WO2015087996A1

WO2015087996A1 - Imidazopyridine derivative

Info

Publication number: WO2015087996A1
Application number: PCT/JP2014/082945
Authority: WO
Inventors: 敏雄斧田; 俊雄金子; 雅巳荒井; 小林　英樹; 直生寺坂
Original assignee: 第一三共株式会社
Priority date: 2013-12-13
Filing date: 2014-12-12
Publication date: 2015-06-18

Abstract

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

Description

Imidazopyridine derivatives

The present invention relates to an imidazopyridine derivative having an excellent lecithin cholesterol acetyltransferase (hereinafter referred to as LCAT) activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof.

In advanced civilized countries, cardiovascular diseases (for example, heart disease, cerebrovascular disease, kidney disease, etc.) caused by hypertension, dyslipidemia, diabetes, etc. are a major problem. Antihypertensive drugs, antilipidemia drugs, and antidiabetic drugs are used for the treatment of hypertension, dyslipidemia, and hyperglycemia, respectively. Clinically, α and β blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists are used as antihypertensive agents, and HMG-CoA reductase inhibitors, Insulin, sulfonylureas, metformin, glitazones, DPP4 inhibitors, and the like are used as antidiabetics such as ion exchange resins, nicotinic acid derivatives, probucol, and fibrates. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels. However, mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these drugs, and development of better therapeutic agents for these diseases is desired.

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.

The results of many epidemiological studies show that the serum lipoprotein concentration is associated with diseases such as dyslipidemia and arteriosclerosis (for example, Non-Patent Document 3). An increase in the concentration of LDL cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol are both risk factors for coronary artery disease.

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.

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.

As the compound having a pyrazolopyridine skeleton, the compound described in Patent Document 2 is known. Patent Document 2 describes an anti-LPA receptor action, but does not describe an LCAT activation action.

WO2008 / 002591 pamphlet WO2012 / 028243 pamphlet

Currently known compounds having an LCAT activating action are not satisfactory in terms of safety and effectiveness, and LCAT activators having excellent safety and effectiveness have been desired.

The present inventors have conducted various synthetic studies aiming at obtaining new anti-arteriosclerotic drugs by having an excellent LCAT activation action and promoting cholesterol withdrawal directly from macrophages. As a result, the present inventors have found that an imidazopyridine derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, thereby completing the present invention.

The present invention provides an imidazopyridine derivative having an excellent LCAT activating action (preferably a reversible LCAT activating action) or a pharmacologically acceptable salt thereof and a medicament containing these.

That is, the present invention
(1) Formula

[Wherein, R represents the formula (X)

{Wherein n is an integer of 1 or 2,
R ¹ represents an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , _{C 1-6} _{alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or
An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C _1-6 _{alkoxy, C 3-7} cycloalkoxy group, a phenyl _{group, C 2-7} alkoxycarbonyl group, benzyloxycarbonyl group, di _{(C 1-6} alkyl) aminocarbonyl Moto及busy _{(C 1-6} alkyl And the same or different groups selected from the group consisting of amino groups. }, A group represented by
R ² is a hydrogen atom or a hydroxyl group. Or a pharmacologically acceptable salt thereof,
(2) The compound or pharmacologically acceptable salt thereof according to (1), wherein n is 1.
(3) The compound according to (1) or a pharmacologically acceptable salt thereof, wherein n is 2.
(4) R ¹ is an aryl group which may be substituted (the substituent is a halogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group) , Cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and di (C _1-6 alkyl) the same or different 1 to 3 groups selected from the group consisting of amino groups), or the pharmacologically of the compound according to any one of (1) to (3) Acceptable salts,
(5) R ¹ is a substituted aryl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, or a C ₁ group) Or a pharmacologically acceptable compound thereof according to any one of (1) to (3), which are the same or different 1 or 2 groups selected from the group consisting of _-3 alkoxy groups). salt,
(6) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) Or the pharmacologically acceptable salt thereof according to any one of (1) to (3),
(7) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). A compound or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
(8) R ¹ is an optionally substituted heteroaryl group (the heteroaryl is a 5-membered or 6-membered ring. The heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Furthermore, it may contain one nitrogen atom, oxygen atom or sulfur atom, and the substituent is a halogen atom, C _1-6 alkyl group, C _3-7 cycloalkyl group, trifluoromethyl group, difluoromethoxy group, Fluoromethoxy group, cyano group, C _1-6 alkoxy group, C _3-7 cycloalkoxy group, phenyl group, C _2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and di is a (C _1-6 alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, in any one of (1) to (3) Compound or a pharmacologically acceptable salt thereof of the mounting,
(9) R ¹ is a substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and one more Or a substituent such as a halogen atom, a C _1-3 alkyl group, a C _3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group. , A cyano group, a C _1-3 alkoxy group, a C _2-4 alkoxycarbonyl group and a benzyloxycarbonyl group, the same or different one or two groups.) The compound according to any one of (3) or a pharmacologically acceptable salt thereof,
(10) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C _1-3 alkoxy group, C _2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to any one of (1) to (3),
(11) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different selected one or two groups), or the pharmacologically acceptable salt thereof according to any one of (1) to (3),
(12) The compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein R ¹ is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group salt,
(13) The compound according to any one of (1) to (12), wherein R ² is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(14) 7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro -5H-imidazo [4,5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine- 1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile,
7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4 , 5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one and
7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,6,7-tetrahydro-5H- The compound or pharmacologically acceptable salt thereof according to (13), selected from the group consisting of imidazo [4,5-b] pyridin-5-one,
(15) (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 , 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H -Imidazo [4,5-b] pyridin-5-one and
(+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro A compound according to (13) or a pharmacologically acceptable salt thereof selected from the group consisting of -5H-imidazo [4,5-b] pyridin-5-one,
(16) The compound according to any one of (1) to (12), wherein R ² is a hydroxyl group, or a pharmacologically acceptable salt thereof,
(17) 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- The compound or a pharmaceutically acceptable salt thereof according to (16), selected from the group consisting of 5H-imidazo [4,5-b] pyridin-5-one,
(18) (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4 , 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
(+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 The compound or a pharmaceutically acceptable salt thereof according to (16), selected from the group consisting of 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(19) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group, and a cyano group) ), R ² is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof according to (1),
(20) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom and n is 2.
(21) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C _1-3 alkoxy group, C _2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R ² is a hydrogen atom and n is 2.
(22) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different 1 or 2 groups selected), R ² is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof according to (1),
(23) The compound according to ( ¹ ), wherein R ¹ is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R ² is a hydrogen atom, and n is 2. Its pharmacologically acceptable salts,
(24) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a chlorine atom, a difluoromethoxy group, a trifluoromethoxy group and a cyano group) ), R ² is a hydroxyl group, and n is 2, the compound according to (1) or a pharmacologically acceptable salt thereof,
(25) R ¹ is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R ² is a hydroxyl group and n is 2.
(26) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C _1-3 alkyl group, a cyclopropyl group) 1 or 2 selected from the group consisting of trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C _1-3 alkoxy group, C _2-4 alkoxycarbonyl group and benzyloxycarbonyl group Or a pharmacologically acceptable salt thereof according to (1), wherein R ² is a hydroxyl group and n is 2.
(27) R ¹ is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) The same or different selected 1 or 2 groups), R ² is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof,
(28) The compound according to ( ¹ ), wherein R ¹ is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R ² is a hydroxyl group, and n is 2. A pharmacologically acceptable salt,
(29) The compound according to any one of (1) to (28), wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis, or a pharmaceutically acceptable salt thereof,
(30) The compound according to any one of (1) to (14), (16), (17) and (19) to (28), wherein the optical rotation is (+), or a pharmacologically acceptable salt thereof Salt,
(31) A pharmaceutical composition comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(32) Arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, peripheral vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease,
(33) A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(34) A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(35) A preventive agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(36) A prophylactic agent for a disease caused by a decrease in the concentration of HDL cholesterol in blood, comprising as an active ingredient the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Or therapeutic agent,
(37) an LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(38) A reversible LCAT activator comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(39) An anti-arteriosclerosis agent comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof as an active ingredient,
(40) A method for activating LCAT comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof,
(41) A method for the prevention or treatment of a disease, comprising administering an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof to a human,
(42) For prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Method,
(43) For prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. Method,
(44) By increasing the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(45) By reducing the concentration of HDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof. A method for the prevention or treatment of the disease caused,
(46) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis,
(47) The compound according to any one of (1) to (30) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing dyslipidemia,
(48) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood Acceptable salts, and
(49) The compound according to any one of (1) to (30) or a pharmacologically thereof for use in a method for treating or preventing a disease caused by a decrease in the concentration of HDL cholesterol in blood It is an acceptable salt.

