JP2003267965A - Coumarin derivative, method for producing the same and use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a coumarin derivative useful as a lipid-rich plaque- involuting agent or an ACAT inhibitor. <P>SOLUTION: A compound represented by formula [I] [R<SP>1</SP>and R<SP>2</SP>are each H, a halogen, a linear hydrocarbon group which may have one or more substituents, or a hydroxyl group that may be substituted with a linear hydrocarbon group which may have one or more substituents, or R<SP>1</SP>and R<SP>2</SP>may together form with the adjacent carbon atom a cyclic hydrocarbon which may have one or more substituents, or a dihydrofuran ring which may be converted into its oxo compound; the ring A is a benzene ring which may further have one or more substituents; the ring B is an aromatic ring which may have one or more substituents; X is a direct bond or a spacer whose main chain has one to six atoms; Y is carboxyl group which may be esterified, carbamoyl group which may have one or more substituents, cyano group, or a heterocyclic group which may have one or more substituents and has one or more proton-removable hydrogen atoms] or its salt. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to prevention of acute myocardial infarction, acute coronary syndrome such as unstable angina, peripheral arterial occlusion, hyperlipidemia, cerebral infarction, stroke, arteriosclerosis, Alzheimer's disease and the like. Or lipids useful for the treatment or prevention or treatment of restenosis after PTCA or stent placement
It relates to a coumarin derivative having a rich plaque retraction effect and / or an ACAT inhibitory effect.

[0002]

2. Description of the Related Art Cholestyramine (Cholestamine) is a drug that lowers blood cholesterol, which causes arteriosclerosis.
yramine), a drug that supplements bile acids such as cholestipol and inhibits its absorption (eg, Patent Document 1),
In addition to a drug that inhibits intestinal absorption of cholesterol by inhibiting acylcoenzyme A cholesterol acyltransferase (ACAT) such as melinamide, a cholesterol synthesis inhibitor, particularly 3-hydroxy-3
-Methylglutaryl coenzyme A (HMG-CoA) reductase-inhibiting lovastatin (Lovastatin) (patent document 2), simvastatin (Simvastatin) (patent document 3), pravastatin (Pravastatin) (patent document 4) and the like are used for medicines. Has been done. However, the HMG-CoA reductase inhibitor inhibits not only the biosynthesis of cholesterol but also the synthesis of components necessary for the living body such as ubiquinone, dolichol and heme A, and thus there is a fear of side effects caused thereby.

Acute coronary syndrome (eg unstable angina,
Acute myocardial infarction and sudden ischemic death, etc., result from the rupture of coronary plaque (atheroma) followed by thrombus formation and obstruction of the lumen of the coronary arteries. In addition, peripheral arterial occlusion
It occurs because a thrombus is formed following the breakdown of an arterial plaque (atheroma), and the lumen of the peripheral artery is occluded. The characteristics of plaque are deeply involved in these diseases, and lipid-rich plaque formed by the accumulation of cholesterol and other lipids in macrophages on the inner wall of blood vessels causes acute coronary syndrome and peripheral arterial occlusion. It is said that. Further, lipid-rich plaques in carotid arteries or blood vessels in the brain are considered to be the cause of stroke or cerebral infarction. Therefore, retraction and removal of lipid-rich plaque is extremely important for the prevention or treatment of acute myocardial infarction, acute coronary syndrome represented by unstable angina, peripheral artery occlusion, stroke or cerebral infarction. Is. Lipid-rich plaques are also found in humans with low blood cholesterol levels, and
Since the lipid-rich plaque once formed is difficult to remove, it has been desired to provide a drug that causes the lipid-rich plaque to regress efficiently. Where Lipid
Since rich plaques are also found in humans whose blood cholesterol levels are not high, it is sufficient to repress and eliminate lipid-rich plaques by inhibiting ACAT and suppressing the intestinal absorption of cholesterol. Not considered. As a result of intensive studies in view of the above circumstances, the present inventors have found a coumarin derivative having a lipid-rich plaque retraction effect or an ACAT inhibitory effect (Patent Document 5). Further, recently, the possibility of preventing and treating Alzheimer's disease by inhibiting ACAT has been suggested (Non-Patent Document 1).

[0004]

[Patent Document 1] US Pat.

[Patent Document 2] US Pat. No. 4,231,938

[Patent Document 3] US Pat. No. 4,444,784

[Patent Document 4] US Pat. No. 4,346,227

[Patent Document 5] International Publication No. 02/06264 Pamphlet

[Non-Patent Document 1] L. Puglielli et al.
"Nature Cell Biol
ogy) ”, 2001, Volume 3, p. 905-912

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a lipid-rich plaque useful for the prevention or treatment of acute coronary syndromes such as acute myocardial infarction and unstable angina, peripheral arterial occlusion, stroke and cerebral infarction. Provided is a coumarin derivative having a retracting action or an ACAT inhibiting action. In addition, the present invention provides a coumarin derivative that exhibits excellent blood vessel / tissue transferability and that acts directly on macrophages accumulating lipids such as cholesterol to exhibit a direct retraction effect on arteriosclerotic lesions. In addition, since the coumarin derivative provided by the present invention has an ACAT inhibitory activity, it has an inhibitory effect on the secretion of ultra-low density lipoprotein from the liver and an inhibitory effect on the cholesterol absorption from the small intestine and the accompanying chylomicron secretion, and As a result, it is also considered to have a blood cholesterol and triglyceride lowering action. Furthermore, it is considered that the coumarin derivative provided by the present invention may be applicable to the prevention / treatment of Alzheimer's disease, multiple risk syndrome and metabolic syndrome.

[0006]

Means for Solving the Problems As a result of continuous studies to find a more clinically useful compound, the present inventors have found that a new coumarin derivative having a specific substituent at the 3-phenyl group of the coumarin skeleton is Unexpectedly excellent ACAT
It was found that the compound has an inhibitory action and a lipid-rich plaque retraction action, and has a sufficient lipid-rich plaque retraction action even at a concentration that does not affect the blood cholesterol level, and to complete the present invention. I arrived.
That is, the present invention provides (1) Formula [I]

[Chemical 3] [Wherein R ¹ and R ² are each substituted by a hydrogen atom, a halogen atom, a chain hydrocarbon group which may have a substituent or a chain hydrocarbon group which may have a substituent] Optionally a hydroxy group, or R ¹ and R ² together form a cyclic hydrocarbon optionally having substituents with adjacent carbon atoms or an optionally oxo-dihydrofuran ring. The ring A may be a benzene ring which may further have a substituent, the ring B may be an aromatic ring which may have a substituent, and X is a bond or a main chain having 1 to 6 atoms. In the spacer of, Y is a carboxyl group which may be esterified, a carbamoyl group which may have a substituent, a cyano group, or a hetero atom having a deprotonizable hydrogen atom which may have a substituent. Indicates a ring group. ] A compound represented by (provided that 3- [3- [7-chloro-3- (2-
[[4-Chloro-2- (trifluoromethyl) phenyl] amino]-
2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propionic acid, 3- [3- [7-chloro-3- (2-
[[4-Chloro-2- (trifluoromethyl) phenyl] amino]-
2-Oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propionate ethyl, (2E) -3- [3- [7-chloro-3- (2- [ Methyl [4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoate, (2E) -3
-[3- [7-Chloro-3- (2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromene-4 -Yl] phenyl] -2-propenoic acid, (2
E) -3- [3- [7-Chloro-3- (2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2
-Oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid ethyl, (2E) -3- [3- [7-chloro-3- (2-[[4-fluoro-2-
(Trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl]
-2-Ethyl propenoate, and (2E) -3- [3- [7-chloro-3-
(2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid (Except) or a salt thereof; (2) Formula [I] is represented by Formula [I ′]

[Chemical 4] [In the formula, the B'ring is a benzene ring which may have a substituent.
Alternatively, R is an pyridine ring which may have a substituent.
Carboxyl group or ester which may be stellized
Chain substituted with an optionally carboxylated carboxyl group
Indicates a hydrocarbon group, and other symbols have the same meaning as described in (1) above.
Indicates. ] The compound according to (1) above, which is: (3) R¹And R²Are hydrogen atom and halogen atom, respectively
Alternatively, a chain hydrocarbon group which may have a substituent is
Or R¹And R²Together with the adjacent carbon atom
By forming a cyclic hydrocarbon which may have a substituent
Optionally, the compound according to the above (1); (4) R¹And R²Are halogen atom or substitution, respectively
C which may have a group _1-7The above is an alkyl group
The compound described in (1); (5) R¹Is a halogen atom, and R²Has a substituent
It is a chain hydrocarbon group substituted with an amino group which may be present.
The compound described in (1) above; (6) R¹Is a halogen atom, and R²Has a substituent
A chain hydrocarbon group substituted with a cyclic amino group
A certain compound according to the above (1); (7) Cyclic hydrocarbon is C_5-7Said is a cyclic hydrocarbon
The compound described in (1); (8) Ring B is a halogenated alkyl group and / or halo
(1) above, which is a benzene ring substituted with a gen atom
A compound of (9) R is the formula-(CH₂)_n-R '[wherein R'is an esthetic
Represents an optionally carboxylated carboxyl group, and n is 0 to
An integer of 6], which is a group represented by the above (2).
Compound; (10) R is of the formula -CH = CH- (CH₂)_{n '}-R '[expression
Wherein R'is a carboxyl group which may be esterified
And n'represents an integer of 0 to 4].
A compound according to (2) above; (11) R is a formula- (CH = CH)_{n ''}-R '[wherein
R'represents an optionally esterified carboxyl group
And n ″ represents an integer of 1 to 3]
A compound according to item (2); (12) 3- [3- [7-chloro-3- (2-[[4-fluoro-2- (trif
Luoromethyl) phenyl] amino] -2-oxoethyl) -6-me
Tyl-2-oxo-2H-chromen-4-yl] phenyl] propio
Acid, (2E) -3- [3- [7-chloro-6-methyl-2-oxo-3- (2-
Oxo-2-[[2- (trifluoromethyl) phenyl] amino]
Ethyl) -2H-chromen-4-yl] phenyl] -2-propene
Acid, 3- [3- [7-chloro-6-methyl-2-oxo-3- (2-oxo-2
-[[2- (Trifluoromethyl) phenyl] amino] ethyl) -2
H-chromen-4-yl] phenyl] propionic acid, (2E) -3- [3
-[6-chloro-3- (2-[[4-fluoro-2- (trifluoromethyl
Lu) phenyl] amino] -2-oxoethyl) -7-methyl-2-o
Xo-2H-chromen-4-yl] phenyl] -2-propenoic acid, 3-
[3- [6-chloro-3- (2-[[4-fluoro-2- (trifluoromethyl
) Phenyl] amino] -2-oxoethyl) -7-methyl-2-
Oxo-2H-chromen-4-yl] phenyl] propionic acid,
(2E) -3- (3- {7-chloro-3- (2-{[4-fluoro-2- (triflu
Oromethyl) phenyl] amino} -2-oxoethyl) -2-oxy
So-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chloro
Men-4-yl} phenyl) acrylic acid, (2E) -3- (3- {7-ku
Lolo-3- (2-{[4-chloro-2- (trifluoromethyl) phenyi
]] Amino} -2-oxoethyl) -2-oxo-6-[(4-phenyl
Piperazin-1-yl) methyl] -2H-chromen-4-yl} fe
Nyl) acrylic acid, 3- {7-chloro-3- (2-{[4-fluoro-2-
(Trifluoromethyl) phenyl] amino} -2-oxoethyl
) -2-oxo-6-[(4-phenylpiperazin-1-yl) methyl
Lu] -2H-chromen-4-yl} benzoic acid, 3- {7-chloro-3- (2-
{[4-chloro-2- (trifluoromethyl) phenyl] amino}-
2-oxoethyl) -2-oxo-6-[(4-phenylpiperazine-
1-yl) methyl] -2H-chromen-4-yl} benzoic acid or its
Salt of; (13) The prod of the compound according to (1) or a salt thereof.
Rag; (14) The compound described in (1) or (13) above, or
A medicament containing the salt; (15) Lipid rich plaque reducer or ACA
The medicament according to (14) above, which is a T inhibitor; (16) Acute coronary syndrome, acute myocardial infarction, unstable angina
, PTCA or coronary restenosis after stent placement,
Peripheral artery occlusion, hyperlipidemia, cerebral infarction, stroke, Alzha
Immer's disease, multiple risk syndrome or metabolic symptoms
Group preventive / therapeutic agent or atherosclerotic plaque
Or a stabilizer according to (14) above; (17) In combination with HMG-CoA reductase inhibitor
In addition, the repression of the atherosclerotic plaque according to the above (16) and the suppression of the progress
Or stabilizers; (18) An effective amount of the compound or salt thereof described in (1) above.
In a mammal, characterized in that
Lipid-rich plaque regression or ACAT inhibition
Law; (19) An effective amount of the compound according to (1) or a salt thereof.
In a mammal, characterized in that
Acute coronary syndrome, acute myocardial infarction, unstable angina, P
Coronary restenosis after TCA or stent implantation, peripheral motion
Pulse obstruction, hyperlipidemia, cerebral infarction, stroke, Alzheimer
Disease, multiple risk syndrome or metabolic syndrome
Preventive treatment or regression of atherosclerotic plaque, suppression of progression or stability
Conversion method; (20) Combined use with HMG-CoA reductase inhibitor
The arteriosclerotic lesion according to (19) above,
Regression, suppression of progress or stabilization method; (21) Lipid rich plaque reducer or ACA
The compound according to (1) above for producing a T inhibitor or
Use of the salt; (22) Acute coronary syndrome, acute myocardial infarction, unstable angina
, PTCA or coronary restenosis after stent placement,
Peripheral artery occlusion, hyperlipidemia, cerebral infarction, stroke, Alzha
Immer's disease, multiple risk syndrome or metabolic symptoms
Group preventive / therapeutic agent or atherosclerotic plaque
Or a compound described in (1) above for the production of a stabilizer.
Or the use of its salt; (23) Combination with HMG-CoA reductase inhibitor
(22) The regression of arteriosclerotic lesions according to the above (22).
Use for the production of shrinkage, development control or stabilizers;
About

In the above formula [I], R ¹ and R ² are each a hydrogen atom, a halogen atom, a chain hydrocarbon group which may have a substituent or a chain carbon group which may have a substituent. R represents a hydroxy group which may be substituted with a hydrogen group, R
¹ and R ² together may form, together with the adjacent carbon atom, a cyclic hydrocarbon which may have a substituent or an optionally oxo-dihydrofuran ring. "A chain hydrocarbon group which may have a substituent" and "a hydroxy group which may be substituted by a chain hydrocarbon group which may have a substituent" represented by R ¹ and R ^2. "
As the "chain hydrocarbon group" in, for example, an alkyl group, an alkenyl group, an alkynyl group, etc. are used,
Like alkadienyl group, alkatrienyl group,
It may be a group in which 2 to 3 carbon-carbon bonds in the alkyl group are converted into double bonds. As the alkyl group, for example, a linear or branched alkyl group having 1 to 7 carbon atoms is used, preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
A linear or branched alkyl group having 1 to 4 carbon atoms such as c-butyl and 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, sec-butenyl and the like is used, and preferably, for example, ethenyl, propenyl, isopropenyl, isobutenyl and the like. Two to four alkenyl groups are used. Examples of the alkynyl group include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec.
An alkynyl group having 2 to 6 carbon atoms such as -butynyl is used, and preferably an alkynyl group having 2 to 4 carbon atoms such as ethynyl, propynyl, isopropynyl and isobutynyl is used. The group in which 2 to 3 carbon-carbon bonds in the alkyl group are converted into a double bond is a linear or branched alkyl group having 1 to 7 carbon atoms (preferably a linear alkyl group). ) Carbon-
Examples thereof include groups in which 2 to 3 of carbon bonds are converted into double bonds, and preferably have 4 carbon atoms such as butadienyl.
Alkadienyl groups No. 6 to 6 and alkatrienyl groups such as 1,3,5-hexatrienyl are used. As the above-mentioned chain hydrocarbon group, for example, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and particularly methyl,
1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
A linear or branched alkyl group of is preferred.

"A chain hydrocarbon group which may have a substituent (s)" represented by R ¹ and R ² and "a chain hydrocarbon group which may have a substituent (s) may be substituted. Examples of the substituent of the “good hydroxy group” include an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, and a substituted group. A heterocyclic group which may have a group, an amino group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an acyl group,
Examples thereof include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an oxo group, a carboxyl group, a nitro group, a cyano group, and an alkyl group which may have a substituent. May be substituted at 1 to 5 (preferably 1 to 3) at positions substitutable with these optional substituents.

The "aryl which may have a substituent"
Examples of the “aryl group” of the “group” include phenyl and naphth
Chill, anthryl, phenanthryl, acenaphthylenyl
Such as C _6-16Aryl groups and the like.
C such as le, 1-naphthyl, 2-naphthyl, etc._6-10Aryl
Groups are preferred. Examples of the substituent of the aryl group include (i)
C which may be rogenated_1-6Alkoxy group (eg,
Toxy, ethoxy, propoxy, trifluoromeroxy
Etc.), (ii) halogen atoms (eg, fluorine, chlorine, bromine, yo
(Arsenic), (iii) optionally halogenated C_1-6Archi
Group (eg, methyl, ethyl, propyl, trifluorome
And the like, and the aryl group is any of these.
It may be substituted with 1 to 2 substituents. The "substituent
"Cycloalkyl" of "cycloalkyl group which may have"
Examples of the “ru group” include cyclopropyl and cyclobutyl.
Ru, cyclopentyl, cyclohexyl, cycloheptyl
Such as C_3-7Examples thereof include a cycloalkyl group. The cyclo
The substituent of the alkyl group and the number of substitutions are
Similar types of substituents on optionally substituted aryl groups
And the number is mentioned. The “optionally substituted substituent
As "cycloalkenyl group" of "chloralkenyl group"
Is, for example, cyclopropenyl, cyclobutenyl, cyclo
C such as pentenyl and cyclohexenyl_3-6Cycloarche
Examples thereof include a nyl group. Substituent of the cycloalkenyl group
And the number of substitutions thereof is the above
Group and the number of substituents
It

The "heterocyclic group which may have a substituent (s)"
The “heterocyclic group” is an aromatic heterocyclic group having at least one, preferably 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as atoms (ring atoms) constituting the ring system, and saturated or An unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) can be mentioned, but a non-aromatic heterocyclic group is preferable. The "aromatic heterocyclic group" is a 5- or 6-membered aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl,
Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3
4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4
-Thiadiazolyl, 1,2,3-triazolyl, 1,
2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and a 5- or 6-membered ring (5- or 6-membered aromatic monocyclic heterocycle, benzene ring, etc.) are condensed in 2-3 units. Fused aromatic heterocyclic group (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, Phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrroloyl. b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazini , Imidazo [1,2-a]
Pyrimidinyl, 1,2,4-triazolo [4,3-a]
Pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc.), among which 5 to 6 of furyl, thienyl, pyrazinyl, pyridyl, pyrimidinyl and the like.
A membered aromatic monocyclic heterocyclic group is preferred. Examples of the "non-aromatic heterocyclic group" include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like 4- to 9-membered non-aromatic monocyclic ring. Formula heterocyclic groups (especially pyrrolidinyl, piperidyl, piperazinyl, morpholinyl,
In addition to nitrogen atoms such as 3,6-dihydropyridin-1 (2H) -yl and the like, 1 hetero atom such as oxygen atom and sulfur atom is included.
To 5 to 9-membered cyclic amino groups which may contain 3 to 3), the above-mentioned non-aromatic monocyclic heterocyclic groups 1 such as 2,3-dihydroindolyl and 1,3-dihydroisoindolyl. To 2 (preferably 1) condensed with 1 to 2 (preferably 1) benzene rings, 1 to 2 (preferably 1) non-aromatic monocyclic heterocyclic group described above Is a heterocyclic ring of the 5- to 6-membered aromatic monocyclic heterocyclic group described above
Heterocyclic groups fused with two (preferably one), and aromatic monocycles such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc. Examples include non-aromatic heterocyclic groups in which some or all double bonds of the formula heterocyclic group or aromatic condensed heterocyclic group are saturated. The heterocyclic group may have 1 to 4, preferably 1 to 2 substituents, and as such a substituent, an optionally halogenated C _1-6 alkyl group (eg, : Methyl, ethyl, propyl, n-butyl, n-hexyl, etc.), an optionally halogenated C _6-12 aryl group (eg, phenyl), hydroxy-C _6-12 aryl group (eg, 4-hydroxy) Phenyl), optionally halogenated C _1-4 alkylsulfonyl group (eg, methylsulfonyl), C _7-15
Aralkyl groups (eg, benzyl), optionally halogenated C _1-4 alkoxy-C _1-4 alkyl groups (eg, propoxyethyl, etc.), heteroatoms such as nitrogen atom, oxygen atom, sulfur atom in addition to carbon atom. 5 containing 1 to 3 atoms
To 9-membered heterocyclic group (for example, piperidyl, piperanidyl, morpholinyl, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzoisoxazolyl, etc.), hydroxy group, oxo Group, thioxo group and the like.

The "amino group which may have a substituent (s)"
(Amino group, mono- or di-substituted amino group is included)
The substituent in is, for example, halogenated
Moyo low grade (C_1-6) Alkyl (eg, methyl, ethyl,
Propyl, etc.), optionally halogenated C_6-12Ants
Group (eg phenyl), nitrogen atom in addition to carbon atom, acid
Contains 1 to 3 heteroatoms such as elementary atoms and sulfur atoms
5- to 9-membered heterocyclic groups (eg, thienyl, furyl, pyri)
Dil, pyrimidinyl, thiazolyl, benzothiazolyl,
Benzisothiazolyl, benzoxazolyl, benzoi
Soxazolyl, etc.), optionally halogenated C
_1-4Alkyl-carbonyl group (eg, methylcarbonyl,
Ethylcarbonyl, etc.), C_6-12Aryl-carbonyl group
(Eg, benzoyl, etc.), optionally halogenated C
_1-4Alkyl-sulfonyl group, even if halogenated
Good C_1-4Alkoxy-C_1-4Alkyl groups, etc.
It Also, two substituents in the di-substituted amino group are
Together with the elementary atom to form a "cyclic amino group"
The "cyclic amino group" may be, for example, 1-aze
Tidinyl, 1-pyrrolidinyl, piperidinyl, morpholi
Nyl, thiomorpholinyl (even if the sulfur atom is oxidized
Good) lower alkyl optionally halogenated at the 4-position
(Eg, methyl, ethyl, propyl, isopropyl, bromo
C such as tyl, tert-butyl, pentyl and hexyl_1-6A
Aralkyl), aralkyl which may be halogenated
(Eg C such as benzyl, phenethyl, etc._7-10Aralkyl
Etc.), optionally halogenated aryl (eg,
C such as nyl, 1-naphthyl, 2-naphthyl, etc. _6-10Aryl
3) such as 1-piperazinyl which may be substituted with
~ 8-membered (preferably 5-6 membered) cyclic amino group etc.
Can be

The "optionally substituted alkyl group" is, for example, a C _1-6 alkyl group (eg, methyl, which may be substituted with a halogen atom (eg, fluorine, chlorine, bromine, iodine)). Ethyl, propyl, n-butyl, n
-Hexyl, etc.) and the like.

The "hydroxyl group optionally having substituent (s)" is, for example, a hydroxyl group or optionally halogenated C.
_1-16 alkoxy group, preferably optionally halogenated C _1-4 alkoxy group, more preferably C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, t-butoxy, etc.), C _{1 -6} alkyl-carbonyloxy group (for example, methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy, etc.),
Examples thereof include an aminocarbonyloxy group and a mono- or di-C _1-4 alkylaminocarbonyloxy group.

Examples of the "thiol group which may have a substituent" include a thiol group, an optionally halogenated C _1-16 alkylthio group, and preferably an optionally halogenated C _{1-. 4} alkylthio groups, more preferably C _1-4 alkylthio groups (eg, methylthio, ethylthio, etc.), 5 to 9 containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom in addition to carbon atom.
Membered heterocycle (eg, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzoisoxazolyl, etc.)-Thio group (eg, 2-pyridylthio), etc. .

The "acyl group" is a formyl group, C
_1-6 alkyl-carbonyl group (preferably C _1-4 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl)), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl), even if halogenated Good C _1-6
Alkyl-sulfonyl group (preferably C _1-4 alkyl-
Sulfonyl group (eg, methylsulfonyl, ethylsulfonyl)), C _1-4 alkoxy-sulfonyl group (eg, methoxysulfonyl), benzyloxycarbonyl group, C _3-6
Cycloalkyl - carbonyl group, a carbamoyl group, mono- - or di -C _{1 -4} alkylcarbamoyl group and the like.

More specifically, the substituent of the chain hydrocarbon group is a halogen atom; an amino group; a mono- or di-C _1-4 alkylamino group; a carboxyl group; a C _1-4 alkoxycarbonyl group. A hydroxy group; an optionally halogenated C _1-4 alkoxy group; a C _3-6 cycloalkyl group; a nitro group; a cyano group; an optionally halogenated C _1-4 alkylthio group; C _1-4 Alkyl group, C _1-4 alkylsulfonyl group, C _6-12 aryl group optionally substituted by halogen atom or hydroxy group, C _7-15
Aralkyl group, C _1-4 alkoxy-C _1-4 alkyl group,
Cyclic amino substituted with 1 or 2 substituents selected from a 5- to 9-membered heterocyclic group containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom, etc. in addition to carbon atom, hydroxy group, etc. A group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms such as oxygen atom and sulfur atom in addition to nitrogen atom, specifically, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc. ); C _1-4 alkyl-carbonylamino group; aminocarbonyloxy group; mono- or di-C _1-4 alkylaminocarbonyloxy group; C _1-4 alkylsulfonylamino group; C _1-4 alkoxy-carbonyl group; benzyloxycarbonyl group; a carboxyl group; C _1-6 alkyl - carbonyl group; C _3-6 cycloalkyl - carbonyl group; Karubamoi Groups; mono- - or di -
C _1-4 alkylcarbamoyl group; C _1-6 alkylsulfonyl group; C _1-6 alkyl-carbonyloxy group; C _1-4 alkyl and 1 hetero atom such as nitrogen atom other than carbon atom, oxygen atom and sulfur atom An amino group substituted with a 5- to 9-membered heterocyclic group containing 3 to 3; an amino group substituted with C _1-4 alkyl and C _1-4 alkyl-carbonyl; C
Amino group substituted with _1-4 alkyl and C _6-12 aryl-carbonyl; C _1-6 alkyl-carbonyloxy group; mono- or di-C _1-4 alkoxy-C _1-4 alkyl-
1 to 4 selected from an amino group; a 5- to 9-membered heterocycle-thio group containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom; oxo group and the like.
Substituents are used.

