JP3211065B2 - Heterocyclic amine derivative, method for producing the same, and ACAT inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an excellent acyl-CoA:
Cholesterol acyltransferase (hereinafter "AC")
AT "(abbreviated as AT").

[0002]

BACKGROUND OF THE INVENTION Heterocyclic amine derivatives containing isocoumarin, isoquinoline, benzothiopyran rings and the like have not been sufficiently investigated as to whether they are useful as arteriosclerosis agents or blood cholesterol lowering agents. Further, for example, the conversion as shown in [Table 1] below
Compounds are also known, but the formula
As V in [A]

Embedded image W is O, S or NR ¹ and X is H.
And compounds having a phenyl group at the same time as B
It has not been considered as an ACAT inhibitor
won.

[Table 1]

[0003]

SUMMARY OF THE INVENTION The present invention provides an excellent AC
It has an AT inhibitory effect and suppresses absorption of cholesterol from the intestinal tract and accumulation of cholesterol ester in the arterial wall in mammals, resulting in hypercholesterolemia, atherosclerosis and various diseases caused by these (eg, myocardium It is a main object to provide a novel heterocyclic amine derivative useful as a preventive or therapeutic agent for ischemic heart disease such as infarction and cerebrovascular disorders such as cerebral infarction and stroke. Another object of the present invention is to provide an industrially excellent method for producing such a novel compound and a composition or agent containing the novel compound which is useful as a medicament.

[0004]

The present inventors have conducted various studies on heterocyclic amine derivatives, and as a result, have found that a novel compound represented by the general formula (I)

Embedded image [Wherein, the A ring and the B ring may each have a benzene ring which may have a substituent,

Embedded image X represents O, S or NR ¹ (R ¹ represents a hydrogen atom or an alkyl group), Y represents NH, O or (CH ₂ ) _n (n represents 0 to 2), and R ² represents a substituent. Shows a hydrocarbon group which may be possessed. ] The heterocyclic amine derivative represented by the formula (1) or a salt thereof exhibits a potent ACAT inhibitory action and is useful as a safe blood cholesterol lowering agent and a therapeutic agent for arteriosclerosis, and based on this, completed the present invention. did. That is, the present invention provides (1) a heterocyclic amine derivative (I) or a salt thereof, and (2) a compound represented by the general formula (I "):

Embedded image [Wherein the A ring and the B ring are benzene rings which may have a substituent, Z is O or S, X is O, S or NR
¹ (R ¹ represents a hydrogen atom or an alkyl group);
H, O or (CH ₂ ) _n (n represents 0 to 2), and R ² represents a hydrocarbon group which may have a substituent. A heterocyclic amine derivative or a salt thereof represented by the general formula (II):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, with a compound formula ^{(III) R 2 -Y'-H} (III) [ wherein represented by], Y 'is NH or O, R ² is as defined above. A compound represented by the general formula (I ′)

Embedded image [Wherein, Y ′ has the same meaning as described above, and other symbols have the same meanings as above. A method for producing a heterocyclic amine derivative or a salt thereof represented by

(4) General formula (IV)

Embedded image [The symbols in the formula are as defined above. Or a salt thereof and a general formula (V) R ² —Y—CO ₂ H (V) wherein the symbols have the same meanings as described above. A method for producing a heterocyclic amine derivative (I) or a salt thereof, characterized by reacting a compound represented by the formula (I) or a salt or a reactive derivative thereof,

Embedded image [R ⁵ is H ₂ or ＣC ＝ O, and other symbols are as defined above. ] The heterocyclic amine derivative represented by these, or its salt. (6) a method for producing a heterocyclic amine derivative (IV) or a salt thereof, which comprises hydrolyzing the heterocyclic amine derivative (II) or a salt thereof; Acyl CoA: a cholesterol transferase inhibitor.