Hereinafter, the definition of the substituent in the compound (I) of the present invention will be described.

In the present application, unless otherwise specified, any isomer of a tautomer (amide-imidic acid) is contained in the present compound (I). In the present application, for convenience, the compound (I) containing any isomer is referred to as a compound (I). Is also represented by the structural formula represented by formula (I) and the corresponding chemical name.

In the compound (I) of the present invention, the “aryl group” is, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.

In the compound (I) of the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom. .

In the compound (I) of the present invention, the “C _1-6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms ( C _1-3 alkyl group), more preferably a methyl group.

In the compound (I) of the present invention, the “C _3-7 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms (C _3-6 cycloalkyl group) is preferable, and a cyclopropyl group is more preferable.

In the compound (I) of the present invention, the “C _1-6 alkoxy group” is an oxygen atom to which the “C _1-6 alkyl group” is bonded. For example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group Alternatively, it may be a butoxy group, preferably an oxygen atom (C _1-3 alkoxy group) to which the “C _1-3 alkyl group” is bonded, and more preferably a methoxy group.

In the compound (I) of the present invention, the “C _3-7 cycloalkoxy group” is an oxygen atom to which the “C _3-7 cycloalkyl group” is bonded, and includes a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group. Group, a cyclohexyloxy group, or a cycloheptyloxy group, preferably an oxygen atom (C _1-3 alkoxy group) to which the “C _1-3 alkyl group” is bonded, more preferably a methoxy group It is.

In the compound (I) of the present invention, the “C _2-7 alkoxycarbonyl group” is a carbonyl group to which the “C _1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Or a butoxycarbonyl group, preferably a carbonyl group to which the “C _1-3 alkoxy group” is bonded (C _2-4 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group. It is.

In the compound (I) of the present invention, the “di (C _1-6 alkyl group) amino group” is an amino group to which two identical or different “C _1-6 alkyl groups” are bonded. Is a dimethylamino group.

In the compound (I) of the present invention, the “di (C _1-6 alkyl group) aminocarbonyl group” is a carbonyl group to which the “di (C _1-6 alkyl group) amino group” is bonded. , A dimethylaminocarbonyl group.

In the compound (I) of the present invention, “a heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The hetero atom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms; 1 nitrogen atom, oxygen atom or sulfur atom may be included.) "Means, for example, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyrrole group, pyrazolyl Group, imidazolyl group, triazolyl group or thiadiazolyl group, preferably a 5- or 6-membered heteroaryl group (the heteroatom on the heteroaryl ring is one nitrogen atom, and one nitrogen atom) More preferably a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyrida group. Nyl group, thiadiazolyl group or thiazolyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group, still more preferably a pyridyl group, pyrimidyl group, pyrazinyl group or thiadiazolyl group Particularly preferred is a pyridyl group, a pyrimidyl group or a pyrazinyl group.

Since the compound (I) of the present invention has a basic group, it can be converted into an acid addition salt with a pharmacologically acceptable acid. In the present invention, “pharmacologically acceptable salts” include, for example, hydrohalides such as hydrofluoric acid salts, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates. Inorganic salts such as sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salts; organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate Can be mentioned.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof may be taken out from the solvent and become a solvate by leaving it in a solvent, and such a solvate is also encompassed in the present invention. Is done.

Compound (I) of the present invention has an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.

The compound (I) of the present invention has a geometric isomer at the 4-5 position of the imidazopyridine ring, and both cis and trans isomers are included in the present invention unless otherwise specified. For example, by producing both geometric isomers and comparing their instrument data, the respective structure can be determined. In the present invention, the 4-position trifluoromethyl group and the 5-position hydroxyl group are preferably cis.

Compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound. Examples of atomic isotopes include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. In addition, the compound may be radiolabeled with a radioisotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

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.

Dose response curve for determining 50% effective concentration (EC ₅₀ ) of LCAT activation in Test Examples 1 and 2 of the present invention

Hereinafter, typical methods for producing the compound (I) of the present invention and the starting compound used for the production of the compound (I) of the present invention will be described, but the present invention is not limited to these methods.

Manufacturing method 1
Production method 1 is a method for producing compound (I) of the present invention from compound (II).

In the formula, R and R ² are as defined above, R ³ is a hydrogen atom or a formula —O—R ⁵ (R ⁵ is a hydrogen atom, a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyl group). -Represents a butyldiphenylsilyl group), and R ⁴ represents a methyl group or an ethyl group.

(Process 1)
This step is a step for producing compound (I) by heating and condensing compound (II) and compound (III) in a solvent inert to the reaction or in the absence of a solvent.

Solvents used in this step include organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; diethyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxy Alcohols such as ethanol, diethylene glycol or glycerine; aromatic hydrocarbons such as benzene, toluene or xylene; or these It is a mixed solvent, preferably a mixed solvent of ethanol and acetic acid.

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.

In order to promote the reaction in this step, in addition to heating the reaction solution, microwaves can be irradiated.

The reaction time in this step is usually 5 minutes to 72 hours, preferably 15 minutes to 24 hours, and more preferably 30 minutes to 3 hours.

When R ⁵ of the compound (III) is a methyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, the compound prepared by the above reaction is exemplified by P.I. G. Wuts, T.W. W. Greene, Greene's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. Etc. can be used to remove the hydroxyl-protecting group to produce compound (I).

Manufacturing method 2
The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.

In the formula, R represents the same meaning as described above, and X represents a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, a methanesulfonyl group or a trifluoromethanesulfonyl group.

(Process 2-1)
This step is a step for producing compound (VI) by reacting compound (IV) with compound (V) in an inert solvent using a base.

Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably amides or sulfoxides An earth, more preferably, N, is N- dimethylformamide or dimethyl sulfoxide.

The base used in this step is preferably an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and more preferably potassium carbonate or cesium carbonate. .

The reaction temperature in this step is preferably −10 ° C. to 150 ° C., and more preferably 20 ° C. to 120 ° C.

The reaction time in this step is preferably 30 minutes to 10 hours, and more preferably 1 minute to 4 hours.

(Step 2-2)
This step is a step for producing compound (II) by catalytic hydrogenation of compound (VI) in the presence of a metal catalyst in an inert solvent.

Solvents used in this step are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol or glycerin. An ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether; an aromatic hydrocarbon such as benzene, toluene or xylene; or a mixed solvent thereof, preferably Is a mixed solvent of alcohols or ethers and alcohols, more preferably a mixture of ethanol or methanol and tetrahydrofuran. It is a medium.

The metal catalyst used in this step may be platinum, palladium-activated carbon, palladium-activated carbon diphenyl sulfide complex or nickel, and is preferably palladium-activated carbon or palladium-activated carbon diphenyl sulfide complex.

The hydrogenating agent used in this step can be hydrogen gas or ammonium formate, preferably hydrogen gas.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 5 ° C. to 40 ° C.

The reaction time in this step is preferably 5 minutes to 10 hours, and more preferably 20 minutes to 2 hours.

Production method 3
Production method 3 is a method for producing compounds (Ib) and (Ic) of the present invention from compound (VIII).

In the formula, R ¹ and R ² are as defined above, Boc represents a tert-butoxycarbonyl group, and n represents 1 or 2.

Compound (VIII) can be produced, for example, according to the methods described in Reference Examples 1 and 2, or Reference Examples 9, 10, 11, and 12.

(Step 4-1)
This step is a step for producing compound (Ib) by removing the Boc group in compound (VIII).

Examples of reagents used for removing Boc in compound (VIII) include P.I. G. Wuts, T.W. W. Greene, Green's Protective Groups in Organic Synthesis. Third Edition, 2006, John Wiley & Sons, Inc. And the like which can remove Boc described in the above.

The solvent used in this step is preferably an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; an alkyl halide such as dichloromethane or chloroform; Esters; aromatic hydrocarbons such as toluene; or a mixed solvent thereof, more preferably ethers or alkyl halides, and even more preferably dichloromethane.

The reagent used in this step is preferably hydrochloric acid or trifluoroacetic acid, and more preferably trifluoroacetic acid.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 50 ° C.

The reaction time in this step is preferably 5 minutes to 24 hours, and more preferably 10 minutes to 6 hours.

(Step 3-2)
This step is a step for producing compound (Ic) by reacting compound (Ib) with an arylating agent or heteroarylating agent.