R ¹ and R ² are each a halogen atom (eg, fluorine atom, chlorine atom, bromine atom) or a C _1-7 alkyl group which may have a substituent (preferably methyl, ethyl or propyl). Such as C _1-4 alkyl group, particularly preferably methyl), optionally substituted C _2-6 alkenyl group (preferably ethenyl) or optionally substituted C _1-7 alkyl group. A hydroxy group which may be substituted with a group (preferably a C _1-4 alkoxy group such as a hydroxy group or methoxy) is preferable, and among them, a C _1-7 alkyl optionally having a halogen atom or a substituent. Groups are preferred. In addition, "C which may have a substituent
The “C _1-7 alkyl group” in the “ _1-7 alkyl group” may have an oxo group as a substituent, and when the oxo group substitutes at the α-position, for example, C ₁ such as formyl or acetyl. _-7 May form an alkanoyl group.

Examples of the substituent in the above-mentioned "C _1-7 alkyl group optionally having substituent (s)" include (i) hydroxy group, (ii) mono- or di-C _1-4 alkylamino group. (Eg, dimethylamino, diethylamino), (ii
i) Including 1 to 3 hetero atoms such as nitrogen atom, oxygen atom and sulfur atom in addition to C _1-4 alkyl and carbon atom 5
To an amino group substituted with a 9-membered heterocyclic group (for example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.) (eg,
Methyl (2-pyridyl) amino), (iv) C _1-4 alkyl and C _1-4 alkyl-carbonyl substituted amino groups (eg, methyl (methylcarbonyl) amino),
(V) C _1-4 alkyl and C _6-12 aryl-carbonyl substituted amino groups (eg, methyl (benzoyl) amino), (vi) mono or di-C _1-4 alkoxy-C _1-4 alkyl An amino group (eg, butoxypropylamino),
(Vii) C _1-4 alkyl (eg, methyl), halogen atom,
Hydroxy group and optionally halogenated C _1-4
C _6-12 aryl _optionally having 1 to 4 substituents selected from alkyl (eg, phenyl, 4-hydroxyphenyl, 4-chlorophenyl, 3-methylphenyl), C _1-4 alkylsulfonyl (eg, , Methylsulfonyl), a halogen atom, a hydroxy group, and a C _7-15 aralkyl (eg, benzyl) _optionally having 1 to 4 substituents selected from C _1-4 alkyl _optionally halogenated, C _1-4 alkoxy-C _1-4 alkyl (for example,
Propoxyethyl, etc.), a 5- to 9-membered heterocyclic group containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom in addition to carbon atom (for example, piperidyl, piperanidyl, morpholinyl, thienyl, furyl, pyridyl,
Pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc.), a hetero atom such as an oxygen atom or a sulfur atom other than the nitrogen atom, which may be substituted with a hydroxy group, To 5 to 9-membered cyclic amino group which may contain 3 to 3 (eg, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, 3,6-dihydropyridine-1
(2H) -yl) (preferably piperazinyl substituted at the 4-position with a phenyl group or the like; the phenyl group may be halogenated), (viii) C _1-6 alkyl-carbonyloxy group (for example, , Methylcarbonyloxy,
Ethylcarbonyloxy, butylcarbonyloxy, etc.), (ix) 5- to 9-membered heterocycles containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom in addition to carbon atom (eg, thienyl, furyl, pyridyl) , Pyrimidinyl, thiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl) -thio group (eg, 2-pyridylthio) and the like are preferable. As the substituent of the C _2-6 alkenyl group, for example, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl) and the like are preferable.

In the above formula [I], when R ¹ and R ² together form a cyclic hydrocarbon which may have a substituent with an adjacent carbon atom, the "cyclic hydrocarbon" means Examples thereof include saturated or unsaturated cycloaliphatic hydrocarbons (eg, cycloalkanes, cycloalkenes, cycloalkadienes, etc.) and aromatic hydrocarbons. Examples of the “cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane,
Examples thereof include cycloheptane, cyclooctane, cyclononane and the like, and among them, C _3-7 cycloalkane such as cyclopropane, cyclobutane, cyclopentane and cyclohexane is preferable. Examples of the "cycloalkene" include, for example,
Examples thereof include C _5-6 cycloalkene such as cyclopentene, cyclohexene, cyclobutene and cyclopentene.
Examples of the "cycloalkadiene" include 2,4-
Cyclopentadiene, 2,4-cyclohexadiene,
Examples thereof include C _5-6 cycloalkadiene such as 2,5-cyclohexadiene. As the “aromatic hydrocarbon”,
Examples thereof include monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 16 carbon atoms, and examples thereof include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and an acenaphthalene ring. C such as ring
Particularly preferred are _6-10 aryls.

A preferred example of the cyclic hydrocarbon which R ¹ and R ² may together form with an adjacent carbon atom is a C _5-7 cyclic hydrocarbon, and a more preferred example is a saturated or unsaturated hydrocarbon. Examples thereof include cycloaliphatic hydrocarbons (for example, cycloalkane, cycloalkene, cycloalkadiene, etc.), and particularly preferable examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and the like. , Cyclopropane, cyclobutane,
Particularly preferred are C _3-7 cycloalkanes such as cyclopentane and cyclohexane. The substituent which the "cyclic hydrocarbon" may have has the same meaning as the substituent in the above-mentioned "chain hydrocarbon group which may have a substituent".
The unsaturated cycloaliphatic substituent is preferably an oxo group or a hydroxy group.

Preferable examples of R ¹ and R ² include a hydrogen atom, a halogen atom, a chain hydrocarbon group which may have a substituent, and the like, together with an adjacent carbon atom together. It may form a cyclic hydrocarbon which may have a substituent. Among these, as R ¹ and R ^2, a halogen atom, which may have a substituent C _1-7
Alkyl group and the like are preferable, and particularly, a halogen atom,
Methyl and the like are preferable. As R ¹ and R ² , a chain hydrocarbon group in which R ¹ is a halogen atom and R ² is substituted with an amino group which may have a substituent (in particular, R ² has a substituent) A preferable example is a chain hydrocarbon group substituted with an optionally substituted cyclic amino group).

In the above formula [I], ring A represents a benzene ring which may further have a substituent.

In the above formula [I], ring B represents an aromatic ring which may have a substituent. Examples of the “aromatic ring” in the “aromatic ring which may have a substituent” represented by ring B include aromatic hydrocarbons and aromatic heterocycles. Examples of the "aromatic hydrocarbon" include monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 16 carbon atoms, and examples thereof include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and an acenaphthalene ring. Among these, a benzene ring is particularly preferable. The "aromatic heterocycle" is 5
6-membered aromatic monocyclic heterocycle (eg, furan, thiophene,
Pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,
2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,
2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc. ), And a fused 5 to 6 membered ring (such as the said 5 to 6 membered aromatic monocyclic heterocycle and benzene ring) 2 to 3 fused to 8 to
16-membered fused aromatic heterocycle (eg, benzofuran, isobenzofuran, benzo [b] thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1, 2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, Phenazine, thianthrene, phenanthridine, phenatroline, indolizine, pyrrolo [1,2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2]
-A] pyridine, imidazo [1,2-b] pyrazole,
Imidazo [1,5-a] pyridine, imidazo [4,5-
c] pyridine, pyrazolo [1,5-a] pyrimidine, pyrazolo [1,5-c] pyrimidine, pyrazolo [3,4-]
d] pyrimidine, imidazo [1,2-b] pyridazine,
Imidazo [1,5-b] pyridazine, pyrazolo [3,4-
b] pyridine, imidazo [1,2-a] pyrimidine, 1,
2,4-triazolo [4,3-a] pyridine, 1,2,4-
Triazolo [4,3-b] pyridazine, [1,2,4] triazolo [1,2-a] pyridazine, [1,2,3] triazolo [1,5-a] pyrimidine, [1,2,4] ] Triazolo [1,5-c] pyrimidine, [1,2,4] triazolo [1,5-a] pyridine, [1,2,4] triazolo [4,3-a] pyridine, benzo [1,2] , 5] thiadiazole, benzo [1,2,5] oxadiazole, pyrazolo [5,1-b] thiazole, pyrrolo [2,1-f]
[1,2,4] triazine, pyrrolo [1,2-b] pyridazine, pyrrolo [2,3-d] pyrimidine, pyrrolo [2,3
-B] pyridine, thieno [3,2-b] pyrimidine, thieno [2,3-b] pyridine, thieno [2,3-c] pyridine, thieno [3,2-b] pyridine, thieno [3,2 −
c] pyridine, pyrido [2,3-b] pyrazine, pyrido [3,4-b] pyrazine, pyrido [2,3-d] pyrimidine, pyrido [3,2-d] pyrimidine, pyrido [4,3-]
d] pyrimidine, etc.), among which furan,
5 such as thiophene, pyrazine, pyridine and pyrimidine
~ 6-membered aromatic monocyclic heterocycles are preferred.

In the above formula [I], a further group represented by ring A
A benzene ring which may have a substituent or a unit represented by B ring
As a substituent on the aromatic ring which may have a substituent
Respectively, for example (i) C which may be halogenated_1-4Alkyl group (eg
For example, methyl, chloromethyl, difluoromethyl, trique
Loromethyl, trifluoromethyl, ethyl, 2-bromo
Ethyl, 2,2,2-trifluoroethyl, propyl, a
Sopropyl, 3,3,3-trifluoropropyl, butyl
Such); (ii) C substituted with an amino group_1-4Alkyl groups (eg,
Aminomethyl, 2-aminoethyl, etc.); (iii) Mono- or di-C_1-4Substituted with an alkylamino group
C_1-4An alkyl group (eg, methylaminomethyl,
Dimethylaminomethyl, 2-methylaminoethyl, 2-
Dimethylaminoethyl etc.); (iv) C substituted with a carboxyl group_1-4Alkyl group (eg
(Eg, carboxymethyl, carboxyethyl, etc.); (v) C_1-4C substituted with an alkoxy-carbonyl group_1-4
Alkyl groups (eg methoxycarbonylethyl, eth
Xycarbonylethyl etc.); (vi) C substituted with a hydroxy group_1-4Alkyl group (eg
For example, hydroxymethyl, hydroxyethyl, etc.); (vii) C_1-4Substituted with an alkoxy or phenoxy group
May be C_1-4C substituted with an alkoxy group_1-4Al
Kill group (eg, methoxymethyl, methoxyethyl, ethyl
Toxiethyl etc.); (viii) C_3-6Cycloalkyl groups (eg cyclopropyi)
R, cyclobutyl, cyclopentyl, cyclohexyl
)); (ix) halogen atom (for example, fluorine, chlorine, bromine, iodine
Elementary etc.); (x) nitro group; (xi) cyano group; (xii) hydroxy group; (xiii) optionally halogenated C_1-4Alkoxy group
(For example, methoxy, difluoromethoxy, trifluor
Romethoxy, ethoxy, 2,2,2-trifluoroethoxy
Ci, proproxy, butoxy, isopropyloxy
DO), C_1-4Substituted with an alkoxy or phenoxy group
May be C_1-4An alkoxy group; (xiv) C which may be halogenated_1-4Alkylthio group
(For example, methylthio, difluoromethylthio, trif
Luoromethylthio, ethylthio, propylthio, isop
Ropyrthio, butylthio, etc.), C_1-4Alkoxy group
Or C optionally substituted with a phenoxy group_1-4Archi
Ruthio group; (xv) amino group; (xvi) mono- or di-C_1-4Alkylamino group (eg
For example, methylamino, ethylamino, propylamino, di
Methylamino, diethylamino, etc.); (xvii) Cyclic amino group (for example, oxygen source other than nitrogen atom)
Containing 1 to 3 heteroatoms such as children and sulfur atoms
Such as a 5 to 9 membered cyclic amino group which may be
For example pyrrolidinyl, piperidyl, piperazinyl, mol
For example holinyl); (xviii) C_1-4An alkyl-carbonylamino group (for example,
Acetylamino, propionylamino, butyrylamino
Such); (xix) aminocarbonyloxy group; (xx) Mono- or di-C_1-4Alkylamino-carboni
Ruoxy group (eg, methylaminocarbonyloxy,
Ethylaminocarbonyloxy, dimethylaminocarbo
Nyloxy, diethylaminocarbonyloxy, etc.); (xxi) C_1-4Alkylsulfonylamino groups (eg, methyl
Lesulfonylamino, ethylsulfonylamino, propyi
Lesulfonylamino etc.); (xxii) C_1-4Alkoxy-carbonyl groups (eg, meth
Xycarbonyl, ethoxycarbonyl, propoxycal
Bonyl, isobutoxycarbonyl, etc.); (xxiii) benzyloxycarbonyl group; (xxiv) carboxyl group; (xxv) C_1-6An alkyl-carbonyl group (e.g.
Rubonyl, ethylcarbonyl, butylcarbonyl
)); (xxvi) C_3-6Cycloalkyl-carbonyl (e.g.
Chlorhexylcarbonyl, etc.); (xxvii) carbamoyl group; (xxviii) mono- or di-C_1-4Alkyl carbamoyl
Groups (eg, methylcarbamoyl, ethylcarbamoyl
Ru, propylcarbamoyl, butylcarbamoyl, die
Tilcarbamoyl, dibutylcarbamoyl, etc.), (xxix) C_1-6Alkylsulfonyl groups (eg methyls
Rufonyl, ethylsulfonyl, propylsulfonyl, etc.
DO); C_3-6Cycloalkylsulfonyl (eg,
Lopentylsulfonyl, cyclohexylsulfonyl
)); (xxx) C_1-4Alkyl (eg methyl), C_1-4Archi
Rusulfonyl (eg methylsulfonyl), halogenated
May be C_1-4Alkyl (eg methyl, trif
Luoromethyl), halogen (eg, fluorine, chlorine) or
C which may have a hydroxy group_6-12Aryl group (eg
For example, phenyl, naphthyl, hydroxyphenyl, methyl
Ruphenyl, chlorophenyl, etc.), C_7-15Aralchi
L (eg, benzyl, etc.), C_1-4Alkoxy-C
_1-4Alkyl (eg propoxyethyl etc.), charcoal
In addition to elementary atoms, nitrogen atoms, oxygen atoms, sulfur atoms, and other
A 5 to 9 membered heterocyclic group containing 1 to 3 B atoms (eg,
For example, piperidyl, piperanidyl, morpholinyl, thie.
Nyl, furyl, pyridyl, pyrimidinyl, thiazolyl,
Benzothiazolyl, benzisothiazolyl, benzox
Sazolyl, benzisoxazolyl, etc.), hydroxy
1 selected from Si, thiol, oxo, thioxo, etc.
Or a cyclic amino group substituted with two substituents (eg,
Heteroatoms such as oxygen and sulfur atoms in addition to nitrogen atoms
5 to 9 membered cyclic amide which may contain 1 to 3
Groups such as pyrrolidinyl and piperidin.
Le, piperazinyl, 3,6-dihydropyridine-1 (2
H) -yl, [1,3] thiazolo [4,5-b] pyridy
3-3 (2H) -yl, morpholinyl, etc.)
C_{1- 6}Alkyl groups (eg morpholinomethyl, 4-
Phenyl-1-piperazinylmethyl, 2-morpholinoe
Cyl, 3-piperazinylpropyl, 4-methylsulfoni
Lu-piperazinylmethyl, 4-benzyl-1-piperazi
Nylmethyl, 4- (4-hydroxyphenyl) -1-pi
Peranidylmethyl, 4-hydroxypiperidylmethyl,
4-hydroxy-4-phenyl-piperidylmethyl, 4
-Phenylpiperidylmethyl, 4- (2-pyridyl)-
1-piperazinylmethyl, 4- (4-hydroxyphenyl)
) -1-Piperanidylmethyl, (4-phenyl-3,
6-dihydropyridin-1 (2H) -yl) methyl
)); (Xxxi) C_1-6Alkyl-carbonyloxy group (eg
For example, methylcarbonyloxy, ethylcarbonyloxy
Ci, butylcarbonyloxy, etc.) substituted C_{1- Four}
Alkyl group; (Xxxii) C_1-4Nitrogen source in addition to alkyl and carbon atoms
1 to 3 heteroatoms such as child, oxygen atom, and sulfur atom
5 to 9-membered heterocyclic groups (eg thienyl, phenyl, etc.)
Ryl, pyridyl, pyrimidinyl, thiazolyl, benzothi
Azolyl, benzisothiazolyl, benzoxazoli
, Benzisoxazolyl, etc.) substituted amino
Substituted with a group (eg, methyl (2-pyridyl) amino)
C_1-4Alkyl group; (Xxxiii) C_1-4Alkyl and C_1-4Alkyl-carbo
Amino group substituted with nyl (eg, methyl (methylcarbohydrate)
C substituted with (nyl) amino)_1-4Alkyl group; (Xxxiv) C_1-4Alkyl and C_6-12Aryl-carbo
Amino group substituted with nil (eg, methyl (benzoyl)
C substituted with amino)_1-4Alkyl group; (Xxxv) C_1-6Alkyl-carbonyloxy group (eg
For example, methylcarbonyloxy, ethylcarbonyloxy
Ci, butylcarbonyloxy, etc.) substituted C_{1- Four}
Alkyl group; (Xxxvi) Mono or di-C_1-4Alkoxy-C_1-4Al
Substituted with a kyl-amino group (eg, butoxypropylamino)
C_1-4Alkyl group; (Xxxvii) In addition to carbon atom, nitrogen atom, oxygen atom, sulfur source
5- to 9-membered containing 1 to 3 heteroatoms such as children
Heterocycles (eg thienyl, furyl, pyridyl, pyrimid
Dinyl, thiazolyl, benzothiazolyl, benzisothi
Azolyl, benzoxazolyl, benzisoxazoly
Substituted with a -thio group (eg, 2-pyridylthio)
C_1-4Alkyl group; (Xxxviii) oxo group; (Xxxix) C_1-4Alkoxy-carbonyl C_2-6Archeni
Group (eg, methoxycarbonylvinyl, etc.); (xxxx) C substituted with a carboxyl group_2-6Alkenyl group
(Eg carboxyvinyl etc.); (xxxxi) C substituted with a cyano group_1-4An alkyl group (eg,
Such as anomethyl); (xxxxii) C_6-10Aryl groups (eg phenyl, naphthyl
), Phenoxy, benzoyl, phenoxycarbo
Nyl, phenyl-C_1-4Alkylcarbamoyl, pheny
Lucarbamoyl, Phenyl-C_1-4Alkyl-carboni
Luamino, benzoylamino, phenyl-C_1-4Archi
Rusulfonyl, phenylsulfonyl, phenyl-C_1-4
Alkylsulfinyl, Phenyl-C_1-4Alkylsul
Fonylamino or phenylsulfonylamino group [that
Each phenyl group or naphthyl group is a substitutable position
To C_1-4Alkyl groups (eg methyl, ethyl, propyl
, Butyl, isopropyl, etc.), C_1-4Alkoxy group
(For example, methoxy, ethoxy, n-propyloxy, i
-Propyloxy, n-butyloxy, etc.), halogen
Atoms (eg chloro, bromo, iodo, etc.), hydroxy
Si group, benzyloxy group, amino group, mono- or di-
C_1-4Alkylamino groups (eg methylamino, dimethyl)
Luamino, ethylamino, diethylamino, diisopro
Pyramino, etc.), nitro group, C_1-6Alkyl Carboni
Group (eg 1-oxoethyl, 1-oxopropyl,
1 to 3 substituents such as 1-oxobutyl)
You may have. ] Etc. are used. These substituents are
At the substitutable position, the same or different 1 to 5
It may be substituted, preferably 1 to 3. this
Preferred as such a substituent are (i) halogen.
Atom (eg, fluorine, chlorine, bromine, etc.), (ii) halogen
C which may be converted to_1-4Alkyl groups (eg, methyl
Chloromethyl, difluoromethyl, trifluorome
Chill, ethyl, propyl, isopropyl, etc.), (iii)
C_3-6Cycloalkyl groups (eg, cyclopropyl, silane
(Crobutyl, etc.), (iv) hydroxy group, (v) halogenated
May be C_1-4Alkoxy groups (eg methoki
Ci, difluoromethoxy, trifluoromethoxy, eth
Xy), (vi) optionally halogenated C_1-4A
A lucylthio group (eg methylthio, trifluoromethyi
(Ruthio, ethylthio, etc.), (vii) amino group, (viii)
No or di-C_1-4Alkylamino groups (eg, methyl
Luamino, ethylamino, dimethylamino, diethyla
Mino etc.), (ix) C _1-4Alkoxy-carbonyl group (eg
For example, methoxycarbonyl and ethoxycarbonyl.
DO), (x) C_6-12Aryl groups (eg phenyl, naphth
Cyclic amino group that may be substituted with chill, etc. (eg,
For example, in addition to nitrogen atoms, heteroatoms such as oxygen and sulfur atoms
5- to 9-membered rings which may contain 1 to 3 offspring
Amino group and the like, specifically, for example, pyrrolidinyl, piperi
C substituted with (zyl, morpholinyl, etc.)_1-6Alkyl
A group (eg, morpholinomethyl, 4-phenyl-1-pi
Perazinylmethyl, 2-morpholinoethyl, 3-pipera
(Dinylpropyl etc.) and (xi) carboxyl group etc.
In particular, (i) a halogen atom (for example, fluorine
B, chloro, etc.), (ii) C_1-4Alkyl (eg, meth
, Ethyl, etc.), (iii) C_3-6Cycloalkyl group (eg
(Eg, cyclopropyl, cyclobutyl, etc.), (iv) hydro
Xy group, (v) C_1-4Alkoxy groups (eg methoxy, eth
Toxi, etc.), (vi) C_6-12Aryl groups (eg, phenyl
Ring, naphthyl, etc.) optionally substituted cyclic amino
Groups (for example, oxygen atom, sulfur atom, etc. in addition to nitrogen atom)
5 to 9 optionally containing 1 to 3 heteroatoms
Member cyclic amino group, such as pyrrolidini
, Piperidyl, piperazinyl, 3,6-dihydropyri
Zin-1 (2H) -yl, morpholinyl, etc.)
C_1-6Alkyl groups (eg morpholinomethyl, 4
-Phenyl-1-piperazinylmethyl, 2-morpholino
Ethyl, (4-phenyl-3,6-dihydropyridine-
1 (2H) -ylmethyl), 3-piperazinylpropyl
Etc.) and (vii) carboxyl groups are preferred.

The ring A is preferably an alkyl group, a halogenated alkyl group or a benzene ring which may be substituted with a halogen atom in addition to the group represented by the formula -X-Y. In addition to the groups described above, a C _1-6 alkyl group, a halogenated C _1-4 alkyl group or a benzene ring optionally substituted with a halogen atom is particularly preferable.

The ring B is preferably a benzene ring or a pyridine ring, each of which may be substituted with a halogenated alkyl group and / or a halogen atom (more preferably, a halogenated alkyl group and / or a halogen atom is substituted). Benzene ring), especially halogenated C
_1-4 alkyl group (preferably trifluoromethyl) and / or benzene ring optionally substituted with a halogen atom are particularly preferable (more preferably halogenated C
_1-4 benzene ring substituted with an alkyl group and / or a halogen atom).

In the above formula [I], X represents a bond or a spacer having 1 to 6 atoms in the main chain. The "spacer having 1 to 6 atoms in the main chain" represented by X is-
O -, - S -, - CO -, - SO -, - SO 2 -, - NR 3 - (R 3 is a hydrogen atom, a C _1-6 alkyl which may be halogenated,
An optionally halogenated C _1-6 alkyl-carbonyl, an optionally halogenated C _1-6 alkylsulfonyl), and an optionally halogenated divalent C
_A divalent group consisting of 1 to 3 selected from _1-6 chain hydrocarbon groups is used. Preferred examples of the “spacer having 1 to 6 atoms in the main chain” include (1) C _1-6 alkylene (eg, —CH ₂ —, — (CH ₂ ) ₂ —, —
(CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, −CH
_{(CH 3) -, - C} (CH 3) 2 -, - (CH (CH 3)) 2 -, - (CF 2) 2 -,
_{- (CH 2) 2 C (} CH 3) 2 -, - (CH 2) 3 C (CH 3) 2 - , etc.); (2) C _2-6 alkenylene (e.g., -CH = CH -, - CH 2 -CH
= CH -, - C (CH 3) 2 -CH = CH -, - CH 2 -CH = CH-CH
_{2 -, - CH 2 -CH 2} -CH = CH -, - CH = CH-CH = CH -, - C
_{H = CH-CH 2 -CH 2} -CH 2 - , etc.); (3) C _2-6 alkynylene (e.g., -C≡C -, - CH ₂ -C≡C
_{-, - CH 2 -C≡C-CH} 2 -CH 2 - , etc.); (4) - (CH 2) w1 O (CH 2) w2 -, - (CH 2) w1 S (CH 2) w2 -, − (C
H ₂ ) _w1 CO (CH ₂ ) _w2 −, − (CH ₂ ) _w1 SO (CH ₂ ) _w2 −, − (CH ₂ ) _w1 S
O ₂ (CH ₂ ) _w2 −, − (CH ₂ ) _w1 NR ³ (CH ₂ ) _w2 −; (5) − (CH ₂ ) _w3 CONR ³ (CH ₂ ) _w4 −, − (CH ₂ ) _w3 NR ³ CO (CH ₂ ) _w4
−, − (CH ₂ ) _w3 SO ₂ NR ³ (CH ₂ ) _w4 −, − (CH ₂ ) _w3 NR ³ SO ₂ (CH ₂ )
_w4 −, − (CH ₂ ) _w3 COO (CH ₂ ) _w4 −, − (CH ₂ ) _w3 OCO (CH ₂ )
_w4 −; (6) − (CH ₂ ) _w5 NR ³ CONR ^3b (CH ₂ ) _w6 −; (R ³ has the same meaning as above; R ^3b has the same meaning as R ³ ; w1 and w2 are 0 to 5 And w1 + w2 is 0 to 5; w3 and w4 are integers from 0 to 4 and w3 + w4 is 0 to 4; w5 and
w6 is an integer of 0 to 3, and w5 + w6 is 0 to 3).

The "spacer having 1 to 6 atoms in the main chain" represented by X is preferably a divalent C _1-6 chain hydrocarbon group which may be halogenated, among which C _{2- 6} alkylene (eg, formula — (CH ₂ ) _n — [wherein n is 0 to 6]
Represents an integer of] or the like; n is 1 to 4
Is an integer (more preferably 2), and C
_2-6 alkenylene (e.g., formula -CH = CH- (CH _{2)
n '} -[in the formula, n'represents an integer of 0 to 4], a group represented by formula- (CH = CH) _{n "} -[wherein n" represents an integer of 1 to 3] ] The group etc. which are represented by these; As n ', 0-2
Is more preferable (more preferably 0), and n ″ is an integer of 1 to 2 (more preferably 1).
Etc. are preferred.

