MXPA06009855A - Coumarin derivative and use thereof - Google Patents

Abstract

The present invention relates to an alkaline earth metal salt or an organic amine salt of a compound represented by the formula [I]:wherein R1 and R2 are each a hydrogen atom, a halogen atom, or an optionally substituted linear hydrocarbon group;ring A is an optionally further substituted benzene ring;B is an optionally substituted benzene ring;R is a carboxyl group or a linear hydrocarbon group substituted with a carboxyl group and the like.

Description

DERIVED FROM COUMARINE AND USE OF THE SAME Field of the Invention The present invention relates to a novel coumarin derivative having lipid-rich plate regression activity and / or acyl coenzyme A cholesterol acyl transferase (ACAT) inhibitor activity (ACAT), which has superior properties as a medicament for preventing or treating coronary syndrome such as myocardial infarction, unstable angina and the like, peripheral arterial occlusion, hyperlipaemia, cerebral infarction, cerebral apoplexy, arteriosclerosis, atherosclerosis, Alzheimer's disease, or the like.

Background of the Invention Coronary syndrome (eg, unstable angina, myocardial infarction, sudden ischemic death, and the like) is caused by rupture of a coronary arterial plaque (atheroma) followed by thrombus formation and occlusion resulting from the lumen of the coronary artery. a coronary artery. The occlusion of a peripheral artery is caused by the rupture of an arterial plaque (atheroma) followed by the formation of a thrombus and the occlusion resulting from the lumen of a peripheral artery. These diseases are closely related to the characteristics of a plaque, and a plate rich in lipids Ref.: 174733 formed by accumulation of lipids that retain macrophage such as cholesterol extensively in the inner wall of a blood spleen, is considered to cause syndrome -coronary and peripheral arterial occlusion. A lipid-rich plaque formed in the carceid artery or intracerebral spleen is considered to cause cerebral apoplexy or myocardial infarction. Consequently, the regression and removal of a plate rich in lipids are very important to prevent or treat coronary syndrome such as myocardial infarction and unstable angina as well as peripheral arterial occlusion, cerebral apoplexy, or cerebral infarction. Also, since a lipid-rich plaque is observed in a human whose blood cholesterol level is not high and a lipid-rich plaque once formed is difficult to remove, an agent capable of effective regression of the lipid is desirable. plate rich in lipids. Prior to this, it was known that coumarin derivatives of a particular structure have lipid-rich plaque regression activity and / or ACAT inhibitory activity, and are useful for preventing or treating coronary syndrome and the like (W002 / 06264 and W003 / 059900).

Brief Description of the Invention, The present invention is directed to providing novel compounds which are clinically useful as well as a medicament for preventing or treating a coronary syndrome such as myocardial infarction and unstable angina, as well as occlusion of peripheral artery, cerebral apoplexy or cerebral stroke . The present inventors find that novel salts of coumarin derivatives have a particular structure that possesses unexpected excellent properties (eg, physicochemical properties such as crystallization capacity, stability and the like) as well as oral absorbency, return of lipid-rich plaques potentially in vivo, and can be extremely superior compounds clinically as an agent to prevent or treat a coronary syndrome such as myocardial infarction and unstable angina, as well as peripheral arterial occlusion, cerebral stroke, cerebral infarction or the like, which results in the termination of the present invention. That is, the present invention relates to: (1) an alkaline earth metal salt or an organic amine salt of a compound represented by the formula [I]: wherein R1 and R2 are each a hydrogen atom, a halogen atom, or an optionally substituted linear hydrocarbon group; Ring A is a benzene ring optionally further substituted; Ring B is an optionally substituted benzene ring; R is a carboxyl group or a linear hydrocarbon group substituted with a carboxyl group; (2) the compound according to the previous one (1), which is hydrate; (3) the compound according to the above (1), wherein R1 and R2 are each a halogen atom or an optionally substituted C7-7 alkyl group; (4) the compound according to the above (1), wherein ring B is a benzene ring which is substituted with a halogenated alkyl group and / or a halogen atom; (5) the compound according to the above (1), wherein R is a group represented by the formula - (CH2) n -R 'wherein R' is a carboxyl group and n is an integer from 0 to 6; (6) the compound according to the above (1), wherein R is a group represented by the formula - wherein R 'is a carboxyl group and n "is an integer from 1 to 3; (7) the compound in accordance with the previous one (1), which is an alkaline earth metal salt; (8) the compound according to the above (7), wherein the alkaline earth metal salt is a calcium salt; (9) the compound according to the above (1), which is an organic amine salt; (10) the compound according to the above (9), wherein the organic amine salt is a primary amine salt; (11) the compound according to the above (10), wherein the primary amine salt is a tris (hydroxymethyl) methylamine salt; (12) a compound selected from the group consisting of bis ((2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2- oxoethyl) -6-methyl-2-oxo-2H-chromo-4-yl] phenyl] acrylate) of monocalcium, (2E) -3- [3- [7-chloro-3- (2- [[4 -fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromo-4-yl] phenyl] tris (hydroxymethyl) methylamine acrylate, salt of (2E) - 3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromium-4- il] phenyl] diethanolamine acrylate, bis (3- [3- [6-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl- 2-oxo-2H-chromo-4-yl] phenyl] propionate) of monocalcium and bis (4- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] ] -2-oxoethyl) -6-methyl-2-oxo-2H-chromo-4-yl] phenyl] butanoate) of monocalcium, or a hydrate thereof; (13) a process for producing an alkaline earth metal salt of a compound represented by the formula [13: wherein each symbol is as defined above, which comprises reacting a compound represented by the formula [I] with an alkaline earth metal hydroxide or an alkaline earth metal hydride, or reacting an alkali metal salt of a compound represented by the formula [I] with an alkaline earth metal halide; (14) a crystal of the compound according to the above (1); (15) a medicament comprising the compound according to the above (1) or a crystal thereof; (16) the medicament according to the above (15), which is an oral preparation; (17) the medicament according to the above (15), which is a lipid-rich plaque regression agent or an ACAT inhibitor; (18) the medication according to the previous one (15), which is a prophylactic or therapeutic agent against coronary syndrome, myocardial infarction, unstable angina, coronary arterial restenosis after stent placement or PTCA, peripheral arterial occlusion, hyperlipemia, cerebral infarction, cerebral apoplexy, Alzheimer's disease, multiple risk syndrome or metabolic syndrome, or a regression agent, inhibition of the progress of a stabilizer or atherosclerotic or atherosclerotic lesion; (19) the regression agent, inhibiting the progress of or stabilizing an atherosclerotic or atherosclerotic lesion according to the previous one (18), which is combined with a reductase inhibitor HMG-CoA; (20) a method for regression of a lipid-rich plate or ACAT inhibition in a mammal, which comprises administering an effective amount of the compound according to the above (1) to the mammal; (21) a method to prevent or treat coronary syndrome, myocardial infarction, unstable angina, coronary artery restenosis after stent placement or PTCA, peripheral arterial occlusion, hyperlipemia, cerebral infarction, cerebral apoplexy, Alzheimer's disease, multiple risk or metabolic syndrome, or regression, inhibition of progress or stabilization of atherosclerotic or atherosclerotic lesion in a mammal, which comprises administering an effective amount of the compound according to the above (1) to the mammal; (22) the regression method, inhibit the progress of or stabilize an atherosclerotic or atherosclerotic lesion according to the previous one (21), which comprises administering to the compound according to the above (1) in combination with a reductase inhibitor HMG -CoA; (23) the use of the compound according to the above (1) for the production of a lipid-rich plaque regression agent or an ACAT inhibitor; _. (24) the use of the compound according to the above (1) for the production of a prophylactic or therapeutic agent against coronary syndrome, myocardial infarction, unstable angina, coronary arterial restenosis after stenting or PTCA, arterial occlusion peripheral, hyperlipidemia, cerebral infarction, cerebral apoplexy, Alzheimer's disease, multiple risk syndrome or metabolic syndrome, or a regression agent, inhibiting the progress of or stabilizing an atherosclerotic or atherosclerotic lesion; (25) the use of the compound according to the above (1) for the production of a regression agent, inhibiting the progress or stabilizing an atherosclerotic or atherosclerotic lesion in accordance with the above (24), which is combined with an inhibitor of HMG-CoA reductase; and similar.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is the X-ray powder diffraction pattern of the crystals obtained by Example 1. FIG. 2 is the X-ray powder diffraction pattern of the crystals obtained by Example 2. FIG. 3 is the X-ray powder diffraction pattern of the crystals obtained by Example 3.

Detailed Description of the Invention In formula [I], R1 and R2 are each a hydrogen atom, a halogen atom, or an optionally substituted linear hydrocarbon group. As the "linear hydrocarbon group" of the "optionally substituted linear hydrocarbon group" represented by R1 and R2, for example, an alkyl group, an alkenyl group, an alkynyl group and the like are used. Alternatively, a group in which two or three of the carbon to carbon bonds of an alkyl group are converted to double bonds, such as an alkadienyl group or an alktrienyl group may be used. As the alkyl group, for example, a linear or branched alkyl group having 1 to 7 carbon atoms is used and, preferably, for example, a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl is used.

As the alkenyl group, for example, an alkenyl group having 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl is used and preferably, for example, an alkenyl group having 2 to 4 Carbon atoms such as ethenyl, propenyl, isopropenyl or isobutenyl is used. As the alkynyl group, an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl or sec-butynyl was used and preferably, an alkynyl group having 2 to 4 carbon atoms such as ethynyl , propynyl, isopropynyl or isobutynyl are used. Examples of the group in which two or three of the carbon to carbon bonds of an alkyl group are converted to double bonds include a group in which two or three of the carbon to carbon bonds of a linear or branched C 3-7 alkyl group (preferably, linear alkyl group) are converted to double bonds and, preferably, an alkadienyl group having 4 to 6 carbon atoms such as butadienyl, and an alktrienyl group such as 1,3,5-hexatrienyl were used. As the linear hydrocarbon group, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and a linear or branched Ca4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl is particularly preferable. Examples of a substituent for the "optionally substituted linear hydrocarbon group" represented by R1 and R2 include an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an acyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an oxo group, a carboxyl group, a nitro group, a cyano group, an optionally substituted alkyl group and the like. The "linear hydrocarbon group" can be substituted with 1 to 5 (preferably, 1 to 3) of these optional substituents in substitutable positions.

Examples of the "aryl group" of the "optionally substituted aryl group" include a C6.16 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, and the like. inter alia, a Cß-io aryl group such as phenyl, 1-naphthyl, 2-naphthyl and the like is preferable. Examples of a substituent for the aryl group include (i) an optionally halogenated C6-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, trifluoromethoxy, etc.), (ii) a halogen atom (e.g., fluorine). , chlorine, bromine, iodine), (iii) an optionally halogenated C? .6 alkyl group (eg, methyl, ethyl, propyl, trifluoromethyl, etc.) and the like. The aryl group can be substituted with 1 to 2 of these optional substituents. Examples of the "cycloalkyl group" of the "optionally substituted cycloalkyl group" include a C3_7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclic pentyl, cyclohexyl, cycloheptyl, and the like. A substituent for the cycloalkyl group and the number of substituents are similar to those for the aryl group optionally substituted above. Examples of the "cycloalkenyl group" of the "optionally substituted cycloalkenyl group" include a C3_6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. A substituent for the cycloalkenyl group and the number of substituents are similar to those of the above-mentioned optionally substituted aryl group. Examples of the "heterocyclic group" of the "optionally substituted heterocyclic group" include an aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) which contains at least one, preferably 1 to 4, heteroatoms selected from oxygen, sulfur and nitrogen as an atom that constitutes a ring system (atom in the ring). The non-aromatic heterocyclic group is preferable. Examples of the "aromatic heterocyclic group" include a 5- to 6-membered aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, , 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3-thiadiazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and an aromatic fused heterocyclic group in which 2 to 3 of the rings of 5 to 6 members (the aromatic monocyclic heterocyclic ring of 5 to 6 members mentioned above, benzene ring, etc.) are fused (for example: benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, IH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1, 2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl or, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, α-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxyntinyl, thiantrenyl, phenyanizinyl, phenanthrolinyl, indolizinyl, pyrrolo [1, 2-b] pyridazinyl, pyrazolo [1, 5-a] pyridyl, imidazo [1, 2-a] iridyl, imidazo [1, 5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1, 2-a] pyrimidinyl, 1,2,4-triazolo [4, 3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc.). inter alia, an aromatic monocyclic 5- to 6-membered heterocyclic group such as furyl, thienyl, pyrazinyl, pyridyl and pyrimidinyl is preferred. Examples of the "non-aromatic heterocyclic group" include a non-aromatic monocyclic group of 4 to 9 heterocyclic members such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like (en in particular, a cyclic amino group of 5 to 9 members which contains 1 to 3 heteroatoms such as an oxygen atom or a sulfur atom in addition to a nitrogen atom, such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and 3,6- dihydropyridin-1 (2H) -yl), a fused heterocyclic group of 1 to 2 (preferably 1) of the above-mentioned non-aromatic monocyclic heterocyclic groups and 1 to 2 (preferably 1) of the benzene rings, such as 2,3-dihydroindolyl, 1,3-dihydroisoindolyl and the like, a fused heterocyclic group of 1 to 2 (preferably 1) of the above-mentioned non-aromatic monocyclic heterocyclic groups and 1 to 2 (preferably 1) of the aforementioned aromatic monocyclic heterocyclic group of 5-6 members, and a non-aromatic heterocyclic group in which a part or all of the double bonds of the aforementioned monocyclic aromatic heterocyclic group or aromatic fused heterocyclic group is saturated, such as 1, 2, 3, 4-tetrahydroquinolyl, 1, 2, 3, 4-tetrahydroisoquinolyl and the like. The heterocyclic group can be substituted with 1 to 4, preferably 1 to 2 substituents. Examples of such a substituent include an optionally halogenated C? _ Alquilo alkyl group, (e.g., methyl, ethyl, propyl, n-butyl, n-hexyl, etc.), an optionally halogenated C 5? 2 aryl group. (e.g., phenyl), a hydroxy-aryl group Ce-? 2 (for example, 4-hydroxyphenyl), an optionally halogenated alkylsulfonyl group Cx_4 (for example, methylsulfonyl), a C7_ aralkyl group? (e.g., benzyl), a C4 alkoxy group, optionally halogenated Cx_ alkyl (e.g., propoxyethyl, etc.), a 5- to 9-membered heterocyclic group which contains 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (for example, piperidyl, piperazinyl, morpholinyl, thienyl, furyl, pyridinyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), a hydroxy group, an oxo group, a thioxo group and the like.