In the above formula, the A ring and the B ring represent a benzene ring which may have a substituent. Examples of such a substituent include a halogen atom (fluorine, chlorine, bromine and iodine), an alkyl group which may be halogenated, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, A C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.), a C _1-3 acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.), a hydroxyl group and the like are used. Examples of halogen as such a substituent include fluorine, chlorine, bromine and iodine, and preferably, for example, chlorine, fluorine and the like are used.

The alkyl group which may be halogenated includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms or a group having one or more halogen atoms as described above.
Used are, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3 ,
3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5 -Trifluoropentyl, 4-trifluoromethylbutyl, hexyl,
6,6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like are commonly used, and preferably, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,2,
2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc. A linear or branched alkyl group having 1 to 4 carbon atoms or a group obtained by substituting one to three halogen atoms as described above is used.

Examples of the optionally halogenated alkoxy and the optionally halogenated alkylthio group include, for example, a halogen formed by bonding the above-mentioned alkyl group or a halogenated alkyl group to an oxygen atom and a sulfur atom, respectively. An optionally substituted alkoxy group, an optionally halogenated alkylthio group, and the like are used.

The optionally halogenated alkoxy group includes, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms or a group obtained by substituting 1 to 5 halogen atoms as described above. Used, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, Hexyloxy and the like are commonly used, preferably, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,
A linear or branched alkoxy group having 1 to 4 carbon atoms such as 2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy or the like; And those in which 1 to 3 halogen atoms are substituted as described above.

Examples of the alkylthio group which may be halogenated include, for example, a linear or branched alkylthio group having 1 to 6 carbon atoms or a group obtained by substituting 1 to 5 halogen atoms as described above. Used, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like are frequently used, and preferably, for example, methylthio, difluoromethylthio, A straight-chain or branched alkylthio group having 1 to 4 carbon atoms such as trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio or a halogen atom as described above; What substituted 1 to 3 pieces is used.

The substituents on ring A and ring B may be substituted at any position on the ring, and when there are two or more substituents, they may be the same or different, and the number is 1 to
The number may be four. Also the adjacent carbon comrades on A ring or B ring _{- (CH 2) l - (} l is an integer of 3-5)
And may form a 5- to 7-membered ring together with the group represented by the formula, and such a case is also included in the target product (I).

[0012]

Embedded image [In the formula, A ¹ represents a halogen such as chlorine, for example, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and isopropyl, an alkoxy group having 1 to 4 carbon atoms such as methoxy or a halogen such as trifluoromethyl. Represents an alkyl group having 1 to 4 carbon atoms],

Embedded image Wherein A ² and A ³ are the same or different and each represent an alkyl group having 1 to 4 carbon atoms such as methyl, or an alkoxy group having 1 to 4 carbon atoms such as methoxy.

Embedded image [In the formula, A ⁴ and A ⁵ are the same or different and each represent an alkyl group having 1 to 4 carbon atoms such as methyl, etc.].

[0013]

Embedded image [In the formula, B ¹ represents, for example, halogen such as chlorine or fluorine, alkyl having 1 to 4 carbons such as methyl, alkoxy having 1 to 4 carbons such as methoxy, etc.],

Embedded image [Wherein B ² and B ³ are the same or different and represent, for example, alkoxy having 1 to 4 carbon atoms such as methoxy] or

Embedded image [Wherein B ² and B ³ have the same meaning as described above, and B ⁴ represents an alkoxy having 1 to 4 carbon atoms such as methoxy, etc.].

In the above formula, X represents O, S or NR ¹ .
R ¹ represents a hydrogen atom or an alkyl group. Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and C
_{A 3-6} cycloalkyl-C _1-4 alkyl group is preferred. Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like are used. A linear or branched alkyl group is used. As the cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclopentyl, cyclohexyl and the like are used. As the C _3-6 cycloalkyl-C _1-4 alkyl group, for example, cyclopropylmethyl and the like are used.