In the above formula [I], Y is a carboxyl group which may be esterified, a carbamoyl group which may have a substituent, a cyano group, or a deprotonated group which may have a substituent. Is a heterocyclic group having a hydrogen atom. Examples of the “optionally esterified carboxyl group” represented by Y include free carboxyl, and also include lower alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl and the like. Examples of the “lower alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, Examples include C _1-6 alkoxycarbonyl such as neopentyloxycarbonyl and the like, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are preferable. As the "aryloxycarbonyl", for example, C _7-12 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable. As the "aralkyloxycarbonyl", for example, C _7-10 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. The "aryloxycarbonyl" and "aralkyloxycarbonyl" may have a substituent, and the substituent may have a "substituent represented by R ¹ and R ² ", respectively. An aryl group as an example of the substituent in the “chain hydrocarbon group”, a group similar to the group mentioned as the substituent of the aralkyl group, and the like are used in the same number.

Examples of the "optionally substituted carbamoyl group" represented by Y include unsubstituted carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl. Examples of the substituent in the “N-monosubstituted carbamoyl” include lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl), Lower alkenyl (eg vinyl,
C _2-6 alkenyl such as allyl, isopropenyl, propenyl, butenyl, pentenyl and hexenyl), cycloalkyl (eg, C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (eg, , C _8-10 arylalkenyl such as cinnamyl, preferably phenyl-C _2-4 alkenyl, etc., and a heterocyclic group (for example, a “optionally substituted chain represented by R ¹ and R ² described above. Group similar to the “heterocyclic group” as an example of the substituent in the “hydrocarbon group”, 1 to 2 C _1-6
Examples thereof include amino which may be substituted with alkyl. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and examples of the substituent include a hydroxyl group and an optionally substituted amino group [ Amino is, for example, lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te,
rt-butyl, pentyl, hexyl and the like C _1-6 alkyl, etc.), acyl (eg, formyl, acetyl, propionyl, pivaloyl and other C _1-6 alkanoyl, benzoyl etc.), carboxyl, C _1-6 -alkoxycarbonyl etc. 1 or 2 of the above may be substituted. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a lower group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Alkyl, lower alkoxy which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) and the like can be mentioned. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec
-Butyl, tert-butyl, pentyl, hexyl, etc. C
_1-6 alkyl and the like can be mentioned, with methyl and ethyl being particularly preferable. Examples of the lower alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-
Examples thereof include C _1-6 alkoxy such as butoxy, isobutoxy, sec-butoxy and tert-butoxy, and methoxy and ethoxy are particularly preferable. In addition, these substituents are
It is preferably the same or different and substituted by 1 or 2 to 3 (preferably 1 or 2). The "N, N
“-Di-substituted carbamoyl” means a carbamoyl group having two substituents on the nitrogen atom, and one example of the substituent is the above-mentioned “N-monosubstituted carbamoyl”.
And the other examples thereof include lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like). , C _3-6 cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _7-10 aralkyl (eg benzyl, phenethyl etc., preferably phenyl-C _1-4 alkyl etc.) and the like. Also, two substituents may be combined with a nitrogen atom to form a cyclic amino,
Examples of the cyclic aminocarbonyl group in such a case include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (sulfur atom may be oxidized). , 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl), aralkyl (eg, benzyl,
C _7-10 aralkyl such as phenethyl), aryl (eg,
3 to 8-membered (preferably 5 to 6-membered) cyclic aminocarbonyl such as 1-piperazinylcarbonyl which may have phenyl, C _6-10 aryl such as 1-naphthyl, 2-naphthyl, etc. Groups and the like.

The "heterocyclic group having a deprotonizable hydrogen atom which may have a substituent (s)" represented by Y means "a heterocyclic group having a deprotonizable hydrogen atom". 5 to 7-membered (preferably 5-membered) containing at least one of a nitrogen atom, a sulfur atom, and an oxygen atom, which has a hydrogen atom (that is, has an active proton) that has a hydrogen atom that can be eliminated (that is, can form a proton upon elimination) The monocyclic heterocyclic group (preferably a nitrogen-containing heterocyclic group) is used. Examples of the “heterocyclic group having a deprotonizable hydrogen atom” include tetrazol-5-yl or the formula

[Chemical 5] [In the Formula, i is -O- or -S-, j is> C = O,>
C = S or> S (O) 2] (in particular, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5- Dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,
5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl and the like) and the like. The above “heterocyclic group having a deprotonizable hydrogen atom” is
An optionally substituted lower alkyl group (preferably C
_1-4 alkyl) or an acyl group or the like. The lower alkyl group which may be the substituent, C _1-3 alkyl, nitro, optionally substituted by C _1-3 alkoxy phenyl optionally substituted or C _1-3 alkoxy C _{1- 4-} alkyl (methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) and the like can be mentioned. Examples of the acyl group include lower (C _2-5 ) alkanoyl and benzoyl.

Y is preferably an optionally esterified carboxyl group, more preferably carboxyl or lower alkoxycarboxyl, and among them, carboxyl is particularly preferable.

The formula [I] is the formula [I ']

[Chemical 6] [Wherein, B'ring represents a benzene ring which may have a substituent or a pyridine ring which may have a substituent, and R represents an optionally esterified carboxyl group or an esterified Represents a chain hydrocarbon group substituted with a carboxyl group, and other symbols have the same meanings as described above. ]
Is preferred. As the “optionally esterified carboxyl group” represented by R, the same groups as the “optionally esterified carboxyl group” represented by Y are used. The “optionally esterified carboxyl group” in the “chain hydrocarbon group substituted with an optionally esterified carboxyl group” represented by R is the “esterified carboxyl group” represented by Y. The same groups as the “optional carboxyl group” are used.
The "chain hydrocarbon group" in the "chain hydrocarbon group substituted with an optionally esterified carboxyl group" represented by R is represented by X, "the number of main chain atoms is 1 to 6". C _1-6 alkylene, C _1-6 alkenylene, groups similar to C _1-6 alkynylene and the like as preferred examples of the “spacer” are used.

In the above formula [I '], R is a formula-(C
H _{2) n} -R group 'wherein, R' represents a carboxyl group which may be esterified, n represents represents an integer of 0 to 6] represented by the formula -CH = CH- (CH ₂ ) _n'- R '[in the formula, R'represents an optionally esterified carboxyl group, and n'represents an integer of 0 to 4], a formula- (CH = CH) _{n "} -R '[In the formula, R'represents an optionally esterified carboxyl group, and n" is 1 to 3
And the like.] Is preferable, and n is preferably an integer of 1 to 4 (more preferably 2),
n ′ is preferably an integer of 0 to 2 (more preferably 0), and n ″ is preferably an integer of 1 to 2 (more preferably 1). As the “optionally esterified carboxyl group” represented by R ′, the same groups as the “optionally esterified carboxyl group” represented by Y and the like are used, and in particular, carboxyl is particularly preferable. preferable.

The compound represented by the formula [I] is included in the present invention in a free form or a pharmacologically acceptable salt. Examples of such a salt include an inorganic base (eg, alkali such as sodium or potassium) when the compound represented by the formula [I] has an acidic group such as a carboxyl group or a heterocyclic group having a deprotonizable hydrogen atom. Metals, alkaline earth metals such as calcium and magnesium, zinc, iron,
Transition metals such as copper) and organic bases (eg, trimethylamine, triethylamine, tris (hydroxymethyl) amine, pyridine, picoline, ethanolamine, dietanol, triethanolamine, dicyclohexylamine, N, N′-dibenzyl) A salt may be formed with an organic amine such as ethylenediamine, a basic amino acid such as arginine, lysine, ornithine, etc.). When the compound represented by the formula [I] has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid,
Acidic amino acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), aspartic acid, glutamic acid, etc. And the like.

The compound represented by the formula [I] or a salt thereof can also be used as a prodrug. The prodrug is a compound which can be converted into a compound represented by the formula [I] or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, enzymatically oxidized, reduced,
A compound which is hydrolyzed to be a compound of the formula [I] or a salt thereof, or a compound which is hydrolyzed by a gastric acid or the like to be a compound of the formula [I] or a salt thereof. As a prodrug of the compound represented by the formula [I] or a salt thereof, when the compound represented by the formula [I] or a salt thereof has an amino group, a compound in which the amino group is acylated, alkylated or phosphorylated (For example, the amino group of the compound represented by the formula [I] or a salt thereof is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl. Compound, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compound); when the compound represented by the formula [I] or a salt thereof has a hydroxyl group, the hydroxyl group is acylated. , Alkylated, phosphorylated, borated compounds (eg hydroxyl group is acetylated, palmitoylated, propanoylated, pivalo) Le reduction,
Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); When the compound represented by the formula [I] or a salt thereof has a carboxyl group, the carboxyl group is esterified or amidated (For example, carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl- 2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound and the like); and the like. These prodrugs can be produced from the compound represented by the formula [I] or a salt thereof by a method known per se. Further, the prodrug of the compound represented by the formula [I] or a salt thereof is a compound represented by the formula under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals", Volume 7, Molecular Design, pages 163 to 198. It may be a compound represented by [I] or a salt thereof. Further, the compound represented by the formula [I] or a salt thereof may be hydrate or non-hydrate. The compound or a salt thereof isotopes represented by the formula [I] ^{(Example, 3 H, 14 C, 3} 5 S, etc. ¹²⁵ I) may be labeled with a.

Among the compounds represented by the formula [I], 3- [3
-[7-Chloro-3- (2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] Phenyl] propionic acid, (2
E) -3- [3- [7-chloro-6-methyl-2-oxo-3- (2-oxo-2-
[[2- (Trifluoromethyl) phenyl] amino] ethyl) -2
H-chromen-4-yl] phenyl] -2-propenoic acid, 3- [3- [7-
Chloro-6-methyl-2-oxo-3- (2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl) -2H-chromene-4
-Yl] phenyl] propionic acid, (2E) -3- [3- [6-chloro-3
-(2-[[4-Fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid , 3- [3- [6-chloro-3
-(2-[[4-Fluoro-2- (trifluoromethyl) phenyl]]
Amino] -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl] propionic acid, (2E) -3- (3- {7-chloro-3- (2-{[ 4-Fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-4-yl} phenyl ) Acrylic acid, (2E) -3- (3- {7-chloro-3- (2-{[4-
Chloro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-4-yl} phenyl) acryl Acid, 3- {7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6
-[(4-Phenylpiperazin-1-yl) methyl] -2H-chromene
-4-yl} benzoic acid, 3- {7-chloro-3- (2-{[4-chloro-2-
(Trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-4-yl} benzoic acid; or salts thereof, etc. Is preferably used.

The compounds represented by the formula [I] and salts thereof are described in, for example, European Patent Application Publication No. 585913, European Patent Application Publication No. 602598, JP-A-6-263736, and International Publication No. WO. 02/06264
It can be manufactured according to the method disclosed in, for example, No. The compound [I] or a salt thereof has, for example, the formula [II]

[Chemical 7] [In the formula, X ′ represents a halogen or a trifluoromethanesulfonyl group, and other symbols have the same meanings as described above. ]
It can be produced by carrying out a carbonylation reaction or a Heck reaction on the compound represented by or a salt thereof, and further performing a hydrogenation reaction or a hydrolysis reaction, or a combination of both reactions, if necessary. The carbonylation reaction is described, for example, in A. Schoenberg et al., Journal of Organic Chemistry, 39, 3318-3.
326, 1974 (A. Schoenberg, et al., J. Org.
Chem., 39, 3318-3326 (1974)), M.S. Hidai et al.
Bulletin of the Chemical Society of Japan, 48, 2075-2077, 1975 (M.Hi
dai, et al., Bull.Chem.Soc.Jpn, 48, 2075-2077 (197
5)), D.I. Valentin Jr. et al., Journal of
Organic Chemistry, Volume 46, 4614-461
P. 7, 1981 (D. Valentine, Jr., et al., J. Org. C
hem., 46, 4616-4617 (1981)) and the like. That is, the compound [II] is treated with a palladium catalyst and a base under a carbon monoxide atmosphere,
Further, it is carried out by reacting with a nucleophile. Carbon monoxide is usually used at 1 to 20 atm, preferably 1 to 10 atm. Palladium catalysts include, for example, palladium (II) acetate, palladium (II) chloride, dihalobis (triarylphosphine) palladium (I
I) (for example, dichlorobis (triphenylphosphine) palladium (II), dibromobis (triphenylphosphine) palladium (II), diiodobis (triphenylphosphine) palladium (II), dichlorobis (tritolylphosphine) palladium (II), etc.) , Or haloarylbis (triarylphosphine) palladium (II) (for example, chlorophenylbis (triphenylphosphine) palladium (II), etc.)
Are used. The amount of the catalyst used is usually 0.005 to 0.1 mol, preferably 0.01 to 0.05 mol, relative to 1 mol of the compound [II].
Further, a triarylphosphine (for example, triphenylphosphine, tri (o-tolyl) phosphine, etc.) in an equimolar amount to 50 times molar amount (preferably 2 times to 20 times molar amount), bis ( When diarylphosphino) alkyl (for example, 1,4-bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino) propane, 1,2-bis (diphenylphosphino) ethane, etc.) coexists It may be possible to proceed the reaction favorably. Examples of the base include secondary amines (eg diethylamine, dicyclohexylamine etc.), tertiary amines (eg triethylamine, tributylamine, tetramethylethylenediamine etc.), carbonates (eg sodium carbonate, potassium carbonate, sodium hydrogencarbonate etc.). Are used. The amount of base used is usually
It is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound [II]. Water or a lower alcohol (eg, methanol, ethanol, butanol, etc.) is used as the nucleophile. The amount of nucleophile used is
Usually, it is used in an amount of 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound [II]. The reaction is carried out in the presence or absence of a solvent, and examples of the solvent include amides (eg, dimethylformamide, N-methylpyrrolidinone, hexamethylphosphoric triamide, etc.), nitriles (acetonitrile, benzonitrile, etc.), etc. Is used. The amount of the solvent used is 1 gram of the compound [I
I] is usually about 1 to 100 ml, preferably about 10 to 50 ml. The reaction temperature is usually about 10 ° C to 200 ° C, and about 20 ° C.
To 150 ° C is preferred. The reaction time is about 1 hour to 100 hours, preferably about 5 hours to 80 hours, depending on the carbon monoxide pressure, the amount and kind of the catalyst, the base and the reaction solvent, and the reaction temperature. The Heck reaction is described, for example, in R.
F. Heck, Organic Reactions, Volume 27, 3
45-390, 1982 (RFHeck, Org. Reaction
s, 27, 345-390 (1982)). That is, it is carried out by reacting compound [II] with an olefin in the presence of a palladium catalyst and a base. The olefin is CH ₂ = CH-
(CH ₂ ) _n'- R '[wherein R'represents an optionally esterified carboxyl group and n'represents an integer of 0 to 4], or CH ₂ = CH- (C
H = CH) _{n '''}-R' (wherein R'represents an optionally esterified carboxyl group, n '''represents an integer of 1 to 2), and a commercially available compound is used. Is used,
Alternatively, methods known per se (eg, RS Sandler and W. Karo, “Organic Functional Group Preparations I”).
Noch ("Organic FunctoinalGroup Preparations I",
Academic Press, 1983, 2nd
Chapter (pages 39 to 81), Chapter 9 (pages 236 to 288), Chapter 10 (28
9 to 315) and the like). The amount of olefin used is usually 1 mol of the compound [I
I] is used in an amount of 1 to 10 mol, preferably 1 to 3 mol. The same catalyst, base and reaction solvent as those used in the above carbonylation reaction are used. Further, the reaction may be favorably promoted when nickel bromide [II] and sodium iodide are allowed to coexist. The reaction temperature is usually about 10 ° C to 200 ° C, preferably about 20 ° C to 150 ° C. The reaction time depends on the amount and kind of the catalyst, the base and the reaction solvent, and the reaction temperature, but it is about 1 hour to 10 hours.
It is 0 hours, preferably about 5 to 80 hours.
The hydrogenation reaction performed after the carbonylation reaction or the Heck reaction is a method known per se (for example, P. relander (P.
Rylander), "Catalytic Hydrogenation
In Organic Synthesis "(" Catalytic Hydrogen
cation in Organic Syntheses "), Academic Press (Academic Press) 1979, etc.) and the like. The starting compound [II] or a salt thereof used in JP-A No. 585913/1987, JP-A-7-
It can be produced by the method described in 10844, WO 02/06264 pamphlet or the like, or a method according to the method, or the method shown below, for example.

[0039]

[Chemical 8] [In the formula, R ^c represents an alkyl group (methyl, ethyl, propyl, t-butyl, etc.), and other symbols have the same meanings as described above. The reaction step 1 is carried out by condensing the compound [II ′] or a salt thereof and a reactive derivative of succinic acid monoester. As the reactive derivative of succinic acid monoester, for example, an acid halide (eg, acid chloride) of succinic acid monoalkyl ester (eg, methyl ester, ethyl ester, propyl ester) is used, and ethyl succinic acid chloride is particularly preferable. The amount of the reactive derivative of succinic acid monoester used is usually the compound [I
I ′] or a salt thereof is an equimolar amount to about 10-fold molar amount, and preferably an equimolar amount to 3-fold molar amount. The reaction is usually carried out advantageously in the presence of a base, and an organic or inorganic base is used as the base. Examples of the organic base include tertiary amines (eg, triethylamine, diisopropylethylamine,
Diazabicycloundecene etc.) and the like are used. Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Metals; alkali metal hydrides such as sodium hydride and potassium hydride are used. The amount of the base used is usually an equimolar amount to about 10-fold molar amount, and preferably an equimolar amount to 3-fold molar amount with respect to the compound [II ′] or a salt thereof. The reaction is
It can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely influence the reaction is used, for example, hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), ether (Eg, diethyl ether, tetrahydrofuran, dioxane, etc.), amides (eg,
N, N-dimethylformamide, hexamethylphosphoric triamide, etc., ureas (for example, 1,3-dimethyl-3,
4,5,6-tetrahydro-2 (1H) -pyrimidine etc.), nitriles (eg acetonitrile, propionitrile etc.) and the like are used. These solvents may be used alone, or if necessary, two or more kinds may be mixed and used in an appropriate ratio. The amount of the solvent to be used is generally about 1-100 ml, preferably about 10-50 ml, relative to 1 gram of compound [II ′] or a salt thereof. The reaction temperature is usually about -20 ° C to the boiling point of the solvent used for the reaction, preferably about 25 ° C to 100 ° C. The reaction time is about 10 minutes to 24 hours, preferably about 20 minutes to 12 hours, depending on the type of base and reaction solvent used and the reaction temperature.

Reaction step 2 is carried out by treating the compound [II ″] with a base. As the base, for example, the same base as described in the reaction step 1 is used, and the amount of the base used is usually about 0.1 times to 10 times the molar amount of the compound [II ″] or a salt thereof. The amount is preferably about 0.1 times to 1 times the molar amount. The reaction can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely influence the reaction is used, for example, hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), ether (Eg, diethyl ether, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethylformamide, hexamethylphosphoric triamide, etc.), ureas (eg, 1,3-dimethyl-3,4,5, 6-tetrahydro-2 (1H) -pyrimidine, etc.), nitriles (eg, acetonitrile, propionitrile, etc.) and the like are used. These solvents may be used alone, or if necessary, two or more kinds may be mixed and used in an appropriate ratio. The amount of the solvent used is 1 gram of the compound [I
It is usually about 1 to 100 ml, preferably about 10 to 50 ml with respect to I ″]. The reaction temperature is usually about 20 ° C to the boiling point of the solvent used in the reaction, preferably about 25 ° C to 120 ° C. The reaction time varies depending on the kind of the base and the reaction solvent and the reaction temperature, but is about 30 minutes to 24 hours, preferably about 1 hour to 1 hour.
2 hours. In some cases, the reaction can be advantageously progressed by removing water generated during the reaction by using a Dean-Stark dehydrator or the like. Further, the reaction step 1 and the reaction step 2 can be performed in one step. For example, as a reactive derivative of succinic acid monoester, for example, an acid halide (for example, acid chloride etc.) of succinic acid monoalkyl ester (eg, methyl ester, ethyl ester, propyl ester), as a base, for example,
By using an excessive amount of a tertiary amine (eg, triethylamine, diisopurpyruethylamine, diazabicycloundecene, etc.), the compound [II ″] or a salt thereof can be obtained in one step from the compound [II ″ ′]. Alternatively, its salt can be produced. The amount of acid halide used in that case is usually compound [II ''] or a salt thereof,
The molar amount is about 1.5 times to 10 times, preferably about 1.5 times to 3 times. The amount of the base used is usually about 2 times to 10 times, and preferably about 2 times to 5 times the molar amount of the compound [II ″] or a salt thereof. To be The reaction can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely influence the reaction is used, and the type and amount of the solvent used are the same as those in the reaction step 1, for example. The reaction temperature is usually about 20 ° C. to the boiling point of the solvent used in the reaction, preferably about 25 ° C. to 60 ° C. The reaction time is about 30 minutes to 24 hours, preferably about 30 minutes to 4 hours, depending on the type of acid halide or base, the type of reaction solvent, and the reaction temperature.

The reaction step 3 is carried out by treating the compound [II '"] with an acid or a base. Examples of the acid include organic acids (eg, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) or inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid, etc.) can be used,
If necessary, two or more kinds can be mixed and used at an appropriate ratio. Examples of the base include alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide, potassium hydroxide etc.), alkali metal carbonates (eg sodium carbonate, potassium carbonate, cesium carbonate etc.), alkali metal hydrogencarbonates (eg Sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) are used. The amount of the acid or base used is usually about 1 to 100 times, and preferably about 1 to 10 times the molar amount of the compound [II ′ ″]. The reaction can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely affect the reaction is used,
For example, hydrocarbons (eg pentane, hexane, cyclohexane, benzene etc.), lower alcohols (eg methanol, ethanol, propanol etc.), ethers (eg diethyl ether, tetrahydrofuran, dioxane etc.), amides (eg N, N-dimethylformamide, hexamethylphosphoric triamide, etc.), ureas (eg, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidine, etc.) are used.
In the case of a reaction using an acid, the above-mentioned acid can be used as a solvent. These solvents can be used alone, or if necessary, two or more kinds can be mixed at an appropriate ratio or can be used as a mixed solvent with water. The amount of the solvent used is usually about 1 to 100 ml, preferably about 10 to 50 ml, relative to 1 gram of the compound [II ′ ″]. The reaction temperature is usually about -20 ° C to the boiling point of the solvent used for the reaction, preferably about 15 ° C to 120 ° C. The reaction time varies depending on the type of acid or reaction solvent and the reaction temperature, but it is about 10 minutes to 24 hours, preferably about 3 minutes.
0 minutes to 12 hours.

In the reaction step 4, compound [II ″ ″], a salt thereof or a reactive derivative of a carboxyl group thereof and a compound of formula [III]

[Chemical 9] [In the formula, symbols have the same meanings as described above. ] It can manufacture by making it react with the compound represented by these, or its salt. Examples of the reactive derivative of the carboxylic acid include acid halides (eg, chloride, bromide, etc.),
Acid anhydride, mixed acid anhydride (for example, anhydride with methyl carbonate, anhydride with ethyl carbonate, anhydride with isobutyl carbonate, etc.), active ester (for example, ester with hydroxysuccinimide, 1-hydroxy) Esters with benzotriazole, N-hydroxy-5-norbornene-
2,3-dicarboximide ester, p-nitrophenol ester, 8-oxyquinoline ester, etc.) are used, and acid halides are particularly preferable. The compound [II] or a salt thereof can also be produced by reacting the compound [II ″ ″] salt thereof with the compound represented by the formula [III] or a salt thereof in the presence of a coupling reagent. You can Examples of the coupling reagent include carbodiimides (eg, dicyclohexylcarbodiimide, N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide, N-cyclohexyl-N′-
(2-morpholin-4-ylethyl) carbodiimide, N-cyclohexyl-N '-[4- (diethylamino) cyclohexyl]
Carbodiimide, etc.), carbonyldiimidazole, N-
Ethyl-5-phenylisoxazolium-3'-sulfonate, N-ethyl-2'-hydroxybenzisoxazolium trifluoroborate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro Quinoline, 2-isobutyloxy-1-isobutyloxycarbonyl-1,2-dihydroquinoline, (benzotriazolyl-N-hydroxytrisdiethylaminophosphonium hexafluorophosphide salt, diphenylphosphoryl azide, etc. are used. When used in combination with an additive, the reaction may be favorably promoted.The additive includes N-hydroxysuccinimide, 1-hydroxybenzotriazole and 3-
Hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, 2-hydroxyimino-2-cyanoacetic acid ethyl, 2
-Hydroxyimino-2-cyanoacetamide and the like are used. As the salt of the compound [II ″ ″] or [III], the same salt as the above-mentioned salt of the compound [I] can be used. The reaction is usually a solvent which does not adversely influence the reaction (for example, chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine, N,
Halogenated hydrocarbons such as N-dimethylformamide, ethers, esters, hydrocarbons, aromatic amines, amides, etc.). This reaction can be carried out in the presence or absence of a base. The reaction temperature is generally about -10 ° C to 120 ° C, preferably about 0 ° C to 100 ° C. Reaction time is usually about 5 minutes to 48 minutes
The time is preferably about 0.5 to 24 hours. The amount of the compound [III] or its salt used is about 1 per mol of the compound [II ″ ″] or its salt or its reactive derivative.
To 5 molar equivalents, preferably about 1 to 3 molar equivalents. Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, sodium carbonate and potassium carbonate. Alkali metal carbonates, alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc. are used.
I ″ ″] or a salt thereof is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents. Also,
When a solvent immiscible with water is used in this reaction, water may be added to the reaction system at an appropriate ratio and the reaction may be carried out in a two-phase system.
When a coupling reagent is used, it is usually preferable to carry out the reaction under anhydrous conditions. The amount of the coupling reagent used is about 1 to 10 molar equivalents, preferably about 1 to 3 molar equivalents, relative to 1 mol of compound [II ″ ″] or a salt thereof. When an additive is further used, the amount used is about 1 to 5 molar equivalents, preferably about 1 to 2 molar equivalents, relative to 1 mole of the coupling reagent. Further, the coumarinamide condensed with the oxolated cycloalkane can also be synthesized by subjecting the coumarinamide condensed with the cycloalkane to an oxidation reaction at an appropriate stage of the synthesis. The oxidation reaction is carried out by using an oxidizing agent (for example, permanganate,
Chromic acid, etc.) and a method known per se [eg A.
B. AB Smith, III, et.al., The Journal of Organic Chemistry
rnal of Organic Chemistry) 50 volumes, 3239-324
P. 1, 1985].