Examples of a substituent for the "optionally substituted amino group" (including an amino group and a mono- or di-substituted amino group) include an optionally halogenated lower alkyl (LS) group (e.g., methyl, ethyl, propyl, etc.), an optionally halogenated C6.12 aryl group (eg, phenyl), a 5- to 9-membered heterocyclic group which contains 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (eg, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), an optionally halogenated C 1 _ 4 -carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, etc.) .), a C6-? 2-carbonyl aryl group (eg, benzoyl, etc.), an optionally halogenated C? _4-sulfonyl alkyl group, and an optionally halogenated C? _4 C4_4alkyl group optionally halogenated. In addition, the two substituents of a di-substituted amino group can be taken together with the nitrogen atom to form a "cyclic amino group". The "cyclic amino group" includes a cyclic amino group (preferably from 5 to 6 members) 3 to 8 members such as 1-azetidinyl, 1-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl (the sulfur atom can be oxidized), and 1-piperazinyl which can be substituted at the 4-position with alkyl optionally substituted lower (e.g., C?-e alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), optionally substituted aralkyl (e.g., C7-10 aralkyl such as benzyl) , phenethyl, etc.), optionally halogenated aryl (eg, C7-? 0 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.) or the like. Examples of the "optionally substituted alkyl group" include a C? .6 alkyl group (eg, methyl, ethyl, propyl, n-butyl, n-hexyl, etc.) which can be substituted with a halogen atom ( example, fluorine, chlorine, bromine, iodine) or the like. Examples of the "optionally substituted hydroxyl group" include a hydroxyl group, an optionally halogenated C 16 alkoxy group, preferably an optionally halogenated C 1-4 alkoxy group, more preferably a C4_4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, t-butoxy, etc.), a C6_6-carbonyloxy alkyl group (e.g., methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy, etc.) , an aminocarbonyloxy group, and a mono- or di-alkylaminocarbonyloxy group Cx_4. Examples of the "optionally substituted thiol group" include a thiol group, an optionally halogenated C 1 -C 6 alkylthio group, preferably optionally halogenated C 1 -4 alkylthio group, more preferably C 4 alkylthio group (eg, methylthio, ethylthio, etc.) and a 5- to 9-membered heterocyclic group, the heterocyclic group contains 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (eg, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazoyl, benzoxazolyl, benzisoxazolyl, etc.), such as 2-pyridylthio. Examples of the "acyl group" include a formyl group, a C? _-Carbonyl alkyl group (preferably C? _4-carbonyl alkyl group (e.g., methylcarbonyl, ethylcarbonyl), a C? -4-carbonyl alkoxy group (by example, methoxycarbonyl)? an optionally halogenated C? _6-sulfonyl alkyl group (preferably C? _4-sulfonyl alkyl group (e.g., methylsulfonyl, ethylsulfonyl), an optionally halogenated C? _6-sulfinyl alkyl group (preferably C?-β-sulfinyl alkyl group (e.g., methylsulfinyl, ethylsulfinyl), a C?-α-sulfonyl alkoxy group (for example, methoxysulfonyl), a benzyloxycarbonyl group, a C 3-6 cycloalkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group C 1-4 and the like. More specifically, as a substituent for the linear hydrocarbon group, 1 to 4 substituents selected from a halogen atom; an amino group; a mono or dialkylamino group C? _4; a carboxyl group; a C4_4 alkoxycarbonyl group; a hydroxy group; an optionally halogenated C 4 -4 alkoxy group; a C3.e cycloalkyl group; a nitro group; a cyano group; an optionally halogenated C 1 _ 4 alkylthio group; a cyclic amino group substituted with 1 to 2 substituents selected from (i) a C? _4 alkyl group, (ii) a C? _4 alkylsulfonyl group, (iii) a C 6 - ar 2 aryl group which can be substituted with an atom of halogen or a hydroxy group, (iv) a C 7_ 15 aralkyl group, (v) a C 4 -4 alkoxy group, L 4 alkyl, (vi) a 5- to 9-membered heterocyclic group containing 1 to 3 heteroatoms as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and (vii) a hydroxy group (for example, a cyclic amino group of 5 to 9 members which may contain 1 to 3 heteroatoms such as oxygen atom and sulfur atom in addition to a nitrogen atom, more specifically, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.); a C4_4-carbamoylamino alkyl group; an aminocarbonyloxy group; a mono- or di-alkylaminocarbonyloxy group Ci_4; an alkylsulfonylamino group C? _4; a C 4 -4-carbonyl alkoxy group; a benzyloxycarbonyl group; a carboxyl group; a C6_6-carbonyl alkyl group; a C3-6-carbonyl cycloalkyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group C? _4; an alkylsulfonyl group C? _6; a C4_4-carbonyloxy alkyl group; an amino group substituted with C 1 -4 alkyl and a 5- to 9-membered heterocyclic group containing 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms; an amino group substituted with C? _4 alkyl and C? -4-carbonyl alkyl; an amino group substituted with C? _4 alkyl and C 6 - 2 2 -carbonyl aryl; a C6-6-carbonyloxy alkyl group; a mono- or di-alkoxy group C? _-C4_4alkyl; a heterocyclic-thio group of 5 to 9 members, the heterocyclic group contains from 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms; and an oxo group are used. Like each of R1 and R2, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom), an optionally substituted C? _7 alkyl group (preferably C? _ Alkyl group such as methyl) , ethyl and propyl, particularly preferably methyl), an optionally substituted C2_6 alkenyl group (preferably ethenyl) and the like are preferred. inter alia, a halogen atom and an optionally substituted C? _7 alkyl group are preferable. The "C? _7 alkyl group" of the "optionally substituted C? _7 alkyl group" may have an oxo group as such a substituent. When the alkyl group Ca_7 is substituted with an oxo group at the a-position, this can form a C? _7 alkanoyl such as formyl and acetyl. As a substituent for the "optionally substituted C 1-7 alkyl group", for example, (i) a hydroxy group, (ii) a mono- or di-alkylamino C? _4 group (e.g., dimethylamino, diethylamino) are preferred. , (iii) an amino group substituted with C alquilo _ alkyl and a 5- to 9-membered heterocyclic group containing 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms ( for example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazoyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.) (e.g., methyl (2-pyridyl) amino), (iv) an amino group substituted with Cx_4 alkyl and C4_4-carbonyl alkyl (e.g., methyl (methylcarbonyl) amino), (v) an amino group substituted with C? _4 alkyl and C6-? 2-carbonyl aryl (for example, methyl (benzoyl) amino), (vi) a mono- or di-alkoxy group C? _4-C? _4 alkyl (eg, butoxypropylamino), (vii) a group 5- to 9-membered cyclic amino which contains 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom, which can be substituted with optionally substituted C6-? 2 aryl with 1 to 4 substituents selected from C 1 alkyl (for example, methyl), a halogen atom, a hydroxy group and optionally substituted C 1 _ 4 alkyl (for example, phenyl, 4-hydroxyphenyl, 4-chlorophenyl, 3-methylphenyl), alkylsulfonyl. C 1 - (for example, methylsulfonyl), C 7 - aralkyl optionally substituted with 1 to 4 substituents selected from a halogen atom, hydroxy group and optionally halogenated C 4 alkyl (for example, benzyl), C 4 - alkoxy C 1 -C 4 alkyl ? 4 (for example, propoxyethyl, etc.), a 5- to 9-membered heterocyclic group containing 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (e.g. , piperidyl, piperazinyl, morpholinyl, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl), a hydroxy group and the like (e.g., pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, 3,6-dihydropyridin-1 (2H) -yl) (preferably piperazinyl substituted with a phenyl group in the 4-position, wherein the phenyl group may be halogenated), (viii ) a C6-6-carbonyloxy alkyl group (for example, methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy, etc.), (ix) a heterocyclic-thio group of 5-9 members, the heterocyclic group containing 1 to 3 heteroatoms such as an atom of nitrogen, an oxygen atom and a sulfur atom in addition to carbon atoms (for example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), such as 2-pyridylthio.

As "a substituent for the C2.6 alkenyl group, for example, C4_4-carbonyl alkoxy (e.g., methoxycarbonyl) is preferable." As R1 and R2, a halogen atom, an optionally substituted C7_7 alkyl group and the like (in particular, methyl) are preferable, respectively, and particularly, R1 is a halogen atom and R2 is a C? _ alkyl group (in particular, methyl). In formula [I], ring A represents a ring of benzene optionally further substituted In the formula [I], the ring-, B represents an optionally substituted benzene ring In the formula [I], a substituent for an optionally substituted benzene ring further represented by the ring A or a ring of optionally substituted benzene represented by ring B includes (i) an optionally halogenated C? _4 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl) , is opropyl, 3,3,3-trifluoropropyl, butyl, etc.); (ii) a C? _4 alkyl group substituted with an amino group (eg, aminomethyl, 2-aminoethyl, etc.); (iii) a C?-substituted alkyl group with a mono- or di-C 1-4 alkylamino group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, etc.); (iv) a C? -4 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl, etc.); (v) a C? _4 alkyl group substituted with a C?-carbonyl alkoxy group (eg, methoxycarbonylethyl, ethoxycarbonylethyl, etc.); (vi) a C? _4 alkyl group substituted with a hydroxy group (eg, hydroxymethyl, hydroxyethyl, etc.); (vii) a C4_4 alkyl group substituted with a C4_4 alkoxy group which can be substituted with a C4_4 alkoxy group or a phenoxy group (e.g., methoxymethyl, methoxyethyl, ethoxyethyl, etc.); (viii) a C3_6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.); (ix) a halogen atom (eg, fluorine, chlorine, bromine, iodine); (x) a nitro group; (xi) a cyano group; (xii) a hydroxy group; (xiii) an optionally halogenated C 1 - alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, butoxy, isopropoxy, etc.), C x alkoxy group which can be substituted with a C4_4 alkoxy group or a phenoxy group; (xiv) an optionally halogenated alkylthio C? _4 group (for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), an alkylthio C 4 group which can be substituted with a C 1-4 alkoxy group or a phenoxy group; (xv) an amino group; (xvi) a mono- or di-alkylamino C? _4 group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.); (xvii) a cyclic amino group (eg, a 5- to 9-membered cyclic amino group which contains 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom, specifically, pyrrolidinyl, piperidyl , piperazinyl, morpholinyl, etc.); (xviii) a C 4 -4 -carbamoylamino alkyl group (for example, acetylamino, propionylamino, butyrylamino, etc.); (xix) an aminocarbonyloxy group; (xx) a mono- or di-alkylamino CX-4-carbonyloxy group (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.); (xxi) a C? -4 alkylsulfonylamino group (eg, methylsulfonyloamino, ethylsulfonylamino, propylsulfonylamino, etc.); (xxii) a C? -4-carbonyl alkoxy group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.); (xxiii) a benzyloxycarbonyl group; (xxiv) a carboxyl group; (xxv) a C6_6-carbonyl alkyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.); (xxvi) a C3.6 carbonyl cycloalkyl (eg, cyclohexylcarbonyl, etc.); (xxvii) a carbamoyl group; (xxviii) a mono- or di-alkylcarbamoyl C? _4 group (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.); (xxix) a C 1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.); C3-6 cycloalkylsulfonyl (for example, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.); (xxx) a C? -6 alkyl group substituted with an aminocyclic group (for example, a 5- to 9-membered cyclic amino group which contains 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to the nitrogen, specifically, pyrrolidinyl, piperidyl, piperazinyl, 3,6-dihydropyridin-1 (2H) -yl, [1, 3] thiazolo [4, 5-b] pyridin-3 (2H) -yl, morpholinyl, etc.) substituted with 1 or 2 substituents selected from (a) C 1 - alkyl (eg, methyl), (b) C 1 - 4 alkylsulfonyl (eg, methylsulfonyl), (c) a C 6 - i 2 aryl group which may have alkyl C 4 optionally halogenated (for example, methyl, trifluoromethyl), halogen (for example, fluorine, chlorine) or a hydroxy group (for example, phenyl, naphthyl, hydroxyphenyl, methylphenyl, chlorophenyl, etc.), (d) C 7 aralkyl -? 5 (for example, benzyl, etc.), (e) C 1-4 alkoxy-CX- alkyl (eg, propoxyethyl, etc.), (f) a 5- to 9-membered heterocyclic group containing and 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms (for example, piperidyl, piperazinyl, morpholinyl, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), (g) hydroxy, thiol, oxo and thioxo (for example, morpholinomethyl, 4-phenyl-1-piperazinylmethyl, 2-morpholinoethyl, 3-piperazinylpropyl, 4-methylsulfonyl-piperazinylmethyl, 4-benzyl- 1-piperazinylmethyl, 4- (4-hydroxyphenyl) -1-piperazinylmethyl, 4-hydroxypiperidinylmethyl, 4-hydroxy-4-phenyl-piperidylmethyl, 4-phenylpiperidylmethyl, 4- (2-pyridyl) -1-piperazinylmethyl, 4- (4 -hydroxyphenyl) -1-piperazinylmethyl, (4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl, etc.); (xxxi) a C4_4 alkyl group substituted with a C s_carbonyloxy alkyl group (e.g., methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy, etc.); (xxxii) C alquilo _ alkyl group substituted with an amino group substituted with C? _4 alkyl and a 5- to 9-membered heterocyclic group containing 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition .. carbon atoms (eg, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.) (eg, methyl (2-pyridyl) amino); (xxxiii) a C? _4 alkyl group substituted with an amino group substituted with C? _4 alkyl and C? _-carbonyl alkyl (eg, methyl (methylcarbonyl) amino); (xxxiv) a C? _4 alkyl group substituted with an amino group substituted with C? _4 alkyl and C ar_?-carbonyl aryl (e.g., methyl (benzoyl) amino); (xxxv) a C? _4 alkyl group substituted with a C?-6-carbonyloxy alkyl group (e.g., methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy, etc.); (xxxvi) a Cx_ alkyl group substituted with a mono- or di-alkoxy C? _4-C? _4 alkyl group (e.g., butoxypropylamino); (xxxvii) a C4_4 alkyl group substituted with a 5- to 9-membered heterocyclic-thio group, the heterocyclic group containing 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to atoms carbon (for example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), such as 2-pyridylthio; (xxxviii) an oxo group; (xxxix) a C2_-carbonyl alkenyl C2_s alkoxy group (e.g., methoxycarbonylvinyl, etc.); (xxxx) a C2.sub.s alkenyl group substituted with a carboxyl group (eg, carboxyvinyl, etc.); (xxxxi) a C? _4 alkyl group substituted with a cyano group (eg, cyanomethyl, etc.); (xxxxii) a C6_? 0 aryl group (eg, phenyl, naphthyl, etc.), phenoxy, benzoyl, phenoxycarbonyl, phenyl-alkylcarbamoyl C? _, phenylcarbamoyl, phenyl-C? _4-carbonylamino, benzoylamino, phenyl-C-4-alkylsulfonyl, phenylsulfonyl, phenyl-C-4-phenylsulfinyl, phenyl-alkylsulfonylamino C? _4 or phenylsulfonylamino [each phenyl group or each Naphthyl group can be substituted with 1 to 3 substituents such as a C? _4 alkyl group (eg, methyl, ethyl, propyl, butyl, isopropyl, etc.), a C? _ alkoxy group (eg, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy etc.), a halogen atom (for example, chlorine, bromine, iodine, etc.), a hydroxy group, a benzyloxy group, an amino group, a mono or dialkylamino group Cx_4 (for example, methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, etc.), a nitro group, and a C6_6 alkylcarbonyl group (for example, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, etc.) in substitutable position] and the like. The benzene ring or the aromatic ring can be substituted with 1 to 5, preferably 1 to 3 of these substituents in the substitutable positions, wherein these substituents can be the same or different from one another. Preferable examples of such a substituent include (i) a halogen atom (e.g., fluorine, chlorine, bromine, etc.), (ii) an optionally halogenated C? -4 alquilo alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, etc.), (iii) a C3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, etc.), (iv) a hydroxy group, (v) a C4-4 alkoxy group optionally halogenated (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, etc.), (vi) an optionally halogenated alkylthio CX group (eg, methylthio, trifluoromethylthio, ethylthio, etc.), (vii) an amino group, (viii) ) a mono- or di-alkylamino C? -4 group (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), (ix) a C? _ -carbonyl alkoxy group (for example, methoxycarbonyl, ethoxycarbonyl etc.), ( x) a C2-6 alkyl group substituted with a cyclic amino group (for example, a cyclic amino group of 5 to 9 members which contains 1 to 3 hetero) atoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom, specifically, pyrrolidinyl, piperidyl, morpholinyl, etc.) which can be substituted with aryl group C6_? 2 (for example, phenyl, naphthyl, etc. ) (for example, morpholinomethyl, 4-phenyl-1-piperazinylmethyl, 2-morpholinoethyl, 3-piperazinylpropyl, etc.) and (xi) a carboxyl group. Particularly preferred are (i) a halogen atom (eg, fluorine, chlorine, etc.), (ii) C4 alkyl (eg, methyl, ethyl, etc.) (iii) a C3-6 cycloalkyl group (e.g. , cyclopropyl, cyclobutyl, etc.), (iv) a hydroxy group, (v) an alkoxy group L4 (for example, methoxy, ethoxy, etc.), (vi) an alkyl group C_e substituted with a cyclic amino group (eg example, a 5- to 9-membered cyclic amino group which contains 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom, specifically, pyrrolidinyl, piperidyl, piperazinyl, 3,6-dihydropyridin-1 (2H) -yl, morpholinyl, etc.) which can be substituted with an aryl group C6-i2 (for example, phenyl, naphthyl, etc.) (eg, morpholinomethyl, 4-phenyl-1-piperazinylmethyl, 2-morpholinoethyl, (4-phenyl-3,6-dihydropyridin-1 (2H) -ylmethyl), 3-piperazinylpropyl, etc.) and (vii) one group carboxyl. As ring A, a benzene ring which can be further substituted with an alkyl group, a halogenated alkyl group or a halogen atom in addition to the substituent represented by R is preferably a benzene ring which can also be substituted with a C? _4 alkyl group / a halogenated C? -4 alquilo alkyl group or a halogen atom in addition to the substituent represented by R is further preferred, and a benzene ring substituted with only the substituent represented by R is particularly preferable. As the ring B, a benzene ring which can be substituted with a halogenated alkyl group and / or a halogen atom is preferably and, inter alia, a benzene ring which can be substituted with a halogenated C 4 alkyl group ( preferably trifluoromethyl) and / or a halogen atom is particularly preferable (more preferably, a benzene ring substituted with a halogenated C? _4 alkyl group and / or a halogen atom). In the formula [I], R represents a carboxyl group or a linear hydrocarbon group substituted with a carboxyl group. As the "linear hydrocarbon group" of the "linear hydrocarbon group substituted with a carboxyl group" represented by R, for example, an alkyl group, an alkenyl group, an alkynyl group and the like are used. Alternatively, a group in which two or three of the carbon to carbon bonds of an alkyl group are converted to double bonds, such as an alkadienyl group can be used.