In the above formula, R ² represents a hydrocarbon group which may have a substituent. As the hydrocarbon group represented by R ² , for example, an alkyl, aryl, aralkyl group or the like is used. Examples of the alkyl group represented by R ² include a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and C _3-8 cycloalkyl-C _1-4 alkyl. Groups and the like are preferred. Examples of the linear or branched alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like are used, and more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, A linear or branched alkyl group having 1 to 6 carbon atoms such as isopentyl, neopentyl and hexyl is used. As the cycloalkyl group having 3 to 8 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl and the like are used. As the C _3-8 cycloalkyl-C _1-4 alkyl group, cyclopropylmethyl and the like are used.

As the aryl group represented by R ² , an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl is preferable, and an aryl group having 6 to 8 carbon atoms such as phenyl is preferably used. . Examples of the aralkyl group represented by R ² include aralkyl groups having 7 to 16 carbon atoms such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, and diphenylmethyl. And more preferably, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl,
An aralkyl group having 7 to 13 carbon atoms such as 2-phenylpropyl, 3-phenylpropyl and diphenylmethyl, particularly preferably benzyl, 1-phenylethyl, 2-
An aralkyl group having 7 or 8 carbon atoms such as phenylethyl is used.

The alkyl, aryl, and aralkyl groups represented by R ² may have the same or different substituents.
It may have up to 5, preferably 1 to 3. Such substituents include, for example, ring A,
The substituents used in the case of B are preferably used, and the following are used.

The aryl group represented by R ² is preferably, for example, a phenyl group. The phenyl group is, for example, a halogen atom, an alkyl group, an alkoxy group,
It may have 1 to 5 hydroxyl groups, acyloxy groups or amino groups which may have a substituent, which may be the same or different. Halogen atom (e.g., fluorine, chlorine, bromine,
(Iodine), particularly those having 1 to 5 chlorines and fluorines are preferable, and specifically, for example, a 2,4-difluorophenyl group and the like are preferable. As the alkyl group which the phenyl group may have, a C _1-4 alkyl group such as methyl, ethyl and isopropyl is preferably used, and 2,6-dimethyl, 2,6-diethyl, 2-methyl- 6-isopropyl,
2,6-diisopropyl and the like are preferred. As the alkoxy group which the phenyl group may have, a C _1-4 alkoxy group such as methoxy and ethoxy is preferably used.
The amino group which the phenyl group optionally has may be an amino group or an amino group having one or two C _1-4 alkyl groups, such as methylamino and ethyl. Preferred are amino, propylamino, dimethylamino, methylethylamino, methylpropylamino, diethylamino, ethylpropylamino and the like. Further, a phenyl group having a C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a C _1-3 acyloxy group or an amino group which may be substituted, for example, 4
-Acetoxy-3,5-dimethylphenyl, 4-hydroxy-3,5-dimethylphenyl, 4-acetoxy-3,5
-Dimethoxyphenyl or 4-hydroxy-3,5-
A dimethoxyphenyl group or the like is preferred as R ² .

Particularly preferred as R ² are, for example, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2,6-dimethyl, 2,6-diisopropyl, -Acetoxy-3,
5-dimethylphenyl, 3,5-diisopropyl-4-
Hydroxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 4-acetoxy-3,5-diisopropylphenyl, 3,5-diisopropyl-4-hydroxyphenyl, 3,5-di-t-butyl-4-hydroxyphenyl , 4-N, N-dimethylaminophenyl, cyclohexyl and the like.

The heterocyclic amine derivative represented by the formula (I) or a salt thereof can be produced, for example, by the following methods. That is, the compound is obtained by reacting a heterocyclic isocyanate compound represented by the general formula (II) or a salt thereof with an amine or alcohol compound represented by the general formula (III) or a salt thereof.
(I ′) (compound (I) wherein Y is NH, O) or a salt thereof, or a heterocyclic amine represented by the general formula (IV) or a salt thereof and a general formula (V) Compound (I) or a salt thereof is produced by reacting a substituted carboxylic acid or a salt thereof or a reactive derivative of the carboxyl group thereof.