R ¹ , R ² , ring A, ring B, Y of compound (I)
In the case where each of the substituents has a functional group (for example, a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a thiol group, an ester group, a sulfo group, a halogen atom, etc.) that can be converted to the substituent, it is known per se. Various compounds can be produced by converting a functional group by the method of 1 or a method analogous thereto. For example, in the case of a carboxyl group, it can be converted by a reaction such as esterification, reduction, amidation, and conversion to an optionally protected amino group. In the case of an amino group, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation and imidation. The hydroxy group can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation and halogenation. In the case of a carbonyl group, reduction,
Oxidation, iminoization (including oxime formation, hydrazone formation),
It can be converted by reactions such as (thio) ketalization, alkylidene formation, and thiocarbonylation. For thiol groups,
It can be converted by reactions such as alkylation and oxidation. The ester group can be converted by a reaction such as reduction or hydrolysis. A sulfo group can be converted by a reaction such as sulfonamidation or reduction. A halogen atom can be converted by various nucleophilic substitution reactions, various coupling reactions and the like.

Compound [II '] used in the above reaction,
As the salts of [II ″], [II ″ ″] and [II ″ ″], the same salts as the salts of the compound [I] are used. In addition, in the respective reactions of the method for producing the compound [I] or a salt thereof and the reactions of synthesizing the starting compound, when the starting compound has an amino group, a carboxyl group or a hydroxy group as a substituent, peptide chemistry is added to these groups. A compound having a protecting group generally used in the above may be introduced, and the target compound can be obtained by removing the protecting group as necessary after the reaction. As the amino-protecting group,
For example, formyl, optionally substituted, C _1-6
Alkylcarbonyl (eg acetyl, ethylcarbonyl etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, C
_7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, etc. are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group, etc. are used. The number of substituents is about 1 to 3. Examples of the carboxyl-protecting group include C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), Phenyl,
Trityl or silyl is used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group, etc. are used. The number of substituents is about 1 to 3. Examples of the protecting group for the hydroxy group include C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), Phenyl,
C _7-10 aralkyl (eg benzyl etc.), formyl, C _1-6 alkyl-carbonyl (eg acetyl,
Ethylcarbonyl), phenyloxycarbonyl,
Benzoyl, C _7-10 aralkyl-carbonyl (eg
Benzyl carbonyl, etc.), pyranyl, furanyl or silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-).
Propyl etc.), phenyl, C _7-10 aralkyl (eg benzyl etc.), nitro group etc. are used, and the number of substituents is about 1 to 4. As a method for removing the protecting group, a method known per se or a method analogous thereto can be used. ,
A method of treating with palladium acetate or the like is used. The compound [I] or a salt thereof obtained by the above method can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. When the compound [I] of the present invention thus obtained is obtained as a free form, it can be converted into a salt by a method known per se or a method analogous thereto (for example, neutralization), and conversely, a salt is obtained. In this case, the free form or other salt can be converted by a method known per se or a method analogous thereto. When the compound [I] may have optical isomers, these individual optical isomers and their mixtures are naturally included in the scope of the present invention, and if desired, these isomers may be known per se. It may be optically separated according to the means, or may be manufactured individually.

The compound [I] in the present invention, a salt thereof, and their prodog (hereinafter sometimes abbreviated as the compound of the present invention) are low in toxicity and safe, and have a lipid-rich plaque retraction effect. Therefore, acute myocardial infarction in mammals (eg, mouse, rat, rabbit, dog, cat, cow, pig, monkey, human etc.), acute coronary syndrome such as unstable angina, peripheral artery occlusion, percutaneous Coronary angioplasty (PTCA)
Subsequent restenosis, restenosis after stent placement, myocardial infarction, ischemic heart disease such as angina, arteriosclerosis, intermittent claudication, stroke (cerebral infarction, cerebral embolism, cerebral hemorrhage, etc.), lacunar infarction, brain It is useful for prevention or treatment of vascular dementia and the like, and is useful as a defoaming drug. Further, the compounds of the present invention are ACAT
It has an inhibitory effect (preferably, an ACAT inhibitory effect on macrophages, an ACAT inhibitory effect on subtype 1), and a mammal (eg, mouse, rat, rabbit, dog, cat, cow,
Hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, atherosclerosis in pigs, monkeys, humans, etc., and diseases caused by these (for example, ischemic heart disease such as myocardial infarction and cerebral infarction / stroke) It is used as a safe preventive / therapeutic agent for cerebrovascular disorders such as. Further, according to the present invention, there is provided an atherosclerotic plaque regression, progression inhibitor or stabilizer comprising the compound of the present invention, wherein the regression, progression inhibitor or stabilizer is an HMG-CoA reductase inhibitor. It is preferable to use them in combination. Also,
The compound of the present invention is used as a prophylactic / therapeutic drug for Alzheimer's disease, multiple risk syndrome and metabolic syndrome.

In the treatment of these diseases, the compounds of the present invention may be used therapeutically alone, or other lipid-lowering or cholesterol-lowering agents, myocardial protective agents, therapeutic agents for coronary artery disease, therapeutic agents for diabetes. , A therapeutic agent for hypothyroidism, a therapeutic agent for nephrotic syndrome, a therapeutic agent for osteoporosis or a therapeutic agent for chronic renal failure, in which case these compounds are preferably administered as an oral preparation. Also, if necessary, it may be administered as a rectal preparation in the form of suppositories. Possible combination components in this case are, for example, fibrates [eg, clofibrate, bezafibrate, gemfiprozil, fenofibrate, Wy-1463, GW957.
8 etc.], nicotinic acid, its derivatives and analogs [eg, acipimox and probucol], bile acid-binding resins [eg, cholestyramine, colestipol, etc.], compounds that suppress cholesterol absorption [eg, sitosterol, neomycin, etc.], cholesterol Compounds that inhibit biosynthesis [eg, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, and other HMG-CoA reductase inhibitors], squalene epoxidase inhibitors [eg, NB-5
98 and related compounds, etc.], HDL-elevating drug by inhibition of cholesterol ester transfer protein [JTT-705, C
P-529-414 and the like]. Further possible combination components are oxidosqualene-lanosterol cyclases, such as decalin derivatives, azadecalin derivatives and indane derivatives. In addition, antidiabetic agents [Actos, Rogiglidason, Kinedac, Benfil, Humarin, Euglucon, Glymicron, Daonyl, Novolin, Monotard, Insulins, Glucobay, Dimerin, Rustinone, Bacilcon, Deamerin S, Isdirin, Biguanides]; Antihyperthyroid drug [dry thyroid (thyreoid), levothyroxine sodium (thyrazine S), liothyronidin sodium (thyronine, thyromine); nephrotic syndrome drug: prednisolone (predonin), prednisolone sodium succinate (predonin), succinate Acid sodium prednisolone sodium (sol medrol), betamethasone (linderone)]; anticoagulant therapy [dipyridamole (versantine), dilazep hydrochloride (comelian), Tyropidine, Clovidogrel, F
Xa inhibitor]; therapeutic drug for chronic renal failure [diuretic drug [eg, furosemide (Rasix), bumetanide (Renetron), azosemide (Diart)]], antihypertensive drug (eg, ACE inhibitor,
(Enalapril maleate (renibase)) and Ca antagonist (manidipine), α receptor blocker, angiotensin II receptor antagonist (candesartan cilexetil)]
When administered in combination with, etc., it may be preferably used by oral administration.

Further, the lipid of the compound of the present invention
Given the rich plaque regression and ACAT inhibitory effects, the compounds of the present invention are suitable for the prevention and treatment of thrombus formation. In that case, they may be used alone or in combination with the known therapeutic agents described below, preferably by oral administration. Anti-thrombosis drug: anticoagulant [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), Xa inhibitor], thrombolytic drug [eg,
tPA, urokinase], antiplatelet drug [eg, aspirin, sulfinpyrazone (anthuran), dipyridamole (persantin), ticlopidine (panardin),
Cilostazol (Pletal), GPIIb / IIIa antagonist (Leopro), Clopidogrel]; Coronary vasodilator: Nifedipine, diltiazem, Nicorandil, Nitrate; Cardioprotectant: Cardiac ATP-K opener, endothelin antagonist, urotensin antagonist Such. Furthermore, when applying the compound of the present invention to each of the above diseases,
It can be used in combination with a biologic (eg, antibody, vaccine formulation, etc.), or can be applied as a combination therapy in combination with a gene therapy method or the like. Antibodies and vaccine preparations include, for example, angiotensin
II vaccine preparation, CETP vaccine preparation,
CETP antibody, antibody against TNFα antibody and other cytokines, amyloid β vaccine preparation, type 1 diabetes vaccine (Pe
In addition to ptor's DIAPEP-277, etc., antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, blood coagulation / line Examples thereof include antibodies or vaccines relating to enzymes and proteins involved in the lysis system, antibodies against proteins relating to sugar metabolism and insulin resistance, vaccine preparations and the like. In addition, gene therapy methods include, for example, therapy methods using genes related to cytokines, renin-angiotensin enzymes and their products, therapeutic methods using DNA decoys such as NFκB decoy, therapeutic methods using antisense, blood Treatment using genes related to enzymes and proteins involved in lipid metabolism (eg, genes related to metabolism, excretion, absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid), peripheral vascular occlusion, etc. The therapeutic method using genes related to enzymes and proteins (eg, growth factors such as HGF and VEGF) involved in angiogenesis therapy targeting the disease, and genes related to proteins involved in glucose metabolism and insulin resistance The therapeutic method used, antisense to cytokines such as TNF, and the like can be mentioned. Further, it can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and blood vessel regeneration, or angiogenesis therapy using transplantation of bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.).

The compound of the present invention can be used orally or parenterally by injection, infusion, inhalation method, rectal injection, or topical administration, as it is or in the form of a pharmaceutical composition (eg powder, powder, Granules, tablets, pills,
Capsules, injections, syrups, emulsions, elixirs, suspensions, solutions, etc.). That is, at least one compound of the present invention can be used alone or as a mixture with a pharmaceutically acceptable carrier (adjuvant, excipient, excipient and / or diluent, etc.).

The pharmaceutical composition can be formulated according to a conventional method. Such a preparation can be usually produced by mixing / kneading the active ingredient with additives such as a excipient, a diluent and a carrier. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution and the like. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration are the drug and suitable non-irritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract, which melts in the rectum. It can be manufactured by mixing with a substance that emits. In addition, with a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc.) It is also effective to use a combination sustained-release preparation.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like mentioned above. Formulations in such dosage forms comprise the active ingredient compound and at least one additive, for example sucrose,
Lactose, lactose, mannitol (D
-Mannitol), maltitol, dextran, starches (eg, corn starch), microcrystalline cellulose, agar, alginates, chitins, chitosans, pectins, tragacanth gums, gum arabic, gelatins,
It can be produced by mixing and / or kneading with collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms can also, as usual, contain further additives such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, Antioxidants such as α-tocopherol and cysteine, disintegrants (eg, croscarmellose sodium), binders (eg, hydroxypropyl cellulose),
Examples thereof include thickeners, buffering agents, sweetening agents, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Examples of liquid preparations for oral administration include pharmaceutically acceptable emulsion preparations, syrup preparations, elixir preparations, suspension preparations and solution preparations, which are inert diluents commonly used in the art such as water and, if necessary, It may contain additives. These oral liquid preparations can be produced by a conventional method such as mixing an active ingredient compound with an inert diluent, and optionally other additives. In oral administration, it is usually about 0.01 to 99 W%, preferably about 0.1 to 90 W% and usually about 0.5 to 50 W% of the active ingredient compound of the present invention, though it depends on the dosage form. Good. The dosage for a particular patient will depend on age, weight, general health, sex, diet, time of administration, mode of administration, excretion rate, drug combination, and the extent of the condition being treated by the patient at that time. , And these or other factors. The lipid-rich plaque-reducing agent containing the compound of the present invention has low toxicity and can be safely used. The daily dose depends on the patient's condition, body weight, type of compound, administration route, etc. Although different, for example, when used as a prophylactic / therapeutic agent for hyperlipidemia, the daily dose for an adult (with a body weight of about 60 kg) is about 1 as an active ingredient [I] in the case of an oral preparation.
To 500 mg, preferably about 10 to 200 mg, and in the case of parenteral agents, it is about 0.1 to 100 m as the active ingredient [I].
g, preferably about 1 to 50 mg, usually about 1 to 20 mg, with no toxicity observed in this range.

Further, the present invention provides (1) a drug comprising the compound of the present invention and a concomitant drug in combination (hereinafter abbreviated as a concomitant drug), and (2) the effect of the compound of the present invention on mammals. Amount and a concomitant drug are administered in combination, and a lipid-rich plaque retraction method or ACAT inhibition method, and (3) an effective amount of a compound of the present invention and a concomitant drug to a mammal Acute myocardial infarction, acute coronary syndrome such as unstable angina, peripheral artery occlusion, restenosis after percutaneous coronary angioplasty (PTCA), stent Restenosis after indwelling, atherosclerosis, myocardial infarction, ischemic heart disease such as angina, arteriosclerosis, intermittent claudication, cerebrovascular disorder such as stroke (cerebral infarction, cerebral embolism, cerebral hemorrhage), Lacunar infarction, cerebrovascular dementia, Alzheimer's disease, multiple risk syndrome and metabolism syndrome, hyperlipidemia, hypercholesterolemia, provides a preventive and therapeutic method for hypertriglyceridemia or thrombus formation.

Examples of the concomitant drug that can be used in combination with the compound of the present invention include, for example, pharmaceutical ingredients other than the compound of the present invention described above and other therapeutic agents for hyperlipidemia, diuretics, therapeutic agents for hypertension, therapeutic agents for heart failure, Antiarrhythmic drug, anticoagulant, antiplatelet drug, antidiabetic drug, HDL increasing drug, vulnerable plaque stabilizing drug, vasodilator, vasoconstrictor, pressor drug, antibacterial drug, antifungal drug, nonsteroidal antidrug Inflammatory drugs, steroid drugs, immunomodulators, antiprotozoal drugs, anti-ulcer drugs, antitussives / antitussives, sedatives, anesthetics,
Anti-anxiety drug, anti-psychotic drug, muscle relaxant drug, anti-epileptic drug, antidepressant drug, narcotics antagonist, anti-tumor drug, anti-allergic drug, vitamin drug, vitamin derivative, bone / calcium metabolizer, osteoporosis therapeutic drug, arthritis treatment Drugs, anti-rheumatic drugs, anti-asthma drugs, frequent urination / urinary incontinence drugs, renal failure / nephropathy therapeutics, atopic dermatitis therapeutics, allergic rhinitis therapeutics, endotoxin antagonists or antibodies, signal transduction inhibitors, Anti-inflammatory mediator action inhibitor, inflammatory mediator action inhibitor antibody, anti-inflammatory mediator action inhibitor, anti-inflammatory mediator action inhibitor antibody, etc., among them, hyperlipidemic drug, diuretic, antihypertensive drug , Heart failure therapeutic agents, antiarrhythmic agents, anticoagulants, antiplatelet agents, antidiabetic agents, HDL-increasing agents, vulnerable plaque stabilizing agents and the like are preferable. Specific examples of the concomitant drug other than the above-mentioned pharmaceutical ingredients include the following.

(1) Antihyperlipidemic drug HMG-CoA reductase inhibitor (eg, fluvastatin, cerivastatin, atorvastatin, etc.), fibrate drug (eg, synfibrate, clofibrate aluminum, clinofibrate, fenofibrate, etc.) ),
Anion exchange resin (eg, cholestyramide, etc.), nicotinic acid preparation (eg, nicomol, niceritrol, tocopherol nicotinate, etc.), polyunsaturated fatty acid derivative (eg, ethyl icosapentate, polyenphosphatidylcholine, melinamide, etc.) , Plant sterols (eg, gamma-oryzanol, soysterol, etc.), elastase, dextran sodium sulfate, squalene synthase inhibitor, CETP inhibitor, 2-chloro-3- [4- (2- (2-
Methyl-2-phenylpropoxy) phenyl] ethyl propionate [Chemical and Pharmaceutical Bulletin (Chem.Pharm. Bull), 38, 2792]
-2796 (1990)] and the like. (2) Diuretics thiazide type diuretics (ventil hydrochlorothiazide, cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, penfluthiazide, polythiazide, trichlormethiazide, etc.), loop diuretics (chlorthalidon, clofenamide, indapamide) , Mefluside, Methiclan, Sotrazone, Trivamide, Quinetazone, Metrazone, Furosemide, Mefluside, etc.), Potassium-retaining diuretics (Spironolactone, Triamterene, etc.). (3) antihypertensive drug sympathetic depressant α ₂ stimulant (eg, clonidine, guanabenz, guanfacine, methyldopa, etc.), ganglion blocker (eg, hexamethonium, trimetaphane, etc.), presynaptic blocker (eg , Alsaroxylone, dimethylaminoreserpinate, resinamine, reserpine, syrosingopine, etc.), neuron blockers (eg, betanidine, guanethidine, etc.), α ₁ blockers (eg, bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.) , Beta blockers (eg, purpranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amos Larol, arotinolol, etc.) etc. Vasodilator calcium channel blockers (eg, manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amlodipine, alanidipine, etc.),
Phthalazine derivatives (eg, butralazine, cadralazine,
Ecarazine, hydralazine, todralazine etc.) etc. ACE inhibitors alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, belindopril, etc. Angiotensin II receptor antagonist losartan, candesartan cilexetil, valsartan, telmisartan, irbesartan, forasartan, etc. Diuretics (for example, the above-mentioned diuretics) (4) Heart failure therapeutic agents Cardiotonic agents (eg, digitoxin, digoxin, methyldigoxin, lanatoside C, proscillaridin, etc.), α, β
Stimulants (eg, epinephrine, norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine,
Denopamine, etc.), phosphodiesterase inhibitors (eg,
Amrinone, milrinone, olprinone hydrochloride, etc.), calcium channel sensitivity enhancer (eg, pimobentan, etc.), nitric acid drug (eg, nitroglycerin, isosorbide dinitrate, etc.), ACE inhibitor (eg, the aforementioned ACE inhibitor, etc.),
Diuretics (such as those listed above), carperitide, ubidecarenone, vesnarinone, aminophylline, etc. (5) Antiarrhythmic drug Sodium channel blocker (eg, quinidine, procainamide, disopyramide, azimarin, cibenzoline,
Lidocaine, diphenylhydantoin, mexiletine,
Propafenone, flecainide, pilsicainide, phenytoin, etc.), β-blockers (eg, propranolol, alprenolol, pfetrol, oxprenolol, atenols, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, alothirol), potassium channel blockers Drugs (eg, amiodarone, etc.), calcium channel blockers (eg, verapamil, diltiazem, etc.), etc. (6) Anticoagulant and antiplatelet agents Sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, argatroban, gabexate, ozacrel sodium, ethyl icosapentate, beraprost sodium, al Prostadil, pentoxifylline, tisokinase, streptokinase, etc. (7) Anti-diabetic agents Sulfonylurea agents (eg, tolbutamide, chlorpropamide, gliclopyramide, acetohexamide, tolazamide, glibenclamide, glybuzole, etc.), biguanides (eg, metformin hydrochloride, buformin hydrochloride, etc.), α-glucosidase Inhibitors (eg, voglibose,
Acarbose), insulin sensitizers (eg, pioglitazone, troglitazone, etc.), insulin, glucagon, diabetic complications (eg, epalrestat), etc. (8) HDL increasing drug Squalene synthase inhibitor, CETP inhibitor, LPL activator, etc. (9) Vulnerable plaque stabilizing agent MMP inhibitor, chymase inhibitor, etc. (10) Vasodilator oxyfedrine, diltiazem, tolazoline, hexobenzine, bamethan, clonidine, methyldopa, guanabenz and the like. (11) Vasoconstrictor drugs such as dopamine, dobutamine and denopamine. (12) Pressor drugs dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like. (13) Antibacterial agents sulfa agents sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like. Quinoline antibacterial agents nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc. Antituberculosis drug isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc. Anti-mycobacterial agents such as diaphenyl sulfone and rifampicillin Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir etc. Anti-HIV drugs zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir, etc. Anti-spirochete drugs antibiotics tetracycline hydrochloride, ampicillin, piperacillin,
Gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, cephalexin, Sefurokisajin, cefadroxil , Cefamandor, Cephtoam, Cefuroxime,
Cefotiam, cefotiam hexetyl, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpyramide, cefthrozine, cefmenoxime, cefpodoxime proxetil, cefpirom, cefazoplan, cefepime, cefthrozine, cefmeznom, cefmeznom, cefepoxim
Cefbuperazone, ratamokinasef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or salts thereof, griseofulvin, lancasidins [Journal of Antibiotics (88, 38, Antibiotics).
5 (1985)] and the like. (14) Antifungal polyene antibiotics (eg, amphotericin B, nystatin, tricomycin) Griseofulvin, pyrrolenitrin and other cytosine antimetabolites (eg, flucytosine) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole) , Croconazole) Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3 , 3
-Tetrafluoropropoxy) phenyl-3- (2H,
4H) -1,2,4-triazolone) Thiocarbamic acid derivative (eg, trinaphthol) Echinocandin derivative (eg, caspofungin, F
K-464, V-echinocancin) and the like. (15) Non-steroidal anti-inflammatory drug acetaminophen, phenacetin, ethenzamid, sulpirine, antipyrine, miglenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin , Flurbiprofen, fenbufen, pranoprofen, floctafenin, epirizole, tiaramid hydrochloride, zaltoprofen, gabexate mesylate, camostat mesilate, ulinastatin, colchicine, probenedide, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, Sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid Atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, etc. oxymorphone or a salt thereof. (16) Steroid drug dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide,
Prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol, etc. (17) Immunomodulators cyclosporine, tacrolimus, gusperimus, azathioprine, antilymph serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like. (18) Antiprotozoal agents metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like. (19) Antiulcer drug metaclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprexone, teprexane, teprexane, teprexane, teprexane, teprexone, tereplex, teprexone, teprexane, teprexane, teprexane, teprexane, teprexane, teprexone, aldioxa, teprexone, teprexane, teprexane, teprexane, teprexone, aldioxa, teprenone .
(20) Antitussive and analgesic ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,
Dihydrocodeine phosphate, Isoproterenol hydrochloride, Ephedrine hydrochloride, Methylephedrine hydrochloride, Noscapine hydrochloride, Alloclamide, Chlorphedianol, Picoperidamine, Cloperastine, Protoxylol, Isoproterenol, Salbutamol, Tereptaline, Oxypetebanol, Morphine hydrochloride, Bromide Dextropetorphan hydrochloride, oxycodone hydrochloride, dimorphan phosphate, tipepidine hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine, carbocysteine, etc. . (21) Sedatives chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamiral sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chlorphosphine chloral hydrate, trichlorphosphine. Sodium and so on. (22) Anesthetic (22-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein) and the like. (22-2) General anesthetic Inhalation anesthetic (eg, ether, halothane, nitrous oxide,
Influrane, enflurane), intravenous anesthetics (eg, ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital), etc. (23) Anxiolytics diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clothiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like. (24) Antipsychotic drug chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine, etc. (25) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine, etc. (26) antiepileptic drug phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine,
Phenobarbital, primidone, sultiam, sodium parproate, clonazepam, diazepam, nitrazepam, etc. (27) Antidepressants imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like. (28) Narcotic antagonist levallorphan, nalorphine, naloxone or a salt thereof and the like. (29) Antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5. -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, hepromycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, dusulfan, thiotepa, procarbazine hydrochloride. , Cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine Methyltestosterone, testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, acetic Eyupurin and buserelin acetate. (30) Antiallergic drug diphenhydramine, chlorpheniramine, tripelenamine, metdilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate,
Tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast etc. (31) Fat-soluble vitamin drugs Vitamin A's: vitamin A ₁ , vitamin A ₂ and retinol palmitate Vitamin D's: vitamins D ₁ , D ₂ , D ₃ , D ₄ and D
₅ Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate Vitamin Ks: vitamins K ₁ , K ₂ , K ₃ and K ₄ folic acid (vitamin M), etc. . (32) Vitamin derivatives Various derivatives of vitamins, for example, vitamin D ₃ derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5,6- Vitamin D ₂ derivatives such as trans-ergocalciferol. (33) anti-asthma drug isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride,
Tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, flutropium bromide,
Theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone,
Ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,
Pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocorthiaone, beclopetazone propionate, etc. (34) Frequent urinary / urinary incontinence drug flavoxate hydrochloride, etc. (35) Atopic dermatitis therapeutic agent sodium cromoglycate, etc. (36) Remedies for allergic rhinitis Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, terfenadine, mequitazine and the like. (37) Dementia treatment acetylcholinesterase inhibitor (eg, donepezil, tacrine, rivastigmine, galantamine, etc.), etc. (38) Other hydroxycam, diacerine, megestrol acetate,
False groins, prostaglandins, etc.

When the compound of the present invention is used in combination with a concomitant drug,
For example, it has the following effects. (1) The dose or side effect when the compound of the present invention or a salt thereof, a prodrug thereof, or a concomitant drug is administered alone can be reduced. (2) Acute myocardial infarction, acute coronary syndrome such as unstable angina, peripheral arterial occlusion, percutaneous coronary angioplasty (PTCA)
Subsequent restenosis, restenosis after stent placement, hypercholesterolemia, atherosclerosis, myocardial infarction, ischemic heart disease such as angina, cerebrovascular disorder such as cerebral infarction / stroke, Alzheimer's disease or A synergistic therapeutic effect is obtained for diseases such as thrombus formation. (3) Acute myocardial infarction, acute coronary syndrome such as unstable angina, peripheral arterial occlusion, percutaneous coronary angioplasty (PTCA)
Subsequent restenosis, restenosis after stent placement, hypercholesterolemia, atherosclerosis, myocardial infarction, ischemic heart disease such as angina, cerebrovascular disorder such as cerebral infarction / stroke, Alzheimer's disease or It exerts a wide therapeutic effect on various diseases that develop with diseases such as thrombus formation. When using the concomitant drug of the present invention, the timing of administration of the compound of the present invention and the concomitant drug is not limited, the compound of the present invention or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof, to the administration subject, It may be administered at the same time or at different times. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such a dosage form include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) preparation of the compound of the present invention and a concomitant drug separately. Administration of two types of preparations obtained by the formulation, (3) two formulations obtained by separately formulating the compound of the present invention and a concomitant drug, with a time difference between the same administration routes (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug through different administration routes, (5) separately preparing the compound of the present invention and a concomitant drug Administration of the two types of pharmaceutical preparations obtained by compounding at different time intervals by different administration routes (for example, administration of the compound of the present invention or a pharmaceutical composition thereof; concomitant drug or a pharmaceutical composition thereof in the order or vice versa) Administration) and the like.