As the alkyl group, for example, a linear or branched alkyl group having 1 to 7 carbon atoms is used and, preferably, for example, a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl are used. As the alkenyl group, for example, an alkenyl group having 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl are used and, preferably, for example, an alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl or isopropenyl are used. As the alkynyl group, an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl or sec-butynyl are preferably used, an alkynyl group having 2 to 4 carbon atoms such as ethynyl , propynyl or isopropynyl are used. Examples of the group in which two or three of the carbon to carbon bonds of an alkyl group are converted to double bonds include a group in which two or three of the carbon to carbon bonds of a linear C3.7 alkyl group or branched (preferably, linear alkyl group) are converted to double bonds and preferably, an alkadienyl group having 4 to 6 carbon atoms such as butadienyl, and 1, 3, 5-hexatrienyl are used. As the linear hydrocarbon group, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and a linear or branched C 1 _ 4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl is particularly preferable. As R, a group represented by the formula - (CH2) n -R ', wherein R' represents a carboxyl group and n represents an integer from 0 to 6; a group represented by the formula -CH = CH- (CH2) n '-R', wherein R 'represents a carboxyl group and n' represents an integer from 0 to 4; and a group represented by the formula - (CH = CH) n .. -R ', where R' represents a carboxyl group and n "represents an integer from 1 to 3, inter alia, a group represented by the formula are preferable. - (CH2) nR / and a group represented by the formula (CH = CH) n »-R 'are preferable, n is preferably an integer from 1 to 4 (more preferably 2 or 3), n 'is preferably an integer from 0 to 2 (more preferably 0), and n "is preferably an integer from 1 to 2 (more preferably 1). The alkaline earth metal salt or the organic amine salt of the compound represented by the formula [I] (hereinafter, abbreviated as the compound of the present invention in some cases) can be any alkaline earth metal salts or organic amine salts, if those are alkaline earth metal salts or pharmaceutically acceptable organic amine salts. Examples of such an alkaline earth metal salt include salts of the carboxyl group in which the compound represented by the formula [I] has an alkaline earth metal such as calcium, magnesium, etc. Examples of such an organic amine salt include salts of the carboxyl group wherein the compound represented by the formula [I] has an organic base (for example, primary amines such as tris (hydroxymethyl) methylamine, ethanolamine and the like; organic amines such as trimethylamine, triethylamine, pyridine, picoline, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like; and basic amino acids such as arginine, lysine, ornithine and the like). As the alkaline earth metal salt of the compound represented by the formula [I], the calcium salt is preferable.

As the organic amine salt of the compound represented by the formula [I], the primary amine salt is preferable, and the tris (hydroxymethyl) methylamine salt is particularly preferable. As the compound of the present invention, the alkaline earth metal salt of the compound represented by the formula [I] is preferable, and the calcium salt of the compound represented by the formula [I] is particularly preferable.

"The compound of the present invention can be a crystal, and both the single crystal form and a mixture of polymorphic crystal forms are encompassed within the scope of the compound of the present invention.Crystals can be produced by crystallization according to a method of crystallization known per se The compound of the present invention is preferably a crystal.With the "crystal of the compound of the present invention, the crystal of the alkaline earth metal salt (in particular, the calcium salt) of the compound represented by Formula [I] is easy to obtain, and it is easy to isolate and purify. Accordingly, the alkaline earth metal salt (in particular, the calcium salt) of the compound represented by the formula [I] is particularly preferable as an active ingredient of a medicament. In addition, the compound of the present invention may be a solvate (eg, hydrate, etc.), and both solvate and non-solvate (eg, non-hydrate, etc.) are encompassed within the scope of the present invention. The hydration number of the compound of the present invention may vary with continuous moisture, and a range of hydration number may be non-hydrate to decahydrate, preferably from monohydrate to tetrahydrate. In addition, the compound of the present invention can be labeled with an isotope element (e.g., 3 H, 14 C, 3 SS, 125 I, etc.). Among the compound of the present invention, bis ((2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) - 6-methyl-2-oxo-2H-chromo-4-yl] phenyl] acrylate) monocalcium; salt of (2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo- 2 H- chromium-4-yl] phenyl] tris (hydroxymethyl) methylamine acrylate; "salt of - (2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2- oxo-2H-chromo-4-yl] phenyl] diethanolamine acrylate; bis (3- [3- [6-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2 -oxoethyl) -7-methyl-2-oxo-2H-chromo-4-yl] phenyl] propionate) of monocalcium; bis (4- [3- [7-chloro-3- (2- [[4-fluoro- 2- (Trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromium-4-yl] phenyl] butanoate) monocalcium, a hydrate thereof and the like are preferably used. alkaline earth metal salt of the compound represented by the formula [I] can be produced by reacting the compound represented by the formula [I] with an alkaline earth metal hydroxide or an alkaline earth metal hydride, or reacting an alkali metal salt of the compound represented by the formula [I] with an alkaline earth metal halide Alternatively, the alkaline earth metal salt of the compound represented by the formula [I] ] can be produced by reacting the ammonium salt of the compound represented by the formula [I] with an alkaline earth metal halide. The compound of the present invention can also be produced from the compound represented by the formula [I] by a method known per se or the like method. It is also possible to change salts by a method known per se or the similar method. The compound represented by the formula [I] can be prepared according to the method described, for example, in EP-A 585913, EP-A "602598, JP-A 6-263736, WO 02/06264 or WO 03/059900. When these are optical isomers of the compound of the present invention, these individual optical isomers and a mixture thereof are included within the scope of the present invention., these isomers can be optically resolved according to means known per se, or can be prepared individually. Since the compound of the present invention is of low toxicity and safe (for example, more superior as a drug from the aspects of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interaction, cardinogenicity and similar) and have lipid-rich plaque regression activity, the compound of the present invention is useful for preventing or treating a coronary syndrome, (acute) such as myocardial infarction, unstable angina and the like; peripheral arterial occlusion, restenosis after percutaneous coronary artery plasty (PTCA), restenosis after stenting, ischemic heart failure such as myocardial infarction and angina, arteriosclerosis, intermittent claudication, cerebral apoplexy (for example, cerebral infarction, "cerebral embolism") , cerebral hemorrhage), lacunar infarction, cerebral vascular dementia, "xanthomatosis and the like of a mammal (for example, mouse, rat, rabbit, dog, cat, cow, pig, monkey, human, etc.), and are useful as an agent antifoaming In addition, the compound of the present invention has ACAT inhibitory activity (preferably, macrophage ACAT inhibitory activity, inhibitory activity of ACAT subtype 1), and can be used as a prophylactic or therapeutic agent safe against hypercholesterolemia, hypertriglyceridemia, high density lipoproteinemia, hyperlipemia, atherosclerosis, and diseases derived therefrom (e.g., ischemic heart failure such as myocardial infarction, and cerebral vascular disorder such as cerebral infarction or cerebral stroke) in a mammal (e.g., mouse, rat, rabbit, dog, cat , cow, pig, monkey, human, etc.).

