * 2003-06-27 2007-06-21 ファイザー・プロダクツ・インク ＧＳＫ−３阻害剤としてのピラゾロ［３，４−ｂ］ピリジン−６−オン
WO2008002591A2 (fr) * 2006-06-26 2008-01-03 Amgen Inc Procédés de traitement de l'athérosclérose
JP2013536807A (ja) * 2010-09-02 2013-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｐａ受容体アンタゴニストとしてのピラゾロピリジノン誘導体
WO2013187462A1 (fr) * 2012-06-14 2013-12-19 第一三共株式会社 Dérivé de pipéridinylpyrazolopyridine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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