Hereinafter, the method (1) will be described in detail. Method: Compound (II) or a salt thereof and compound (III) or a salt thereof (compounds (II) or (III) include, for example, salts with mineral acids such as hydrochloric acid and sulfuric acid, methanesulfonic acid and benzenesulfonic acid) , Salts with organic acids such as toluenesulfonic acid, oxalic acid, fumaric acid, and maleic acid are used.)
When the compound (III) is reacted with the compound (III), the compound (III) itself may be used as a solvent, but the reaction may be performed in another solvent. Such other solvent may be any solvent as long as it does not hinder the reaction, for example, ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene and the like) ), Esters (eg, methyl acetate, ethyl acetate, etc.), amides (eg, N, N-dimethylformamide, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.) and the like are preferably used. Compound (III)
When is used in the form of a salt, the reaction can be significantly advanced by adding a desalting agent as necessary. In this case, as the desalting agent, for example, tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine, and aromatic amines such as pyridine, picoline and N, N-dimethylaniline are preferably used. The amount of the desalting agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the salt of (III). The reaction temperature is usually -10C to 180C, preferably 0C to 120C. The reaction time is usually 15 minutes to 40 hours, preferably 30 minutes.
Minutes to 20 hours. (III) or a salt thereof is used in an amount of 1 to 5 molar equivalents per mole of (II) or a salt thereof,
Preferably it is 1 to 3 molar equivalents.

Method: The reaction of the substituted carboxylic acid represented by the general formula (V) or a salt thereof or a reactive derivative thereof with the compound (IV) or a salt thereof is an amide bond formation reaction, and is carried out by various methods. . For example, compound (IV) or a salt thereof (e.g., a salt with a mineral acid such as hydrochloric acid or sulfuric acid or a salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, or maleic acid) And the compound (V) or a salt thereof (e.g., sodium, potassium, an alkali metal such as magnesium, a salt with an alkaline earth metal, or the like), ordinarily using an appropriate condensing agent, or (V) or Preferably, the salt is once introduced into the reactive derivative (IV) or reacted with the salt. Examples of such a condensing agent include dicyclohexylcarbodiimide (DCC) and diethyl cyanophosphate (D
EPC), diphenylphosphoryl azide (DPPA) and the like are used. When using these condensing agents, usually
(Examples: ethers such as tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, N, N-dimethylformamide, dimethyl sulfoxide, esters, hydrocarbons, amides, sulfoxides, etc.)
It is better to do it inside. This reaction may be promoted in the presence of a base, and may be carried out at about -10 ° C to 100 ° C, preferably about 0 ° C.
The reaction is carried out at a temperature between 60C and 600C. The reaction time is usually 1 to 96
Hours, preferably 1 to 72 hours. (V) or a salt thereof and a condensing agent are used in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the (IV) or a salt thereof. As the base, for example, alkylamines such as triethylamine, and cyclic amines such as N-methylmorpholine and pyridine are used. The amount of the base used is 1 to 5 mole equivalents, preferably 1 mole, per mole of (IV) or a salt thereof. ~ 3 molar equivalents.

Examples of the reactive derivative (V) include acid halides (eg, chloride, bromide, etc.), acid anhydrides, mixed acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, isobutyl Activated anhydride, etc.)
(E.g., esters with hydroxysuccinimide, esters with 1-hydroxybenzotriazole, esters with N-hydroxy-5-norbornene-2,3-dicarboximide, esters with p-nitrophenol, 8-oxy And the like, and an ester with quinoline). Compound (IV) or a salt thereof
When reacting with the reactive derivative of (V), usually a solvent
(Examples, chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine, N, N-dimethylformamide and other halogenated hydrocarbons, ethers, esters, hydrocarbons, Amides). This reaction may promote the reaction in the presence of a base.
The reaction temperature is usually about -10 ° C to 120 ° C, preferably about 0 ° C.
C. to 100C. The reaction time is generally 1 to 48 hours, preferably 1 to 24 hours. The amount of the reactive derivative (V) used is 1 to 5 molar equivalents relative to 1 mol of (IV) or a salt thereof,
Preferably it is 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, and sodium carbonate and potassium carbonate. Alkali metal carbonate, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, etc. are used, and the amount used is (IV)
Or 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of a salt thereof. When a solvent that is immiscible with water is used in this reaction, water may be added to the reaction system and the reaction may be performed in a two-phase system.