The compound of the present invention can preferably be used to prevent the primary presence and / or secondary presence of cardiovascular events (eg, coronary syndrome (acute), cerebral infarction and the like) in high-risk patients (patients having risks such as smoking , aging, gender (male), history or family history of hyperlipidemia, diabetes, hypertension, myocardial infarction, angina, cerebral apoplexy and the like). The present invention also provides a regression agent, suppressing the progress of or stabilizing an arteriosclerotic lesion, which contains the present compound. Such a regression agent, suppressing the progress of or stabilizing an arteriosclerotic lesion is preferably used in combination with a reductase inhibitor HMG-CoA. The compound of the present invention can also be used as a prophylactic or therapeutic agent against Alzheimer's disease, multiple risk syndrome and metabolism syndrome. Since the compound of the present invention is superior in absorbency capacity after oral administration, it is preferable that it be administered as an oral preparation. In the treatment of these diseases, the compound of the present invention can be used alone or can be used in combination with other pharmaceutical components including other lipid-lowering agents or cholesterol-lowering agents, myocardial protective agents, agents that treat coronary heart disease, agents treating diabetes, agents treating thyroid dysfunction, agents treating nephrotic syndrome, agents treating osteoporosis and agents treating chronic renal failure In this case, each of these compounds is preferably administered as an oral formulation or, if necessary, it can be administered in a suppository form as a rectal formulation.In this case, examples of a possible component to be combined include fibrates [eg, clofibrate, bezafibrate, gemfibrosyl, fenofibrate, Wy-1463, GW9578 etc.], nicotinic acid, derivatives and analogues thereof [eg, acipimox], probcol and markers thereof, resin that binds bile acid [eg, cholestyramine, colestipol, etc.], compounds that suppress cholesterol absorption [eg, sitosterol, neomycin, etc.], compounds that inhibit cholesterol biosynthesis [ for example, HMG-CoA reductase inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, atrovastatin, pitavastatin, rosuvastatin, etc.], squalene epoxidase inhibitors [eg, NB-598 and the like, etc.], and agents that increase HDL due to inhibition of cholesterol ester transporting protein, cholesterol absorption inhibitors [eg, ezetimibe], inhibitors of the gallstone acid carrier [eg, HMR-1453-A, S-8921], squalene synthase inhibitors [e.g., TAK-475]. Still other possible components to be combined are oxidoesqualene-lanosterol cyclase, for example, a decalin derivative, an azadecalin derivative and an indane derivative. In addition, when combined with: agents that treat diabetes [acts, losiglitazon, kinedak, penfill, humalin, euglucon, glimicron, daonil, novolin, monotard, insulins, 'glucobay, dimelin, rastinon, bacillin, deamelin S, iszilines, agent of biguanide]; agents that treat thyroid dysfunction [dried thyroid gland (thyroid), sodium levothyroxine (tiradin-S), sodium liothyronidine (thyronine, Tironamin)]; agent that treats the nephrotic syndrome: prednisolone (predonine), prednisolone sodium succinate (predoninae), methylprednisolone sodium succinate (Soiu-Medrol), betamethasone (rinderon)]; vasodilators [dipyridamole (Persantin), dilazep dichlorohydrate (cornelian)]; agent treating chronic renal failure [diuretics [eg, furosemide (Lasix), bumetanide (lunetoron), azosemide (diart)], suppressants (eg, ACE inhibitor) (enalapril maleate (renivase)) and antagonist Ca (manidipine), receptor blocker a, beta-blocker, angiotensin II receptor agonist (candesartan cilexetil); in oral administration are preferred. In view of the fact that the regression activity of lipid-rich plaques and ACAT inhibitory activity, the compound of the present invention is suitable for preventing and treating thrombus formation. For this purpose, the compound of the present invention is administered alone or in combination with the following known treatments, preferably by means of an oral route: - agent for preventing or treating thrombus formation: anticoagulant inhibitor [eg, sodium heparin, potassium heparin, potassium warfarin (warfarin), thrombin inhibitors (eg, ximelagatran), FXa inhibitors], thrombolytic agent [eg, tPA, urokinase], anti-platelet agent [eg, aspirin, sulfinpyrazone (anthurium) ), dipyridamole (persantine), ticlopidine (panaldin), cilostazol (pletaal), GPIIb / lIIa antagonist (ReoPro), clopidogrel]; coronary vasodilator agent: nifedipine, diltiazem, nicorandil, nitrous acid agent; myocardial protective agent: cardiac ATP-K opener, endothelin antagonist, urotensin antagonist, or the like. The compound of the present invention can also be used against the aforementioned diseases, in combination with a biological preparation (e.g., antibodies, vaccine preparation, etc.) or as a combination therapy in combination with gene therapy or the like. Examples of the antibody and the vaccine preparation include, in addition to an angiotensin II vaccine preparation, a CETP vaccine preparation, a CETP antibody, a TNF a antibody, an antibody against another cytokine, a β amyloid vaccine preparation, • and type 1 diabetes vaccine (Peptor DIAPEP-277, etc.), an antibody or a vaccine preparation against cytokine, renin or angiotensin enzyme and a product thereof, an antibody or a vaccine preparation against an enzyme and a protein involved in the metabolism of lipids in the blood, an antibody or a vaccine against an enzyme and a protein involved in a system of coagulation or fibrinolysis in the blood, and an antibody or a vaccine preparation against a protein involved in a saccharide metabolism or insulin resistance. Examples of gene therapy include therapy using a cytosine-related gene, an angiotensin enzyme or renin and a product thereof, therapy using a DNA decoy such as NFKB decoy, therapy using antisense, therapy using RNA interference, therapy using a gene relationship to an enzyme and a protein that involves a metabolism of lipids in the blood (for example, gene related to metabolism, excretion and absorption of cholesterol, triglycerides, HDL cholesterol or phospholipids in the blood), therapy using a gene related to an enzyme and a protein (for example, growth factors such as HGF and VEGF) involved in vascularization therapy directed at obstruction of peripheral spleens or the like, therapy using a gene related to a protein involved in a saccharide metabolism or insulin resistance and antisense against cytokine such as TNF. Alternatively, the compound of the present invention can also be used in combination with vascularization therapy using regeneration of various organs such as heart regeneration, kidney regeneration, pancreas regeneration and spleen regeneration or bone marrow cell transplantation (bone marrow cells). mononuclear cells, marrow stem cells, etc.). The compound of the present invention can be used orally or parenterally by injection, drip, administration of rectal inhalation or local administration and can be used as is, or as a pharmaceutical composition (for example, powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions, etc.). That is, at least one of the compounds of the present invention can be used alone, or as a mixture with a pharmaceutically acceptable carrier (adjuvant, excipient, additive and / or diluent). A pharmaceutical composition can be formulated in accordance with a conventional method. Such a formulation can usually be prepared by mixing / kneading an active component with additives such as an excipient, a diluent, a carrier or the like. Herein, a parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and drip infusion. A formulation for injection, for example, an aqueous suspension of sterile injection or oily suspension can be prepared using a suitable dispersing agent or wetting agent and a suspending agent by a method known in the art. The sterile formulation for injection may be a sterile injectable solution or suspension in a diluent or a solvent which is non-toxic and may be administered parenterally, such as an aqueous solution. Examples of an acceptable vehicle or solvent which may be used include water, Ringer's solution and isotonic saline. As a solvent or a suspension solvent, a non-volatile aseptic oil can also be used usually. For such purpose, any non-volatile oil or fatty acid may be used, including natural or synthetic or semi-synthetic fatty oil and fatty acid, as well as synthetic or semi-synthetic natural mono or di or triglycerides. A suppository for rectal administration can be prepared by mixing an active ingredient with a suitable non-stimulating additive, for example, a substance which is solid at a normal temperature but is liquid at the temperature of the intestinal tract to melt in the rectum thereby releasing, the active ingredient, such as cocoa butter and polyethylene glycols. It is also effective to combine with a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of a butyric acid polymer and a glycolic acid polymer, fatty acid ester of polyglycerol, etc.) to obtain a sustained release formulation. Examples of a solid dosage form for oral administration include the powders, granules, tablets, pills and capsules mentioned above. The formulation with such dosage form can be prepared by mixing and / or kneading a compound of active ingredient with at least one additive, for example, sucrose, lactose, cellulose, mannitol (D-mannitol), maltitol, dextran, starch (e.g. , corn starch), microcrystalline cellulose, agar, alginates, chitins, chitosans, pectins, tragacanth gums, gum arabic, jellies, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such a dosage form may contain additional additives as is usual, including inert diluents, lubricants such as magnesium stearate, preservatives such as parabens and sorbic acids, antioxidants such as ascorbic acid, α-tocopherol and cysteine, disintegrants (eg, croscarmellose from sodium), binders (eg, hydroxypropyl cellulose), thickening agents, buffers, sweeteners, flavoring agents- and perfumes. The tablets and pills can also be enteric coated. Examples of oral liquid formulations include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, which may contain inert diluents which are conventionally used in the art, for example, water and, if necessary, additives. Such oral liquid formulations can be prepared by the conventional method, for example, by mixing an active ingredient, an inert diluent and if necessary, other additives. An oral formulation usually contains about 0.01 to 99% by weight, preferably about 0.1 to 90% by weight, usually about 0.5 to 50% by weight of the compound of the active ingredient of the present invention, although the amount can vary depending on the dosage form. The dose for a certain patient is determined depending on the age, body weight, general condition, sex, diet, time of administration, mode of administration, excretion ratio, combination of the drug, and a degree of the disease generally treated as well as other factors . A lipid-rich plaque regression agent containing the compound of the present invention is low in toxicity, and can be used safely. This daily dose varies depending on the condition and body weight of a patient, the type of the compound, the route of administration and the like and, for example, when used as a prophylactic or therapeutic agent against hyperlipidemia, this may be about 1 to 500 mg, preferably about 10 to 200 mg as the compound represented by the formula [I] in an oral formulation, and about 0.1 to 100 mg, preferably about 1 to 500 mg, usually about 1 to 20 mg as the compound represented by the formula [I] in a parenteral formulation for an adult (about 60 kg). No toxicity is observed in these ranges. The present invention also provides: (1) a pharmaceutical composition comprising the compounds of the present invention with a concomitant drug (hereinafter, abbreviated as a concomitant formulation), (2) a method for regression of lipid-rich plaques or a method for inhibiting ACAT, which comprises administering a combination of an effective amount of the compound of the present invention and an effective amount of a concomitant drug to a mammal, (3) a method of preventing or treating a coronary syndrome (acute) such as myocardial infarction, unstable angina and "similar; peripheral arterial occlusion, restenosis after percutaneous coronary plasty (PTCA), restenosis after stenting, atherosclerosis, myocardial infarction, ischemic heart failure such as angina, arteriosclerosis, intermittent claudication, cerebral vascular disorder such as cerebral apoplexy (e.g. , cerebral infarction, cerebral embolism, cerebral hemorrhage), lacunar infarction, cerebral vascular dementia, Alzheimer's disease, multiple risk syndrome and metabolism syndrome, xanthomatosis, hyperlipaemia, hypercholesterolemia, hypertriglyceridemia, high-hypo-density lipoproteinemia) or thrombus formation , which comprises administering a combination of an effective amount of the compound of the present invention and an effective amount of a concomitant drug to a mammal, and (4) a method for regression, inhibiting the progress of or stabilizing an atherosclerotic lesion, which understands administr A combination of an effective amount of the compound of the present invention and an effective amount of a concomitant drug to a mammal. Examples of a concomitant drug which can be used with the compound of the present invention include the aforementioned pharmaceutical components other than the compound of the present invention and another agent that treats hyperlipemia, a diuretic, an agent that treats hypertension, a agent that treats heart failure, an agent that treats arrhythmia, an anti-coagulant, an anti-platelet agent, an agent that treats diabetes, an agent that increases HDL, an agent that stabilizes the unstable plaque, a vasodilator, a vasoconstrictor, a vasopressor, an antibacterial agent, an antifungal agent, non-spheroidal anti-inflammatory agent, a spheroidal agent, an immunoregulator, an antiprotozoal agent, an anti-ulcer agent, an antitussive or expectorant, a sedative, an anesthetic, an anti-anxiety agent , an antipsychotic agent, a muscle relaxant, an anti-epilepsy agent, an antidepressant, a narcotic antagonist, an anticancer agent i-tumor, an anti-allergic agent, a vitamin, a vitamin derivative, a calcium metabolizing agent in bones, an agent that treats osteoporosis, an agent that treats arthritis, an anti-rheumatic agent, an anti-inflammatory agent, -asmatic, an agent that treats urinary incontinence or urinary incontinence, an agent that treats kidney failure or nephropathy, an agent that treats atopic dermatitis, an agent that treats allergic rhinitis, an endotoxin antagonist or antibody, a transmission inhibitor of signal, an inhibitor of inflammatory mediating effect, an antibody that inhibits the inflammatory mediating effect, an inhibitor that has an anti-inflammatory mediating effect, and an agent that inhibits the anti-inflammatory mediating effect. inter alia, an agent treating hyperlipemia, a diuretic, an agent treating hypertension, an agent treating heart failure, an agent treating the arrhythmia, an anti-coagulant, an anti-platelet agent, an agent that treats diabetes, an agent that increases HDL, and an agent that stabilizes the unstable plaque are preferred. The. Examples of a concomitant drug different from the aforementioned pharmaceutical components are specifically listed below: (1) Agent treating hyperlipemia HMG-CoA reductase inhibitor (eg, fluvastatin, cerivastatin, atorvastatin, simvastatin, etc.), fibrates (eg, simfibrate, aluminum clofibrate, clinofibrate, fenofibrate, etc.), anion exchange (eg, cholestilramide, etc.), nicotinic acid formulation (eg, nicomol, niceritrol, nicotinate tocopherol, etc.), polyvalent unsaturated fatty acid derivative (eg, ethyl icosapentate, polyphenidylcholine, melinamide, etc.), plant sterol (for example, gamma-oryzanol, soisterol, etc.), elastase, sodium dextran sulfate, squalene synthetase inhibitor, CETP inhibitor, cholesterol absorption inhibitors [ezetimibe, for example], bilious ileo acid transport inhibitors [e.g. , HMR-1453-A, S-8921], ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull], 38, 2792-2796 (1990)], PPARa agonists, PPAR agonists, PPARd agonists, LXR agonists, FXR antagonists, DGAT inhibitors, MGAT inhibitors, MTP inhibitors and the like. (2) Diuretic diuretic thiazide (benzylhydrochlorothiazide, cyclopentiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide, methiclothiazide, penflutiazide, polythiazide, trichloromethiazide, etc.), diuretic of curl (Chlorthalidone, Clofenamide, Indapamide, Mefruside, Methycin, Sotolazone, Tripamide, Quinetazone, metolazole, Furosemide, Mefruside, etc.), Potassium retaining diuretic (spironolacton, triamterene, etc.). (3) Agent that treats hypertension [1] Suppressor of the sympathetic nerve stimulant a2 (for example, clonidine, guanabenz, guanfacine, methyldopa, etc.), ganglionic blocking agent (for example, hexamethonium, trimethaphan, etc.), presympathetic blocker ( for example, alseroxylone, dimethylaminoreserpinate, rescinamine, reserpine, sirosingopine, etc.), neuron blocker (e.g., betanidine, guanaethidine, etc.), ax blocker (e.g., bunazosin, doxazocin, prazosin, terazosin, urapidil, etc.). ), β-blocker (for example, propranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amosulalol, arotinolol, etc.). [2] Calcium channel antagonist vasodilator (eg, manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amiodipine, aranidipine, etc.), phthalazine derivative (eg, budralazine, cadralazine, ecarazine, hydralazine, todraiazine, etc.). [3] ACE inhibitor alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, perindopril, etc. [4] Angiotensin II receptor antagonist losartan, candesartan cilexetil, valsartan, telmisartan, irbesartan, forasartan, olmesartan medoxomil, 2-ethoxy-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic etc. [5] Diuretic (for example, the aforementioned diuretics) [6] β-blocker (eg, propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol, etc.) (4) Agent for treatment of heart failure cardiotonic agent (eg, digitoxin, digoxin, metildigoxin, lanatoside C, proscillaridine), a, β-stimulant (eg, epinephrine, norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine etc. .), phosphodiesterase inhibitor (eg, amrinone, milrinone, olprinone hydrochloride etc.), calcium channel sensitivity promoter (eg, pimobendan etc.), nitrate agent (eg nitroglycerin, isosorbide nitrate etc.) .), ACE inhibitor (for example, ACE inhibitors mentioned above, etc.), diuretic (for example, the aforementioned diuretics, etc.), carperitide, ubidecarenone, vesnarinone, aminophylline, etc.). (5) Agent for the treatment of sodium channel blocker arrhythmia (for example, quinidine, procainamide, disopyramide, ajimaline, cibenzoline, lidocaine, diphenyl hydantoin, mexiletine, propafenone, flecainide, pilsicanide, phenytoin etc.), β-blocker (eg, propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol, metoprolol , bisoprolol, pindolol, carteolol, arotinolol, etc.), potassium channel blocker (for example, amiodarone etc.), calcium channel blocker (for example, verapamil, diltiazem etc.) etc. (6) Anticoagulant and antiplatelet agent sodium citrate, activated protein C, tissue factor pathway inhibitor, anti-thrombin III, dalteparin sodium, argatroban, gabexate, sodium ozagrel, ethyl icosapentate, beraprost sodium, alprostadil, pentoxifillin , tisocinase, streptokinase, heparin sodium, heparin potassium, warfarin potassium (warfarin), thrombin inhibitors (eg, ximelagatran), FXa inhibitor], thrombolytic agent [eg, tPA, urokinase], anti-platelet agent [eg, aspirin, sulfinpyrazone (anturan) ', dipyridamole (persantin), ticlopidine (panaldin), cilostazol (pletaal), GPIIb / IIIa antagonist (ReoPro), clopidogrel, etc. (7) Diabetes sulphonylurea treatment agent (eg, tolbutamide, chloropropamide, glycopyramide, acetohexamide, tolazamide, glibenclamide, glibuzole etc.), biguanide (eg, metformin hydrochloride, buformin hydrochloride etc.), inhibitor of -glucosidase (eg voglibose, acarbose etc.), insulin sensitizer (eg, pioglitazone, troglitazone, rosiglitazone etc.), insulin, glucagon, agent for the treatment of diabetic complication (eg, epalrestat etc.) etc . (8) HDL augmentation agent inhibitor of the esqualeno synthetase, CETP inhibitor, LPL activator, endothelial lipase inhibitor etc. (9) MMP inhibitory plate stabilizing agent, kinase inhibitor, etc. (10) Vasodilator oxyfedrine, diltiazem, tolazoline, hexobendine, bametan, clonidine, methyldopa, guanabenzo etc. (11) Vasoconstrictor dopamine, dobutamine, denopamine etc. (12) Hypertensive agent dopamine, dobutamine, denopamine, digitoxin, digoxin, metildigoxina, lanatosida C, estrofantina G etc. (13) Antibacterial agent [1] Sufonamide sulfametizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine, silver sulfadiazine, etc. [2] Nalidixic acid quinoline, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin, tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin etc. [3] Anti-tuberculous agent isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid (calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine etc. [4] Anti-acid-fast bacterial agent diaphenylsulfone, rifampicin etc. [5] Anti-viral agent idoxuridine, acielovir, vidarabine, ganciclovir etc. [6] Anti-HIV agent zidovudine, didanosine, zaicitabine, adduct of ethanol sulfate indinavir, ritonavir etc. [7] Anti-spirochete agent [8] Antibiotic tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibecacin, canendomicin, lividomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ticarcillin, cephalothin, cephapirin, cephaloridin, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandol, cefotoam, cefroxima, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpyramide, cefsulodin, cefmenoxim, proxetil of cefpodoxime, cefpiroma, cefozopran, cefepime, cefmetazol, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef , cefazolin, cefotaxime, cefoperazon, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt thereof, griseofulvin, lancacidin [J. Antibiotics, 38, 877-885 (1985)] etc. (14) Antifungal agent [1] Antibiotic based on polyethylene (for example, amphotericin B, nystatin, trichomycin) [2] Griseofulvin, pyrrolnitrin etc. [3] Cytosine metabolism antagonist (eg, flucytosine) [4] Derivative of imidazole (for example, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) [5] Triazole derivative (eg, fluconazole, itraconazole, azole-based compound [2- [(IR, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-l-methyl-3- (1H -1, 2,4-triazol-1-yl) propyl] -4- [4- (2, 2, 3, 3-tetrafluoropropoxy) phenyl-3- (2H, 4H) -1,2,4-triazole] [6] Derivative of thiocarbamic acid (for example, trinaphthol) [7] Derivative based on echinocandin (eg, caspofamgina, FK-463, Equinocadine V) etc. (15) Non-spheroidal anti-inflammatory agent acetaminophen, phenacetin, etenzamide, sulpirin, antipyrin, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprodin, flurbiprofen, fenbufen , pranoprofen, floctafenin, epirizol, thiaramide hydrochloride, zaitoprofen, gabexate mesylate, camostate mesylate, ulinastatin, colcicin, probenecid, sulfinpyrazone, benzobromarone, allopurinol, sodium and gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride , salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone or a salt thereof. - (16) Spheroidal agent dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluoroquinone, fluoroquinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol etc. (17) Immunoregulation agent cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymph serum, dry sulphonated immunoglobulin, erythropoietin, colony stimulation factor, interleukin, interferon, etc. (18) Antiprotozoal agent metronidazole, tinidazole, diethylcarbamadine citrate, quinine hydrochloride, quinine sulfate etc. (19) Anti-ulcer agent metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxetazain, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin etc. (20) Bronchospasmolytic expectorant ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, methylephedrine hydrochloride, aroclamide, chlorphenianol, picoperidamine, cloperastine, protocilol, isoproterenol, sulbutamol, terbutaline, oxymetebanol, hydrochloride morphine, dextromethorphan bromohydrate, oxycodone hydrochloride, dimemorphane phosphate, tipepidine hibenzarate, pentoxiverin citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine etc. (21) Sedative chlorpromazine chlorohydrate, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamilal sodium, nitrazepam, estazolam, flunitrazepam, haloxazolam, triazolam, flunitrazepam, bromovalerilurea, doral hydrate, sodium triclofos etc. (22) Anesthetic (22-1) Local anesthetic cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxetazain etc. (22-2) Systemic anesthetic [1] Anesthetic inhalation (eg, ether, halothane, nitrous oxide, enflurane), [2] Intravenous anesthetic (eg, ketamine, droperidol, thiopental sodium, tiamilal sodium, pentobarbital) etc. (23) AgeVité ansiolítico diazepan, lorazepan, oxazepan, chlordiazepoxide, medazepan, oxazolan, cloxazolan, clotiazepan, prazepan, etizolan, fludiazepan, hydroxyzine etc. (24) Antisychotic agent chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol, spiperone, reserpine, clomipramine hydrochloride, sulpiride , zotepine etc. (25) Muscle relaxant pridinol, tubocura ina, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine, etc. (26) Antieptile agent phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepae etc. (27) Antidepressant imipramine, clomipramine, noxiptiline, pheneridine, amitriptyline hydrochloride, nortriptyline, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride, etc. (28) Levalorfan anesthetic antagonist, nalorphine, naloxone or a salt thereof. (29) 6-0- (N-Chloroacetylcarbamoyl) antitumor agent, fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarcinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole , bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, zisulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine , mercaptoprine, tegafur, carmofur, cytarabine, methyltestosterone, testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate etc. (30) Anti-allergic agent diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repirinast, amiexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlucast hydrate , seratrodast, etc. (31) Lipid soluble vitamin - [1] Vitamin A: vitamin Aa, vitamin A2 and retinol palmitate [2] Vitamin D: vitamin Dx, D2, D3, D4 and Ds [3] Vitamin E: nicotinate of α-tocopherol, β-tocopherol, α-tocopherol, d-tocopherol, dl-a-tocopherol [4] Vitamin K: vitamin Kx, K2, K3 and K [5] Folic acid (vitamin M) etc. (32) Derived from vitamin various vitamin derivatives, for example, vitamin D3 derivatives including 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol and 1-a-hydroxycholecalciferol, vitamin D 2 derivatives including 5,6- trans-. ergocalciferol etc. (33). Anti-asthmatic agent isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tubobuterol chlorhydrate, orciprenaline sulfate, fenoterol bromohydrate, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, bromide of flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, arnlexanox, ibudilast, ketotifen, terfenadine; mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlucast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclomethasone dipropionate, etc. (34) Agent for the treatment of urinary frequency or urinary incontinence flavoxate hydrochloride etc. (35) Agent for the treatment of atopic dermatitis sodium cromoglycate etc. (36) Agent for the treatment of allergic rhinitis sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, ciernastina fumarate, homoclorcyclizine hydrochloride, terfenadine, mequitazine etc. (37) Agent for the treatment of estradiol acetylcholine inhibitor dementia (eg, donepezil, tacrine, rivastigmine, galantamine etc.) etc. (38) Other hydroxyamics, diaserin, megestrol acetate, nicergoline, prostaglandins, etc.