The combination agent of the present invention has low toxicity, and for example,
The compound of the present invention or (and) the above-mentioned concomitant drug are mixed with a pharmaceutically acceptable carrier according to a method known per se, to obtain a pharmaceutical composition such as tablets (including sugar-coated tablets and film-coated tablets), powders and granules. It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.), as a capsule, (including soft capsule), solution, injection, suppository, sustained-release agent and the like. The injection can be administered intravenously, intramuscularly, subcutaneously or intra-organly, or directly to the lesion. Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances conventionally used as a formulation material, for example, an excipient in a solid formulation, a lubricant. , Binders and disintegrants, or solvents for liquid preparations, solubilizers, suspending agents, isotonic agents, buffering agents, soothing agents and the like. Further, if necessary, conventional additives such as antiseptics, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be appropriately used in appropriate amounts. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. As the binder, for example, crystalline cellulose, sucrose, D
-Mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. As the disintegrant, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium,
L-hydroxypropyl cellulose etc. are mentioned. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil,
Examples include olive oil. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D
-Mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, surface active agents such as polyvinyl alcohol, polyvinyl pyrrolidone, Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Examples of the isotonicity agent include glucose, D-sorbitol, sodium chloride,
Examples thereof include glycerin and D-mannitol. Examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, and the like. Examples of soothing agents include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Examples include dehydroacetic acid and sorbic acid. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

The compounding ratio of the compound of the present invention to the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. And more preferably about 0.5 to 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably the total preparation. It is about 0.5 to 20% by weight. The content of additives such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . Also, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.

These formulations can be produced by a method known per se which is generally used in the formulation process. For example, the compound of the present invention or a concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose). ,
Dextrin, etc.), stabilizers (eg, ascorbic acid,
Sodium pyrosulfite etc.), surfactants (eg polysorbate 80, macrogol etc.), solubilizers (eg glycerin, ethanol etc.), buffers (eg phosphoric acid and its alkali metal salts, citric acid and its alkali metals) Salt, etc.), isotonicity agent (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjuster (eg,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizing agents (eg, propylene) Glycols, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) in aqueous injections, or vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., and solubilizing agents such as propylene glycol. Alternatively, it can be emulsified and molded into an oil-based injection to prepare an injection. In order to prepare a preparation for oral administration, the compound of the present invention or the concomitant drug is, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg,
Add starch (calcium carbonate, etc.), binder (eg starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose etc.) or lubricant (eg talc, magnesium stearate, polyethylene glycol 6000 etc.) etc. Then, the composition can be compression-molded, and then, if necessary, coated by a method known per se for the purpose of taste masking, enteric coating or sustainability, to give an oral administration preparation. As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose,
Hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 8
0, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymerization) and dye (eg, red iron oxide,
Titanium dioxide etc.) is used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation. For example, in the case of a suppository, the compound of the present invention or the concomitant drug can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include higher fatty acid glycerides [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) ) And the like], or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Further, as the aqueous base, for example, polyethylene glycols, propylene glycol, as the aqueous gel base, for example, natural gums, cellulose derivatives,
Examples thereof include vinyl polymers and acrylic acid polymers.
Examples of the sustained-release preparation include sustained-release microcapsules. To make sustained-release microcapsules,
Although a method known per se can be adopted, for example, it is preferable to mold and administer the sustained release preparation shown in the following [2]. The compound of the present invention is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository. Particularly preferred is a preparation for oral administration. The concomitant drug can be in the above-mentioned dosage forms depending on the type of drug.

In the following, [1] an injection of the compound of the present invention or a concomitant drug and its preparation, [2] a sustained release preparation or an immediate release preparation of the compound of the present invention or a concomitant drug, and its preparation,
[3] A sublingual tablet, buccal or buccal disintegrant of the compound of the present invention or a concomitant drug and its preparation, and [4] a solid dispersion of the compound of the present invention or a concomitant drug and its preparation will be specifically described. [1] Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or a concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate. The injection can be obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or a salicylate in water. Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol. The concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of benzoate and / or salicylate is preferably 0.5 to 50 w / v%, more preferably 3 to 20 w / v%.

In addition, the present agent contains additives generally used for injection, such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), soluble agents (glycerin, Ethanol, etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin), pH adjustment Agents (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (glucose, Benzyl alcohol etc.) can be appropriately blended. These additives are generally added in the proportions usually used for injections. The pH of the injection is 2-12, preferably 2.5-8, by adding a pH adjusting agent.
It is better to adjust to 0. The injectable preparation is obtained by dissolving both the compound of the present invention or the concomitant drug, and optionally benzoate and / or salicylate, and, if necessary, the above-mentioned additive in water. These may be dissolved in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injectable solution. The aqueous solution for injection is preferably heated, and can be provided as an injectable solution by performing, for example, filter sterilization, high-pressure heat sterilization, etc. in the same manner as a normal injectable solution.
The aqueous solution for injection is, for example, 5 to 100 ° C to 121 ° C.
It is preferable to sterilize under high pressure heat for 30 to 30 minutes. Furthermore, it may be a preparation in which the solution has antibacterial properties so that it can be used as a multiple-dose preparation.

[2] Sustained-release preparation or rapid-release preparation and preparation thereof A sustained-release preparation obtained by coating a core containing the compound of the present invention or a concomitant drug with a film-forming agent such as a water-insoluble substance or a swelling polymer, if desired. Release formulations are preferred. For example, a once-daily type sustained release preparation for oral administration is preferable. Examples of the water-insoluble substance used for the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer,
Ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, polymethacrylamide, aminoalkylmethacrylate copolymer Polymer, poly (methacrylic acid anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-100, RS-
30D, RL-30D, RL-PO, RS-PO (Ethyl acrylate / Methyl methacrylate / Trimethyl / ammonium ethyl methacrylate copolymer), Eudragit NE-30D (Methyl methacrylate / Ethyl acrylate) Polymers) and other acrylic acid polymers such as Eudragits (ROHM PHARMA CO., LTD.), Hydrogenated castor oil (eg Lovely wax (Freund Industries) etc.) and other hardened oils, carnauba wax, fatty acid glycerin ester, waxes such as paraffin And polyglycerin fatty acid ester. As the swelling polymer, a polymer having an acidic dissociative group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as small intestine or large intestine. Polymers having acidic dissociative groups are preferred. Polymers having such acidic dissociative groups and exhibiting pH-dependent swelling include, for example, Carbomer 934P and 94.
0, 941, 974P, 980, 1342, etc., polycarbophil, calcium polycarbophil (carfium polycarbophil)
Goods Wako 103, 104,
Examples thereof include crosslinked polyacrylic acid polymers such as 105 and 304 (both manufactured by Wako Pure Chemical Industries, Ltd.). The film forming agent used in the sustained-release preparation may further contain a hydrophilic substance. Examples of the hydrophilic substance include polysaccharides that may have a sulfate group such as pullulan, dextrin, and alkali metal alginates, hydroxyalkyl groups such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose, or carboxyalkyl groups. Examples thereof include polysaccharides, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol. The content of the water-insoluble substance in the film preparation of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w).
w), more preferably about 40 to 75% (w / w), the content of swellable polymer is about 3 to about 30% (w / w),
It is preferably about 3 to about 15% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w). Here, the above-mentioned% (w / w) indicates the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohols such as methanol and ethanol) from the coating agent liquid.

The sustained-release preparation is a film prepared by preparing a core containing a drug as exemplified below, and then dissolving the resulting core by heating or dissolving or dispersing a water-insoluble substance or a swelling polymer in a solvent. It is manufactured by coating with a chemical solution. I. Preparation of drug-containing nuclei. The form of the core containing the drug to be coated with the coating agent (hereinafter sometimes simply referred to as the core) is not particularly limited, but is preferably formed into particles such as granules or fine particles. When the core is a granule or a fine granule, its average particle size is preferably about 1
50 to 2,000 μm, more preferably about 500
To about 1,400 μm. The core can be prepared by an ordinary manufacturing method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer, etc.,
It is prepared by a wet extrusion granulation method, a fluidized bed granulation method, or the like. The drug content of the nucleus is about 0.5 to about 95% (w / w),
It is preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w). As the excipient contained in the core, for example, saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferable. As the binder, for example, polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. Examples of disintegrants include carboxymethyl cellulose calcium (ECG
505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropyl cellulose, polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose are preferable. Examples of lubricants and anti-agglomeration agents include talc, magnesium stearate and its inorganic salts, and lubricants such as polyethylene glycol. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as the stabilizer.

In addition to the above-mentioned production method, the core is sprayed with a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles which are the core of the core. It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method, in which a drug or a mixture thereof with an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those produced from sucrose, lactose, starch, crystalline cellulose, waxes can be used, and the average particle diameter thereof is preferably about 100 μm to about 1,500 μm. The surface of the core may be coated with a protective agent in order to separate the drug contained in the core from the coating agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance or the like is used. The protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose. The protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid or maleic acid as a stabilizer, and a lubricant such as talc. When a protective agent is used, its coverage is about 1 to about 15% (w /
w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w). The protective agent can be coated by a conventional coating method, and specifically, the core can be spray-coated with the protective agent by, for example, a fluidized bed coating method, a pan coating method or the like.

II. Coating of the core with a coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. To produce a sustained release formulation. Examples of the method for coating the core with the coating agent liquid include a spray coating method. The composition ratio of the water-insoluble substance, the swelling polymer or the hydrophilic substance in the coating agent liquid is appropriately selected so that the content of each component in the coating is the above content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), and more preferably to the core (excluding the coating amount of the protective agent). About 5 to 3
It is 5% (w / w). As the solvent for the coating agent liquid, water or an organic solvent may be used alone or a mixture of both may be used. The mixing ratio of water and the organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be varied in the range of 1 to 100%, and preferably 1 to about 30%.
The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance, for example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferable, and ethyl alcohol and isopropyl alcohol are particularly preferable. Water and a mixed liquid of water and an organic solvent are preferably used as the solvent of the film forming agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid or maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method, and specifically, it is carried out by spray coating the core with a coating agent solution by, for example, a fluidized bed coating method, a pan coating method or the like. You can If necessary at this time, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. are plasticized. You may add as an agent. After coating with the coating agent, an antistatic agent such as talc may be mixed if necessary.

The immediate-release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.)
May be Oral administration agents, parenteral administration agents such as injection agents are used, and oral administration agents are preferred. The immediate-release preparation may usually contain, in addition to the active ingredient drug, a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the field of formulation. . The formulation excipient used is not particularly limited as long as it is an excipient that is commonly used as a formulation excipient. For example, as an excipient for an oral solid preparation, lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar,
Granulose sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine and the like can be mentioned, preferably corn starch and mannitol and the like. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w based on the total amount of the immediate release preparation.
%, Preferably about 20 to about 98.5 w / w%, more preferably about 30 to about 97 w / w%. The content of the drug in the immediate-release preparation was about 0.
It can be appropriately selected from the range of 5 to about 95%, preferably about 1 to about 60%. When the immediate release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such a disintegrant include carboxymethylcellulose calcium (manufactured by Gotoku Yakuhin, ECG-505), croscarmellose sodium (for example, manufactured by Asahi Kasei Corporation,
Acdisol), crospovidone (for example, BASF, Kollidon CL), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), sodium carboxymethyl starch (Kimura Sangyo, extract) Protab), partially pregelatinized starch (PCS manufactured by Asahi Kasei Co., Ltd.) and the like are used, for example, a channel is formed between an active ingredient that absorbs water, swells, or forms a core by contact with water and an excipient. The disintegrating agent may be used alone or in combination of two or more. The amount of the disintegrating agent may be selected depending on the type and amount of the drug used, and the release property. It is appropriately selected depending on the formulation design and the like, but for example, about 0.05 to about 30 w / w%, preferably about 0.5 to about 15 w / w%, relative to the total amount of the immediate release preparation. A.

When the immediate release preparation is an oral solid preparation, in the case of an oral solid preparation, it may further contain, if desired, an additive conventionally used in the solid preparation, in addition to the above composition. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose,
Polyvinylpyrrolidone, pullulan, dextrin, etc., lubricants (eg, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anions such as sodium alkylsulfate) -Based surfactants, polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (for example, tar dyes, caramel, red iron oxide, titanium oxide) , Riboflavins), if necessary, cross-linking agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives,
Wetting agents, antistatic agents, etc. are used. Further, an organic acid such as tartaric acid, citric acid, succinic acid or fumaric acid may be added as a stabilizer. As the binder, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used. The quick-release preparation can be prepared by mixing the above-mentioned components, and if necessary, further kneading and molding, based on the usual manufacturing technology for preparations. The above-mentioned mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when forming an immediate release preparation in the form of particles, by the same method as the method for preparing the core of the sustained release preparation, a vertical granulator, a universal kneader (manufactured by Hata Tekko Co., Ltd.), a flower It can be prepared by mixing using a layer granulator FD-5S (manufactured by Powrex) or the like, and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like. The immediate-release preparation and the sustained-release preparation thus obtained are formulated as they are or separately separately with a formulation excipient by a conventional method, and then administered simultaneously or in combination with an arbitrary administration interval interposed. Alternatively, both may be directly or appropriately formulated into one orally-administered preparation (eg, granules, fine granules, tablets, capsules, etc.) together with a preparation excipient and the like. Both preparations may be made into granules or fine granules and filled in the same capsule or the like to give a preparation for oral administration.

[3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation and intraoral rapid disintegrating agent may be solid preparations such as tablets, or tablets for oral mucosa sticking ( the film)
May be As the sublingual tablet, buccal or intraoral quick disintegrant, a formulation containing the compound of the present invention or a concomitant drug and an excipient is preferable. Further, an auxiliary agent such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer and a stabilizer may be contained. In addition, in order to facilitate absorption and increase bioavailability, β-cyclodextrin or β-cyclodextrin derivative (eg, hydroxypropyl-β-
Cyclodextrin, etc.) and the like.
The above-mentioned excipients include lactose, sucrose, D-mannitol,
Starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Sodium chloride as a tonicity agent,
Glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like can be mentioned, with mannitol being particularly preferred. Examples of the hydrophilic carrier include swelling hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose). Is preferred. Water dispersible polymers include gums (eg,
Tragacanth gum, acacia gum, guar gum), alginates (eg sodium alginate), cellulose derivatives (eg methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, water-soluble starch, polyacrylic acid (eg , Carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbic acid palmitate, and the like, hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene. Glycol and the like are preferred. Hydroxypropyl methylcellulose is particularly preferred. As a stabilizer,
Examples thereof include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine and sodium sulfite, and citric acid and ascorbic acid are particularly preferable.

Sublingual tablets, buccal or buccal disintegrants are
It can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se. Further, if desired, the above-mentioned lubricants, isotonic agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and other auxiliary agents may be mixed. Sublingual tablets, buccal tablets, or rapidly disintegrating buccal tablets can be obtained by mixing the above components at the same time or with a time lag and compression-molding. In order to obtain an appropriate hardness, it may be produced by moistening / wetting with a solvent such as water or alcohol as needed before and after the tableting process, followed by molding and drying.
When forming into a mucous membrane adhesive tablet (film), the compound of the present invention or a concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients, etc. are dissolved in a solvent such as water. And cast the resulting solution into a cast film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, a sweetener and the like may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film an appropriate elasticity, and bioadhesive polymers (eg, polycarbophil, carbopol) to enhance adhesion of the film to the mucosal lining of the oral cavity You may let me. Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with a coating tool such as a doctor blade, and then drying the solution to form a film. To be achieved. The film thus formed may be dried at room temperature or under heating and cut into a desired surface area.

As a preferable oral rapid disintegrating agent, a solid form consisting of a reticulate body of the compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier inert to the compound of the present invention or a concomitant drug Examples include rapid diffusion administration agents. The reticulate body can be obtained by sublimating a solvent from a solid composition composed of a solution of the compound of the present invention or a concomitant drug in an appropriate solvent. It is preferable that the composition of the quick disintegrating agent in the oral cavity contains a matrix forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug. Examples of the matrix-forming agent include gelatins, dextrins and soybeans, wheat and psyllium seed proteins, and other animal or plant proteins; gum arabic, guar gum,
Rubber substances such as agar and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; substances derived from gelatin-arabic gum complex, etc. . Further, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and amino acids having 2 to 12 carbon atoms such as L-phenylalanine are included. One or more matrix forming agents may be introduced into the solution or suspension prior to solidification. Such a matrix forming agent may be present in addition to the surfactant, or the surfactant may be excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusional state of the compound of the invention or the concomitant drug in the solution or suspension.

The composition may contain secondary components such as a preservative, an antioxidant, a surfactant, a thickener, a coloring agent, a pH adjusting agent, a flavoring agent, a sweetener or a taste masking agent. Suitable colorants include red, black and yellow iron oxides and FD from Eris and Everard.
& C Blue No. 2 and F such as FD & C Red No. 40
D & C dyes may be mentioned. Suitable flavors include mint,
Includes raspberries, licorice, oranges, lemons, grapefruit, caramel, vanilla, terry and grape flavors and combinations thereof. Suitable pH
Modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbent materials and microencapsulated apomorphine. The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound of the present invention or the concomitant drug, and the period of about 1 minute to about 60 minutes, preferably about 1 minute. 90 minutes of the compound of the present invention or a combination drug (in water) between minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes.
Formulation capable of dissolving at least 100% (above, sublingual tablet,
Buccal or the like) or an intraoral quick disintegrating agent which disintegrates within 1 to 60 seconds, preferably within 1 to 30 seconds, and more preferably within 1 to 10 seconds after being placed in the oral cavity. The content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
Is. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
Is. The content of the isotonicity agent in the whole preparation is about 0.
1 to about 90% by weight, preferably about 10 to about 70% by weight
Is. The content of the hydrophilic carrier in the whole preparation is about 0.
1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is
It is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent and a preservative, if necessary.

[4] Solid Dispersion of Compound of the Present Invention or Concomitant Drug and Preparation Thereof The compound of the present invention [hereinafter, also referred to as lipid-rich plaque reductive substance] or the concomitant drug is sparingly soluble or insoluble in water. In this case, it may be formulated as a solid dispersion (eg, a solid dispersion containing a poorly water-soluble or insoluble lipid-rich plaque retraction substance and a hydrophilic polymer). Here, the "solid dispersion" may be prepared by, for example, a melting method, a solvent method, a melting-solvent method, or the like.
A carrier which is inert in the solid state (eg, hydrophilic polymer, etc.) or a matrix in which one or more active ingredients (preferably, amorphous active ingredients) are dispersed (J.
Pharm. Sci., Vol. 60, 1281-1302, 1971). The average particle size of the solid dispersion is not particularly limited, but the lower limit is usually about 0.05 μm or more, preferably about 0.1 μm.
m or more, more preferably about 1 μm or more, even more preferably larger than 3 μm, and the upper limit is about 30 mm.
Or less, preferably about 100 μm or less, more preferably about 50 μm or less, still more preferably about 10 μm or less.

As the hydrophilic polymer used in the solid dispersion, for example, a water-soluble polymer, an enteric polymer, a gastric soluble polymer and the like are used, and among them, the enteric polymer is preferably used. Examples of the water-soluble polymer include hydroxyalkyl cellulose such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; cellulose derivatives such as alkyl cellulose such as methyl cellulose and ethyl cellulose; polyalkenylpyrrolidone such as polyvinyldone; polyalkylene glycol such as polyethylene glycol. Is used. Examples of enteric polymers include hydroxyalkyl cellulose phthalates such as hydroxypropyl methyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropyl methyl cellulose acetate succinate; carboxyalkyl celluloses such as carboxymethyl ethyl cellulose; cellulose acetate phthalate; meta. Acrylic acid copolymer L-100-55
And the like, copolymers of ethyl acrylate and methacrylic acid; and copolymers of methyl methacrylate and methacrylic acid such as methacrylic acid copolymer L and methacrylic acid copolymer S. As the gastric soluble polymer, for example, aminoalkyl methacrylate copolymer E; polyvinyl acetal diethylaminoacetate and the like are used. In addition, copolymers containing a small amount of quaternary ammonium groups of ethyl acrylate and methyl methacrylate such as methacrylic acid copolymer RL and methacrylic acid copolymer RS, carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, gum arabic, alginic acid Sodium, propylene glycol alginate, agar, gelatin,
A hydrophilic polymer capable of dispersing a poorly water-soluble or insoluble lipid-rich plaque reductive substance such as chitosan is used. You may use these hydrophilic polymers in mixture of 2 or more types.

Among the above, as the hydrophilic polymer,
Hydroxyalkyl cellulose, alkyl cellulose,
Polyalkenylpyrrolidone, polyalkylene glycol, methacrylic acid copolymer, carboxymethylcellulose and the like are preferable, and hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylethylcellulose, methacrylic acid copolymer L and the like are particularly preferable. The solid dispersion may contain additives generally used in the field of pharmaceutical preparation. As additives, pharmaceutically acceptable carriers such as various organic and inorganic carrier substances conventionally used as formulation materials are used, and as excipients, lubricants, binders, disintegrants, surfactants, etc. Be compounded. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and sucrose.
S, perforated starch, mannitol, calcium silicate (trade name: Fluorite RE), magnesium metasilicate aluminate (trade name: Neusilin), light anhydrous silicic acid (trade name: Sylysia), sucrose / starch spherical granules (product name) : Non-pareil), crystalline cellulose / carboxymethyl cellulose (trade name: Avicel RC), hydroxypropyl starch and the like are used. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, methylcellulose (trade name: Metroze SM), croscarmellose sodium, carmellose calcium, low-substituted. Hydroxypropyl cellulose
Soluble starch, sodium starch glycolate, partially pregelatinized starch and the like are used. As the lubricant, for example, talc, crystalline cellulose, magnesium stearate, corn starch, magnesium oxide and the like are used. Examples of the surfactant include polyoxyethylene polyoxypropylene glycol (trade name: Pluronic), glycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, and cetanol. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. These additives may be used alone or in combination of two or more.

The above-mentioned solid dispersion can be produced by a method known per se. Specifically, for example, a solvent method such as a spray drying method or a rotary evaporation method; a melting method such as a twin-screw extruder method; Mixed grinding method;
It can be manufactured by an ultrasonic method using an ultrasonic molding machine or the like. More specifically, the above solid dispersion can be produced by the solvent method described below. (1) A lipid-rich plaque reductive substance is dissolved in a suitable organic solvent, (2) A hydrophilic polymer is added to this solution,
A suspension is prepared, (3) if necessary, additives such as excipients, disintegrants, lubricants and surfactants are suspended in this suspension or solution, and then (4) From this homogeneous suspension, the organic solvent is distilled off under reduced pressure or normal pressure by a conventional method such as a spray drying method or a rotary evaporation method. Further, when a more homogeneous solid dispersion is desired, a homogeneous suspension is prepared in the above step (2) and then successively subjected to the following steps. (5) Step (2) above
The suspension prepared in (1) is dissolved in a suitable organic solvent, and (6) if necessary, additives such as an excipient, a disintegrating agent, a lubricant and a surfactant are suspended, and then (7). The organic solvent is distilled off under reduced pressure or normal pressure by a conventional method such as a spray drying method or a rotary evaporation method.

The organic solvent used in the above step (1) is not particularly limited as long as it can dissolve the sparingly water-soluble or insoluble lipid-rich plaque reductive substance and the hydrophilic polymer, and examples thereof include methanol. Alcohols such as alcohol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol, ethylene glycol monomethyl ether, etc .; ethers such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol, etc. ; N
-Aromatic hydrocarbons such as hexane, cyclohexane and n-heptane: Aromatic hydrocarbons such as benzene, toluene and xylene: Nitriles such as acetonitrile;
Organic acids such as acetic acid and propionic acid; esters such as ethyl acetate; aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; ketones such as acetone and methyl ketone; amides such as dimethylformamide and dimethylacetamide; or A liquid mixture of these in an appropriate ratio is used. Among them, low boiling point solvents such as ketones and alcohols are preferable, and among them, acetone and ethanol are preferable.

The operating conditions such as processing temperature and processing time vary depending on the raw material compounds used, organic solvents, etc.
The processing temperature is usually 200 ° C. or lower. In the melting method, a poorly water-soluble or insoluble lipid-rich plaque reductive substance is heated to a temperature above its melting point to melt it, and then a hydrophilic polymer, if necessary, an excipient, a disintegrant, a lubricant and a surface active agent. It can be manufactured by dissolving an additive such as an agent therein and quenching. For example, in the twin-screw extruder method, a poorly water-soluble or insoluble lipid-rich plaque reductive substance and a hydrophilic polymer, and if necessary, additives such as excipients, disintegrants, lubricants and surfactants are added. It can be produced by heating a physical mixture of the above substances under high pressure to melt a poorly water-soluble or insoluble lipid-rich plaque-reducing substance at a temperature below the melting point and then quenching. In the mixing and pulverizing method, a sparingly water-soluble or insoluble lipid-rich plaque reductive substance and a hydrophilic polymer, and if necessary, additives such as an excipient, a disintegrant, a lubricant and a surfactant are physically mixed. It can be produced by mixing and pulverizing the materials. In the ultrasonic method, a sparingly water-soluble or insoluble lipid-rich plaque reductive substance and a hydrophilic polymer, and if necessary, additives such as an excipient, a disintegrant, a lubricant and a surfactant are physically mixed. It can be manufactured by filling a die in a die and preforming it, and then irradiating it with ultrasonic waves, for example, using an ultrasonic molding machine.

The amount of the hydrophilic polymer is not particularly limited, and may be any amount as long as it can disperse the poorly water-soluble or insoluble lipid-rich plaque reductive substance. For example,
A preferable weight ratio of the hydrophilic polymer to the sparingly water-soluble or insoluble lipid-rich plaque retraction material is 0.01: 1.
To 100: 1, preferably 0.0
2: 1 to 50: 1, more preferably 0.1: 2 to 2
0: 1, more preferably 0.3: 1 to 1
0: 1, more preferably 1: 1 to 10: 1,
Particularly, 3 to 5 (particularly 4): 1 is preferable. The amount of the additive is not particularly limited, but when the additive is used, an excipient,
A suitable weight ratio of additives such as disintegrants, lubricants, surfactants and poorly water-soluble or insoluble lipid-rich plaque retraction material is usually in the range of 0.1: 1 to 20: 1. , Preferably 0.3: 1 to 10: 1, more preferably 1: 1 to 3: 1. Step (5) above
The organic solvent used in step 1 is not particularly limited, and may be any solvent as long as it can dissolve the suspension of the above step (2), such as chloroform and dichloromethane.