Solvents used in this step are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert- Ethers such as butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or propionitrile; formamide, N, N-dimethylformamide, dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone or hexamethylphosphorotriamide; or sulfoxides such as dimethyl sulfoxide; preferably sulfoxides More preferably a dimethyl sulfoxide.

The base used in this step is an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, N-methylmorpholine, pyridine, dimethylaminopyridine or 2,6-lutidine. Preferred are triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine or dimethylaminopyridine.

The arylating agent or heteroarylating agent used in this step is a compound having the formula R ¹ -F, the formula R ¹ -Cl or the formula R ¹ -Br, preferably the formula R ¹ -F or the formula R ^1- Cl-containing compound (R ¹ is as defined above).

The reaction temperature in this step is preferably 20 ° C to 200 ° C.

The reaction time in this step is preferably 5 minutes to 120 hours, more preferably 10 minutes to 96 hours.

Manufacturing method 4
Of the intermediate (IV) of the compound of the present invention, the compound represented by the formula (IVc) can be produced, for example, by the following method.

In the formula, n and R ¹ are as defined above.

(Step 4-1)
(I) This step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a ligand and a base in addition to a palladium catalyst.

The palladium catalyst, ligand, base and reaction conditions used in this step are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. 2002, 219, p. 131.

The solvent used in this step is an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl-methyl ether; or an aromatic hydrocarbon such as benzene, toluene or xylene. , Preferably toluene or dioxane, and more preferably toluene.

The palladium catalyst used in this step is preferably palladium (II) acetate or palladium (0) dibenzylideneacetone.

The ligand used in this step is preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane, 2, 2′-bis (diphenylphosphanyl) 1,1′-binaphthyl, 2- (dicyclohexylphosphino) biphenyl or 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, more preferably 2- (di-tert-butylphosphino) biphenyl, tri-tert-butylphosphine or 2,2′-bis (diphenylphosphanyl) 1,1′-binaphthyl.

The base used in this step is preferably sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, and more preferably tert-butoxy sodium.

The arylating or heteroarylating agent used in this step is a compound having the formula R ¹ -Cl, the formula R ¹ -Br or the formula R ¹ -I, preferably the formula R ¹ -Cl or the formula R ^1- Br (R ¹ is as defined above).

The reaction temperature in this step is preferably 20 ° C. to 150 ° C., and more preferably 50 ° C. to the reflux temperature of the solvent.

The reaction time in this step is preferably 30 minutes to 12 hours, and more preferably 1 hour to 4 hours.

(Ii) Alternatively, this step is a step of producing compound (IVb) by reacting compound (IVa) with an arylating agent or heteroarylating agent in the presence of a base in an inert solvent.

This step can be performed under the same conditions as in step 3-2.

(Step 4-2) In this step, the hydroxyl group in compound (IVb) is methanesulfonylated to produce compound (Ic).

The solvent used in this step is preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or tert-butyl methyl ether; aromatic hydrocarbons such as benzene, toluene or xylene, or a mixed solvent thereof, more preferably alkyl halides, and still more preferably Is dichloromethane.

The reagent used in this step is preferably methanesulfonyl chloride or methanesulfonic anhydride, and more preferably methanesulfonyl chloride.

The reaction temperature in this step is preferably 0 ° C. to 100 ° C., and more preferably 0 ° C. to 30 ° C.

The product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) ) The crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration. The isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary. Alternatively, the product of each step can be used in the next step without isolation or purification.

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. For example, a racemic mixture can be converted to an optically pure isomer, such as by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column. Further, the diastereo mixture can be separated by fractional crystallization or various chromatographies. An optically active compound can also be produced by using an appropriate optically active raw material.

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. For example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms. In the case of intravenous administration, the lower limit is 0.01 mg / kg body weight (preferably 0.03 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 100 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.

EXAMPLES Hereinafter, although an Example, a test example, and a formulation example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these. In the following examples, hexane represents n-hexane, THF represents tetrahydrofuran, IPA represents 2-propanol, DMF represents N, N′-dimethylformamide, and DMSO represents dimethyl sulfoxide.

Reference Example 1 4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] Piperidine-1-carboxylate tert-butyl

Tert-Butyl 4- (4-nitro-1H-imidazol-1-yl) piperidine-1-carboxylate (compound described in WO 2005/92864, 210 mg, 0.709 mmol) and 10% palladium-activated carbon ( A suspension of 100 mg) in ethanol (5 mL) was stirred under a hydrogen atmosphere for 3.5 hours. After filtration through Celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (3 mL) and acetic acid (1 mL) of the residue obtained by distilling off the solvent under reduced pressure. Stir for minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 100 (gradient)] to give the title compound (220 mg, yield). : 77%).

¹ H-NMR (500Hz, DMSO-D ₆ ) δ: 10.30 (1H, s), 7.81 (1H, s), 7.21 (1H, s), 4.42 (1H, m), 4.19-4.01 (2H, m) , 3.07 (1H, d, J = 17Hz), 2.93-2.65 (2H, m), 2.77 (1H, d, J = 17Hz), 2.10-2.00 (1H, m), 1.94 (1H, m), 1.88- 1.79 (1H, m), 1.65 (1H, m), 1.42 (9H, s).

(Reference example 2)

4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 -Il] piperidine-1-carboxylate tert-butyl (400 mg, 0.989 mmol) in ethyl acetate-methanol (1/1) (4 mL) was adsorbed on neutral silica gel, and the solvent was distilled off under reduced pressure. The powder obtained in this manner was divided into 3 portions by flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 93/7, flow rate: 12 mL / min]. The product was purified to obtain the target compound (188 mg, yield: 47%, optically active substance).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate 1.0 mL / min].

Optical purity 99% or more (retention time: 5.0 minutes).

(Reference Example 3) 1- (5-Isopropoxypyridin-2-yl) piperidin-4-ol

To a solution of 2-bromo-5-isopropoxypyridine (3.25 g, 15.0 mmol) and 4-hydroxypiperidine (1.98 g, 19.6 mmol) in toluene (50 mL) was added tert-butoxy sodium (3.18 g, 33.1 mmol), tris (dibenzylideneacetone) dipalladium (0) (689 mg, 0.752 mmol) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (468 mg, 0.752 mmol). In addition, the mixture was stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-0 / 100 (gradient)] to give the title compound (2.67 g, yield: 75%). It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.91 (1H, d, J = 3Hz), 7.13 (1H, dd, J = 9Hz, 3Hz), 6.65 (1H, d, J = 9Hz), 4.42-4.31 (1H, m), 3.98-3.84 (3H, m), 3.10-3.01 (2H, m), 2.03-1.94 (2H, m), 1.67-1.53 (2H, m), 1.48 (1H, d, J = 4Hz), 1.30 (6H, d, J = 6Hz).

(Reference Example 4) 1- {1- (5-Isopropoxypyridin-2-yl) piperidin-4-yl} -1H-imidazol-4-amine

To a solution of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol and triethylamine (2.63 mL, 19.0 mmol) prepared in Reference Example 3 in dichloromethane (30 mL) at 0 ° C., Methanesulfonyl chloride (1.28 mL, 16.4 mmol) was added and stirred at room temperature for 30 minutes. Ice water was added to the reaction solution and the phases were separated, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed successively with ethyl acetate and hexane to obtain a synthetic intermediate B.

To a solution of 4-nitro-1H-imidazole (651 mg, 5.76 mmol) and the synthetic intermediate B obtained by the above operation in DMF (20 mL), cesium carbonate (2.25 g, 6.91 mmol) was added, and 120 ° C. For 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to give the title compound (0.76 g, yield: 36%). It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.94 (1H, d, J = 3Hz), 7.83 (1H, d, J = 2Hz), 7.54 (1H, d, J = 2Hz), 7.18 (1H, dd , J = 9Hz, 3Hz), 6.71 (1H, d, J = 9Hz), 4.47-4.30 (3H, m), 4.28-4.17 (1H, m), 3.00-2.90 (2H, m), 2.29-2.20 ( 2H, m), 2.09-1.97 (2H, m), 1.32 (6H, d, J = 6Hz).

(Reference Example 5) 1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-ol

To a solution of 5-chloro-2- (trifluoromethyl) pyrimidine (1.71 g, 9.37 mmol) and 4-hydroxypiperidine (1.20 g, 11.9 mmol) in DMSO (10 mL) was added 1,8-diazabicyclo [ 5.4.0] -7-undecene (2.90 mL, 19.4 mmol) was added and stirred at 80 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the solvent of the obtained organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-0 / 1000 (gradient)] to give the title compound (1.95 g, yield: 84%). It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.42 (2H, s), 4.06-3.96 (1H, m), 3.74-3.66 (2H, m), 3.26-3.17 (2H, m), 2.08-2.00 ( 2H, m), 1.77-1.67 (2H, m), 1.56-1.53 (1H, m).