By means of "a combination of the compound of the present invention with a concomitant drug, for example, the following effects are extruded. (1) The dose or side effects of the compound of the present invention or a concomitant drug may be lower than those when they are alone (2) A synergistic therapeutic effect can be obtained against diseases such as coronary (acute) syndrome such as myocardial infarction and unstable angina, peripheral arterial occlusion, intermittent claudication, restenosis after percutaneous coronary plasty (PTCA), restenosis after stenting, hypercholesterolemia, hypertriglyceridemia, hyperlipaemia, hypo-high density lipoproteinemia, atherosclerosis, myocardial infarction, ischemic heart failure such as angina , _ cerebral vascular disorder such as cerebral apoplexy or cerebral infarction, lacunar infarction, cerebral vascular dementia, xanthomatosis, Alzheimer's disease, thrombus formation or the like. (3) A broad therapeutic effect can be obtained against various diseases accompanied by diseases such as coronary (acute) syndrome such as myocardial infarction, unstable angina, peripheral arterial occlusion, intermittent claudication, restenosis after percutaneous coronary plasty (PTCA), restenosis after stenting, hypercholesterolemia, hypertriglyceridemia, hyperlipemia, hypo-high density lipoproteinemia, atherosclerosis, myocardial infarction, ischemic heart failure such as angina, cerebral vascular disorder such as cerebral stroke or cerebral infarction, lacunar infarction, cerebral vascular dementia, Xanthomatosis, Alzheimer's disease, thrombus formation or the like. When the concomitant formulation of the present invention is used, the schedule of administration of the compound of the present invention and a concomitant drug are limited, and the compound of the present invention or its pharmaceutical composition and a concomitant drug or its pharmaceutical composition can be administer at the same time, or can be administered at a certain time interval to a subject. The dose of a concomitant drug may be in accordance with a dose used clinically, and may be appropriately selected depending on a subject of administration, a route of administration, disease, a combination and the like. The mode of administration of the concomitant formulation of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and a concomitant drug are combined during administration. Examples of such mode of administration include (1) administration of a simple formulation obtained by formulating the compound of the present invention and a concomitant drug simultaneously, (2) simultaneous administration of two formulations obtained in formulating the compound of the present invention and a concomitant drug separately, by means of an identical route, (3) sequential and intermittent administration of two formulations obtained by formulating the compound of the present invention and a concomitant drug separately, by means of an identical route, (4) simultaneous administration of two formulations obtained by formulating the compound of the present invention and a concomitant drug separately, by means of different routes, (5) sequential and intermittent administration of two formulations obtained in formulating the compound of the present invention and a concomitant drug separately, by means of different routes (for example, the compound of the present invention or this pharmaceutical composition followed by a concomitant drug or its pharmaceutical composition, or reverse order) and the like. The concomitant formulation of the present invention is of low toxicity, and thus the compound of the present invention and / or a concomitant drug described above are mixed with a pharmaceutically acceptable carrier in accordance with a method known per se to form a pharmaceutical composition such as as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release formulations and the like, which can be given orally or parenterally ( for example, topically, rectally, intravenously). The injections can be administered intravenously, intramuscularly, subcutaneously, in organs, or directly in lesions. Examples of the acceptable pharmacological carrier that can be used in the preparation of the concomitant formulation of the present invention include various organic or inorganic carrier materials that are conventionally used as pharmaceutical materials, for example, excipients, lubricants, binders and disintegrants in a solid formulation, or solvents, dissolving aids, suspension agents, isotonization agents, buffering agents and soothing agents in a liquid formulation. In addition, if necessary, usual additives such as preservatives, antioxidants, coloring agents, sweeteners, absorbents, wetting agents and the like can be conveniently added in suitable amounts. The relationship between the compound of the present invention and a concomitant drug in the concomitant formulation of the present invention can be appropriately selected, depending on a subject of administration, a route of administration, disease and the like. For example, the content of the compound of the present invention in the concomitant formulation of the present invention varies depending on the dosage form, and is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight of the entire formulation. The content of a concomitant drug in the concomitant formulation of the present invention varies depending on the dosage form, and is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to about 20% by weight of the entire formulation. The content of additives such as a carrier and the like in the concomitant formulation of the present invention varies depending on the dosage form, and is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight of the entire formulation . In addition, the same content can also be used when the compound of the present invention and "a concomitant drug are formulated separately." Such a formulation can be prepared by a method known per se that is generally used in a pharmaceutical process. The concomitant formulation of the present invention varies depending on the class of the compound of the present invention, age, body weight, symptom, dosage form, method of administration, administration period, and the like For example, the daily dose for a patient with hyperlipidemia (adult, about 60 kg) is usually about 0.01 to about 100 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, particularly about 0.1 to about 50 mg / kg, inter alia, about 1.5 to about 30 mg / kg of the compound of the present invention and administered intra venously once or in different portions. Of course, since a dose varies depending on various conditions as described above, a smaller amount than the aforementioned dose may be sufficient or an excess dose of the aforementioned range may be necessary. The dose of a concomitant drug can be fixed in any range so that it does not cause a problematic side effect. The daily dose of a concomitant drug is not particularly limited and varies depending on the severity of the symptom, age, sex, body weight and susceptibility of the subject to be administered, schedule and interval of administration, nature, preparation and type of a pharmaceutical formulation, type of an active ingredient, and the like. The daily oral dose per kg of body weight in a mammal is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg of a concomitant drug, which are usually given in 1 to 4. portions. During administration of the concomitant formulation of the present invention, the compound of the present invention and a concomitant drug can be administered at the same time, but after a concomitant drug is administered, the compound of the present invention can be administered. Alternatively, after the compound of the present invention is administered, a concomitant drug can be administered. When administered at a certain time interval, the range varies depending on the active ingredient to be administered, a dosage form, a method of administration and the like. For example, when a concomitant drug is administered in advance, the compound of the present invention is administered at 1 minute up to 3 days, preferably 10 minutes, up to 1 day, more preferably 15 minutes up to 1 hour after the administration of a concomitant drug. . For example, when the compound of the present invention is administered in advance, a concomitant drug is administered at 1 minute up to 1 day, preferably 10 minutes up to 6 hours, more preferably 15 minutes up to 1 hour after the administration of the compound of the present invention. As a preferable administration method, for example, about 0.001 to 200 mg / kg of a concomitant drug which has been formulated in an oral formulation is administered orally and, after about 15 minutes, about 0.005 to 100 mg / kg of the compound of the present invention which has been formulated in an oral formulation is administered orally as the daily dose. The compound of the present invention possesses excellent lipid-rich plate regression activity and / or ACAT inhibitory activity. The following examples, Formulation Examples and Experimental Examples further illustrate the present invention, but the present invention is not limited thereto. An NMR spectrum was measured with a Varian Mercury 300 spectrometer (300 MHz) using tetramethylsilane as an internal standard, and each d value is plotted in ppm. X-ray powder diffraction was measured by using RIGAKU RINT2100U1tima-i- (CuKa rays (? = 1.5418Á)). Unless indicated otherwise, a numerical value shown for a mixed solvent is a volume ratio of each solvent. Unless stated otherwise,% means% by weight. In addition, the ratio of a solvent eluted for column chromatography on silica gel indicates a volume ratio, unless otherwise indicated. In the present, ambient temperature (normal temperature) represents a temperature of about 20 ° C to about 30 ° C. The respective symbols in the Examples represent the following meanings. Et: ethyl, Bu: butyl, DBU: diazabicycloundecene, s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sext; sextet, dd: double doublet, dt: double triplet, m: multipleto, br: broad, J: coupling constant.

Reference Example 1 (3-bromophenyl) (4-chloro-2-hydroxy-5-methylphenyl) ethanone Aluminum chloride (20.4 g) was added to a solution of 3-chloro-4-methylanisole (20 g) in chlorobenzene (56 ml) at 20-30 ° C, and then 3-bromobenzoyl chloride (28 g) was further added dropwise during about minutes at 25 to 30 ° C. After the addition was complete, the mixture was stirred at 25 ° C for 1 hour, and then heated at 40 ° C for 1 hour: After the reaction was complete, the mixture was cooled, and toluene / tetrahydrofuran (1: 1, 200 ml) was added dropwise at 20 to 30 ° C. Then, 4N hydrochloric acid (80 ml) was added dropwise. The organic layer was separated, washed successively with 2N hydrochloric acid (60 ml) and a 10% aqueous sodium chloride solution. The organic layer was concentrated to 80 g. After that methanol (100 ml) was added, the mixture was again concentrated to 90 g. Methanol (80 ml) was added to the residue, the mixture was stirred at room temperature for 30 minutes, and under 5 ° C for 1 hour. The crystals were collected, washed with cold methanol (40 ml) and dried under reduced pressure to obtain the title compound (35.4 g, yield 85.1%). -5 ^ -RMN (300MHz, CDCl3) d (ppm): 2.28 (3H, s), 7.12 (1H, s), 7.36-7.42 (2H, m), 7.54-7.57 (1H, m), 7.72-7.80 (2H, m), 11.7 (1H, s).

Reference Example 2 [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromo-3-yl] ethyl acetate The DBU (211 ml) was added to a solution of (3-bromophenyl) (4-chloro-2-hydroxy-5-methylphenyl) methanone (170 g) in 0-acetonitrile (510 ml) at 25 to 30 ° C. Then, a solution of ethyl succinic chloride (146 g) in acetonitrile (340 ml) was added dropwise over 30 minutes at 25 to 40 ° C. After the drip was complete, the mixture was stirred at 30 ° C for 1 hour. The water (94 ml) was added dropwise maintaining the reaction solution at 25 to 30 ° C. After the mixture was stirred at the same temperature for 1 hour, the resulting crystals were filtered, and washed with a mixture of acetonitrile and water (9/1, 170 ml) four times, dried under reduced pressure to obtain the compound of the title (174 g, yield 76.7%). XH-NMR (300MHz, CDCl3) d (ppm): 1.24 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 3.35 (2H, s), 4.14 (2H, q, J = 7.2 Hz) , 6.80 (1H, s), 7.20-7.23 (1H, s), 7.42-7.45 (3H, m), 7.65-7.68 (1H, m).

Reference Example 3 [4- (3-Bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromyl-3-yl] acetic acid The? AOH 2? (51.6 ml) was added to a mixture of ethyl [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromo-3-yl] acetate (15 g) and ethanol (135 ml), and the mixture was stirred at 70 ° C for 1 hour. After the mixture was cooled to 25 ° C, the pH was adjusted to 2.0 by adding HCl 6? (17.7 ml) dropwise at the same temperature to make precipitated crystals. After the mixture was stirred at 25 ° C for 1 hour, the crystals were collected, washed with ethanol / water (2/1, 30 ml) and dried under reduced pressure to obtain the title compound (13.5 g, 96.4% yield). XH-NMR (300MHz, CDCl3) d (ppm): 2.31 (3H, s), 3.35 (2H, s), 6.81 (1H, s), 7.24-7.27 (1H, s), 7.41-7.47 (3H, m ), 7.65-7.69 (1H, m).

Reference Example 4 2- [4- (3-Bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chrom-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide N, N-Dimethylformamide (0.2 ml) was added to a solution "of [4- (3-bromo-phenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetic acid (13.5 g) in tetrahydrofuran (135 ml), and then thionyl chloride (5.12 g) was added dropwise to the resulting mixture as nitrogen passed through the reaction vessel at 25 ° C. After the addition was complete, the mixture was added to the reaction mixture. The mixture was heated to 40 ° C and stirred for 1.5 hours, then 2-amino-5-fluorobenzotrifluoride (6.53 g) was added thereto, and the mixture was heated to 60 ° C and then stirred for 2.5 hours. ml) and water (67.5 ml) were successively added dropwise thereto at 40 to 50 ° C. The resulting mixture was stirred at 40 ° C. for 1 hour and at 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, and washed with cold tetrahydrofuran / acetonitrile / water (2/1/1, 40.5 ml). The resulting crystals (17.3 g) were dissolved in acetone (173 ml) upon heating. The activated charcoal (0.865 g) was added to the solution, and the mixture was stirred for 10 minutes. The activated charcoal was removed by filtration, and washed with acetone (86.5 ml). The combined filtrate and washings were maintained at 40 ° C, and water (51.9 ml) was added dropwise thereto with stirring. The mixture was cooled to 5 ° C and stirred for 1 hour. The crystals were collected by filtration and washed with acetone / cold water (5/1, 51.9 ml) to obtain the title compound (16.1 g, yield 85.7%). ^ -NMR (300 MHz, CDC13) d (ppm): 2.31 (3H, s), 3.35-3.52 (2H, m), 6.85 (1H, s), 7.19-7.32 (3H, m), 7.41-7.50 ( 3H, m), 7.67-7.69 (1H, m), 7.94-7.99 (1H, m), 8.11 (1H, brs).

Reference example 5 (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} acrylate A mixture of 2- [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (2.00 g), palladium acetate (0.0079 g) and tri-o-tolyl phosphine (0.0214 g) was placed in a reaction vessel, and the nitrogen was passed through the reaction vessel for 10 minutes to replace the atmosphere of the reaction vessel with nitrogen, N, N-Dimethylformamide (10 ml), butyl acrylate (0.677 g) and sodium acetate (0.317 g) were added successively thereto, and the mixture was stirred at room temperature for about After 20 minutes, the mixture was stirred at 110 ° C for 3 hours and cooled to room temperature, ethyl acetate (20 ml) and water (20 ml) was emptied into the reaction mixture and, after stirring, a The organic layer was separated, the organic layer was washed successively with a mixture of 10% saline solution (18 ml) and conc. hydrochloric acid (2 ml), and 10% saline (20 ml). ctivated (0.1 g) and tributyl phosphine (0.0712 g) were added to the organic layer, and the mixture was stirred at room temperature for 10 minutes. Then, the activated charcoal was removed by filtration and washed with ethyl acetate (4 ml). The combined filtrate and washings were concentrated to 6.0 g under reduced pressure, and n-heptane (12 ml) was added dropwise to the residue to precipitate the crystals. After stirring at 5 ° C for 1 hour, the crystals were collected by filtration and washed with cold ethyl acetate / n-heptane (1/3, 4 ml). A mixture of the resulting crystals (2.06 g) and acetone (10 ml) was heated to 50 ° C to dissolve the mixture, activated charcoal (0.1 g) was added thereto, and the mixture was stirred for 10 minutes. The activated charcoal was removed by filtration, and washed with acetone (4 ml). Water (4.6 ml) was added dropwise to the combined filtrate and washed, and the mixture was stirred at 5 ° C for 1 hour. The crystals were collected by filtration, and washed with acetone / cold water (2/1, 4 ml) to obtain the title compound (1.84 g, yield 84.9%). XH-NMR (300 MHz, CDCl2) d (ppm): 0.95 (3H, t, J = 7.4Hz), 1.42 (2H, sext, J = 7.4Hz), 1.68 (2H, quint, J = 6.7Hz), 2.29 (3H, s), 3.39-3.50 (2H, m), 4.20 (2H, t, J = 6.6Hz), 6.50 (1H, d, J = 16Hz), 6.86 (1H, s), 7.19-7.32 ( 3H, m), 7.35 (1H, s), 7.44 (1H, s), 7.56-7.61 (1H, m), 7.69-7.74 (2H, m), 7.98-8.01 (1H, m), 8.17 (1H, brs).