In the above method, when Y is O in the compound (V), the reactive derivative (V) is preferably an acid halide, an active ester or the like. When Y is NH in the compound (V), as a reactive derivative of (V),
For example the formula ^{R 2 -N = C = O (} VI) [ symbols in the formula are as defined above. ] Is preferably used. When the compound (VI) and the compound (IV) or a salt thereof are used, the desired compound ( I) (Y = NH) can be obtained. In this reaction, when (IV) is used in the form of a salt, the same desalting agent as used in the method is used. The amount of compound (VI) to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of (IV) or a salt thereof.

When the compound (I) or a salt thereof produced by the above method contains a lower alkoxy group on the benzene ring in the ring A, the ring B or the group represented by R ² , if necessary, the compound may be added to, for example, By reacting with boron oxide or the like, it can be converted to a hydroxyl group. This reaction is usually carried out in a solvent (e.g., dichloromethane, chloroform, carbon tetrachloride, benzene,
Halogenated hydrocarbons such as toluene, hydrocarbons, etc.) at about -20 ° C to 80 ° C, preferably at about 0 ° C to 30 ° C.
C., and the amount of boron tribromide used is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per one lower alkoxy group. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours. Also, the above method
, The compound (I) or a salt thereof is a ring A, B
When a hydroxyl group is contained in the ring or the benzene ring in the group represented by R ² , this can be converted to an alkoxy or acyloxy group by performing an alkylation or acylation reaction, if necessary. The alkylation reaction is carried out in a solvent
(E.g., alcohols such as methanol, ethanol, and propanol, ethers such as dimethoxyethane, dioxane, and tetrahydrofuran, ketones such as acetone, and amides such as N, N-dimethylformamide) in a base (e.g., trimethylamine , Triethylamine, N-methylmorpholine, pyridine, picoline, N,
In the presence of an organic base such as N-dimethylaniline, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide), a halide of an optionally substituted alkane (eg, chloride, bromide) , Iodide, etc.), an alkylating agent such as a sulfate ester or a sulfonic ester (eg, methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc.). The reaction temperature is usually -1
The temperature is from 0 ° C to 100 ° C, preferably from about 0 ° C to 80 ° C. The amount of these alkylating agents used is as follows:
It is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, per mol. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

The acylation reaction is carried out by reacting a desired carboxylic acid or a reactive derivative thereof. This reaction differs depending on the type of the acylating agent and the type of the starting phenolic derivative.
-Hydrocarbons such as dimethylformamide, pyridine,
Ethers, esters, halogenated hydrocarbons, amides, aromatic amines, etc.) and an appropriate base for promoting the reaction (e.g., sodium bicarbonate, bicarbonate such as potassium bicarbonate, Carbonates such as sodium and potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and aromatic amines such as pyridine can also be given. As the reactive derivative of the carboxylic acid, an acid anhydride, a mixed acid anhydride, an acid halide (eg, chloride, bromide) and the like are used. The amount of the acylating agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction temperature is usually 0 ° C to 150 ° C, preferably about 10 ° C.
C. to 100C. The reaction time is generally 15 minutes to 12 hours, preferably 30 minutes to 6 hours.

When the compound (I) is obtained in a free state by the above method, for example, a mineral acid (eg, hydrochloric acid,
Sulfuric acid, hydrobromic acid, etc.), organic acids (e.g., methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.) can be used as a salt with the compound ( When I) is obtained in salt form,
It can be converted to a free form or another salt according to a conventional method. The target compound (I) or a salt thereof obtained by the above method can be purified and collected by using a separation and purification means known per se (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.). .