(Reference Example 6) 1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1H-imidazol-4-amine

Instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol, 1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4- 4 prepared in Reference Example 5 was used. The reaction was carried out in the same manner as in Reference Example 4 using all (1.92 g, 7.77 mmol) to obtain the title compound (1.07 g, yield: 43%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.70 (2H, s), 8.60 (1H, s), 8.00 (1H, s), 4.57-4.47 (1H, m), 4.22 (2H, d, J = 14Hz), 3.08 (2H, t, J = 12Hz), 2.14-1.96 (4H, m).

Reference Example 7 1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-ol

Instead of 2-bromo-5-isopropoxypyridine, 2-bromo-5- (difluoromethoxy) pyridine (compound described in J. Med. Chem., 2010, 53, 8421-8439, 2.85 g, 12.7 mmol) was used in the same manner as in Reference Example 3 to obtain the title compound (2.11 g, yield: 68%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.05 (1H, d, J = 3Hz), 7.30 (1H, dd, J = 9Hz, 3Hz), 6.65 (1H, d, J = 9Hz), 6.39 (1H , t, J = 74Hz), 4.06-3.98 (2H, m), 3.97-3.88 (1H, m), 3.21-3.11 (2H, m), 2.02-1.93 (2H, m), 1.64-1.51 (3H, m).

(Reference Example 8) 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -1H-imidazol-4-amine

1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-ol prepared in Reference Example 7 instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol (1.91 g, 7.82 mmol) was used in the same manner as in Reference Example 4 to obtain the title compound (447 mg, yield: 25%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.09 (1H, d, J = 3Hz), 7.83 (1H, d, J = 2Hz), 7.54 (1H, d, J = 2Hz), 7.37 (1H, dd , J = 9Hz, 3Hz), 6.71 (1H, d, J = 9Hz), 6.43 (1H, t, J = 74Hz), 4.52-4.43 (2H, m), 4.33-4.22 (1H, m), 3.06- 2.95 (2H, m), 2.29-2.20 (2H, m), 2.05-1.92 (2H, m).

(Reference Example 9) tert-butyl 3- (4-nitro-1H-imidazol-1-yl) pyrrolidine-1-carboxylate

Reference Example 4 was carried out using tert-butyl 3-hydroxypyrrolidine-1-carboxylate (13.0 g, 69.4 mmol) instead of 1- (5-isopropoxypyridin-2-yl) piperidin-4-ol. To give the title compound (7.54 g, yield: 77%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 7.81 (1H, d, J = 2Hz), 7.51 (1H, d, J = 2Hz), 4.84-4.79 (1H, m), 3.91 (1H, dd , J = 12Hz, 6Hz), 3.76-3.63 (3H, m), 2.57-2.48 (1H, m), 2.28-2.20 (1H, m), 1.49 (9H, s).

(Reference Example 10) Compound A-1 and Compound A-2

as well as,

Tert-butyl 3- (4-nitro-1H-imidazol-1-yl) pyrrolidine-1-carboxylate (3.17 g, 12.6 mmol) and 10% palladium-activated carbon (550 mg) prepared in Reference Example 9 ) In methanol (110 mL) was stirred under a hydrogen atmosphere for 3 hours. After filtration through celite, the solvent was distilled off under reduced pressure, and a solution of the resulting residue in ethanol (45 mL) was added to acetic acid (15 mL) and ethyl 4,4,4-trifluoroacetoacetate (5.1 mL, 35 mmol) And stirred at 80 ° C. for 2.5 hours. The reaction solution was cooled to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [developing solvent: (i) hexane / ethyl acetate = 25 / 75-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-97 / 3 (gradient). The compound A-1 eluting first (2 g, yield: 42%) and the compound A-2 eluting later (1.77 g, 37%) were obtained respectively.

Compound A-1:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.36 (1H, s), 7.73-7.71 (1H, m), 7.32 (1H, s), 5.07-4.94 (1H, m), 3.79-3.69 ( 1H, m), 3.61-3.54 (1H, m), 3.42-3.27 (2H, m), 3.11 (1H, d, J = 17Hz), 2.77 (1H, d, J = 17Hz), 2.37-2.28 (2H , m), 1.41-1.39 (9H, m).

Compound A-2:
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.37 (1H, s), 7.63 (1H, s), 7.33 (1H, s), 5.09-5.04 (1H, m), 3.71-3.66 (1H, m), 3.49-3.31 (3H, m), 3.09 (1H, d, J = 17Hz), 2.78 (1H, d, J = 17Hz), 2.39-2.13 (2H, m), 1.42-1.41 (9H, m ).

(Reference Example 11)

The ethyl acetate solution of compound A-1 (2.72 g, 6.97 mmol) produced in Reference Example 10 was adsorbed on silica gel, and the solvent was distilled off under reduced pressure. Column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min], and purified by the target compound (1.19 g, yield: 43%). Optically active substance) was obtained.

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate: 1.0 mL / min].

Optical purity 99% or more (retention time: 4.6 minutes).

(Reference Example 12)

Obtained by adsorbing a mixed solution of compound A-2 (2.49 g, 6.38 mmol) prepared in Reference Example 10 in ethyl acetate and methanol onto silica gel, and distilling off the solvent under reduced pressure. The powder was purified by flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 95/5, flow rate: 12 mL / min], and the target compound (820 mg, yield). : 33%, optically active substance).

Optical purity 99% or more (retention time: 4.2 minutes).

Example 1 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 To a suspension of tert-butyl-yl] piperidine-1-carboxylate (100 mg, 0.247 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and N, N-diisopropylethylamine (126 μL, 0.741 mmol) and 2-fluoro-5- (trifluoromethyl) pyridine were added to a solution of the obtained residue in DMSO (1 mL). (44.6 μL, 0.370 mmol) was added and stirred overnight. The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 10 (gradient)], and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 88 / 12-0 / 10 (gradient)] to give the title compound (53.5 mg, yield: 48%). .

¹ H-NMR (500Hz, DMSO-d ₆ ) δ: 10.31 (1H, s), 8.45-8.38 (1H, m), 7.80 (1H, dd, J = 10Hz 3Hz), 7.79 (1H, s), 7.25 (1H, s), 7.03 (1H, d, J = 10Hz), 4.71-4.55 (3H, m), 3.09 (1H, d, J = 17Hz), 2.97 (2H, m), 2.79 (1H, d, J = 17Hz), 2.21-2.12 (1H, m), 2.04 (1H, m), 1.98-1.90 (1H, m), 1.74 (1H, m);
MS (ESI) m / z: 450 (M + H) ^<+> .

Example 2 (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4 prepared in Example 1 A mixed solution of 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (480 mg, 1.07 mmol) in ethyl acetate-methanol (1/1) (8 mL) was adsorbed on neutral silica gel. The powder obtained by distilling off the solvent under reduced pressure was obtained by flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 12 mL. / Min] to obtain the title compound (233 mg, yield: 49%, optically active substance).

Optical purity 99% or more (retention time: 7.6 minutes);
[α] _D ²⁵ = + 31 ° (DMF, c = 0.970).

Example 3 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 prepared in Reference Example 1 To a suspension of tert-butyl-yl] piperidine-1-carboxylate (647 mg, 1.60 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to diethyl ether, and the resulting precipitate was collected by filtration to obtain a solid (813 mg).

To a solution of a part (100 mg) of the solid obtained in the above operation in DMSO (1 mL), N, N-diisopropylethylamine (203 μL, 1.20 mmol) and 2-chloro-5- (trifluoromethyl) pyrazine (44 3 μL, 0.359 mmol) was added and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane was added to the resulting residue, and the resulting solid was collected by filtration to obtain the title compound (73.0 mg, yield: 67%).

¹ H-NMR (500Hz, DMSO-d ₆ ) δ: 10.31 (1H, s), 8.53-8.49 (2H, m), 7.79 (1H, s), 7.26 (1H, s), 4.77-4.59 (3H, m), 3.14-3.02 (2H, m), 3.09 (1H, d, J = 17Hz), 2.79 (1H, d, J = 17Hz), 2.25-2.03 (2H, m), 2.01-1.92 (1H, m ), 1.86-1.75 (1H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 4 (+)-7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4, prepared in Example 3 A mixed solution of 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (420 mg, 0.933 mmol) in ethyl acetate-methanol (1/1) (16 mL) was adsorbed onto neutral silica gel. The powder obtained by distilling off the solvent under reduced pressure was obtained by flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 80/20, flow rate: 12 mL. / Min] to give the title compound (141 mg, yield: 22%, optically active substance).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 70/30, flow rate 1.0 mL / min].