Reference Example 6 Acetone solvate of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} acrylic 0. 9 mol acetone A mixture of (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} butyl acrylate (3.0 g), ethanol (9 ml) and 2N NaOH (9 ml) was stirred at 50 ° C for 1.5 hours. After the reaction was completed, acetone (27 ml) was added to the reaction mixture at 50 ° C, and 6N HCl (3.5 ml) was added dropwise thereto to adjust the pH to 0.6. The mixture was stirred at 50 ° C for 30 minutes and then at 25 ° C for 1 hour, and the crystals were collected by filtration, and washed with acetone / water (2/1, 6 ml). To a mixture of the resulting crystals (2.79 g), acetone (2 ml) and water (6 ml) was added dropwise 5% aqueous ammonia (2.1 ml) with stirring at room temperature to adjust the pH to 9.2 and dissolves the mixture Toluene (4.5 ml) was added to the remaining solution and the mixture was stirred for 5 minutes and allowed to stand for 5 minutes to separate an aqueous layer. Acetone (12 ml) and activated charcoal (0.15 g) were added to the obtained aqueous layer and the mixture was stirred at room temperature for 15 minutes. The activated charcoal was removed by filtration, and washed with acetone (6 ml). The filtrates and washings were combined and heated to 50 ° C., and 6N HCl (1.25 ml) was added dropwise thereto maintaining the temperature almost the same and with stirring to adjust the pH to 0.5 and the crystals were precipitated. The mixture was stirred at 50 ° C for 30 minutes and then at about 25 ° C for 1 hour, and the crystals were collected by filtration and washed with acetone / water (2/1, 6 ml) to obtain the title compound. title (2.54 g, yield 84.8%). This product contains 0.9 mole of acetone. XH-NMR (300 MHz, CDC13) d (ppm): 2.07 (6H x 0.9, s),. 2.29 (3H, s), 3.38-3.51 (2H, m), 6.43 (1H, d, J = 16Hz), 6.85 (1H, s), 7.24-7.38 (3H, m), 7.46 (1H, s), 7.50 (1H, s), 7.57-7.62 (1H, m), 7.69-7.75 (2H, m), 7.97-8.01 (1H, m), 8.15 (1H, brs).

Reference example 7 (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} sodium acrylate A mixture of acetone solvate of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- '(trifluoromethyl) phenyl] amino.} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen- 4-yl] phenyl} Acrylic (1.13 g) and acetone (20.5 ml) was heated to 50 ° C, and 2N NaOH (0.91 ml) was added dropwise thereto with stirring. The mixture was stirred at 50 ° C for 2 hours and then at 5 ° C for 1 hour, and the precipitated crystals were collected by filtration. The crystals were washed successively with acetone / cold water (95/5, 2 ml) and cold acetone (2 ml) to obtain the title compound (0.974 g, yield 91.9%). ^ • H-NMR (300 MHz-, DMS0-d6) d (ppm): 2.23 (3H, s), 3.37 (2H, br), 6.44 (1H, d, J = 16Hz), 6.94 (1H, s) , 7.13 (1H, d, J = 16Hz), 7.20-7.22 (1H, m), 7.36-7.43 (2H, m), 7.52-7.61 (3H, m), 7.67-7.69 (2H, m), 9.70 ( 1H, brs).

Example 1 Bis ((2E) -3-. {3- [7-chloro-3- (2- {[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) - 6-methyl-2-oxo-2H-chromen-4-yl] phenyl.} Acrylate) monocalcium trihydrate A mixture of (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Sodium acrylate (5.0 g), ethanol (45 ml) and water (9 ml) were dissolved upon heating to 60 ° C. The impurities in the solution were removed by filtration and washed with ethanol / hot water (5/1, 6 ml). A solution of calcium chloride (0.524 g) in water (10 ml) was added dropwise to the combined filtrate and the washings were stirred at 60 ° C. The mixture was stirred at 60 ° C for 3 hours and then at 25 ° C for 1 hour. The crystals were collected by filtration, and washed successively with ethanol / water (1/1, 10 ml) and water (10 ml, 3 times) to obtain the title compound as colorless crystals (4.47 g yield 89.8%). The crystals obtained shows the X-ray powder diffraction pattern as shown in Fig. 1 and the crystallinity was 66%. XH-NMR (300 MHz, DMSO-d6) d (ppm): 2.17 (3H, s), 3.32 (2H, br), 6.47 (1H, d, J = 16Hz), 6.87 (1H, s), 7.21- 7.23 (1H, m), 7.32-7.54 (6H, m), 7.66 (2H, s), 9.65 (1H, brs). The variation of the hydration number of the title compound in the range of monohydrate to tetrahydrate was observed depending on the humidity.

Example 2 Bis ((2E) -3-. {3- [7-chloro-3- (2- {[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) - 6-Methyl-2-oxo-2H-chromen-4-yl] phenyl.} Acrylate) monocalcium trihydrate A mixture of acetone solvate of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Asyllic (60 g), ethanol (540 ml) and water (108 ml) was heated to 60 ° C, and 5% aqueous ammonia (54 ml) was added dropwise thereto with stirring to dissolve the mixture. The solution was stirred around the same temperature for 30 minutes and, after filtration, the solution was washed with a mixture of ethanol (60 ml) and water (12 ml). The filtrate was combined with the washings to obtain a solution of ammonia (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Acrylate The solution was heated to 75 ° C, and an aqueous solution of calcium chloride (5.9 g / 120 ml) was added dropwise thereto maintaining the temperature almost the same and with stirring. The reaction mixture was heated to 78 ° C, and stirred at the same temperature for 3 hours and then at 25 ° C for 1 hour. The crystals were collected by filtration, washed with ethanol / water (120 ml / 120 ml), dried and stored at room temperature to obtain the title compound as colorless crystals (49 g, yield 80.1%). The crystals obtained show the X-ray powder diffraction pattern as shown in Fig. 2 and have the following representative cross-linked spacers. The crystallinity was 75%. 3.1 weak angstrom 3.4 angstrom medium 3.5 angstrom weak 3.6 angstrom weak 4.1 angstrom weak 4.4 angstrom weak 4.5 angstrom weak 5.9 angstrom weak 6.2 angstrom medium 6.7 angstrom medium 6.9 angstrom medium 8.1 angstrom strong 8.8 angstrom strong 10.2 angstrom medium 10.9 angstrom medium XH-NMR (300 MHz, DMSO-d6) d (ppm): 2.17 (3H, s), 3.32 (2H, br), 6.47 (1H, d, J = 16Hz), 6.87 (1H, s), 7.21-7.23 (1H, m) , 7.32-7.54 (6H, m), 7.66 (2H, s), 9.65 (1H, brs).

Reference example 8 (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} ammonia acrylate A mixture of acetone solvate of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Acrylic (6.18 g), ethanol (56 ml) and water (11 ml) was heated to 60 ° C, and 5% aqueous ammonia (6 ml) was added dropwise thereto with stirring to dissolve the mixture. The solution was concentrated under reduced pressure and the obtained crystals were dried at 45 ° C for 8 hours under reduced pressure to obtain the title compound as colorless crystals (5.20 g, yield 90.1%). ^ • H-NMR (300 MHz, DMS0-d6) d (ppm): 2.18 (3H, s), 3.34 (2H, br), 3.80 (4H, brs), 6.46 (1H, d, J = 16Hz), 6.85 (1H, s), 7.25-7.60 (8H, m), 7.76 (1H, d, J = 8Hz), 9.68 (1H, brs).

EXAMPLE 3 (3E) -3- (tris (hydroxymethyl) methylamine salt). { 3- [7- chloro-3- (2 - { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} acrylic A mixture of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Acrylic (10.0 g), tris (hydroxymethyl) methylamine (2.2 g), ethanol (70 ml) and acetonitrile (100 ml) was heated and stirred at 70 ° C to dissolve the mixture. Acetonitrile (200 ml) was slowly added to the reaction mixture, and the mixture was stirred at 70 ° C for 3 hours, gradually cooled to room temperature, and then stirred at room temperature overnight. The obtained crystals were collected by filtration, washed with acetonitrile, and dried at 60 ° C for 8 hours under reduced pressure to obtain the title compound as colorless crystals (10.5 g, 86% yield). The crystals obtained show the X-ray powder diffraction pattern as shown in Fig. 3 and the crystallinity was 64%.

XH-NMR (300 MHz, DMSO-d6) d (ppm): 2.54 (3H, s), 3.38 (8H, m), 6.52 (1H, d, J = 16Hz), 6.93 (1H, s), 7.3- 7.4 (3H, m), 7.5- 7.6 (4H, m), 7.71 (1H, s), 7.80 (1H, d, J = 7.8Hz), 9.67 (1H, brs).

Example 4 Diethanolamine salt of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen- il] phenyl} acrylic A solution of diethanolamine (0.20 g) in ethanol (20 ml) was added to a solution of (2E) -3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} Acrylic (1.0 g) in a mixture of tetrahydrofuran (30 ml) and ethanol (100 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethanol, and dried at 60 ° C for 8 hours under reduced pressure to obtain the title compound as colorless crystals (0.8 g, 67% yield).

^? - NMR (300 MHz, DMSO-d6) d (ppm): 2.25 (3H, s), 2.75 (4H, t, J = 5.6Hz), 3.36 (2H, m), 3.54 (4H, t, J = 5.6Hz), 6.54 (1H, d, J = 16Hz), 6.93 (1H, s), 7.30-7.4 (3H, m), 7.5-7.7 (4H, m), 7.71 (1H, s), 7.84 ( 1H, d, J = 7.6Hz), 9.67 (1H, brs).

Example 5 Bis (3- {3- [7-chloro-3- (2. {[[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl- Monocalcium 2-oxo-2H-chromen-4-yl] phenyl} propionate) A mixture of 3- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} propionic (100 mg) and acetone (2 ml) was heated to 50 ° C, and 1N NaOH (0.18 ml) was added dropwise thereto with stirring. The mixture was stirred at 50 ° C for 2 hours and at 5 ° C for 1 hour, and the precipitated crystals were collected by filtration. The crystals were washed successively with acetone / cold water (95/5, 2 ml) and cold acetone (2 ml) to obtain the corresponding sodium salt. A mixture of the sodium salt thus obtained, ethanol (1 ml) and water (0.2 ml) was heated to 50 ° C to dissolve the mixture, and a solution of calcium chloride (11 mg) in water (0.2 ml) was added dropwise thereto with stirring at 60 ° C. After stirring at 60 ° C for 2 hours, the mixture was stirred at room temperature overnight. The crystals were collected by filtration, and washed successively with ethanol / water (1/1) and water (10 ml x 3) to obtain the title compound as colorless crystals (63 mg, 61% yield). ^ - MR (300 MHz, DMS0-de) d (ppm): 2.20 (3H, s), 2.2-2.4 (2H, m), 2.7-2.9 (2H, m), 3.36 (2H, m), 6.90 ( 1H, s), 7.06 (1H, d, J = 7.2Hz), 7.15 (1H, s), 7.3-7.7 (5H, m), 7.69 (1H, s), 9.78 (1H, brs).

Example 6 Bis (3- {3- [6-chloro-3- (2- {[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -7-methyl -2-oxo-2H-chromen-4-yl] phenyl.} Propionate) monocalcium A mixture of 3- acid. { 3- [6-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4 phenyl] Jpropionic acid (100 mg) and acetone (2 ml) was heated to 50 ° C, and INN NaOH (0.18 ml) was added dropwise thereto with stirring. The mixture was stirred at 50 ° C for 2 hours and at 5 ° C for 1 hour, and the precipitated crystals were collected by filtration. The crystals were washed successively with acetone / cold water (95/5, 2 ml) and cold acetone (2 ml) to obtain the corresponding sodium salt. A mixture of the sodium salt thus obtained, ethanol (1 ml) and water (0.2 ml) was heated at 50 ° C to dissolve the mixture, and a solution of calcium chloride (11 mg) in water (0.2 ml) was added dropwise thereto with stirring at 60 ° C.

After stirring at 60 ° C for 2 hours, the mixture was stirred at room temperature overnight. The crystals were collected by filtration, and washed successively with ethanol / water (1/1) and water (10 ml x 3) to obtain the title compound as colorless crystals (70 mg, yield 68%). XH-NMR (300 MHz, DMSO-ds) d (ppm): 2.2-2.4 (2H, m), 2.40 (3H, s), 2.7-2.9 (2H, m), 3.38 (2H, m), 6.88 ( 1H, s), 7.09 (1H, d, J = 7.2Hz), 7.18 (1H, s), 7.3-7.6 (6H, m), 9.75 (1H, brs).

Example 7 Bis (4-. {3- [7-chloro-3- (2. {[[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl 2-oxo-2H-chromen-4-yl] phenyl.} Butanoate) monocalcium A mixture of 4- acid. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} butanoic (100 mg) and acetone (2 ml) was heated to 50 ° C, and INN NaOH (0.18 ml) was added dropwise thereto with stirring. The mixture was stirred at 50 ° C for 2 hours, cooled, and concentrated under reduced pressure. The residue was dissolved in a mixture of ethanol (1 ml) and water (0.2 ml) and a solution of calcium chloride (11 mg) in water (0.2 ml) was added dropwise thereto with stirring at 50 ° C.

The mixture was stirred at 60 ° C for 2 hours and then at room temperature overnight. The crystals were collected by filtration, washed successively with ethanol / water (1/1) and water (10 ml x 3) to obtain the title compound as colorless crystals (89 mg, 86% yield). XH-NMR (300 MHz, DMSO-d6) d (ppm): 1.7-1.9 (2H, m), 1.9-2.1 (2H, m), 2.19 (3H, s), 2.5-2.7 (2H, m), 3.36 (2H, m), 6.87 (1H, s), 7.08 (1H, d, J = 7.2Hz), 7.10 (1H, s), 7.3-7.6 (5H, m), 7.64 (1H, s), 9.82 (1H, brs).

EXAMPLE 8 Bis ((2E) -3-. {3- [7-chloro-3- (2. {[[2- (trifluoromethyl) phenyl] amino} - 2-oxoethyl) -6-methyl- 2-oxo-2H-chromen-4-yl] 'phenyl.} Acrylate) monocalcium According to the same manner as described in Example 7, the title compound was obtained (73% yield). ^ -NMR (300 MHz, DMSO-dg) d (ppm): 2.20 (3H, s), 3.35 (2H, m), 6.47 (1H, d, J = 16Hz), 7.2-7.8 (10H, m), 9.60 (1H, br).

Reference example 9 Acid 4-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifiuoromethyl) phenyl] amino} -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4 -il] phenyl} butanoic A solution of 0.4 N-borabicyclo [3.3.1] nonane in tetrahydrofuran (300 ml, 0.12 mol) was added dropwise to a solution of methyl 3-butenoate (12.01 g, 0.12 mol) in tetrahydrofuran- (5 ml). ) at room temperature -under nitrogen atmosphere, and the mixture was stirred during 3 hours. This reaction mixture was added dropwise to a solution of 2- [4- (3-bromo-phenyl) -7-chloro-6-methyl-2 -oxo-2H-chromen-3-yl] -? - [4- fluoro-2- (trifluoromethyl) phenyl] acetamide obtained in Reference Example 4 (34.12 g, 0.06 mol), sodium methoxide (9.72 g, 0.18 mol) and (1,1 '-bis- (diphenylphosphino) ferrocene dichloride) ) palladium (9.8 g, 0.012 mol) in tetrahydrofuran (150 ml) at room temperature under nitrogen atmosphere, and the mixture was refluxed for 17 hours. An aqueous solution of hydrochloric acid was added to the reaction mixture., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over magnesium sulfate. The extract was concentrated, and deeply purified by silica gel column chromatography to obtain a crude product of 4-. { 3- [7-chloro-3 - (2 { [4-fluoro-2 - (trifluoromethyl) phenyl] amino} -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4 -yl] phenyl methyl Jbutanoate (34.96 g). This was dissolved in a mixed solvent of ethanol (300 ml) and tetrahydrofuran (300 ml), a 2N aqueous solution of sodium hydroxide (118.5 ml, 0.237 mol) was added thereto, and the mixture was stirred at room temperature for 12 hours. hours. The reaction mixture was extracted with water. The extract was washed with diethyl ether, neutralized with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography and then recrystallized from acetonitrile to obtain the title compound (12.04 g): mp 196 ° C. ^? - NMR (300 MHz, DMSO-dg) d (ppm): 1.77-1.89 (2H, m), 2.17-2.28 (5H, m), 2.60-2.72 (2H, m), 3.34 (2H, s) , 6.90 (1H, s), 7.12-7.19 (2H, m), 7.33-7.43 (2H, m), 7.47-7.63 (3H, m), 7.68 (1H, s), 9.62 (1H, s), 12.04 (1H, s).