Compound (I) or a pharmaceutically acceptable salt thereof has excellent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory activity, and has low acute toxicity and toxicity due to continuous administration, and is safe as a pharmaceutical. is there. ACAT is an enzyme involved in higher fatty acid esterification of cholesterol in cells and is known to play an important role in the accumulation of cholesterol ester in the small intestine. Therefore, the ACAT inhibitory substance inhibits the absorption of dietary cholesterol from the intestinal tract, suppresses a rise in blood cholesterol level, suppresses the accumulation of intracellular cholesterol ester in atherosclerotic lesions, and prevents the progression of atherosclerosis. Can be. Therefore, the compound (I) of the present invention or a salt thereof having an excellent ACAT inhibitory action can be used for the production of hypercholesterolemia in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, horses, cows, sheep, monkeys, humans, etc.). It is useful as a safe prophylactic / therapeutic agent for diseases, atherosclerosis, and diseases resulting therefrom (eg, ischemic heart disease such as myocardial infarction and cerebrovascular disorder such as cerebral infarction and stroke).

The compound (I) or a salt thereof includes those exhibiting a lipid peroxide production inhibitory action (antioxidant action). It is known that peroxidation of lipids in a living body is closely related to arteriosclerosis and the development of ischemic diseases in the brain and cardiovascular system. Therefore, the compound (I) or a salt thereof having both an ACAT inhibitory action and an antioxidant action can prevent and treat various vascular lesions caused by both blood cholesterol and lipid peroxide, so that it can be used as a pharmaceutical. High usefulness.

When the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as the above-mentioned drug, an appropriate pharmacologically acceptable carrier and excipient (eg, starch, lactose, sucrose) , Calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin,
Polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, etc.), disintegrants (eg, carboxymethylcellulose calcium, talc, etc.), diluents (eg, physiological saline, etc.), etc. Powders, fine granules, granules,
Although it can be administered orally or parenterally in the form of tablets, capsules or injections, it is more preferably administered orally when used for the purpose of inhibiting cholesterol absorption. The dose varies depending on the type of compound (I) or a salt thereof, the administration route, the symptoms, the age of the patient, and the like. About 0.005 per
It is preferable to administer this amount in an amount of about 50 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg once to three times a day.

The starting compound (II) or a salt thereof used for producing the compound (I) of the present invention or a salt thereof, or
(IV) or a salt thereof is a novel compound and can be industrially advantageously produced, for example, by the method shown in the following reaction (FIG. 1) or a method analogous thereto. [Reaction Diagram 1]

Embedded image [In the formula, A ring, B ring, R ¹ and X have the same meanings as described above, R ³ represents a carboxyl protecting group, and R ⁴ represents a hydrogen atom or a carboxyl protecting group. In the above figure, a 2-benzoylbenzoic acid derivative represented by the formula (VII) is used as a starting material.

The first step is 4-phenylisocoumarin-3
-A step of obtaining a carboxylic acid (VIII), for example, by a known method [eg, F. Duro and P. Condorelli, Boll. Accad.
Gioenia Sci. Nat. Catania, Vol 5, p606, 196
0] or a method equivalent thereto. Second
The step is a step of converting the carboxyl group of (VIII) into an isocyanate group to obtain (II ') (X = O), and usually employs a method of converting (VIII) into an isocyanate form as an acid azide form. Although various methods are known in the literature, (VIII)
Any of these methods can be applied.