Optical purity 99% or more (retention time: 5.6 minutes);
[α] _D ²⁵ = + 38 ° (DMF, c = 1.01).

Example 5 1- {1- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Similar to Example 3 using 3-chloro-2-fluoro-5- (trifluoromethyl) pyridine (46.9 μL, 0.359 mmol) instead of 2-chloro-5- (trifluoromethyl) pyrazine The title compound (72.0 mg, yield: 62%) was obtained.

¹ H-NMR (500Hz, DMSO-d ₆ ) δ: 10.31 (1H, s), 8.59-8.56 (1H, m), 8.21 (1H, d, J = 2Hz), 7.83 (1H, s), 7.25 ( 1H, s), 4.55 (1H, m), 4.27-4.13 (2H, m), 3.09 (1H, d, J = 17Hz), 2.98 (2H, m), 2.78 (1H, d, J = 17Hz), 2.27-2.15 (2H, m), 2.03-1.87 (2H, m);
MS (ESI) m / z: 484 (M + H) ^<+> .

Example 6 7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] piperidin-4-yl}- 1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Example 2 with 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole (75 mg, 0.398 mmol) instead of 2-chloro-5- (trifluoromethyl) pyrazine and The reaction was carried out in the same manner, and the resulting residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20] to give the title compound (78 mg, yield: 68%). It was.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.34 (1H, s), 7.84 (1H, s), 7.29 (1H, s), 4.65-4.55 (1H, m), 4.15-4.03 (2H, m), 3.48-3.35 (2H, m), 3.09 (1H, d, J = 16Hz), 2.78 (1H, d, J = 16Hz), 2.27-2.15 (1H, m), 2.02-1.90 (3H, m );
MS (ESI) m / z: 457 (M + H) ⁺ .

Example 7 7-Hydroxy-7- (trifluoromethyl) -1- {1- [4- (trifluoromethyl) -1,3-thiazol-2-yl] piperidin-4-yl} -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 2-chloro-4- (trifluoromethyl) -1,3-thiazole (108 mg, 0.578 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (43 mg, yield: 26%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.33 (1H, s), 7.84 (1H, s), 7.55 (1H, s), 7.28 (1H, s), 4.60-4.50 (1H, m) , 4.11-4.00 (2H, m), 3.29-3.05 (3H, m), 2.78 (1H, d, J = 16Hz), 2.21-2.10 (2H, m), 2.00-1.82 (2H, m);
MS (ESI) m / z: 456 (M + H) ^<+> .

Example 8 7-Hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 , 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 4-chloro-2-isopropyl-6- (trifluoromethyl) pyrimidine (138 mg, 0.614 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (129 mg, yield: 71%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.32 (1H, s), 7.81 (1H, s), 7.27 (1H, s), 7.16 (1H, s), 4.66-4.55 (1H, m) , 3.37-2.88 (6H, m), 2.79 (1H, d, J = 17Hz), 2.22-1.70 (4H, m), 1.23 (6H, d, J = 7Hz);
MS (ESI) m / z: 493 (M + H) ^<+> .

Example 9 (+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Trifluoroacetic acid (3.4 mL, 44.0 mmol) was added to a dichloromethane (20 mL) solution of the compound produced in Reference Example 2 (2.15 g, 5.32 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was added dropwise to a mixed solvent of diethyl ether (90 mL) and hexane (20 mL) at 0 ° C. and stirred at room temperature for 3 hours. The resulting solid was collected by filtration to obtain a trifluoroacetate compound (2.36 g).

The obtained trifluoroacetate compound (220 mg) and 4-chloro-2-isopropyl-6- (trifluoromethyl) pyrimidine (compound described in WO2010 / 134478, 180 mg, 0.801 mmol) in DMSO (3 0.0 mL) solution was added N, N-diisopropylethylamine (0.25 mL, 1.50 mmol) and stirred at room temperature for 18 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the solvent of the obtained organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100] to give the title compound (205 mg, yield: 79%, optically active substance).

Optical purity 99% or more (retention time: 4.6 minutes);
[α] _D ²⁵ = + 32 ° (DMF, c = 0.996).

Example 10 7-Hydroxy-7- (trifluoromethyl) -1- {1- [6- (trifluoromethyl) pyridazin-3-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Using 3-chloro-6- (trifluoromethyl) pyridazine (48.0 mg, 0.263 mmol) instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole The reaction was carried out in the same manner as in 6 to obtain the title compound (12 mg, yield: 11%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.33 (1H, s), 7.83 (1H, d, J = 10Hz), 7.80 (1H, s), 7.49 (1H, d, J = 10Hz), 7.28 (1H, s), 4.79-4.58 (3H, m), 3.15-3.01 (3H, m), 2.79 (1H, d, J = 17Hz), 2.23-2.03 (2H, m), 2.01-1.93 (1H , m), 1.86-1.74 (1H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 11 6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1 -Yl] piperidin-1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile

Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 6-chloro-4- (trifluoromethyl) pyridine-3-carbonitrile (57.0 mg, 0.276 mmol) was used. And the reaction was carried out in the same manner as in Example 6 to obtain the title compound (46 mg, yield: 39%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.33 (1H, s), 8.73 (1H, s), 7.79 (1H, s), 7.36 (1H, s), 7.28 (1H, s), 4.96 -4.56 (3H, m), 3.20-3.04 (3H, m), 2.79 (1H, d, J = 17Hz), 2.23-2.14 (1H, m), 2.14-2.00 (1H, m), 2.00-1.92 ( 1H, m), 1.84-1.71 (1H, m);
MS (ESI) m / z: 475 (M + H) ^<+> .

Example 12 7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro- 5H-imidazo [4,5-b] pyridin-5-one

1- {1- (5-Isopropoxypyridin-2-yl) piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 4 (0.76 g, 2.3 mmol) and 10% Acetic acid (3 drops of Pasteur pipette) was added to a suspension of palladium-activated carbon (0.25 g) in methanol (20 mL) and THF (10 mL), and the mixture was stirred under a hydrogen atmosphere for 1 hr. After filtration through Celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (9 mL) and acetic acid (3 mL) of the residue obtained by evaporating the solvent under reduced pressure. Stir for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (gradient)] to give the title compound (546 mg, yield). : 49%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.32 (1H, s), 7.84 (1H, d, J = 3Hz), 7.79 (1H, s), 7.26 (1H, dd, J = 9Hz, 3Hz ), 7.23 (1H, s), 6.85 (1H, d, J = 9Hz), 4.53-4.27 (4H, m), 3.09 (1H, d, J = 16Hz), 2.81-2.66 (3H, m), 2.18 -2.00 (2H, m), 1.96-1.88 (1H, m), 1.84-1.72 (1H, m), 1.23 (6H, d, J = 6Hz);
MS (ESI) m / z: 440 (M + H) ^<+> .

Example 13 (+)-7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

7-Hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7 prepared in Example 12 -A mixed solution of tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (506 mg, 1.15 mmol) in ethyl acetate-methanol (1/1) (5 mL) was adsorbed onto neutral silica gel, The powder obtained by distilling off the solvent was flash LC [column: Chiralflash IA (30 mm id × 100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 90/10, flow rate: 12 mL / min] In three steps, the title compound (240 mg, yield: 47%, optically active substance) was obtained.

Optical purity 99% or more (retention time: 7.8 minutes);
[α] _D ²⁵ = + 17 ° (DMF, c = 0.890).

Example 14 7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7 -Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 6 (1.07 g, 3.13 mmol) And a suspension of 10% palladium-activated carbon (640 mg) in methanol (15 mL) and THF (5 mL) was stirred under a hydrogen atmosphere for 6 hours. After filtration through Celite, ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a mixed solution of ethanol (30 mL) and acetic acid (10 mL) of the residue obtained by distilling off the solvent under reduced pressure, and 80 ° C. For 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted 3 times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 40 / 60-0 / 100 (gradient)] to give the title compound (342 mg, yield: 28%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.33 (1H, s), 8.68 (2H, s), 7.83 (1H, s), 7.26 (1H, s), 4.62-4.52 (1H, m) , 4.22 (2H, t, J = 16Hz), 3.13-2.97 (3H, m), 2.79 (1H, d, J = 17Hz), 2.22-2.10 (2H, m), 1.97-1.81 (2H, m);
MS (ESI) m / z: 451 (M + H) ^<+> .