EXAMPLE 9 Bis (4-. {3- [7-chloro-3- (2- { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl- Monocalcium 2-oxo-2H-chromen-4-yl] phenyl.} Butanoate) To a solution of the acid 4-. { 3- [7-chloro-3- (2 { [4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4 -il] phenyl} butanoic obtained in Reference Example 9 (26.7 g, 0.0463 mol) in acetone (534 ml) was added 25% aqueous ammonia (4 ml) at 50 ° C, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of acetonitrile (534 ml) and water (107 ml). The reaction mixture was heated to 70 ° C, and a solution of calcium chloride (3.14 g, 0.0255 mol) in water (107 ml) was slowly added dropwise thereto. The reaction mixture was stirred at 70 ° C for 3.5 hours, water (214 ml) was added thereto and the mixture was further stirred at 70 ° C for 1 hour and at room temperature for 12 hours. The obtained crystals were collected by filtration, washed with water (100 ml) and dried at 50 ° C under reduced pressure to obtain the title compound (26.67 g). XH-NMR (300 MHz, DMSO-dg) d (ppm): 1.71-1.85 (2H, m), 2.03 (2H, t, J = 7.1Hz), 2.20 (3H, s), 2.62 (2H, t, J = 7.2Hz), 3.30-3.44 (2H, m), 6.88 (1H, s), 7.07-7.16 (2H, m), 7.32-7.41 (2H, m), 7.45 (1H, t, J = 7.7Hz), 7.50-7.61 (2H, m), 7.65 (1H, s), 9.77 (1H, s).

Reference example 10 [4-. { 3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-4-yl] phenyl} acetate] of 4-methoxybenzyl Potassium carbonate (1.52 g) was added to a solution of [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetic acid obtained in Reference Example 3 (4.08 g) and p-methoxybenzyl chloride (1.63 ml) in DMF (20 ml), and the mixture was stirred at room temperature for 60 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain the title compound (4.35 g, 82%). aH-NMR (300 MHz, CDC13) d (ppm): 2.29 (3H, s), 3.38 (3H, s), 3. 81 (3H, s), 5.06 (2H, s), 6.78 (1H, s),. 6..88 (2H, ddd, J = 8. 8Hz, 2.8Hz, 2.0 Hz), 7.12-7.17 (1H, m), 7.26 (2H, ddd, J = 8. 8Hz, 2.8Hz, 2.0 Hz), 7.32-7.41 (3H, m), 7.56 (1H, ddd, J = 8.8 Hz, 1.8 Hz, 1.2 Hz).

Reference Example 11 (2E) -3- [3- (7-Chloro-3. {2 - 2- [(4-methoxybenzoyl) oxy] -2-oxoethyl] -6-methyl-2-oxo-2 ethyl-chromen-4-yl) phenyl] acrylate Palladium acetate (850 mg) and triphenylphosphine (2.0 g) were added to a solution of [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetate from 4-methoxybenzyl obtained in Reference Example 10 (20 g), ethyl acrylate (5.1 ml) and triethylamine (6.3 ml) in DMF (100 ml), and the mixture was stirred at 100 ° C for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 3) to obtain the title compound as crystals (17 g, 36%).

XH-NMR (300 MHz, CDCl3) d (ppm): 1.34 (3H, t, J = 7.2Hz), 2.28 (3H, s), 3.39 (2H, s), 3.80 (3H, s), 4.28 (2H , q, J = 7.2Hz), 5.05 (2H, s), 6.47 (1H, d, J = 16.2Hz), 6.78 (1H, s), 6.87 (2H, d, J = 8.7Hz), 7.20- 7.25 (3H, m), 7.38-7.42 (2H, m), 7.51 (1H, t, J = 7.8Hz), 7.64-7.72 (2H, m).

Reference Example 12 Acid (7-chloro-4- { 3- [(1 E) -3-ethoxy-3-oxo-l-propen-1-yl] phenyl}. 6-methyl-2-oxo-2H-chromen-3-yl) acetic acid Trifluoroacetic acid (12 ml) was added to a mixture of (2E) -3- [3- (7-chloro-3-. {2- 2- [(4-methoxybenzoyl) oxy] -2-oxoethyl.} -6 ethyl-2-oxo-2-chromen-4-yl) phenyl] acrylate obtained in Reference Example 11 (2.95 g) and anisole (2 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to obtain the title compound as crystals (2.0 g, 87%).

XH-NMR (300 MHz, CDC13) d (ppm): 1.33 (3H, t, J = 7.2Hz), 2.28 (3H, s), 3.36 (1H, d, J = 16.-8Hz), 3.44 (1H , d, J = 16.8Hz), 4.26 (2H, q, J = 7.2Hz), 6.48 (1H, d, J = 13.2Hz), 6.80 (1H, S), 7.26-7.29 (1H, m), 7.40 -7.42 (2H, m), 7.59 (1H, t, J = 7.8Hz), 7.67-7.73 (2H, m).

Reference Example 13 N- (5-Fluoro-4-methoxy-2-nitrophenyl) acetamide Acetic anhydride (5 ml) was added to 3-fluoro-4-methoxyaniline (5.0 g), and the mixture was stirred for 30 minutes. The reaction mixture was cooled to room temperature, and nitric acid (2.3 ml) was added dropwise thereto. The mixture was stirred for 30 minutes, and water was added thereto. The resulting precipitate was collected and washed with water to obtain the title compound as crystals (5.7 g, 71%). XH-NMR (300 MHz, CDC13) d (ppm): 2.29 (3H, s), 3.94 (3H, s), 7.80 (1H, d, J = 8.4Hz) # 8.66 (1H, d, J = 10.5Hz ), 10.39 (1H, brs).

Reference Example 14 5-Fluoro-4-methoxy-2-nitroaniline N- (5-Fluoro-4-methoxy-2-nitrophenyl) acetamide obtained in Reference Example 13 (5.7 g) was suspended in ethanol (20 ml), and 6N hydrochloric acid (100 ml) was added thereto. The mixture was refluxed for 30 minutes. The reaction mixture was cooled with ice, and the resulting precipitate was collected and washed with water to obtain the title compound as crystals (4.1 g, 88%). XH-NMR (300 MHz, CDCl 3) d (ppm): 3.87 (3H, s), 6.00 (1H, brs), 6.54 (1H, d, J = 14.7Hz), 7.68 (1H, d, J = 8.7Hz ).

Reference Example 15 l-Bromo-5-fluoro-4-methoxy-2-nitrobenzene -Fluoro-4-methoxy-2-nitroaniline obtained in Reference Example 14 (4.1 g) was dissolved in a mixed solvent of water (20 ml) and 1,4-dioxane (10 ml), 48% hydrobromic acid (12 ml) was added to the solution under reflux, and then the mixture was refluxed for 15 minutes. The reaction mixture was cooled to 0 ° C, sodium nitrite was added dropwise thereto, and the mixture was stirred at 0 ° C for 15 minutes. The resulting mixture was added dropwise to a solution of copper (I) bromide (3.6 g) in a mixture of water (20 ml) and 48% hydrobromic acid (12 ml) at 0 ° C. The mixture was stirred at 60 ° C for 15 minutes, cooled to room temperature, and further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 8) to obtain the title compound as crystals (5 g, 91%). XH-NMR (300 MHz, CDC13) d (ppm): 3.96 (3H, s), 7.46 (1H, d, J = 9.9Hz), 7.58 (1H, d, J = 8.1Hz).

Reference example 16 l-Fluoro-2-methoxy-4-nitro-5- (trifluoromethyl) benzene Bromide of copper (I) (0.16 g) and FS02CF2C02Me (4.2 ml) were added to a solution of l-bromo-5-fluoro-4-methoxy-2-nitrobenzene obtained in Reference Example 15 (5 g) in DMF (40 ml), and the mixture was stirred at 80 ° C overnight under atmosphere: The reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 8) to obtain the title compound as an oily substance (3.1 g, 79%). ^? - NMR (300 MHz, CDCl 3) d (ppm): 4.03 (3H, s), 7.53 (1H, d, J = 10.8Hz), 7.56 (1H, d, J = 7.2Hz).

Reference example 17 2-Fluoro-5-nitro-4- (trifluoromethyl) phenol A 1N solution of boron tribrorride in dichloromethane (15 ml) was added dropwise to a solution of l-fluoro-2-methoxy-4-nitro-5- (trifluoromethyl) benzene obtained in Reference Example 16 (1.4 g) in dichloromethane (5 ml) with ice cooling. After stirring at room temperature overnight, water and 1N hydrochloric acid were added to the reaction mixture. After stirring for 30 minutes, an organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 3) to obtain the title compound as crystals (0.5 g, 38% -). XH-? MR (300 MHz, CDC13) d (ppm): 6.72 (1H, brs), 7.55 (1H, d, J = 10.5Hz), 7.62 (1H, d, J = 7.5Hz).

Reference example 18 (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-5-hydroxy-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo- 2H-chromen-4-yl] phenyl} ethyl acrylate Raney nickel (0.5 g) was added to a solution of 2-fluoro-5-nitro-4- (trifluoromethyl) phenol obtained in Reference Example 17 (0.5 g) in THF (5 ml), and the mixture was stirred for 2 hours in a hydrogen atmosphere. The catalyst was removed by filtration and the catalyst was washed with THF. The combined filtrate and washings were diluted with THF to obtain a solution of 5-amino-2-fluoro-4- (trifluoromethyl) phenol in THF (50 ml). DMF (one drop) was added to an acid solution (7-chloro-4-. {3- [(1E) -3-ethoxy-3-oxo-l-propen-1-yl] phenyl]. 6-methyl-2-oxo-2H-chromen-3-yl) acetic obtained in Reference Example 12 (800 mg) in THF (20 ml), and oxalyl chloride (0.2 ml) was added dropwise to this . After stirring for 30 minutes, the reaction mixture was concentrated, the above-mentioned solution of 5-amino-2-fluoro-4- (trifluoromethyl) phenol in THF (50 ml) was added to the residue, and the mixture was stirred for the night. The reaction mixture was concentrated, and the residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 3) to obtain the title compound as crystals (0.84 g, 74%). ^? - NMR (300 MHz, CDCl 3) d (ppm): 1.31 (1H, t, J = 6.9Hz), 2.28 (3H, S), 3.42 (1H, d, J = 14.7Hz), 3.62 (1H , d, J = 14.7Hz), 4.23 (2H, g, J = 6.9Hz), 6.48 (1H, d, J = 15.6Hz), 6.84 (1H, s), 7.21 (1H, d, J = 10.2Hz ), 7.34 (1H, d, J = 7.5Hz), 7.37 (1H, s), 7.56-7.75 (5H, m), 8.16 (1H, brs), 8.50 (1H, brs).

Reference Example 19 Acid (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-5-hydroxy-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl-6-methyl-2-oxo-2H- chromen-4-yl) phenyl] acrylic (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-5-hydroxy-2 - (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H -chromen-4-yl] phenyl} Ethyl acrylate obtained in Reference Example 18 (0.84 g) was dissolved in a mixture of THF (40 ml) and ethanol (40 ml), and 2N aqueous sodium hydroxide solution (5 ml) was added thereto. After stirring for 5 hours, the reaction mixture was concentrated, and IN hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain the title compound as crystals (0.346 g, 43%). XH-NMR (300 MHz, CDC13) d (ppm): 2.26 (3H, s), 3.34 (2H, m), 6.57 (1H, d, J = 16.2Hz), 6.92 (1H, s), 6.95 (1H , d, J = 8.2Hz), 7.35 (1H, d, J = 8.4Hz), 7.50 (1H, d, J = 11.4Hz), 7.61-7.66 (3H, m), 7.73 (1H, s), 7.92 (1H, d, J = 7.8Hz), 9.52 (1H, brs), 10.94 (1H, brs), 12.41 (1H, brs).

Reference example 20 5-Fluoro-2-nitro-3- (trifluoromethyl) phenol -Fluoro-3- (trifluoromethyl) phenol (1.27 g) was dissolved in acetic acid (3 ml) and water (1.5 ml), and nitric acid (3.0 ml) was added thereto. The reaction mixture was stirred at 50 ° C for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developed solution: ethyl acetate-hexane = 1: 3) to obtain the title compound as oil (0.33 g, 21%). XH-NMR (300 MHz, CDC13) d (ppm): 7.06 (1H, dd, J = 8.7Hz, 2.7Hz), 7.15 (1H, m). 25 as an oil: XH-NMR (CDC13) d: 6.92 (1H, dd, J = 10.5Hz, 2.7Hz), 7.02 (1H, m).

Reference Example 21 2-Amino-5-fluoro-3- (trifluoromethyl) phenol -Fluoro-2-nitro-3- (trifluoromethyl) phenol obtained in Reference Example 20 was dissolved in ethanol (15 ml), 10% Pd-C (100 mg) was added to the solution, and the mixture was stirred overnight in a hydrogen atmosphere. The catalyst was removed by filtration and the reaction mixture was concentrated to obtain the title compound as an oil (0.22 g, 77%). XH-NMR (300 MHz, CDC13) d (ppm): 6.67 (1H, d, J = 8.7Hz), 6.77 (1H, d, J = 8.1Hz).

Reference example 22 (2E) -3 -. { 3- [7-chloro-3 ~ (2- {[4-f-luoro-2-hydroxy-6- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo- 2H-chromen-4-yl] f-enyl} ethyl acrylate DMF (one drop) was added to an acid solution (7- chloro-4- { (3- [(1 E) -3-ethoxy-3-oxo-l-propen-l-yl] phenyl) -6 -methyl-2-oxo-2H-chromen-3-yl.} acetic acid (430 mg) in THF (20 ml), and oxalyl chloride (0.11 ml) was added dropwise thereto. The reaction mixture was concentrated, the residue was dissolved in THF (10 ml), 2-amino-5-fluoro-3- (trifluoromethyl) phenol obtained in Reference Example 21 (0.22 g) was added thereto, and the mixture was stirred overnight, water was added to the reaction mixture, and the mixture was extracted with water.The extract was washed with IN hydrochloric acid, a solution of saturated aqueous sodium bicarbonate and water, dried over sulfate magnesium, and concentrated The residue was purified by column chromatography (developed solvent: ethyl acetate-hexane = 1: 3) to obtain the title compound as crystals (0.31 g, 45%).

^? - NMR (300 MHz, CDC13) d (ppm): 1.33 (3H, t, J = 7.2Hz), 2.31 (3H, s), 3.48 (1H, d, J = 14.7Hz), 3.54 (1H, d, J = 14.7Hz), 4. 27 (2H, q, J = 7.2Hz), 6.51 (1H, d, J = 15.9Hz), 6.88 (1H, s), 6.95 (2H, d, J = 8.1Hz), 7.35 (1H, m), 7.48 (2H, m), 7.61 (1H, t, J = 8.1Hz), 7.72 (2H, m), 8.21 (1H, brs).

Reference Example 23 Acid (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2-hydroxy-6- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H -chromen-4-yl] phenyl} cric (2E) -3-. { 3- [7-chloro-3- (2 { [4-fluoro-2-hydroxy-6- (trifluoromethyl) phenyl] mino} -2-oxoethyl) -6-methyl-2-oxo-2H -chromen-4-yl] phenyl} Ethyl acrylate obtained in Reference Example 22 (0.31 g) was dissolved in a mixture of THF (5 ml) and ethanol (5 ml), and 2N aqueous sodium hydroxide solution (1.5 ml) was added thereto. After stirring for 5 hours, the reaction mixture was concentrated. IN hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to obtain the title compound as crystals (0.155 g, 52%). XH-NMR (300 MHz, CDCl 3) d (ppm): 2.25 (3H, s), 3.33 (2H, m), 6.57 (1H, d, J = 16.2Hz), 6.89-6.99 (3H, m), 7.37. (1H, d, J = 7.5Hz), 7.57-7.69 (4H, m), 7.91 (1H, d, J = 7.5Hz), 9.17 (1H, brs), 10.53 (1H, brs), 12.32 (1H, brs). In the following Formulation Examples and Experimental Examples, compounds A through E mean the following compounds.