The above solid dispersion can be used per se as a pharmaceutical preparation for oral administration, and can be made into a pharmaceutical preparation such as fine granules, fine granules, granules, tablets, capsules and injections by a conventional method. You can also Pharmaceutical formulations containing the above solid dispersions may, if desired, have the additives mentioned above, in particular colorants, sweeteners, fragrances such as sucrose.
Soluble powder, lactose, starch, crystalline cellulose, synthetic ammonium silicate, magnesium stearate, talc, or its diluent or lubricant may be mixed with the pharmaceutical preparation for oral administration. In addition, a sustained release preparation can be prepared by coating the surface of the preparation. Usually, lipid-rich plaque reductive substances are poorly soluble or insoluble in water, and when administered orally, they have a shortcoming of low bioavailability due to the small proportion of the dose actually absorbed in blood. ing. However, various preparations produced by arbitrarily changing the above solid dispersions into the above various dosage forms have higher solubility and oral doses than crystals of the poorly water-soluble or insoluble lipid-rich plaque retractor itself. The absorption or / and the absorption in blood is significantly improved. Thus, the solid dispersion, solubilization of sparingly water-soluble or insoluble lipid-rich plaque reductive substance is achieved, by which the bioavailability of sparingly water-soluble or insoluble lipid-rich plaque reductive substance is dramatically. Has been improved.

The content of the sparingly water-soluble or insoluble lipid-rich plaque-reducing substance in the above solid dispersion is
Although it varies depending on the dosage form, administration method, carrier, etc., it is usually 0.1 to 99% (w / w) based on the total amount of the preparation. The content of the hydrophilic polymer in the solid dispersion varies depending on the dosage form, administration method, carrier, etc., but is usually 1 to 99.9% (w / w) based on the total amount of the preparation. The content of additives in the above solid dispersion varies depending on the dosage form, administration method, etc., but is usually 0 to 99% (w / w) based on the total amount of the preparation.
Is. The content of the solid dispersion in the pharmaceutical preparation of the present invention varies depending on the dosage form, administration method, carrier, etc., but is usually 0.1 to 100% (w / w) based on the total amount of the preparation. The content of additives in the pharmaceutical preparation of the present invention varies depending on the dosage form, administration method, etc.,
It is usually 0 to 99.9% (w / w). The dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention, but is, for example, a hyperlipidemic patient (adult, body weight: about 60 kg). ) Per person, as a compound of the present invention, usually about 0.01 to about 1000 mg / kg per day, preferably about 0.01 to about.
About 100 mg / kg, more preferably about 0.1 to about 100 m
g / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / kg is intravenously administered once to several times a day. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases. It is possible to set any amount of the concomitant drug as long as side effects do not cause a problem. The daily dose as a concomitant drug depends on the degree of symptoms, the age of the subject,
Gender, body weight, difference in sensitivity, administration timing, interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc., and is not particularly limited, but the amount of the drug is usually, for example, per oral body weight of 1 kg of mammal. About 0.001
The dose is 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg, which is usually administered in 1 to 4 divided doses per day.

When the concomitant drug of the present invention is administered, it may be administered at the same time, but the compound of the present invention may be administered after the concomitant drug is administered first. It may be administered first, followed by the concomitant drug. When the administration is performed with a time lag, the time lag varies depending on the active ingredient to be administered, the dosage form, and the administration method. The method includes administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. There is a method. As a preferable administration method, for example, a concomitant drug formed into an oral administration preparation is about 0.0
Oral administration of 01 to 200 mg / kg, and about 15 minutes later, about 0.005 to about 0.005 of the compound of the present invention formed into an oral administration preparation.
The daily dose of 100 mg / kg is orally administered.

[0080]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Examples, Formulation Examples, and Experimental Examples, but the present invention is not limited to these. ¹ H-NMR spectrum is obtained by using Varian Gemini 200 (200 MHz) type or 300 (3
(00 MHz) type spectrometer and all δ values are shown in ppm. Numerical values shown for mixed solvents are volume mixing costs of each solvent unless otherwise specified. Unless otherwise specified,% means% by weight. The ratio of the eluting solvent in silica gel chromatography is a volume ratio unless otherwise specified. The room temperature (normal temperature) in the present specification means a temperature of about 20 ° C to about 30 ° C. The symbols in the examples have the following meanings. AcOEt: ethyl acetate, Me: methyl, Et: ethyl, THF: tetrahydrofuran, IPE: isopropyl ether, Et ₂ O: diethyl ether, decomp .: decomposition, s: singlet, d: doublet, t: triplet, q: Kuarutetto, dd: double doublet, d
t: double triplet, m: multiplet, br:
Wide range, J: Coupling constant, Py: Pyridyl, DB
U: diazabicycloundecene, DMF: dimethylformamide, DPPA: diphenylphosphoryl azide, N
BS: N-bromosuccinimide, AIBN: azobisisobutyronitrile, hex: hexane, Ac: acetyl, Ph: phenyl, Ts: tosyl, mCPBA: metachloroperbenzoic acid, ^t Bu: tert-butyl.

[0081]

EXAMPLES Reference Example 1 (2E) -3- [5- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6 Synthesis of ethyl-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoate (a) of (3-bromophenyl) (4-chloro-2-hydroxy-5-methylphenyl) methanone Synthesis

[Chemical 10] A solution of 3-chloro-4-methylanisole (97 g) in chlorobenzene (300 ml) under ice-cooling aluminum chloride (102 g)
Was added, and 3-bromobenzoyl chloride (136 g) was added.
Was added dropwise over 1 hour. After the completion of dropping, the mixture was stirred at room temperature for 30 minutes and further heated at 120 ° C. for 30 minutes. The reaction mixture was ice-cooled, ethyl acetate (600 ml) methanol (100 ml) 4N
Hydrochloric acid (400 ml) was sequentially added, and the mixture was stirred at room temperature for 30 minutes.
The organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane and purified to give the title compound (186 g, yield 89%). Melting point: 115-117 ° C. (B) Synthesis of [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetic acid

[Chemical 11] (3-Bromophenyl) (4-chloro-2-hydroxy-5-methylphenyl) methanone (186 g) in acetonitrile (400 m
l) After adding DBU (230 ml) to the suspension, a solution of ethylsuccinic acid chloride (157 g) in acetonitrile (250 ml) was added dropwise over 1 hour while heating at 40 ° C., and the mixture was stirred for 30 minutes. Water (450 ml) was added to the reaction solution, and the mixture was stirred under ice cooling for 30 minutes. The generated crystals were collected by filtration and washed with ethanol. The obtained crude crystals of ethyl [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetate (182 g) were concentrated in acetic acid (1600 ml) and concentrated. Hydrochloric acid (600 ml)
And was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with water, dried (phosphorus pentoxide), recrystallized from ethyl acetate and purified to give the title compound (166 g,
Yield 71%) was obtained. Melting point: 270 ° C (decomp.). (c) 2- [4- (3-Bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) Synthesis of phenyl] acetamide

[Chemical 12] [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2
Dimethylformamide (5 drops) and oxalyl chloride (11 ml) were added to a solution of H-chromen-3-yl] acetic acid (42 g) in THF (400 ml), and the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with THF (400 m
l), 4-fluoro-2- (trifluoromethyl) aniline (14.7 ml) and sodium hydride (100 mg)
Was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over magnesium sulfate and concentrated. The residue obtained is ethyl acetate
-Recrystallized from THF to purify the title compound (60 g, yield 77
%) Was obtained. Melting point: 222-223 ° C. (D) (2E) -3- [5- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl ] -6-
Synthesis of ethyl methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoate

[Chemical 13] 2- [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo
-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (30 g) in DMF (300 m
l) solution in a nitrogen atmosphere under ethyl acrylate (5.8 m
l), triethylamine (7.9 ml), palladium acetate (I
I) (0.6 g) and triphenylphosphine (1.3 g) were added and heated at 100 ° C. for 5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane
-Ethyl acetate = 3: 1), and recrystallized from ethyl acetate to give the title compound as colorless crystals (16.7 g, yield).
55%). Melting point: 193-196 ° C.

Reference Example 2 (3-Bromophenyl) (4-chloro-2-hydroxyphenyl)
Synthesis of methanone

[Chemical 14] The title compound is Tetrahedro Letters.
n. Lett.), 42, 4841 (2001). Under ice cooling, 4-chloro-2-hydroxybenzoic acid (13.8 g), N, O-dimethylhydroxylamine hydrochloride (15.6 g), 1-hydroxybenzotriazole (24.5 g)
g), and N, N-dimethylformamide (20 ml) of triethylamine (22.3 ml) and dichloromethane (300 m
l) 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (30.7 g) was added little by little to the mixed suspension, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solvent was concentrated and distilled off under reduced pressure, water was poured into the residue, and the organic matter was extracted with ethyl acetate. After washing the extract with saturated saline,
It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 4-chloro-
2-hydroxy-N-methoxy-N-methylbenzamide (14.2
g, yield 82%) was obtained. Butylmagnesium chloride (2M tetrahydrofuran solution, 5 m
Butyllithium (1.6M hexane solution, 12.5 ml) was added dropwise to (l) and stirred for 30 minutes. To this, a solution of 1,3-dibromobenzene (5.90 g) in toluene (15 ml) was added dropwise. After the dropping was completed, the reaction solution was stirred for another 1.5 hours. The suspension was cooled under ice-cooling with 4-chloro-2-hydroxy-N-methoxy-N as described above.
-Methylbenzamide (1.73 g) was gradually added to a toluene (15 ml) solution, and the mixture was further stirred for 1 hour. 10% reaction solution
It was poured into an aqueous citric acid solution, and the organic matter was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1), and the obtained crystals were recrystallized from methanol to give the title compound (1.79 g, yield 71%). . Melting point: 105 ° C. NMR (CDCl ₃ ) δ: 6.89 (1H, dd, J = 8.4,2.2Hz), 7.11 (1
H, d, J = 2.2Hz), 7.40 (1H, t, J = 8.0Hz), 7.49 (1H, d, J = 8.
4Hz), 7.57 (1H, ddd, J = 8.0,1.4,1.0Hz), 7.74 (1H, ddd,
J = 8.0,1.8,1.0Hz), 7.79 (1H, dd, J = 1.8,1.4Hz), 12.00
(1H, s). IR (KBr): 3067, 1626, 1329, 1235, 1215 cm ^-1 . Elemental analysis: Calculated as C ₁₃ H ₈ BrClO ₂ (%): C: 50.12, H: 2.59, measured value (%): C: 50.07, H: 2.53.

Reference Examples 3 to 6 In the same manner as in Reference Example 1 (c), the compounds of [Table 1] (Reference Example 3: 2- [4- (3-bromophenyl) -7-chloro-6-methyl-2) were used. -Oxo-2H-chromen-3-yl] -N- [2- (trifluoromethyl)
Phenyl] acetamide, Reference Example 4: 2- [4- (3-Bromophenyl) -6-chloro-7-methyl-2-oxo-2H-chromene-3-
Ile] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide, Reference Example 5: 2- [4- (3-Bromophenyl)
-7-Chloro-6-fluoro-2-oxo-2H-chromen-3-yl]-
N- [4-Fluoro-2- (trifluoromethyl) phenyl] acetamide, Reference Example 6: 2- [4- (3-Bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2-
(Trifluoromethyl) phenyl] acetamide) was obtained.

[Table 1]

Reference Example 7 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-chloro-2- (tri Synthesis of (fluoromethyl) phenyl] acetamide (a) [7-chloro-4- (3-formylphenyl) -6-methyl-2-
Synthesis of [oxo-2H-chromen-3-yl] acetic acid

[Chemical 15] 2- (3-Bromophenyl) -1,3-dioxolane (26.0 g) T
Butyllithium (1.6M hexane solution, 85 ml) was added dropwise to the HF (200 ml) solution at -78 ° C under nitrogen atmosphere at -78 ° C.
After stirring at room temperature for 1 hour, 4-chloro-2-hydroxy-N-methoxy-N, 5-dimethylbenzamide (10.0 g) in THF (100 m
l) The solution was added dropwise and stirred at -78 ° C for 2 hours. In the reaction solution
2N hydrochloric acid (200 ml) was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, the obtained residue was dissolved in THF (100 ml), 2N hydrochloric acid (150 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the extract was washed with water,
The extract was dried over magnesium sulfate and concentrated. 3- (4-chloro-2-hydroxy-5-methylbenzoyl) benzaldehyde (10 g) obtained as an oil was added to acetonitrile (40 m
l) and DBU (15 ml) were added, and a solution of ethylsuccinic acid chloride (10.2 g) in acetonitrile (20 ml) was added dropwise over 1 hour while heating at 40 ° C., and the mixture was stirred for 30 minutes. Water (40 ml) was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and water, dried over magnesium sulfate, and concentrated. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane-
Purified with ethyl acetate = 3: 1). The obtained crude crystals of ethyl [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] acetate (2.8 g) were added to acetic acid (1
It was dissolved in 50 ml) and concentrated hydrochloric acid (75 ml) and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was washed with water,
After drying, it was recrystallized from ethyl acetate for purification to obtain the title compound (2.5 g, yield 15%). Melting point: 230-232 ° C. (B) 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-
Synthesis of oxo-2H-chromen-3-yl] -N- [4-chloro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 16] The title compound (yield 50%) was obtained in the same manner as in Reference Example 1 (c). _{Mp:. 232-233 ℃ NMR (CDCl 3} ) δ: 2.29 (3H, s), 3.37 (1H, d, J = 14.
0 Hz), 3.51 (1H, d, 14.0 Hz), 6.79 (1H, s), 7.47
(2H, m), 7.58 (1H, s), 7.66 (1H, d, J = 7.4 Hz),
7.78 (1H, t, J = 7.4 Hz), 7.87 (1H, s), 8.07 (2H,
m), 8.28 (1H, brs), 10.11 (1H, s). Elemental analysis: Calculated as C ₂₆ H ₁₆ Cl ₂ F ₃ NO ₄ (%): C: 58.45, H: 3.02, N: 2.62, actual measurement Value (%): C: 58.41, H: 3.03, N: 2.39.

Reference Example 8 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2- (tri Synthesis of (fluoromethyl) phenyl] acetamide

[Chemical 17] The title compound was obtained in the same manner as in Reference Example 7 (yield 68%). _{Mp:. 214-215 ℃ NMR (CDCl 3} ) δ: 2.29 (3H, s), 3.36 (1H, d, J = 14.
0 Hz), 3.50 (1H, d, J = 14.0 Hz), 6,80 (1H, s), 7.3
1 (2H, m), 7.48 (1H, s), 7.68 (1H, m), 7.77 (1H, t,
J = 7.7 Hz), 7.87 (1H, s), 7.98 (1H, m), 8.09 (1
H, d, J = 7.6 Hz), 8.19 (1H, brs), 10.11 (1H, s). Elemental analysis: C ₂₆ H ₁₆ ClF ₄ NO ₄・ 0.3 H ₂ O Calculated as (%): C: 59.68, H: 3.20, N: 2.68, Measured value (%): C: 59.45, H: 3.01, N: 2.63.

Example 1 3- [7-chloro-3- [2-[[4-chloro-2- (trifluoromethyl))
Phenyl] amino] -2-oxoethyl] -6-methyl-2-oxo
Synthesis of -2H-chromen-4-yl] benzoic acid

[Chemical 18] 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-chloro-2- (trifluoromethyl) phenyl] acetamide To a mixed suspension of (2.0 g) t-butyl alcohol (30 ml), THF (10 ml) and water (8 ml), sodium dihydrogen phosphate (450 mg), 2-methyl-2-butene ( 1.8 ml) was added and the mixture was stirred at room temperature. After gradually adding sodium chlorite (1.2 g) to the reaction solution,
The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was recrystallized from acetic acid to give the title compound (2.0 g, yield 92%). Melting point: 270-272 ° C. NMR (CDCl ₃ ) δ: 2.28 (3H, s), 3.34 (1H, d, J = 14.
8 Hz), 3.57 (1H, d, J = 14.8 Hz), 6.82 (1H, s), 7.4
-7.7 (5H, m), 7.99 (2H, m), 8.23 (1H, d, J = 7.8
Hz), 8.38 (1H, brs). Elemental analysis: Calculated as C ₂₆ H ₁₆ Cl ₂ F ₃ NO ₅ (%): C: 56.75, H: 2.93, N: 2.55, Found (%): C: 56.46, H: 3.02, N: 2.58.

Example 2 3- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6-methyl-2-oxo-2H -Chromen-4-yl] benzoic acid synthesis

[Chemical 19] The title compound was obtained in the same manner as in Example 1 (yield 86%). _{Mp:. 278-280 ℃ NMR (CDCl 3} ) δ: 2.28 (3H, s), 3.35 (1H, d, J = 16.
0 Hz), 3.59 (1H, d, J = 16.0 Hz), 6.82 (1H, s), 7.2
9 (2H, m), 7.45 (1H, d, J = 9.2 Hz), 7.55 (2H, m),
7.75 (1H, m), 7.98 (1H, s), 8.22 (1H, d, J = 7.6
Hz), 8.77 (1H, brs). Elemental analysis: Calculated as C ₂₆ H ₁₆ ClF ₄ NO ₅ (%): C: 58.49, H: 3.02, N: 2.62, Found (%): C: 58.41, H: 3.25, N: 2.43.

Example 3 (2E) -3- [5- [7-chloro-3- [2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6- Methyl
-2-oxo-2H-chromen-4-yl] -2-fluorophenyl]-
Synthesis of ethyl 2-propenoate

[Chemical 20] The title compound (yield 28%) was obtained in the same manner as in Reference Example 1- (d). Melting point: 160-162 ° C. NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.0Hz), 2.31 (3H,
s), 3.45 (2H, s), 4.27 (2H, q, J = 7.0 Hz), 6.60
(1H, d, J = 16.4 Hz), 6.86 (1H, s), 7.3-7.4 (2H,
m), 7.5-7.6 (4H, m), 7.74 (1H, d, J = 16.4 Hz),
8.07 (1H, d, J = 8.8 Hz), 8.30 (1H, brs). Elemental analysis: Calculated as C ₃₀ H ₂₁ Cl ₂ F ₄ NO ₅ (%): C: 57.89, H: 3.40, N: 2.25 , Actual value (%): C: 57.95, H: 3.61, N: 2.10.

Examples 4 to 7 In the same manner as in Example 1, the compounds of [Table 2] (Example 4: (2
E) -3- [3- [7-Chloro-6-methyl-3- [2-[[2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2
Ethyl H-chromen-4-yl] phenyl] -2-propenoate, Example 5: (2E) -3- [3- [6-chloro-3- [2-[[4-fluoro-2-
(Trifluoromethyl) phenyl] amino] -2-oxoethyl] -7-methyl-2-oxo-2H-chromen-4-yl] phenyl]
-2-Ethyl propenoate, Example 6: (2E) -3- [3- [7-chloro
-6-Fluoro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl] phenyl] -2- Ethyl propenoate, Example 7: (2E) -3- [3- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl]- 2-
Oxo-2H-chromen-4-yl] phenyl] -2-ethyl propenoate) was obtained.

[Table 2]

Example 8 3- [5- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6-methyl-2-
Synthesis of ethyl oxo-2H-chromen-4-yl] phenyl] propionate

[Chemical 21] 3- [5- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6-methyl-2-
Oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid ethyl (1.0 g) in THF (50 ml) and ethanol (50 m
Raney nickel (about 1 g) was added to the mixed solution of l), and the mixture was stirred under a hydrogen atmosphere for 1 day. After completion of the reaction, the catalyst was removed by filtration through Celite and the filtrate was concentrated. The obtained residue was recrystallized from ethyl acetate to give the title compound (0.7 g, yield 69%). Melting point: 121-123 ° C. NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.0 Hz), 2.30 (3
H, s), 2.67 (2H, t, J = 7.5 Hz), 3.03 (2H, t, J =
7.5 Hz), 3.45 (2H, s), 4.11 (2H, q, J = 7.0 Hz),
6.91 (1H, s), 7.2-7.5 (7H, m), 7.99 (1H, m), 8.1
8 (1H, brs). Elemental analysis: Calculated as C ₃₀ H ₂₄ ClF ₄ NO ₅ (%): C: 61.08, H: 4.10, N: 2.37, Found (%): C: 61.03, H: 4.16 , N: 2.41.

Examples 9 to 12 In the same manner as in Example 8, the compounds shown in Table 3 (Example 9: 3-
[3- [7-Chloro-6-methyl-3- [2-[[2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl] phenyl] Ethyl propionate, Example 10: 3- [3- [6-Chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -7-methyl- Ethyl 2-oxo-2H-chromen-4-yl] phenyl] propionate, Example 11: 3- [3- [7-chloro-6-fluoro-3-
[2-[[4-Fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl]
Ethyl phenyl] propionate, Example 12: 3- [3- [7-
Ethyl chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl] phenyl] propionate) was obtained. It was

[Table 3]

Example 13 3- [3- [3- [2-[[4-Fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromene
Of ethyl-4-yl] phenyl] propionate

[Chemical formula 22] (2E) -3- [3- [7-Chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromene- To a mixed solution of ethyl 4-yl] phenyl] propenoate (2.54 g) in ethanol (50 ml) and N, N-dimethylformamide (20 ml) was added 10% palladium-carbon (50% water-containing product, 0.30 g), and the mixture was added. Was stirred at room temperature under a hydrogen atmosphere for 4 hours. After filtering the reaction solution to remove the catalyst, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate: chloroform = 4: 1: 2 to hexane: ethyl acetate = 3: Purification in 1) gave the title compound (1.29 g, 54% yield). _{Mp:. 163-164 ℃ NMR (CDCl 3} ) δ: 1.21 (3H, t, J = 7.2 Hz), 2.62-2.7
2 (2H, m), 3.03 (2H, t, J = 7.5 Hz), 3.46 (1H, d,
J = 14.4 Hz), 3.52 (1H, d, J = 14.4 Hz), 4.11 (2H,
q, J = 7.2 Hz), 7.10 (1H, dd, J = 7.8, 1.5 Hz),
7.18-7.28 (4H, m), 7.32 (1H, dd, J = 8.4, 3.0 Hz),
7.35-7.38 (1H, m), 7.42-7.50 (2H, m), 7.52-7.58 (1
H, m), 8.01 (1H, dd, J = 9.0, 5.1 Hz), 8.28 (1H,
s). IR (KBr): 3256, 1723, 1713, 1665, 1526, 1431, 13
21, 1123 cm ^-1 . Elemental analysis: Calculated as C ₂₉ H ₂₃ F ₄ NO ₅ (%): C: 64.32, H: 4.28, N: 2.59, Measured value (%): C: 64.32, H: 4.16 , N: 2.30.

Example 14 3- [5- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6-methyl-2-
Synthesis of oxo-2H-chromen-4-yl] phenyl] propionic acid

[Chemical formula 23] 3- [5- [3- [2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -6-methyl-2-oxo-2H-chromen-4-yl] Phenyl] ethyl propionate (580 m
To a mixed solution of g) in THF (10 ml) and ethanol (5 ml) was added 1N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. The obtained residue was recrystallized from ethyl acetate to give the title compound (500 mg, yield 91%). Melting point: 212-214 ° C. NMR (CDCl ₃ ) δ: 2.29 (3H, s), 2.68 (2H, t, J = 7.2)
Hz), 3.01 (2H, t, J = 7.2 Hz), 3.37 (1H, d, J = 1
3.5 Hz), 3.54 (1H, d, J = 13.5 Hz), 6.89 (1H, s),
7.1-7.5 (7H, m), 7.90 (1H, m), 8.46 (1H, brs). Elemental analysis: Calculated as C ₂₈ H ₂₀ ClF ₄ NO ₅ (%): C: 59.85, H: 3.59, N : 2.49, measured value (%): C: 59.88, H: 3.88, N: 2.52.

Examples 15 to 24 In the same manner as in Example 14, the compounds of [Table 4] (Example 1)
5: (2E) -3- [3- [7-chloro-6-methyl-2-oxo-3- (2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl) -2H -Chromen-4-yl] phenyl] -2-propenoic acid,
Example 16: (2E) -3- [3- [6-chloro-3- (2-[[4-fluoro-
2- (Trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid, Example 17: (2E) -3 -[3- [7-Chloro-
6-Fluoro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl] phenyl] -2-propene Acid, Example 18:
(2E) -3- [3- [7-Chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromene- 4-yl] phenyl] -2-propenoic acid, Example 19: (2E) -3- [5- [7-chloro-3- [2-[[4-chloro-2- (trifluoromethyl) phenyl]] Amino] -2-oxoethyl]-
6-Methyl-2-oxo-2H-chromen-4-yl] -2-fluorophenyl] -2-propenoic acid, Example 20: 3- [3- [7-chloro-6
-Methyl-2-oxo-3- (2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl) -2H-chromen-4-yl] phenyl] propionic acid, Example 21: 3 -[3- [6-chloro-3-
(2-[[4-Fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl] propionic acid, Example 22 : 3- [3-
[7-Chloro-6-fluoro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2H-chromen-4-yl] phenyl ] Propionic acid, Example 23: 3- [3- [7-chloro-3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo- 2H-chromen-4-yl] phenyl] propionic acid, Example 24: 3- [3- [3- [2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] -2-oxo-2
H-chromen-4-yl] phenyl] propionic acid) was obtained.

[Table 4]

Examples 25 to 40 In the same manner as in Example 3, compounds shown in [Table 5] to [Table 6] were obtained.

[Table 5]

[Table 6]

Example 41 2- (7-Chloro-6-methyl-2-oxo-4- {3-[(E) -2- (1H-tetrazol-5-yl) ethenyl] phenyl} -2H-chromene -3-
Yl) -N- [4-Fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical formula 24] 2- (7-chloro-4- {3-[(E) -2-cyanoethenyl] phenyl} -6
-Methyl-2-oxo-2H-chromen-3-yl) -N- [4-fluoro
-2- (Trifluoromethyl) phenyl] acetamide (1.24
g) and triethylamine hydrochloride (0.95 g) were suspended in toluene (10 ml) and sodium azide (0.4
49 g) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction solution, which was acidified with 1N hydrochloric acid, and then extracted with a mixed solvent of ethyl acetate-methanol. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform-1% chloroform / methanol-2% -5%), and the obtained crystals were recrystallized from 2-propanol to give the title compound (0.832
g, yield 62%) was obtained as colorless crystals. Melting point: 216-218 ° C. NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.36 (2H, br s),
6.95 (1H, s), 7.35-7.76 (9H, m), 7.96 (1H, d, J =
8.0 Hz), 9.67 (1H, s), hidden (1H). IR (KBr): 3119, 3044, 1688, 1321. Elemental analysis: Calculated as C ₂₈ H ₁₈ N ₅ O ₃ ClF ₄ (%): C , 57.59; H, 3.11; N, 11.99.Actual value (%): C, 57.33; H, 3.18; N, 11.92.