Example 15 1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -1H-imidazol-4-amine prepared in Reference Example 8 (447 mg, 1.32 mmol) and 10% Acetic acid (3 drops of Pasteur pipette) was added to a suspension of palladium-activated carbon (0.15 g) in methanol (10 mL) and THF (10 mL), and the mixture was stirred under a hydrogen atmosphere for 1 hour. After filtration through celite, ethyl trifluoroacetoacetate (313 μL, 2.13 mmol) was added to a mixed solution of ethanol (9 mL) and acetic acid (3 mL) of the residue obtained by distilling off the solvent under reduced pressure. Stir for hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 50 / 50-0 / 100 (gradient), (ii) ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)], and further purified by silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (gradient)]. To give the title compound (195 mg, yield: 33%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.31 (1H, s), 8.02 (1H, d, J = 3Hz), 7.78 (1H, s), 7.45 (1H, dd, J = 9Hz, 3Hz ), 7.24 (1H, s), 7.06 (1H, t, J = 74Hz), 6.95 (1H, d, J = 9Hz), 4.58-4.38 (3H, m), 3.09 (1H, d, J = 17Hz) , 2.92-2.74 (3H, m), 2.19-1.97 (2H, m), 1.97-1.88 (1H, m), 1.82-1.69 (1H, m);
MS (ESI) m / z: 448 (M + H) ^<+> .

Example 16 (+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4 6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6 prepared in Example 15 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (190 mg, 0.425 mmol) is dissolved in IPA (4 mL) and methanol (30 mL) and concentrated under reduced pressure until crystals precipitate. did. Methanol (4 mL) was added to the resulting residue, the heated solution was adsorbed on neutral silica gel, the solvent was distilled off under reduced pressure, and the resulting powder was obtained by flash LC [column: Chiralflash IA (30 mm i. x. x100 mm); manufactured by Daicel, elution solvent: hexane / IPA = 85/15, flow rate: 12 mL / min] to obtain the title compound (79.5 mg, yield: 42%, optically active substance).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / IPA = 50/50, flow rate 1.0 mL / min].

Optical purity 98% or more (retention time: 4.9 minutes);
[α] _D ²⁵ = + 22 ° (DMF, c = 0.943).

(Example 17)

4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine-1-carvone The reaction was conducted in the same manner as in the method described in Example 3 using the compound prepared in Reference Example 11 instead of tert-butyl acid, and the target compound (109 mg, yield: 83%, optically active substance) )

Optical purity 99% or more (retention time: 6.4 minutes)
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.39 (1H, s), 8.51 (1H, s), 8.12 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 5.26 -5.23 (1H, m), 4.07-4.02 (1H, m), 3.96-3.90 (1H, m), 3.74-3.68 (2H, m), 3.12 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.58-2.46 (2H, m);
MS (ESI) m / z: 437 (M + H) ⁺ .

(Example 18)

The reaction was conducted in the same manner as described in Example 17 using 2-fluoro-5- (trifluoromethyl) pyridine in place of 2-chloro-5- (trifluoromethyl) pyrazine, and the target compound ( 99 mg, yield: 75%, optically active substance).

Optical purity 99% or more (Retention time: 5.4 minutes)
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.38 (1H, s), 8.41 (1H, brs), 7.82 (1H, dd, J = 9Hz, 2Hz), 7.72 (1H, s), 7.38 ( 1H, s), 6.62 (1H, d, J = 9Hz), 5.52-5.16 (1H, m), 4.00-3.95 (1H, m), 3.87-3.80 (1H, m), 3.65-3.56 (2H, m ), 3.45 (1H, brs), 3.12 (1H, d, J = 16Hz), 2.79 (1H, d, J = 16Hz), 2.55-2.45 (1H, m);
MS (ESI) m / z: 436 (M + H) ^<+> .

(Example 19)

4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine-1-carvone The reaction was conducted in the same manner as in the method described in Example 3 using the compound prepared in Reference Example 12 instead of tert-butyl acid, and the target compound (89 mg, yield: 66%, optically active substance) )

Optical purity 99% or more (retention time: 6.7 minutes)
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.39 (1H, s), 8.53 (1H, s), 8.17 (1H, brs), 7.67 (1H, s), 7.38 (1H, s), 5.32 -5.26 (1H, m), 4.04-3.99 (1H, m), 3.88-3.68 (3H, m), 3.13 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.58- 2.30 (2H, m);
MS (ESI) m / z: 437 (M + H) ⁺ .

(Example 20)

The reaction was conducted in the same manner as described in Example 19 using 2-fluoro-5- (trifluoromethyl) pyridine in place of 2-chloro-5- (trifluoromethyl) pyrazine, and the target compound ( 99 mg, yield: 75%, optically active substance).

Optical purity 99% or more (retention time: 5.6 minutes)
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.39 (1H, s), 8.43 (1H, brs), 7.83 (1H, d, J = 9Hz, 2Hz), 7.62 (1H, s), 7.38 ( 1H, s), 6.68 (1H, d, J = 9Hz), 5.29-5.23 (1H, m), 3.96-3.92 (1H, m), 3.79-3.53 (3H, m), 3.13 (1H, d, J = 17Hz), 2.80 (1H, d, J = 17Hz), 2.56-2.29 (2H, m);
MS (ESI) m / z: 436 (M + H) ^<+> .

Example 21 1- {1- [2-Cyclopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1, 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Instead of 2-chloro-5- (trifluoromethyl) -1,3,4-thiadiazole, 4-chloro-2-cyclopropyl-6- (trifluoromethyl) pyrimidine (95 mg, 0.427 mmol) was used. The reaction was carried out in the same manner as in Example 6 to obtain the title compound (71 mg, yield: 58%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 10.28 (1H, s), 7.75 (1H, s), 7.23 (1H, s), 7.06 (1H, s), 4.63-4.35 (1H, m) , 3.07-2.87 (3H, m), 2.74 (1H, d, J = 16Hz), 2.13-1.66 (7H, m), 0.97-0.89 (4H, m);
MS (ESI) m / z: 491 (M + H) ^<+> .

(Reference Example 15)
To a suspension of sodium hydride (63%, 5.13 g, 135 mmol) in toluene (80 mL) at room temperature, ethyl 2-triethylsilyloxyacetate (reference J. Org. Chem., 2008, Vol. 73, No. 6268). -A compound described on page 6278, 18.4 g, 84.1 mmol) and a solution of ethanol (0.148 mL, 2.52 mmol) in toluene (40 mL) were added followed by ethyl trifluoroacetate (15.07 mL). , 126.2 mmol) in toluene (20 mL) was added and stirred for 5 minutes, followed by stirring at 80 ° C. for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. An oily crude product (23.6 g) was obtained.

Reference Example 16 4- [6,7-dihydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine-1- Yl] piperidine-1-carboxylate

Tert-Butyl 4- (4-nitro-1H-imidazol-1-yl) piperidine-1-carboxylate (compound described in WO 2005/92864, 6.2 g, 21 mmol) and 10% palladium-activity A suspension of carbon (1 g) in methanol (180 mL) was stirred under a hydrogen atmosphere for 5.5 hours. After filtration through Celite, the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the resulting powder was filtered off. The filtrate was further evaporated under reduced pressure to give a synthetic intermediate (5 .4 g) was obtained.

A part (2 g) of the synthetic intermediate obtained by the above operation and a part (7.1 g) of the oily crude product produced in Reference Example 15 in ethanol (30 mL) and acetic acid (10 mL) ) Was stirred at 80 ° C. for 5.5 hours. After cooling the reaction solution to room temperature, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: dichloromethane / methanol = 100 / 0-85 / 15], and further silica gel column chromatography [elution solvent: (i) hexane / ethyl acetate = 25/75. −0/100 (gradient), (ii) ethyl acetate / methanol = 97/3 (gradient)], and further silica gel column chromatography [NH-silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5 (gradient)] to give the title compound (280 mg, yield: 8.9%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.38 (1H, s), 7.81 (1H, s), 7.31 (1H, s), 5.80 (1H, d, J = 4Hz), 4.52-4.41 (2H, m), 4.21-3.99 (2H, m), 2.92-2.61 (2H, m), 2.12-2.03 (1H, m), 2.01-1.88 (1H, m), 1.86-1.78 (1H, m), 1.69- 1.54 (1H, m), 1.42 (9H, s).