Compound A: bis ((2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2 -oxo-2H-chromen-4-yl] phenyl] acrylate) monocalcium trihydrate, Compound B: tris (hydroxymethyl) methylamine salt (2E) -3- [3- [7-chloro-3- (2- [[ 4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] acrylate Compound C: diethanolamine salt (2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] acrylate Compound D: bis (3- [3- [6-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2- oxo-2H-chromen-4-yl] phenyl] propionate) monocalcium Compound E: bis (4- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] ] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] butanoate monocalcium Formulation Example A lipid-rich plaque regression agent or an ACAT inhibitor contains the compound of the present invention as an active ingredient that can be produced, for example, by the following formulations. In the following formulations, as ingredients (additives) other than an active ingredient, the products listed in Japanese Pharmacopoeia, Japanese Pharmaceutical Code or Japanese Pharmaceutical Excipients may be used. 1. Capsule (1) Compound A: 10 mg (2) Lactose: 90 mg (3) Microcrystalline cellulose: 70 mg (4) Magnesium stearate: 10 mg One capsule 180 mg (1), (2), (3) and 1/2 of (4) are mixed and then granulated. To this the remainder of (4) is added and the complete one is encapsulated in a gelatin capsule. 2. Tablet (1) Compound A: 2,705 mg (2) Mannitol: 438,295 mg (3) Microcrystalline cellulose: 90 mg (4) Povidone: 30 mg (5) Croscarmellose sodium: 30 mg (6) Magnesium stearate: 9 mg ( 7) Hydroxypropylmethylcellulose 16.72 mg (8) Macrogol: 3.6 mg (9) Titanium dioxide: 3.6 mg (10) Ferric oxide: 0.08 mg One tablet 624 mg (1), (2), (3) and (4) are granulated . To this granule, (5) and (6) were added and compressed into a tablet. The resulting tablet was coated with the aqueous solution of the mixture of (7), (8), (9) and (10) to give the film-coated tablet. 3. Injection formulation (1) Compound A: 10 mg (2) Inositol: 100 mg (3) Benzyl alcohol: 20 mg One ampoule 130 mg (1), (2) and (3) were dissolved in distilled water for injection to make the total volume of 2 ml, and it is loaded in an ampoule. All stages were carried out aseptically. 4. Capsule (1) Compound B: 10 mg (2) Lactose: 90 mg (3) Microcrystalline cellulose: 70 mg (4) Magnesium stearate: 10 mg One capsule 180 mg (1), (2), (3) and 1 / 2 of (4) are mixed and then granulated. To this the remainder of (4) is added and the complete one is encapsulated in a gelatin capsule.

. Tablet (1) Compound B: 2705 mg (2) Mannitol: 438.295 mg (3) Microcrystalline cellulose: 90 mg (4) Povidone: 30 mg (5) Croscarmellose sodium: 30 mg (6) Magnesium stearate: 9 mg ( 7) Hydroxypropylmethylcellulose 16.72 mg (8) Macrogol: 3.6 mg (9) Titanium dioxide: 3.6 mg (10) Ferric oxide: 0.08 mg One tablet 624 mg (1), (2), (3) and (4) are granulated . To this granule, (5) and (6) were added and compressed into a tablet. The resulting tablet was coated with the aqueous solution of the mixture of (7), (8), (9) and (10) to give the film-coated tablet. 6. Injection formulation (1) Compound B: 10 mg (2) Inositol: 100 mg (3) Benzyl alcohol: 20 mg One ampoule 130 mg (1), (2) and (3) were dissolved in distilled water for injection to make the total volume of 2 ml, and it is loaded in an ampoule. All stages were carried out aseptically. 7. Capsule (1) Compound C: 10 mg (2) Lactose: 90 mg (3) Microcrystalline cellulose: 70 mg (4) Magnesium stearate: 10 mg One capsule 180 mg (1), (2), (3) and 1 / 2 of (4) are mixed and then granulated. To this the remainder of (4) is added and the complete one is encapsulated in a gelatin capsule. 8. Tablet (1) Compound C: 2705 mg (2) Mannitol: 438.295 mg (3) Microcrystalline cellulose: 90 mg (4) Povidone: 30 mg (5) Croscarmellose sodium: 30 mg (6) Magnesium stearate: 9 mg ( 7) Hydroxypropylmethylcellulose 16.72 mg (8) Macrogol: 3.6 mg (9) Titanium dioxide: 3.6 mg (10) Ferric oxide: 0.08 mg One tablet 624 mg (1), (2), (3) and (4) are granulated . To this granule, (5) and (6) were added and compressed into a tablet. The resulting tablet was coated with the aqueous solution of the (7), (8), (9) and (10) to give the film coated tablet. 9. Injection formulation (1) Compound C: 10 mg (2) Inositol: 100 mg (3) Benzyl alcohol:. 20 mg One ampoule 130 mg (1), (2) and (3) were dissolved in distilled water for injection to make the total volume of 2 ml, and loaded in an ampule. All stages were carried out aseptically.

. Capsule (1) Compound D: 10 mg (2) Lactose: 90 mg (3) Microcrystalline cellulose: 70 mg (4) Magnesium stearate: 10 mg One capsule 180 mg (1), (2), (3) and 1 / 2 of (4) are mixed and then granulated. To this the remainder of (4) is added and the complete one is encapsulated in a gelatin capsule. 11. Tablet (1) Compound D: 2705 mg (2) Mannitol: 438.295 mg (3) Microcrystalline cellulose: 90 mg (4) Povidone: 30 mg (5) Croscarmellose sodium: 30 mg (6) Magnesium stearate: 9 mg ( 7) Hydroxypropylmethylcellulose 16.72 mg (8) Macrogol: 3.6 mg (9) Titanium dioxide: 3.6 mg (101 Ferric Oxide: 0.08 mg One tablet 624 mg (1), (2), (3) and (4) are granulated. To this granule, (5) and (6) were added and compressed into a tablet. The resulting tablet was coated with the aqueous solution of the (7), (8), (9) and (10) to give the film coated tablet. 12. Injection formulation (1) Compound D: 10 mg (2) Inositol: 100 mg (3) Benzyl alcohol: 20 mg One ampoule 130 mg (1),. (2) and (3) were dissolved in distilled water for injection to make the total volume of 2 ml, and loaded in an ampoule. All stages were carried out aseptically. 13. Capsule (1) Compound E: 10 mg (2) Lactose: 90 mg (3) Microcrystalline cellulose: 70 mg (4) Magnesium stearate: 10 mg One capsule 180 mg - (1), (2), (3) and 1/2 of (4) are mixed and then granulated. To this the remainder of (4) is added and the complete one is encapsulated in a gelatin capsule. Í4. Tablet (1) Compound E: 2705 mg (2) Mannitol: 438.295 mg (3) Microcrystalline cellulose: 90 mg (4) Povidone: 30 mg (5) Croscarmellose sodium: 30 mg (6) Magnesium stearate: 9 mg ( 7) Hydroxypropylmethylcellulose 16.72 mg (8) Macrogol: 3.6 mg (9) Titanium dioxide: 3.6 mg (10) Ferric oxide: 0.08 mg One tablet 624 mg (1), (2), (3) and (4) are granulated . To this granule, (5) and (6) were added and compressed into a tablet. The resulting tablet was coated with the aqueous solution of the (7), (8), (9) and (10) to give the film coated tablet.

. Injection formulation (1) Compound E: 10 mg (2) Inositol: 100 mg (3) Benzyl alcohol: 20 mg One ampoule 130 mg (1), (2) and (3) were dissolved in distilled water for injection to make the total volume of 2 ml, and it is loaded in an ampoule. All stages were carried out aseptically.

Experimental Example 1 (oral absorbency capacity) The oral absorbency capacity of the compound of the present invention will be illustrated by the following Experimental Example. [Method] Male New Zealand white rabbits are forced to take compound A, B or X orally (n = 3) (0.5% suspension in methylcellulose, the dose was 10 mg / kg in terms of compound X). A blood level of compound X is measured over time to determine the maximum blood level (Cmax) and the time required to reach the maximum blood level (Tmax).

Compound X: acid (2E) -3-. { 3- [7-chloro-3- (2- { [4-fluoro-2- (trifluoromethyl) phenyl] amino) -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl } acrylic described in the ~: International Publication WO 02/06264. [Results] The results are shown in table 1. When compound A or B is administered orally, a blood level higher than that of oral administration of Compound X is observed.

Table 1 As seen from these results, the compound of the present invention shows excellent oral absorbency.

Experimental Example 2 (ACAT inhibitory activity) [Preparation of mouse macrophage microsome ACAT] According to the method of Hakamada et al.

(Experimental Medicine Suppliment vol 14., No. 12, Circulation Research Protocol, p, 49-52, 1996), an abdominal macrophage of a C57BL6J mouse stimulated with thioglycolate is taken and cultured for 24 hours in an RPMl medium 1640-25 M HEPES (pH 7.0) containing very low density lipoprotein ß rabbit (ß-VLDL, 150 μg cholesterol / ml) that has been prepared by the method of Ishii et al. (Ishii I et al., Arterioscler, Thromb., 12, 1139-1145, 1992). The abdominal macrophage is then collected by centrifugation (4 ° C, 1,000 rpm, 5 minutes) and sonicated. The sonicated liquid is centrifuged (4 ° C, 5000 rpm, 15 minutes) and then ultracentrifuged (4 ° C, 50,000 rpm, 90 minutes) to prepare a microsome. The microsome thus obtained is used to measure the ACAT inhibitory activity of the test compound as ACAT from mouse abdominal macrophage microsome.

[Method for measuring ACAT inhibitory activity] A mixture of test compound, Tris-HCL buffer solution containing albumin-cholesterol (pH 7.5) and mouse macrophage microsome ACAT of mouse are previously incubated at 37 ° C for 10 minutes, and it is added to react at 37 ° C for 20 minutes. A solution composed of distilled water-methyl alcohol-chloroform (2: 2: 1 v / v) was added to stop the reaction, and the produced cholesteryl ester (CE) was removed with stirring. The extract is subjected to thin chromatography on silica gel (petroleum ester: diethyl ether: acetic acid = 9: 1: 0.1 v / v), and the resulting 3H-CE fraction is measured with a scintillation counter. The ACAT inhibitory ratio is calculated from the ratio based on the ACAT activity without the test compound, and an IC5o value is calculated as the concentration of the test compound showing an ACAT inhibition ratio of 50%. As a result, the IC50 value of compound A was 1956 nM. As apparent from the above results, the compound of the present invention has excellent inhibitory activity, and is useful as an agent for treating arteriosclerosis resulting in inhibited formation and regression of an arteriosclerotic lesion.

INDUSTRIAL APPLICABILITY Since the compound of the present invention has a regressive activity of the lipid-rich plaque excellent and / or an ACAT inhibitory activity, excellent physicochemical properties and oral absorbency, are useful as a drug to prevent or treat, coronary syndrome such as myocardial infarction and unstable angina; peripheral arterial occlusion, hyperlipemia, cerebral infarction, cerebral apoplexy, arteriosclerosis, atherosclerosis, Alzheimer's disease, multiple risk syndrome and metabolism syndrome, etc., in a mammal (for example, mouse, rat, rabbit, dog, cat, cow , pig, monkey, human etc.) or prevent or treat restenosis after PTCA or after stenting. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

1. Claims: Having described the invention as above, the content of the following claims is claimed as property. 1. An alkaline earth metal salt or an organic amine salt of a compound represented by the formula [I]: characterized in that R1 and R2 are each a hydrogen atom, a halogen atom, or an optionally substituted linear hydrocarbon group; ring A is an optionally substituted benzene ring; ring B is an optionally substituted benzene ring; R is a carboxyl group or a linear hydrocarbon group substituted with a carboxyl group.
2. 2. The compound according to claim 1, characterized in that it is a hydrate.
3. 3. The compound according to claim 1, characterized in that R1 and R2 are each a halogen atom or an optionally substituted C? -7 alkyl group.
4. 4. The compound according to claim 1, characterized in that ring B is a benzene ring which is substituted with a halogenated alkyl group and / or a halogen atom.
5. 5. The compound according to claim 1, characterized in that R is a group represented by the formula - (CH2) nR 'wherein R' is a carboxyl group and n is an integer from 0 to 6.
6. 6. The compound in accordance with claim 1, characterized in that R is a group represented by the formula - (CH = CH) n »-R 'where R' is a carboxyl group and n" is an integer from 1 to 3.
7. 7. The compound in accordance with claim 1, characterized in that it is an alkaline earth metal salt
8. 8. The compound according to claim 1, characterized in that the alkaline earth metal salt is a calcium salt
9. 9. The compound according to claim 1, characterized in because it is an organic amine salt
10. 10. The compound according to claim 9, characterized in that the organic amine salt is a primary amine salt
11. 11. The compound according to claim 10, characterized in that the primary amine salt is a tris (hydroxymethyl) methylamine salt.
12. 12. The compound characterized in that it is selected from the group consisting of bis ((2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] mino] -2- oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] acrylate) of monocalcium, tris (hydroxymethyl) ethylamine salt of (2E) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] acrylate, diethanolamine salt of (2E ) -3- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] mino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen- 4-yl] phenyl] -crylate, bis (3- [3- [6-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl- 2-oxo-2H-chromen-4-yl] phenyl] propionate) of monocalcium and bis (4- [3- [7-chloro-3- (2- [[4-fluoro-2- (trifluoromethyl) phenyl] amino] ] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] butanoate) of monocalcium, or a hydrate thereof.
13. 13. A process for producing an alkaline earth metal salt of a compound represented by the formula [I] wherein each symbol is as defined in accordance with claim 1, characterized in that it comprises contacting a compound represented by the formula [I] with an alkaline earth metal hydroxide or an alkaline earth metal hydride, or by contacting a alkali metal salt of a compound represented by the formula [I] with an alkaline earth metal halide.
14. 14. A crystal characterized in that it is of the compound according to claim 1.
15. 15. A medicament characterized in that it comprises the compound according to claim 1 or a crystal thereof.
16. 16. The medicament according to claim 15, characterized in that it is an oral preparation.
17. 17. The medicament according to claim 15, characterized in that it is a lipid-rich plaque regression agent or an ACAT inhibitor.
18. 18. The medicament according to claim 15, characterized in that it is a prophylactic or therapeutic agent against coronary syndrome, myocardial infarction, unstable angina, coronary artery restenosis after PTCA or after a stent graft placement, peripheral arterial occlusion, hyperlipemia, cerebral infarction, cerebral apoplexy, Alzheimer's disease , multiple risk syndrome or metabolism syndrome, or an agent for the regression, inhibition or progression of or stabilizing an atherosclerotic or atherosclerotic lesion. 19 The agent for regression, progress of inhibiting or stabilizing an arteriosclerotic or atherosclerotic lesion according to claim 18, characterized in that it is combined with a HMG-CoA reductase inhibitor. twenty . The use of the compound according to claim 1 for the production of a lipid-rich plaque regression agent or an ACAT inhibitor. twenty-one . The use of the compound according to claim 1 for the production of a prophylactic or therapeutic agent against coronary syndrome, myocardial infarction, unstable angina, coronary artery restenosis after PTCA or stenting, peripheral arterial occlusion, hyperlipidemia, cerebral infarction , cerebral apoplexy, Alzheimer's disease, multiple risk syndrome or metabolism syndrome, or an agent for regression, inhibiting the progress of or stabilizing an arteriosclerotic or atherosclerotic lesion. 22. The use of the compound according to claim 1 for production of an agent for regression, inhibition of the progress of or to stabilize an arteriosclerotic or atherosclerotic lesion according to claim 24, which is combined with a reductase inhibitor HMG- CoA.