Examples 42-44 [Table 7] Compound was obtained in the same manner as in Example 41.

[Table 7]

Reference Example 9 2- [4- (4-bromophenyl) -7-chloro-6-methyl-2-oxo
-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (a) (4-bromophenyl) (4-chloro-2-hydroxy-5-methylphenyl) Methanone

[Chemical 25] The title compound was obtained in the same manner as in Reference Example 1 (a) (yield: 90
%). Melting point: 129-130 ° C (methanol). NMR (CDCl ₃ ) δ: 2.88 (3H, s), 7.12 (1H, s), 7.37
(1H, s), 7.54 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J =
8.4 Hz), 11.76 (1H, s). IR (KBr): 3088, 1630, 1586, 1333, 1003. Elemental analysis: Calculated as C ₁₄ H ₁₀ O ₂ BrCl (%): C, 51.65; H, 3.10 Actual value (%): C, 51.99; H, 2.95. (B) [4- (4-Bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromen-3-yl] acetic acid

[Chemical formula 26] The title compound was obtained in the same manner as in Reference Example 1 (b) (yield: 85
%). Mp:. 238-239 ℃ (2- _{propanol) NMR (CDCl 3) δ:} 2.29 (3H, s), 3.40 (2H, s), 6.83
(1H, s), 7.16 (2H, d, J = 8.4 Hz), 7.42 (1H, s), 7.
72 (2H, d, J = 8.4 Hz), hidden (1H). IR (KBr): 3011, 2959, 2930, 1721. Elemental analysis: Calculated as C ₁₈ H ₁₂ O ₄ BrCl (%): C, 53.03 H, 2.97. Found (%): C, 53.23; H, 2.91. (C) 2- [4- (4-bromophenyl) -7-chloro-6-methyl-2-oxo-2H-chromene- 3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 27] The title compound was obtained in the same manner as in Reference Example 1 (b) (yield: 88.
%). Melting point: 262-264 ° C (ethyl acetate-THF). NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.40 (2H, s), 6.83
(1H, s), 7.16 (2H, d, J = 8.4 Hz), 7.42 (1H, s), 7.
72 (2H, d, J = 8.4 Hz), hidden (1H). IR (KBr): 3241, 1717, 1659, 1535, 1186, 1127. Elemental analysis: Calculated as C ₂₅ H ₁₅ NO ₃ BrClF ₄ (% ): C, 52.80; H, 2.66; N, 2.46. Actual value (%): C, 52.54; H, 2.62; N, 2.67.

Example 45 4- (7-chloro-3- {2- [4-fluoro-2- (trifluoromethyl) anilino] -2-oxoethyl} -6-methyl-2-oxo-2H-
Chromen-4-yl) methyl benzoate

[Chemical 28] 2- [4- (4-bromophenyl) -7-chloro-6-methyl-2-oxo
-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (1.17 g) in methanol
(10 ml) and DMF (20 ml) solution with palladium acetate.
(89.8 mg), 1,3-bis (diphenylphosphino) propane
(206 mg) and triethylamine (1 ml),
The mixture was stirred at 80 ° C. for 2 days in a carbon monoxide atmosphere (atmospheric pressure).
The reaction solvent was concentrated and evaporated under reduced pressure, water was added, and the organic matter was extracted with a chloroform-methanol mixed solvent. The extract was washed with saturated saline and dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform = 5: 1: 3-4: 1: 1) to give the title compound (0.559 g, yield 49%). It was Melting point: 202-204 ° C (hexane-ethyl acetate). NMR (CDCl ₃ ) δ: 2.28 (3H, s), 3.43 (2H, s), 3.98.
(3H, s), 6.81 (1H, s), 7.21-7.27 (1H, m), 7.32 (1H,
dd, J = 8.4, 3.0 Hz), 7.43-7.46 (3H, m), 7.97 (1
H, dd, J = 9.0, 4.8 Hz), 8.17 (1H, s), 8.24 (2H,
IR (KBr): 3258, 1719. Elemental analysis: Calculated as C ₂₇ H ₁₈ NO ₅ ClF ₄ (%): C, 59.19; H, 3.31; N, 2.56. %): C, 59.09; H, 3.40; N, 2.60.

Examples 46 to 48 The compound of [Table 8] was obtained in the same manner as in Example 45.

[Table 8]

Example 49 {3- [7-Chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo- 2H-chromen-4-yl] phenyl} methyl acetate

[Chemical 29] 3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl ] Benzoic acid (2.0 g) in THF (1
Oxalyl chloride (0.4 ml) was added to a mixed solution of 00 ml) and DMF (3 drops), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in THF (50 ml),
Diazomethane diethyl ether solution prepared from N-methyl-N'-nitroso-N-nitroguanidine (3.0 g) (50 m
l). After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue is methanol (100 ml)
The solution was dissolved in, and silver oxide (1.2 g) was added, and the mixture was heated under reflux for 2 hours. The insoluble matter was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 3: 1) to obtain the title compound (1 g). The obtained crude crystal was used in the next step without further purification. NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.42 (1H, d, J = 10
Hz), 3.47 (1H, d, J = 10 Hz), 3.70 (3H, s), 3.72 (3
H, s), 6.94 (1H, s), 7.25-7.33 (4H, m), 7.43-7.52
(4H, m), 7.97 (1H, m), 8.16 (1H, brs).

Example 50 {3- [7-Chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo- Methyl 2H-chromen-4-yl] phenyl} butanoate

[Chemical 30] The title compound was obtained in the same manner as in Example 49. NMR (CDCl ₃ ) δ: 2.00 (2H, m), 2.30 (3H, s), 2.36
(2H, t, J = 7.6 Hz), 2.74 (2H, t, J = 7.7 Hz), 3.4
6 (2H, s), 3.64 (3H, s), 6.92 (1H, s), 7.15-7.37
(5H, m), 7.48 (2H, m), 8.00 (1H, m), 8.19 (1H, br
s).

Reference Example 10 2- (7-chloro-6-methyl-2-oxo-4- {3-[(E) -3-oxo-1
-Propenyl] phenyl} -2H-chromen-3-yl) -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 31] 2- [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo
-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (11.4 g) in DMF (60 m
l) Add the acrolein diethyl acetal (3.12
g), palladium acetate (0.225 g), tris (2-methylphenyl) phosphine (0.609 g) and sodium acetate (1.
97 g) was added, and the mixture was stirred at 120 ° C. for 4 hours under a nitrogen atmosphere. The reaction solvent was evaporated under reduced pressure, ethyl acetate and water were added, and the insoluble material was removed by Celite filtration. The organic layer of the filtrate was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate / chloroform = 5: 1: 3 to 4: 1: 2) to obtain a single yellow crystal. The obtained crystals were dissolved in THF (100 ml), 1N hydrochloric acid (20 ml) was added, and the mixture was stirred at room temperature for 20 min. After the reaction solvent was distilled off under reduced pressure, water was added and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform =
4: 1: 3 to 3: 1: 2 to 2: 1: 2) and the title compound (2.79
g, yield 25%) was obtained as colorless crystals. Melting point: 232-235 ° C (ethyl acetate). NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.42 (1H, d, J = 13.
8 Hz), 3.47 (1H, d, J = 13.8 Hz), 6.78 (1H, dd, J =
15.9, 7.5 Hz), 6.85 (1H, s), 7.21-7.27 (1H, m),
7.31 (1H, dd, J = 8.7, 3.0 Hz), 7.42 (1H, d, J =
7.8 Hz), 7.46 (1H, s), 7.53 (1H, d, J = 15.9 Hz),
7.58 (1H, s), 7.64 (1H, t, J = 7.8 Hz), 7.76 (1H,
d, J = 7.8 Hz), 7.95 (1H, dd, J = 8.7, 4.8 Hz), 8.
23 (1H, s), 9.72 (1H, d, J = 7.5 Hz). IR (KBr): 3231, 1719, 1680, 1657, 1134. Elemental analysis: Calculated as C ₂₈ H ₁₈ NO ₄ ClF ₄ (% ): C, 61.83; H, 3.34; N, 2.58. Actual value (%): C, 61.81; H, 3.35; N, 2.50.

Example 51 (2E, 4E) -5- [3- (7-chloro-3- {2- [4-fluoro-2- (trifluoromethyl) anilino] -2-oxoethyl} -6-methyl -2-
Oxo-2H-chromen-4-yl) phenyl] -2,4-pentadienoic acid ethyl ester

[Chemical 32] Triethyl phosphonoacetate (0.927 g) in THF (15
ml) solution in sodium hydride (60%, oily) (0.132 g)
Was added little by little, and the mixture was stirred under a nitrogen atmosphere for 20 minutes. 2- (7-chloro-6-methyl-2-oxo-4- {3-[(E) -3-oxo-1-propenyl] phenyl} -2H-chromen-3-yl) -N- was added to the reaction solution. [Four
-Fluoro-2- (trifluoromethyl) phenyl] acetamide (1.50 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hr. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate-THF. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform = 4: 1: 3) to give the title compound (1.59 g, yield 95%) as colorless crystals. Melting point: 216-218 ° C (ethyl acetate). NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.30 (3
H, s), 3.46 (2H, s), 4.23 (2H, q, J = 7.2 Hz), 5.9
8 (1H, d, J = 15.4 Hz), 6.90-6.95 (3H, m), 7.19-7.
66 (8H, m), 7.99 (1H, dd, J = 9.2, 5.0 Hz), 8.17
(1H, s) .IR (KBr): 3258, 2984, 1717, 1663, 1532, 1433, 131
9, 1175, 1132. Elemental analysis: Calculated as C ₃₂ H ₂₄ NO ₅ ClF ₄ (%): C, 62.60; H, 3.94; N, 2.28. Measured value (%): C, 62.71; H, 3.90; N, 2.26.

Example 52 (2E) -3- {3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6- Methyl-2-oxo-2H-chromen-4-yl] phenyl} -2-methylethyl acrylate

[Chemical 33] The title compound was obtained in the same manner as in Example 51. Melting point: 172-174 ° C (hexane-ethyl acetate). NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2 Hz), 2.11 (3
H, d, J = 1.5 Hz), 2.29 (3H, s), 3.42 (1H, d, J = 1
3.8 Hz), 3.52 (1H, d, J = 13.8 Hz), 4.27 (2H, q, J
= 7.2 Hz), 6.87 (1H, s), 7.19-7.26 (1H, m), 7.29-
7.32 (3H, m), 7.45 (1H, s), 7.55-7.62 (2H, m), 7.7
0 (1H, d, J = 1.5 Hz), 7.97 (1H, dd, J = 9.0, 5.2 H
z), 8.13 (1H, s).

Examples 53 to 61 The compound of [Table 9] was obtained in the same manner as in Example 13.

[Table 9]

Example 62 ({3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-
Oxo-2H-chromen-4-yl] benzyl} amino) ethyl acetate

[Chemical 34] 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (1.04 g) in dichloromethane (30 ml), glycine ethyl ester hydrochloride (0.307 g), molecular sieves (4A, beaded)
And triethylamine (0.307 ml) were added, and the mixture was allowed to stand at room temperature for 24 hours.
Stir vigorously for hours. The reaction solution was filtered through Celite, the filtrate was concentrated, water was added to the residue, and the mixture was extracted with an ethyl acetate-THF mixed solvent. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Suspend the obtained residue in a mixed solvent of ethanol (10 ml) and THF (30 ml), add 10% palladium-carbon (50% water-containing product), and under a hydrogen atmosphere (atmospheric pressure) at room temperature for 20 minutes. It was stirred.
After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with a mixed solvent of ethyl acetate-THF. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate-
Chloroform = 2: 1: 2 to 2: 2: 1 to ethyl acetate only) and purified by reverse phase HPLC (mobile phase: water-acetonitrile, containing 0.1% TFA) to give the title compound (0.49 g, yield 41%). ) Was obtained as colorless crystals. Melting point: 153-155 ° C (hexane-ethyl acetate). NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 2.29 (3
H, s), 3.44 (4H, s), 3.90 (2H, s), 4.17 (2H, q, J
= 7.2 Hz), 6.91 (1H, s), 7.19-7.32 (4H, m), 7.44
(1H, s), 7.48-7.54 (2H, m), 7.99 (1H, dd, J = 9.0,
4.8 Hz), 8.24 (1H, s), hidden (1H). IR (KBr): 3252, 1717, 1663, 1528, 1433, 1319, 117
3, 1128. Elemental analysis: Calculated as C ₃₀ H ₂₅ N ₂ O ₅ ClF ₄ (%): C, 59.56; H, 4.17; N, 4.63. Measured value (%): C, 59.37; H, 4.16; N, 4.61.

Example 63 ({3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-
Oxo-2H-chromen-4-yl] benzyl} thio) ethyl acetate

[Chemical 35] Under ice cooling, 2- [7-chloro-4- (3-formylphenyl) -6-methyl-2-oxo-2H-chromen-3-yl] -N- [4-fluoro-2-
(Trifluoromethyl) phenyl] acetamide (3.96 g)
1,2-dimethoxyethane (35 ml) and THF (35 ml)
Sodium borohydride (0.145 g) was added to the solution little by little, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. The reaction mixture was treated with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate / chloroform = 2: 1: 2 to 1: 1: 1) to give colorless crystals.
(3.61 g) was obtained. The obtained crystals (1.56 g) were mixed with thionyl chloride (5 ml), and the mixture was stirred at room temperature for 2 hours. Pyridine (5 drops) was added to the reaction solution, and the mixture was further stirred for 30 minutes. After completion of the reaction, excess thionyl chloride was concentrated and distilled off. The obtained residue was dissolved in DMF (10 ml), ethyl thioglycolate (0.658 ml) and cesium fluoride (0.775 g) were added, and the mixture was heated with stirring at 80 ° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform = 5: 1: 3 to 4: 1: 2) to give the title compound (1.6
4 g, yield 80%) was obtained as a single yellow crystal. Melting point: 106-108 ° C (hexane-ethyl acetate). NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2 Hz), 2.29 (3
H, s), 3.09 (1H, d, J = 14.7 Hz), 3.15 (1H, d, J =
14.7 Hz), 3.43 (1H, d, J = 14.1 Hz), 3.51 (1H, d,
J = 14.1 Hz), 3.90 (2H, s), 4.13 (2H, q, J = 7.2 H
z), 6.91 (1H, s), 7.19-7.32 (4H, m), 7.44 (1H, s),
7.51-7.53 (2H, m), 7.97 (1H, dd, J = 8.7, 5.1 Hz),
8.20 (1H, s). IR (KBr): 3265, 3029, 1721, 1607, 1522, 1433, 132
1, 1171, 1134. Elemental analysis: Calculated as C ₃₀ H ₂₄ NO ₅ ClF ₄ S (%): C, 57.93; H, 3.89; N, 2.25. Measured value (%): C, 57.92; H, 3.97 ; N, 2.23.

Example 64 ({3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-
Oxo-2H-chromen-4-yl] benzyl} sulfonyl) ethyl acetate

[Chemical 36] Under ice cooling, ({3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H Meta-chloroperbenzoic acid (0.705 g) was added little by little to a dichloromethane (35 ml) solution of -chromen-4-yl] benzyl} thio) ethyl acetate (0.732 g), and the mixture was warmed to room temperature and stirred for 18 hours. The reaction solution was treated with an aqueous sodium thiosulfate solution and then extracted with a mixed solvent of ethyl acetate-THF. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.66 g, yield 86%) as single yellow crystals. Mp: 230-231 ° C. (ethyl _{acetate) NMR (CDCl 3) δ:} . 1.29 (3H, t, J = 7.2 Hz), 2.29 (3
H, s), 3.42 (1H, d, J = 13.5 Hz), 3.51 (1H, d, J =
13.5 Hz), 3.82 (1H, d, J = 15.0 Hz), 4.06 (1H, d,
J = 15.0 Hz), 4.16-4.28 (2H, m), 4.51 (1H, d, J =
14.1 Hz), 4.73 (1H, d, J = 14.1 Hz), 6.89 (1H, s),
7.18-7.24 (1H, m), 7.31 (1H, dd, J = 8.4, 3.0 Hz),
7.41 (1H, dt, J = 7.5, 1.5 Hz), 7.45 (1H, s), 7.
48 (1H, t, J = 1.5 Hz), 7.63 (1H, t, J = 7.5 Hz),
7.68 (1H, dt, J = 7.5, 1.5 Hz), 7.89 (1H, dd, J
= 9.0, 4.8 Hz), 8.31 (1H, s) IR (KBr): 3264, 1732, 1663, 1532, 1433, 1319, 117
7, 1127. Elemental analysis: Calculated as C ₃₀ H ₂₄ NO ₇ ClF ₄ S ・ 0.5H ₂ O (%): C, 54.34; H, 3.80; N, 2.11. Measured value (%): C, 54.54; H, 3.75; N, 2.11.

Examples 65 to 97 In the same manner as in Example 14, compounds shown in [Table 10] to [Table 12] were obtained.

[Table 10]

[Table 11]

[Table 12]

Example 98

[Chemical 37] The title compound was obtained in the same manner as in Example 41. Melting point: 244-246 ° C (ethyl acetate). NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.05 (1H, d, J = 13.
5 Hz), 3.10-3.30 (3H, m), 3.42-3.52 (1H, m), 3.95
(1H, d, J = 13.5 Hz), 6.84 (1H, s), 6.93-7.01 (2H,
m), 7.11 (1H, s), 7.23-7.31 (2H, m), 7.38 (1H, d
d, J = 8.7, 3.0 Hz), 7.51 (1H, s), 7.72 (1H, dd, J
= 8.7, 4.8 Hz), 9.20 (1H, s). Elemental analysis: Calculated as C ₂₈ H ₂₀ N ₅ O ₃ ClF ₄ (%): C, 57.40; H, 3.44; N, 11.95. Measured value (% ): C, 57.18; H, 3.48; N, 11.74.

Reference Example 11 2- (4- {3- [amino (hydroxyimino) methyl] phenyl}-
7-Chloro-6-methyl-2-oxo-2H-chromen-3-yl] -N-
[4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 38] 2- [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo
-2H-chromen-3-yl] -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (11.4 g) in DMF (50 m
l) Tetrakis (triphenylphosphine) palladium (0) (1.16 g) and zinc cyanide (2.47 g) were added to the solution, and the mixture was stirred at 80 ° C. for 6 hours under a nitrogen atmosphere. 2 reaction solutions
It was treated with an 8% aqueous ammonia solution and extracted with a toluene-THF mixed solvent. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform = 3: 1: 3 to 3: 1: 2 to 2: 1:
Purification in 1) yielded colorless crystals (8.48 g). Hydroxylamine hydrochloride (3.47 g) was suspended in DMSO (20 ml), and triethylamine (6.97 ml) was added. The precipitated triethylamine hydrochloride was filtered off and washed with THF. THF in the filtrate was distilled off under reduced pressure, and the crystals obtained above (5.15 g)
Was added and the mixture was stirred at 75 ° C. for 7 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.08 g). Melting point: 220-222 ° C (decomp.) (Ethyl acetate). NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.17 (1H, d, J = 13.
5 Hz), 3.69 (1H, d, J = 13.5 Hz), 5.41 (2H, s), 7.0
3 (1H, s), 7.21-7.27 (1H, m), 7.31-7.37 (2H, m),
7.47 (1H, s), 7.58 (1H, t, J = 7.8 Hz), 7.66 (1H,
t, J = 1.8 Hz), 7.86-7.93 (2H, m), 8.79 (1H, s). IR (KBr): 3272, 3050, 1779, 1746.

Example 99 2- {7-chloro-6-methyl-2-oxo-4- [3- (5-oxo-4,5-
Dihydro-1,2,4-oxadiazol-3-yl) phenyl] -2
H-chromen-3-yl} -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical Formula 39] 2- (4- {3- [amino (hydroxyimino) methyl] phenyl}-
7-chloro-6-methyl-2-oxo-2H-chromen-3-yl) -N-
[4-Fluoro-2- (trifluoromethyl) phenyl] acetamide (0.822 g) was suspended in THF (10 ml), 1,1'-carbonyldiimidazole (0.365 g) and DBU (0.897 m)
l) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, the pH was adjusted to 2 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane
-Ethyl acetate-chloroform = 1: 2: 1 to ethyl acetate-chloroform = 1: 1), and the title compound (0.302 g,
Yield 35%) was obtained. Melting point: 285-287 ° C (2-propanol-ethyl acetate). NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.33-3.42 (2H, m),
6.91 (1H, s), 7.39 (1H, dd, J = 8.7, 5.4 Hz), 7.4
8-7.62 (3H, m), 7.71 (1H, s), 7.78-7.83 (2H, m), 8.
00 (1H, d, J = 7.8 Hz), 9.65 (1H, s), hidden (1H). IR (KBr): 3272, 3050, 1779, 1746. Elemental analysis: C ₂₇ H ₁₆ N ₃ O ₅ ClF ₄ Calculated as (%): C, 56.51; H, 2.81; N, 7.32. Measured value (%): C, 56.49; H, 2.95; N, 7.10.

Examples 100 to 101 The compound of [Table 13] was obtained in the same manner as in Example 99.

[Table 13]

Example 102 2- {7-chloro-6-methyl-2-oxo-4- [3- (5-thioxo-4,5
-Dihydro-1,2,4-oxadiazol-3-yl) phenyl]-
2H-chromen-3-yl} -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 40] 2- (4- {3- [amino (hydroxyimino) methyl] phenyl}-
7-chloro-6-methyl-2-oxo-2H-chromen-3-yl) -N-
[4-Fluoro-2- (trifluoromethyl) phenyl] acetamide (0.822 g) was suspended in THF (10 ml) to prepare 1,1'-thiocarbonyldiimidazole (0.365 g) and DBU (0.89).
7 ml) was added and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added and the pH was adjusted to 2 with 1N hydrochloric acid, then ethyl acetate-THF
It was extracted with a mixed solvent. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / chloroform = 1: 1) to obtain the title compound (0.463 g, yield 52%). Melting point: 178-180 ° C (hexane-ethyl acetate). NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.06 (1H, d, J = 13.
5 Hz), 3.89 (1H, d, J = 13.5 Hz), 7.11 (1H, s), 7.2
4-7.36 (2H, m), 7.50 (1H, s), 7.58 (1H, d, J = 7.8
Hz), 7.73-7.78 (2H, m), 7.97 (1H, dd, J = 9.0, 5.1
Hz), 8.09 (1H, t, J = 7.8 Hz), 9.18 (1H, s), hidd
en (1H). IR (KBr): 3248, 1705, 1493, 1433, 1321. Elemental analysis: Calculated as C ₂₇ H ₁₆ N ₃ O ₄ ClF ₄ S ・ 0.5H ₂ O (%): C, 54.14; H, 2.86; N, 7.02. Found (%): C, 54.35; H, 2.87; N, 6.68.

Example 103 2- {7-chloro-6-methyl-2-oxo-4- [3- (5-thioxo-4,5
-Dihydro-1,2,4-oxadiazol-3-yl) phenyl]-
2H-chromen-3-yl} -N- [2- (trifluoromethyl) phenyl] acetamide

[Chemical 41] The title compound (yield 33%) was obtained in the same manner as in Example 102. Melting point: 202 ° C. (decomp.) (THF-ethyl acetate). NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 3.38 (2H, br), 6.9
3 (1H, s), 7.38 (1H, d, J = 8.2 Hz), 7.45 (1H, d,
J = 7.6 Hz), 7.58-7.75 (4H, m), 7.81 (1H, d, J = 7.
6 Hz), 7.87 (1H, br d, J = 1.4 Hz), 8.10 (1H, d, J
= 8.0 Hz), 9.62 (1H, s).

Example 104 2- {7-chloro-6-methyl-2-oxo-4- [3- (5-oxo-4,5-
Dihydro-1,2,4-thiadiazol-3-yl) phenyl] -2H-
Chromen-3-yl} -N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide

[Chemical 42] 2- (4- {3- [amino (hydroxyimino) methyl] phenyl}-
7-chloro-6-methyl-2-oxo-2H-chromen-3-yl) -N-
[4-Fluoro-2- (trifluoromethyl) phenyl] acetamide (0.822 g) was suspended in THF (10 ml), 1,1'-thiocarbonyldiimidazole (0.365 g) was added, and the mixture was stirred at room temperature for 3 hours. It was stirred. After the reaction was completed, water was added and ethyl acetate-TH
It was extracted with an F mixed solvent. After washing the extract with saturated saline,
It was dried over magnesium sulfate and the solvent was distilled off under reduced pressure.
The obtained residue was suspended in THF (15 ml), boron trifluoride diethyl ether complex (0.76 ml) was added, and the mixture was stirred at room temperature for 12 hours.
Stir for hours. After completion of the reaction, water was added, acidified with 1N hydrochloric acid, and extracted with a mixed solvent of ethyl acetate-THF. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is chloroform-
Recrystallization from methanol gave the title compound (0.801 g, yield 68%). Melting point: 269-271 ° C (decomp.). NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.28-3.42 (2H, m),
6.91 (1H, s), 7.38 (1H, dd, J = 9.0, 5.1 Hz), 7.4
8-7.55 (2H, m), 7.60 (1H, dd, J = 9.0, 3.0 Hz), 7.
72 (1H, s), 7.76 (1H, t, J = 7.8 Hz), 7.92 (1H,
s), 8.12 (1H, t, J = 7.8 Hz), 9.64 (1H, s), hidden
(1H). IR (KBr): 3264, 1746, 1686, 1659, 1541, 1327, 110
9. Elemental analysis: Calculated as C ₂₇ H ₁₆ N ₃ O ₄ ClF ₄ S ・ 0.5H ₂ O (%): C, 54.14; H, 2.86; N, 7.02. Found (%): C, 53.85; H, 2.81; N, 6.91.

Example 105 2- {7-chloro-6-methyl-2-oxo-4- [3- {2- (5-oxo-4,
5-Dihydro-1,2,4-thiadiazol-3-yl) ethyl} phenyl] -2H-chromen-3-yl} -N- [2- (trifluoromethyl) phenyl] acetamide

[Chemical 43] The title compound (yield 23%) was obtained in the same manner as in Example 104. Melting point: 181 ° C (decomp.) (Hexane-ethyl acetate). NMR (DMSO-d ₆ ) δ: 2.29 (3H, s), 2.76-3.13 (5H, m),
3.90 (1H, d, J = 13.5Hz), 6.86 (1H, s), 7.04-7.09
(2H, m), 7.17 (1H, d, J = 7.8 Hz), 7.24-7.29 (1H,
m), 7.35 (1H, dd, J = 8.4, 3.0 Hz), 7.42 (1H, t,
J = 7.8 Hz), 7.49 (1H, s), 7.76 (1H, dd, J = 9.0,
5.1 Hz), 9.07 (1H, s), 10.96 (1H, s).