Example 22 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

4- [6,7-Dihydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridine prepared in Reference Example 16 To a suspension of tert-butyl-1-yl] piperidine-1-carboxylate (0.265 g, 0.630 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was further stirred for 1 hour. Diethyl ether was added to the reaction solution to form a powder, and the solvent was removed by decantation to obtain a synthetic intermediate.

To a DMSO (3 mL) solution of the synthetic intermediate obtained by the above operation, 2-fluoro-5- (trifluoromethyl) pyrazine (0.142 mL, 1.26 mmol) and N, N-diisopropylethylamine (0 .429 mL, 2.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then left overnight. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50: 50-0 / 100 (gradient)] to give the title compound (0.28 g, yield: 95%). It was.

¹ H-NMR (DMSO-d ₆ ) δ: 10.39 (1H, s), 8.52-8.50 (2H, m), 7.79 (1H, s), 7.36 (1H, s), 5.83 (1H, d, J = 4Hz), 4.76-4.60 (3H, m), 4.51-4.46 (1H, m), 3.14-2.99 (2H, m), 2.24-2.16 (1H, m), 2.15-2.03 (1H, m), 1.97- 1.90 (1H, m), 1.84-1.70 (1H, m);
MS (ESI) m / z: 467 (M + H) ^<+> .

Example 23 (+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1 , 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1, prepared in Example 22 A mixed solution of 4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (0.28 g, 0.60 mmol) in ethyl acetate and methanol was adsorbed onto silica gel, The solvent was distilled off, and the resulting powder was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 70/30, flow rate: 12 mL / min] To obtain the title compound (107 mg, yield: 38%, optically active substance).

Optical purity was measured using HPLC [column: Chiralpak IA (4.6 mm id x 250 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 50/50, flow rate 1.0 mL / min].

Optical purity 99% (retention time: 10.6 minutes);
[α] _D ²⁵ = + 48 ° (DMF, c = 1.00).

Example 24 6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 , 7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

Using the method described in Example 22 using 2-fluoro-5- (trifluoromethyl) pyridine (0.13 mL, 1.1 mmol) instead of 2-fluoro-5- (trifluoromethyl) pyrazine. The reaction was conducted in the same manner to obtain the title compound (0.22 g, yield: 86%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.38 (1H, s), 8.41 (1H, d, J = 3Hz), 7.80 (1H, dd, J = 9Hz, 3Hz), 7.78 (1H, s), 7.34 (1H, s), 7.03 (1H, d, J = 9Hz), 5.80 (1H, d, J = 4Hz), 4.70-4.56 (3H, m), 4.51-4.47 (1H, m), 3.04-2.89 (2H, m), 2.22-2.14 (1H, m), 2.10-1.98 (1H, m), 1.96-1.88 (1H, m), 1.77-1.64 (1H, m);
MS (ESI) m / z: 466 (M + H) ^<+> .

Example 25 (+)-6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1 , 4,6,7-Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one

6,7-Dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1, prepared in Example 24 A mixed solution of 4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one (0.22 g, 0.47 mmol) in ethyl acetate (2 mL) and methanol (1 mL) was added to silica gel ( 3g), the solvent was distilled off under reduced pressure, and the obtained powder was flash LC [column: Chiralflash IA (30 mm id x 100 mm); manufactured by Daicel, elution solvent: hexane / ethanol = 80 / 20, flow rate: 12 mL / min] to obtain the title compound (96 mg, yield: 44%, optically active substance).

Optical purity 99% (retention time: 8.3 minutes);
[α] _D ²⁵ = + 45 ° (DMF, c = 0.958).

(Test Example 1) Measurement of LCAT activity (in vitro)
A density gradient centrifugation was performed to obtain a fraction composed of HDL3 (1.125 <specific gravity <1.210 g / mL) from plasma of a healthy person. The obtained fraction was dialyzed with phosphate buffered saline (pH 7.4) and used as an enzyme source and acceptor of LCAT. The test drug was prepared by dissolving in dimethyl sulfoxide. Phosphate buffered saline (pH 7.4) containing 1 mg / mL HDL3, DTNB (Ielman reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin [ ¹⁴ C] cholesterol containing, and various concentrations of test drug were added to make the total volume 80 μL. After this mixture was incubated at 37 ° C. for about 16 hours, a mixture of hexane and isopropanol (mixing ratio = 3: 2) was added to stop the reaction. After stirring, the hexane layer was collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) was added thereto, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate was measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Samples to which no test drug was added were similarly processed and measured. Using the following equation, compared with no addition of test drug was calculated EC ₅₀ values of LCAT activation. The results are shown in Table 1.

In the formula, X represents the logarithm of the concentration of the test drug,
Y represents the response of the test drug (LCAT activity),
Top indicates the maximum value (maximum plateau),
“Bottom” indicates a minimum value (minimum flat area);
EC ₅₀ indicates a 50% effective concentration.

Table 1
――――――――――――――――――――――――――――――
Test compound EC ₅₀ (μM)
――――――――――――――――――――――――――――――
Compound of Example 1 0.13
Compound of Example 2 0.069
Compound of Example 3 0.092
Compound of Example 4 0.049
Compound of Example 5 0.69
Compound of Example 6 0.46
Compound of Example 7 0.71
Compound of Example 8 0.054
Compound of Example 9 0.048
Compound of Example 10 0.46
Compound of Example 11 0.12
Compound of Example 12 0.39
Compound of Example 13 0.26
Compound of Example 14 0.14
Example 15 Compound 0.27
Compound of Example 16 0.21
Compound of Example 17 1.44
Compound of Example 18 0.52
Compound of Example 19 0.39
Compound of Example 20 0.14
Compound of Example 21 0.14
Compound of Example 22 0.034
Compound of Example 23 0.015
Compound of Example 24 0.065
Compound of Example 25 0.026
――――――――――――――――――――――――――――――

As described above, the compound of the present invention has an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.

(Test Example 2) Measurement of LCAT activity (plasma)
Human, cynomolgus monkey or human LCAT transgenic mouse plasma is used as an enzyme source and acceptor for LCAT. The test drug is prepared by dissolving in dimethyl sulfoxide. [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.5 mM), mercaptoethanol (final concentration 12.5 mM), and 0.6% bovine serum albumin was added to 5 μL of each plasma and 45 μL of PBS. Add the test drug at a concentration to make the total volume 80 μL. After incubating this mixture at 37 ° C. for about 16 hours, the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). The same processing and measurement is performed for the sample to which the test drug is not added. Using the following formula, the EC ₅₀ value of LCAT activation is calculated in comparison with the case where no test drug is added.

(Test Example 3) Measurement of LCAT activity (Ex vivo)
LCAT activity in plasma of cynomolgus monkeys or human LCAT transgenic mice administered with the test drug is measured. [25C] Each plasma is added with [14C] cholesterol containing DTNB (Ielman's reagent, final concentration 0.26 mM), mercaptoethanol (final concentration 2 mM), and 0.6% bovine serum albumin to a total volume of 40 μL. This mixture is incubated at 37 ° C. for 1 hour, and then the reaction is stopped by adding a mixture of hexane and isopropanol (mixing ratio = 3: 2). After adding water and stirring, the hexane layer is collected and concentrated to dryness. Chloroform solution (concentration 10 mg / mL) is added to this, spotted on a silica gel thin layer plate, and developed with a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio = 85: 15: 2). The radioactivity of the portion corresponding to cholesterol oleate is measured with an imaging analyzer BAS-2500 (manufactured by Fuji Film). Compared with the LCAT activity before administration, the rate of change in LCAT activation at each time point is calculated.

(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.

Table 2
――――――――――――――――――――――――――――――
Test compound Increased HDL after a single dose -------------
Compound of Example 2 897
Compound 1093 of Example 4
Compound 521 of Example 23
――――――――――――――――――――――――――――――

(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)
As described above, the compound of the present invention exhibits an excellent LCAT activation action and is useful as a medicament for the treatment or prevention of diseases such as dyslipidemia and arteriosclerosis.

Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.

Formulation Example 2 Soft Capsules A mixture of the compound of Example 2 in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into gelatin with a positive displacement pump, Soft capsules containing 100 mg of active ingredient are obtained, washed and dried.

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.

In addition, if desired, apply a coating.

(Formulation example 4) Suspension agent In 5 mL, 100 mg of the compound of Example 4 finely divided, 100 mg sodium carboxymethyl cellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia ) And 0.025 mL of vanillin.

(Formulation Example 5) Injection: 1.5% by weight of the compound of Example 6 is stirred in 10% by weight of propylene glycol, adjusted to a certain volume with water for injection, and then sterilized to give an injection. .

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent LCAT activation action, and in particular, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease. (Including acute coronary syndrome, heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorders and angiogenic restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (peripheral arterial disease, Treatment of diabetic vascular complications), dyslipidemia, LCAT deficiency, low HDL cholesterolemia, high LDL cholesterolemia, diabetes, hypertension, metabolic syndrome, Alzheimer's disease, corneal opacity, or renal disease or It is useful as an active ingredient of prophylactic agents, particularly anti-arteriosclerotic agents.

Claims

formula

[Wherein, R represents the formula (X)

{Wherein n is an integer of 1 or 2,
R 1 represents an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 Alkyl) an identical or different 1 to 3 group selected from the group consisting of amino groups), or
An optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is 1 or 2 nitrogen atoms, and further 1 nitrogen atom, An oxygen atom or a sulfur atom may be contained, and the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 alkyl And the same or different groups selected from the group consisting of amino groups. }, A group represented by
R 2 is a hydrogen atom or a hydroxyl group. Or a pharmacologically acceptable salt thereof.
The compound according to claim 1, wherein n is 1, or a pharmacologically acceptable salt thereof.
2. The compound according to claim 1, wherein n is 2, or a pharmacologically acceptable salt thereof.
R 1 is an aryl group which may be substituted (the substituent is a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group; , C 1-6 alkoxy, C 3-7 cycloalkoxy group, a phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl Moto及busy (C 1-6 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the alkyl group is the same or different 1 to 3 groups selected from the group consisting of amino groups.
R 1 represents a substituted aryl group (the substituent includes a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group, and a C 1-3 alkoxy group). The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, which is the same or different 1 or 2 groups selected from the group consisting of groups.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group). Item 4. The compound according to any one of Items 1 to 3, or a pharmacologically acceptable salt thereof.
R 1 is an optionally substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatoms on the ring of the heteroaryl group are 1 or 2 nitrogen atoms, Or a substituent such as a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group. , Cyano group, C 1-6 alkoxy group, C 3-7 cycloalkoxy group, phenyl group, C 2-7 alkoxycarbonyl group, benzyloxycarbonyl group, di (C 1-6 alkyl) aminocarbonyl group and di (C 6alkyl) the same or different 1 or 2 groups selected from the group consisting of amino groups.) is, of according to any one of claims 1 to 3 Object or a pharmaceutically acceptable salt thereof.
R 1 is a substituted heteroaryl group (the heteroaryl is a 5- or 6-membered ring. The heteroatom on the ring of the heteroaryl group is one nitrogen atom, and further one nitrogen atom May contain an oxygen atom or a sulfur atom, and the substituent is a halogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyano group. Or the same or different groups selected from the group consisting of a C 1-3 alkoxy group, a C 2-4 alkoxycarbonyl group, and a benzyloxycarbonyl group. Or a pharmacologically acceptable salt thereof.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound is a different one or two groups.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group.
The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12, wherein R 2 is a hydrogen atom.
7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
6- {4- [7-Hydroxy-5-oxo-7- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-b] pyridin-1-yl] piperidine- 1-yl} -4- (trifluoromethyl) pyridine-3-carbonitrile,
7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4 , 5-b] pyridin-5-one,
7-Hydroxy-7- (trifluoromethyl) -1- {1- [2- (trifluoromethyl) pyrimidin-5-yl] piperidin-4-yl} -1,4,6,7-tetrahydro-5H- Imidazo [4,5-b] pyridin-5-one,
1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one and
7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] pyrrolidin-3-yl} -1,4,6,7-tetrahydro-5H- 14. The compound according to claim 13 or a pharmacologically acceptable salt thereof selected from the group consisting of imidazo [4,5-b] pyridin-5-one.
(+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7- Tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- [2-isopropyl-6- (trifluoromethyl) pyrimidin-4-yl] piperidin-4-yl} -7- (trifluoromethyl) -1,4 6,7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one,
(+)-7-hydroxy-1- {1- (5-isopropoxypyridin-2-yl) piperidin-4-yl} -7- (trifluoromethyl) -1,4,6,7-tetrahydro-5H -Imidazo [4,5-b] pyridin-5-one and
(+)-1- {1- [5- (Difluoromethoxy) pyridin-2-yl] piperidin-4-yl} -7-hydroxy-7- (trifluoromethyl) -1,4,6,7-tetrahydro 14. The compound according to claim 13 or a pharmacologically acceptable salt thereof selected from the group consisting of -5H-imidazo [4,5-b] pyridin-5-one.
The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12, wherein R 2 is a hydroxyl group.
6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- 5H-imidazo [4,5-b] pyridin-5-one, and
6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6,7-tetrahydro- The compound or pharmacologically acceptable salt thereof according to claim 16, selected from the group consisting of 5H-imidazo [4,5-b] pyridin-5-one.
(+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyrazin-2-yl] piperidin-4-yl} -1,4,6 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one, and
(+)-6,7-dihydroxy-7- (trifluoromethyl) -1- {1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-4-yl} -1,4,6 The compound or pharmacologically acceptable salt thereof according to claim 16, selected from the group consisting of 7-tetrahydro-5H-imidazo [4,5-b] pyridin-5-one.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydrogen atom and n is 2.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group), and R The compound according to claim 1, wherein 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydrogen atom, and n is 2.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different one or two groups.), R 2 is a hydrogen atom, and n is 2, or a pharmacologically acceptable salt thereof.
The compound according to claim 1 , wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydrogen atom, and n is 2. Acceptable salt.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of chlorine atom, difluoromethoxy group, trifluoromethoxy group and cyano group). The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R 2 is a hydroxyl group and n is 2.
R 1 is a substituted phenyl group (the substituent is the same or different 1 or 2 groups selected from the group consisting of a difluoromethoxy group, a trifluoromethoxy group, and a cyano group), and R The compound according to claim 1, wherein 2 is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, thiadiazolyl group or thiazolyl group (the substituent is a chlorine atom, a fluorine atom, a C 1-3 alkyl group, a cyclopropyl group, a trifluoro group) 1 or 2 same or different groups selected from the group consisting of methyl group, difluoromethoxy group, trifluoromethoxy group, cyano group, C 1-3 alkoxy group, C 2-4 alkoxycarbonyl group and benzyloxycarbonyl group The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 2 is a hydroxyl group and n is 2.
R 1 is a substituted pyridyl group, pyrimidyl group, pyrazinyl group or pyridazinyl group (the substituent is the same selected from the group consisting of isopropyl group, trifluoromethyl group, difluoromethoxy group, cyano group and isopropoxy group) Or a different one or two groups.), R 2 is a hydroxyl group, and n is 2, or a pharmacologically acceptable salt thereof.
The compound according to claim 1 , wherein R 1 is a pyridyl group, pyrimidyl group or pyrazinyl group substituted with a trifluoromethyl group, R 2 is a hydroxyl group, and n is 2. Salt.
The compound according to any one of claims 1 to 28 or a pharmacologically acceptable salt thereof, wherein the 4-position trifluoromethyl group and the 5-position hydroxyl group of the imidazopyridine ring are cis.
The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 14, 16, 17, and 19 to 28, wherein the optical rotation is (+).
A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
An arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral, comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient A pharmaceutical composition for the prevention or treatment of vascular disease, dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, or renal disease.
A prophylactic or therapeutic agent for arteriosclerosis comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
A prophylactic or therapeutic agent for dyslipidemia comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
A preventive or therapeutic agent for a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
A preventive or therapeutic agent for a disease caused by a decrease in blood HDL cholesterol concentration, comprising as an active ingredient the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
An LCAT activator comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
A reversible LCAT activator comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
An anti-arteriosclerotic agent comprising the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof as an active ingredient.
A method for activating LCAT, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
A method for preventing or treating a disease, comprising administering an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof to a human.
A method for the prevention or treatment of arteriosclerosis, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
A method for the prevention or treatment of dyslipidemia, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof.
Prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof. Or a method for treatment.
Prevention of a disease caused by a decrease in the concentration of HDL cholesterol in the blood, comprising administering to a human an effective amount of the compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof. Or a method for treatment.
The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for treating or preventing arteriosclerosis.
The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for the treatment or prevention of dyslipidemia.
The compound according to any one of claims 1 to 30 or a pharmacologically acceptable salt thereof for use in a method for the treatment or prevention of a disease caused by an increase in the concentration of LDL cholesterol in blood.
The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30, for use in a method for the treatment or prevention of a disease caused by a decrease in the concentration of HDL cholesterol in blood.