Reference Example 12 Ethyl [6-bromomethyl-4- (3-bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] acetate

[Chemical 44] [4- (3-bromophenyl) -7-chloro-6-methyl-2-oxo-2
H-chromen-3-yl] ethyl acetate (10 g) in t-butyl acetate (70 ml) suspension in NBS (4.9 g) and AIBN (190 m
g) was added and the mixture was stirred at 80 ° C. for 2 hours. Ethyl acetate was added to the reaction solution, which was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was washed with isopropyl ether to give crude crystals of the title compound (9.8 g: 83%).
The obtained crude crystal was used in the next step without further purification. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 3.66 (2
H, s), 4.16 (2H, q, J = 7.4 Hz), 4.49 (2H, m), 7.04
(1H, s), 7.27 (2H, m), 7.44 (2H, m), 7.72 (1H,
m).

Reference Example 13 [6-Bromomethyl-4- (3-bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] acetic acid

[Chemical formula 45] [6-Bromomethyl-4- (3-bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] ethyl acetate in acetic acid (150 m
l) and concentrated hydrochloric acid (75 ml) were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with water and dried to give crude crystals of the title compound (8.5 g: 92%). The obtained crude crystal was used in the next step without further purification. NMR (CDCl ₃ ) δ: 3.42 (2H, m), 4.61 (2H, m), 7.07
(1H, s), 7.27 (2H, m), 7.49 (2H, m), 7.71 (1H, m).

Reference Example 14 2- {4- (3-Bromophenyl) -7-chloro-2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-3-yl} -N- [4-fluoro-2- (trifluoromethyl) phenyl]
Acetamide

[Chemical formula 46] [6-Bromomethyl-4- (3-bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] acetic acid (5.5 g) in THF (100 m
Oxalyl chloride (1.2 ml) was added to a mixed solution of l) and DMF (3 drops), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in THF (100 ml). 2
-Amino-5-fluorobenzotrifluoride (1.6 ml) was added, and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with THF (1
(00 ml), phenylpiperazine (2.0 ml) was added, and the mixture was heated under reflux overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as crude crystals.
(3.2 g, yield 39%) was obtained. The obtained crude crystal was used in the next step without further purification. NMR (CDCl ₃ ) δ: 2.60 (4H, m), 3.09 (4H, m), 3.48
(2H, m), 3.60 (2H, s), 6.90 (4H, m), 7.2-7.5 (6H,
m), 7.65 (1H, m), 7.97 (1H, m), 8.14 (1H, brs).

Example 106 (2E) -3- (3- {7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2- Oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-
Chromen-4-yl} phenyl) butyl acrylate

[Chemical 47] 2- {4- (3-Bromophenyl) -7-chloro-2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-3-yl} -N- [4- Fluoro-2- (trifluoromethyl) phenyl]
To a solution of acetamide (13.3 g) in DMF (140 ml), palladium acetate (1.2 g) and triphenylphosphine (2.9
g), triethylamine (3.8 ml) and butyl acrylate (2.9 ml) were added, and the mixture was stirred at 100 ° C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent:
Purified with hexane-ethyl acetate = 3: 1) to give the title compound
(5.7 g, yield 40%) was obtained. NMR (CDCl ₃ ) δ: 0.94 (2H, t, J = 7.2 Hz), 1.41 (2
H, m), 1.66 (2H, m), 2.56 (4H, m), 3.01 (4H, m),
3.49 (2H, m), 3.58 (2H, m), 4.49 (2H, t, J = 7.2 H
z), 6.48 (1H, d, J = 15.9 Hz), 6.86 (3H, m), 7.2-
7.7 (11H, m), 7.97 (1H, m), 8.18 (1H, brs).

Example 107 (2E) -3- (3- {7-chloro-3- (2-{[4-chloro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2- Oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromen-4-yl} phenyl) butyl acrylate

[Chemical 48] The title compound (yield 37%) was obtained in the same manner as in Example 106. NMR (CDCl ₃ ) δ: 0.95 (2H, t, J = 6.8 Hz), 1.43 (2
H, m), 1.67 (2H, m), 2.55 (4H, m), 3.01 (4H, m),
3.49 (2H, m), 3.59 (2H, m), 4.19 (2H, t, J = 6.6 H
z), 6.50 (1H, d, J = 16.0 Hz), 7.00 (3H, m), 7.2-
7.7 (11H, m), 8.09 (1H, d, J = 8.8 Hz), 8.27 (1H, b
rs).

Example 108 Examples 108-109 The compound of [Table 14] was obtained in the same manner as in Example 45.

[Table 14]

Examples 110 to 113 The compound of [Table 15] was obtained in the same manner as in Example 14.

[Table 15]

Examples 114 to 115 The compound of [Table 16] was obtained in the same manner as in Example 13.

[Table 16]

Reference Example 15 Acetic acid [4- (3-bromophenyl) -7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2 -Oxo-2H-chromen-6-yl] methyl

[Chemical 49] [6-Bromomethyl-4- (3-bromophenyl) -7-chloro-2-oxo-2H-chromen-3-yl] acetic acid (5.0 g) in THF (100 m
Oxalyl chloride (1.8 ml) was added to a mixed solution of l) and DMF (3 drops), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in THF (100 ml). 2
-Amino-5-fluorobenzotrifluoride (2.2 ml) was added, and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was added to DMF (5
0 ml) and add sodium acetate (1.0 g),
The mixture was stirred at 0 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1: 4), and further crystallized from ethyl acetate to give the title compound (2.3
g) got. NMR (CDCl ₃ ) δ: 2.04 (3H, s), 3.42 (1H, d, J = 21
Hz), 3.54 (1H, d, J = 21 Hz), 5.08 (1H, d, J = 20 H
z), 5.16 (1H, d, J = 20 Hz), 7.07 (1H, s), 7.1-7.8
(7H, m), 7.9-8.1 (2H, m).

Example 116 (2E) -3- {3- [6-[(acetyloxy) methyl] -7-chloro-3-
(2-{[4-fluoro-2- (trifluoromethyl) phenyl]
Amino} -2-oxoethyl) -2-oxo-2H-chromen-4-yl] phenyl} ethyl acrylate

[Chemical 50] The title compound was obtained in the same manner as in Reference Example 1- (d). NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7 Hz), 1.98 (3H,
s), 3.4-3.5 (2H, m), 4.26 (2H, q, J = 7 Hz), 5.09
(2H, s), 6.50 (1H, d, J = 16 Hz), 7.06 (1H, s), 7.2
-7.7 (8H, m), 7.9-8.0 (1H, m), 8.11 (1H, brs).

Example 117 (2E) -3- {3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6- (Hydroxymethyl) -2-oxo-2H-chromen-4-yl] phenyl} acrylic acid

[Chemical 51] (2E) -3- {3- [6-[(acetyloxy) methyl] -7-chloro-3-
(2-{[4-fluoro-2- (trifluoromethyl) phenyl]
Amino} -2-oxoethyl) -2-oxo-2H-chromen-4-yl] phenyl} ethyl acrylate (600 mg) was added to methanol (18 ml) with ice-cooled DBU (0.21 ml) at room temperature. Stir for hours. 1N Hydrochloric acid was added to the reaction solution, and the resulting precipitates were collected and dissolved in a mixed solvent of ethyl acetate. The solution was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is THF
(7.5 ml), dissolved in methanol and 1N aqueous sodium hydroxide solution (2.5 ml), and stirred overnight. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: dichloromethane-methanol = 95: 5) and further purified by TH
Treatment with F-diisopropyl ether gave the title compound (85 m
g) was obtained as a white powder. NMR (CDCl ₃ ) δ: 3.44 (1H, d, J = 11 Hz), 3.50 (1H,
d, J = 11 Hz), 4.65 (2H, s), 6.48 (1H, d, J = 7 H
z), 7.2-7.7 (9H, m), 7.8-8.0 (1H, m), 8.42 (1H, br
s).

Example 118 (2E) -3- {3- [7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6- Methyl-2-oxo-2H-chromen-4-yl] phenyl} -N- (methylsulfonyl) acrylamide

[Chemical 52] (2E) -3- {3- [7-Chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo- Carbonyldiimidazole (116 mg) was added to 2H-chromen-4-yl] phenyl} acrylic acid (200 mg) in DMF (2 ml), and the mixture was stirred at room temperature for 1 hour. Methanesulfonamide (68 mg) and DBU (82 mg) were added to the reaction mixture.
In addition, the mixture was stirred at 100 ° C for 3 hours. 1N Hydrochloric acid was added to collect the resulting precipitate, which was washed with water and then dissolved in a mixed solvent of THF and ethyl acetate. The solution was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 2: 1), and recrystallized from THF-hexane to give the title compound (86
mg, yield 38%) was obtained as colorless crystals. NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.30 (3H, s), 3.33
(1H, d, J = 14 Hz), 3.58 (1H, d, J = 14 Hz), 6.56
(1H, d, J = 16 Hz), 6.91 (1H, s), 7.2-7.4 (3H, m),
7.42 (1H, s), 7.5-7.8 (5H, m), 7.80 (1H, d, J = 1
6 Hz), 8.44 (1H, brs).

Example 119 (2E) -N- (butylsulfonyl) -3- {3- [7-chloro-3- (2-{[4-
Fluoro-2- (trifluoromethyl) phenyl] amino}-
2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl} acrylamide

[Chemical 53] The title compound (yield 44%) was obtained in the same manner as in Example 118. NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7 Hz), 1.3-1.6 (2
H, m), 1.7-1.9 (2H, m), 2.30 (3H, s), 3.37 (1H, d,
J = 14 Hz), 3.4-3.5 (2H, m), 3.53 (1H, d, J = 14 H
z), 6.56 (1H, d, J = 16 Hz), 6.89 (1H, s), 7.2-7.9
(9H, m), 8.34 (1H, brs), 8.58 (1H, brs).

Example 120 3- [7-chloro-3- (2-{[4-chloro-2- (trifluoromethyl)
Phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] -N-ethylbenzamide

[Chemical 54] 3- [7-chloro-3- (2-{[4-chloro-2- (trifluoromethyl)
Phenyl] amino} -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] benzoic acid (150 mg) in THF (5 m
l) and DMF (1 drop) in a mixed solution of oxalyl chloride (35
μl) was added and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Dissolve the obtained residue in THF (10 ml),
% Ethylamine aqueous solution (1 ml) and THF (5 ml) were added dropwise. After stirring for 30 minutes at room temperature, add to the reaction solution.
1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (136 m
g: yield 86%) was obtained as colorless crystals. Melting point: 220-222
° C.

Examples 121 to 148 In the same manner as in Example 120, the compounds shown in [Table 17] to [Table 18] were obtained.

[Table 17]

[Table 18]

In the formulation examples and experimental examples described below, compounds A to E mean the following compounds. Compound A: 3- [3- [7-chloro-3- (2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-
Methyl-2-oxo-2H-chromen-4-yl] phenyl] propionic acid compound B: (2E) -3- [3- [7-chloro-6-methyl-2-oxo-3-
(2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl) -2H-chromen-4-yl] phenyl] -2-propenoic acid compound C: 3- [3- [7-chloro -6-Methyl-2-oxo-3- (2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl) -2H-chromen-4-yl] phenyl] propionic acid compound D :( 2E) -3- [3- [6-chloro-3- (2-[[4-fluoro-2-
(Trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl]
-2-Propenoic acid compound E: 3- [3- [6-chloro-3- (2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-
Methyl-2-oxo-2H-chromen-4-yl] phenyl] propionic acid

Formulation Example A lipid-rich plaque reducing agent or ACAT inhibitor containing the compound [I] or a salt thereof as an active ingredient in the present invention can be produced, for example, by the following formulation. In addition, in the following prescription, as components (additives) other than the active ingredient, those listed in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards or Pharmaceutical Additive Standards can be used. 1. Capsule (1) Compound A 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1/2) of (1), (2) and (3) and (4) After mixing, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound A 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2 / 3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 3. Injection (1) Compound A 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2) and (3) are dissolved in distilled water for injection to a total volume of 2 ml and made into ampoules. Encapsulate. All steps are performed aseptically. 4. Tablet A mixture consisting of 175 g of compound A, 175 g of D-mannitol, 118.65 g of corn starch and 105 g of croscarmellose sodium according to the composition below:
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex Co., Ltd.), the mixture is kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose is dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluidized dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). Sift through a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180 g of these granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound A 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg Total 180.0 mg (per tablet) 1. Capsule (1) Compound B 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1/2) of (1), (2) and (3) and (4) After mixing, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound B 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2 / 3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 3. Injectable (1) Compound B 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) were dissolved in distilled water for injection to a total volume of 2 ml and made into ampoules. Encapsulate. All steps are performed aseptically. 4. Tablet According to the composition below, a mixture consisting of 175 g of compound B, 175 g of D-mannitol, 118.65 g of corn starch and 105 g of croscarmellose sodium,
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex Co., Ltd.), the mixture is kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose is dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluidized dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). Sift through a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180 g of these granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound B 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg Total 180.0 mg (per tablet)

1. Capsule (1) Compound C 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and 1/2 of (4) After mixing, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound C 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2 / 3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 3. Injectable (1) Compound C 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) were dissolved in distilled water for injection to a total volume of 2 ml and made into ampoules. Encapsulate. All steps are performed aseptically. 4. Tablet According to the composition below, a mixture consisting of Compound C 175 g, D-mannitol 175 g, corn starch 118.65 g and croscarmellose sodium 105 g,
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex Co., Ltd.), the mixture is kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose is dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluidized dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). Sift through a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180 g of these granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound C 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg Total 180.0 mg (per tablet)

1. Capsule (1) Compound D 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1/2) of (1), (2) and (3) and (4) After mixing, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound D 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2 / 3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 3. Injection (1) Compound D 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg Dissolve (1), (2), (3) in distilled water for injection to a total volume of 2 ml, and make an ampoule. Encapsulate. All steps are performed aseptically. 4. Tablets A mixture consisting of Compound D 175 g, D-mannitol 175 g, corn starch 118.65 g and croscarmellose sodium 105 g according to the composition below:
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex Co., Ltd.), the mixture is kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose is dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluidized dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). Sift through a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180 g of these granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound D 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg Total 180.0 mg (per tablet)

1. Capsule (1) Compound E 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and 1/2 of (4) After mixing, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound E 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2 / 3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 3. Injection (1) Compound E 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) were dissolved in distilled water for injection to a total volume of 2 ml, and made into ampoules. Encapsulate. All steps are performed aseptically. 4. Tablet A mixture of Compound E 175 g, D-mannitol 175 g, corn starch 118.65 g and croscarmellose sodium 105 g according to the following composition:
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex Co., Ltd.), the mixture is kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose is dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluidized dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). Sift through a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180 g of these granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound E 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg Total 180.0 mg (per tablet)

Test Example AC possessed by the compound [I] or salts thereof according to the present invention
The AT inhibitory activity will be described with reference to test examples. Test Example 1 (ACAT inhibitory activity) [Preparation of mouse peritoneal macrophage microsome ACAT]
Peritoneal macrophages were collected from thioglycollate-stimulated C57BL6J mice according to the method of Hakamada et al. al., Arterio
scler.Thromb., 12, 1139-1145, 1992) containing RPMI 1640-25 mM HEPES (pH 7.0) containing rabbit β-ultra-low density lipoprotein (β-VLDL, 150 μg cholesterol / ml)
After culturing in the medium for 24 hours, peritoneal macrophages were collected by centrifugation (4 ° C., 1,000 rpm, 5 minutes) and disrupted by ultrasonication.
The disrupted solution was centrifuged (4 ° C, 5,000 rpm, 15 minutes) and then ultracentrifuged (4 ° C, 50,000 rpm, 90 minutes) to prepare microsomes. The microsomes thus obtained were used as mouse peritoneal macrophage microsomal ACAT to measure the ACAT inhibitory activity of the test compound. [ACAT inhibitory activity assay] Test compound, cholesterol-
A mixture of albumin-containing Tris-HCL buffer (pH 7.5) and mouse peritoneal macrophage microsomal ACAT was preincubated at 37 ° C for 10 minutes and then ³ H-oleyl.
-CoA was added and reacted at 37 ° C for 20 minutes. Chloroform-
A stop solution consisting of methyl alcohol-distilled water (2: 2: 1 v / v) was added, and the produced cholesteryl ester (CE) was extracted by shaking. Silica gel thin layer chromatography (petroleum ether: diethyl ether: acetic acid = 9: 1: 0.1 v / v) was performed, and the obtained ³ H-CE fraction was measured by a scintillation counter. The ACAT inhibition rate was calculated from the ratio to the ACAT activity without the test compound, and the IC ₅₀ value was calculated as the concentration (μM) of the test compound showing the ACAT inhibition rate of 50%. The results are shown in [Table 1
9].

[Table 19] As is clear from the above results, the compound of the present invention has excellent AC
It has AT inhibitory activity and is useful as a novel therapeutic agent for arteriosclerosis that suppresses the formation of atherosclerotic plaque and causes regression. Further, since it is considered that the subtypes of ACAT derived from macrophage and ACAT derived from liver are the same in humans, it is considered to be useful as a therapeutic drug for hyperlipidemia.

[0140]

INDUSTRIAL APPLICABILITY The compound [I] of the present invention, a salt thereof, and a prodrug thereof have an excellent lipid-rich plaque retraction effect and / or ACAT.
As it has an inhibitory action, it causes acute myocardial infarction in mammals (eg, mouse, rat, rabbit, dog, cat, cow, pig, monkey, human, etc.), acute coronary syndrome such as unstable angina, and peripheral arterial occlusion. It is useful for the prevention or treatment of hyperlipidemia, cerebral infarction, stroke, arteriosclerosis, Alzheimer's disease, multiple risk syndrome and metabolic syndrome, or the prevention or treatment of restenosis after PTCA or stent implantation.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4709 A61K 31/4709 31/4725 31/4725 31/496 31/496 45/00 45/00 A61P 3/00 A61P 3/00 3/06 3/06 9/10 9/10 101 101 25/28 25/28 43/00 111 43/00 111 121 121 121 123 123 C07D 405/10 C07D 405/10 405/12 405/12 413/10 413/10 417/10 417/10 (72) Inventor Masaki Ogino 14-59-205 Notocho, Nishinomiya-shi, Hyogo Prefecture F-term (reference) 4C062 FF03 4C063 AA01 BB06 BB09 CC79 DD14 DD15 DD47 DD58 DD67 EE01 4C084 AA19 MA02 NA14 ZA15 ZA16 ZA36 ZA45 ZC20 ZC21 ZC33 ZC75 4C086 AA01 AA02 AA03 BA19 BC28 BC30 BC50 BC71 BC85 GA02 GA07 GA09 GA10 GA12 MA01 MA02 MA04 NA14 ZA15 ZA16 Z75CZ ZC45 ZC45 ZC45

Claims (23)

[Claims] 1. The formula [I]: [Wherein R ¹ and R ² are each substituted by a hydrogen atom, a halogen atom, a chain hydrocarbon group which may have a substituent or a chain hydrocarbon group which may have a substituent] Optionally a hydroxy group, or R ¹ and R ² together form a cyclic hydrocarbon optionally having substituents with adjacent carbon atoms or an optionally oxo-dihydrofuran ring. The ring A may be a benzene ring which may further have a substituent, the ring B may be an aromatic ring which may have a substituent, and X is a bond or a main chain having 1 to 6 atoms. In the spacer of, Y is a carboxyl group which may be esterified, a carbamoyl group which may have a substituent, a cyano group, or a hetero atom having a deprotonizable hydrogen atom which may have a substituent. Indicates a ring group. ] A compound represented by (provided that 3- [3- [7-chloro-3- (2-
[[4-Chloro-2- (trifluoromethyl) phenyl] amino]-
2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propionic acid, 3- [3- [7-chloro-3- (2-
[[4-Chloro-2- (trifluoromethyl) phenyl] amino]-
2-Oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propionate ethyl, (2E) -3- [3- [7-chloro-3- (2- [ Methyl [4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoate, (2E) -3
-[3- [7-Chloro-3- (2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromene-4 -Yl] phenyl] -2-propenoic acid, (2
E) -3- [3- [7-Chloro-3- (2-[[4-chloro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2
-Oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid ethyl, (2E) -3- [3- [7-chloro-3- (2-[[4-fluoro-2-
(Trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl]
-2-Ethyl propenoate, and (2E) -3- [3- [7-chloro-3-
(2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl] -2-propenoic acid Except) or its salt. 2. The formula [I] is represented by the formula [I ′] [Wherein, B'ring represents a benzene ring which may have a substituent or a pyridine ring which may have a substituent, and R represents an optionally esterified carboxyl group or an esterified ring. Represents a chain hydrocarbon group substituted with a carboxyl group, and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 which is these. 3. R ¹ and R ² each represent a hydrogen atom, a halogen atom or a chain hydrocarbon group which may have a substituent, or R ¹ and R ² together with an adjacent carbon atom. The compound according to claim 1, which may form a cyclic hydrocarbon which may have a substituent. 4. The compound according to claim 1, wherein R ¹ and R ² are each a halogen atom or a C _1-7 alkyl group which may have a substituent. 5. The compound according to claim 1, wherein R ¹ is a halogen atom and R ² is a chain hydrocarbon group substituted with an amino group which may have a substituent. 6. The compound according to claim 1, wherein R ¹ is a halogen atom, and R ² is a chain hydrocarbon group substituted with a cyclic amino group which may have a substituent. 7. The compound according to claim 1, wherein the cyclic hydrocarbon is a C _5-7 cyclic hydrocarbon. 8. The ring B is a benzene ring substituted with a halogenated alkyl group and / or a halogen atom.
The described compound. 9. R is of the formula-(CH ₂ ) _n --R '[wherein R'is a carboxyl group which may be esterified, and n
Is an integer of 0 to 6], The compound according to claim 2. 10. R is of the formula --CH═CH-(CH ₂ ) _{n '} -
The compound according to claim 2, which is a group represented by R'wherein R'represents an optionally esterified carboxyl group and n'represents an integer of 0 to 4. 11. R is a formula-(CH = CH) _{n "} -R '[wherein R'is a carboxyl group which may be esterified, and n" is an integer of 1 to 3] ] The compound of Claim 2 which is a group represented by these. 12. 3- [3- [7-chloro-3- (2-[[4-fluoro-2-
(Trifluoromethyl) phenyl] amino] -2-oxoethyl) -6-methyl-2-oxo-2H-chromen-4-yl] phenyl]
Propionic acid, (2E) -3- [3- [7-chloro-6-methyl-2-oxo-3- (2-oxo-2-[[2- (trifluoromethyl) phenyl] amino] ethyl)- 2H-chromen-4-yl] phenyl] -2-
Propenoic acid, 3- [3- [7-chloro-6-methyl-2-oxo-3- (2-
Oxo-2-[[2- (trifluoromethyl) phenyl] amino]
Ethyl) -2H-chromen-4-yl] phenyl] propionic acid,
(2E) -3- [3- [6-Chloro-3- (2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2-oxoethyl) -7-methyl-2-oxo- 2H-chromen-4-yl] phenyl] -2-propenoic acid, 3- [3- [6-chloro-3- (2-[[4-fluoro-2- (trifluoromethyl) phenyl] amino] -2 -Oxoethyl) -7-methyl-2-oxo-2H-chromen-4-yl] phenyl] propionic acid, (2E) -3- (3- {7-chloro-3- (2-{[4-fluoro- 2- (trifluoromethyl) phenyl] amino} -2-oxoethyl)-
2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2
H-chromen-4-yl} phenyl) acrylic acid, (2E) -3- (3-
{7-chloro-3- (2-{[4-chloro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4-phenylpiperazin-1-yl) Methyl] -2H-chromen-4-yl}
Phenyl) acrylic acid, 3- {7-chloro-3- (2-{[4-fluoro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4- (Phenylpiperazin-1-yl)
Methyl] -2H-chromen-4-yl} benzoic acid, 3- {7-chloro-3
-(2-{[4-chloro-2- (trifluoromethyl) phenyl] amino} -2-oxoethyl) -2-oxo-6-[(4-phenylpiperazin-1-yl) methyl] -2H-chromene -4-yl} benzoic acid or a salt thereof. 13. A prodrug of the compound according to claim 1 or a salt thereof. 14. A pharmaceutical comprising the compound according to claim 1 or 13, or a salt thereof. 15. The drug according to claim 14, which is a lipid-rich plaque repressor or an ACAT inhibitor. 16. Acute coronary syndrome, acute myocardial infarction, unstable angina, coronary restenosis after PTCA or stent implantation, peripheral arterial occlusion, hyperlipidemia, cerebral infarction, stroke, Alzheimer's disease, multiple risk syndrome. 15. The pharmaceutical according to claim 14, which is a preventive / therapeutic agent for metabolic syndrome, or an agent for suppressing regression or progression of arteriosclerotic lesions or stabilizing agent. 17. The agent for suppressing regression or progression of arteriosclerotic plaque according to claim 16, which is combined with an HMG-CoA reductase inhibitor, or a stabilizer. 18. A method of inhibiting lipid-rich plaque regression or ACAT in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 19. An acute coronary syndrome, acute myocardial infarction, unstable angina, PTCA, or stent implantation in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. Coronary artery restenosis,
A method for preventing or treating peripheral arterial occlusion, hyperlipidemia, cerebral infarction, stroke, Alzheimer's disease, multiple risk syndrome or metabolic syndrome, or reducing, stabilizing or stabilizing atherosclerotic plaque. 20. The method for suppressing or suppressing the regression, progression, or stabilization of an arteriosclerotic lesion according to claim 19, which is administered in combination with an HMG-CoA reductase inhibitor. 21. Use of the compound according to claim 1 or a salt thereof for the manufacture of a lipid-rich plaque retractor or an ACAT inhibitor. 22. Acute coronary syndrome, acute myocardial infarction, unstable angina, coronary restenosis after PTCA or stent implantation, peripheral arterial occlusion, hyperlipidemia, cerebral infarction, stroke, Alzheimer's disease, multiple risk syndrome Alternatively, the use of the compound or a salt thereof according to claim 1 for the manufacture of a preventive / therapeutic agent for metabolic syndrome, or a stabilizer for suppressing regression, progression of arteriosclerotic lesions or stabilizing agent. 23. Use for the production of a stabilizer for suppressing regression or progression of arteriosclerotic plaque according to claim 22, which is used in combination with an HMG-CoA reductase inhibitor.