For example, an azidating agent (eg, diphenylphosphoryl azide (hereinafter abbreviated as DPPA), etc.) and (VI
By reacting with (II), the acid azide of (VIII) can be produced. This reaction is usually performed in a solvent inert to the reaction.
(Examples: ethers such as ethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, benzene, toluene, aromatic hydrocarbons such as xylene, methyl acetate, esters such as ethyl acetate, acetone, 2-butanone and the like Ketones, aromatic amines such as pyridine, amides such as N, N-dimethylformamide, etc.). Base
The reaction may proceed in the presence of (eg, trimethylamine, triethylamine, N-methylmorpholine, etc.). The reaction time is generally about 5 minutes to 12 hours, preferably about 10 minutes to 6 hours. The reaction temperature is usually about −10 ° C. to 150
° C, preferably about -5 ° C to 120 ° C. The amount of the azidating agent (eg, DPPA) used is 1 to (VIII).
３3 molar equivalents, preferably 1-2 molar equivalents.

The produced acid azide can be isolated and purified by a method known per se. However, the reaction solution is generally heated without isolation to convert it into the isocyanate (II '). This conversion reaction is preferably carried out by using the same solvent as that used for the azidation, usually by heating to about 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. The reaction time is generally about 5 minutes to 10 hours, preferably about 5 minutes to 6 hours. The obtained compound (II ') may be isolated by a means known per se or the compound without isolation.
It can be used as a raw material for producing (I) or (IV ′).

In the third step, isocoumarin carboxylic acid (VII
This is a step of converting I) to isoquinolone carboxylic acid (XIII), for example, by a known method [eg, NA Santagati, E. Bou.
squet, G. Romeo, A. Caruso and A. Prato, Bolletino
Chimico Farmaceutico, Vol. 125, p437, 198
6] or a method equivalent thereto. Isoquinolonecarboxylic acid (XIII) can also be produced from (VII) through the fourth to seventh steps. That is, the fourth step is a step of reacting the carboxyl group of (VII) with the amino group of the glycine derivative (IX) to obtain an amide (X). In this reaction (VI
I) or its reactive derivative at the carboxyl group
The reaction with (IX) can be carried out under the same conditions as in the reaction (method) in the production of (I) by the reaction of (IV) and (V).

The fifth step is a step of treating the compound (X) with a base and subjecting it to an intramolecular addition reaction to obtain a ring-closure form (XI).
Bases used in this reaction include 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). , N-
Benzyltrimethylammonium hydroxide (Trito
Organic bases such as nB), inorganic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium hydride, n-butyllithium, lithium diisopropylamide are preferably used, Bases such as those used in the reaction (method) of IV) and (V) can also be used. The amount of the base to be used is generally 0.5 to 20 equivalents, preferably 1 to 5 equivalents, relative to (X). This reaction is usually performed in a solvent. As the solvent, those used in the reaction (method) of (IV) and (V) are used. The reaction temperature varies depending on the type of the base used, but is usually about -80 ° C to 200 ° C, preferably about -50 ° C to 150 ° C. The reaction time varies depending on the starting materials, the base, the reaction temperature and the type of the solvent used, but is usually about 10 minutes to 24 hours.

The sixth step is a step of subjecting compound (XI) to a dehydration reaction to give an isoquinolone derivative (XII). This reaction is usually preferably performed in the presence of an acidic catalyst. Examples of the acidic catalyst include sulfonic acid compounds such as p-toluenesulfonic acid and methanesulfonic acid, carboxylic acid compounds such as acetic acid and trifluoroacetic acid, inorganic acid compounds such as hydrogen chloride, hydrogen bromide and sulfuric acid, and boron trifluoride. Lewis acid compounds such as ethyl ether and aluminum chloride are used. The amount of the acidic catalyst used is 0.1 to 20 with respect to (XI).
Equivalents, preferably 0.1 to 5 equivalents, are used. This reaction is usually performed in a solvent. As the solvent, those used in the reaction (method) of (IV) and (V) are used. The reaction temperature depends on the type of acid used, but is usually about-
It is carried out at a temperature of 10 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time depends on the starting materials, base, reaction temperature,
Although it depends on the type of the solvent, it is usually about 30 minutes to 24 hours. In the fifth step, depending on the type of compound (X), the base used, the type of solvent or the reaction temperature and the reaction time, the product is a dehydration ring (XII).
May be obtained.

The seventh step is a step of obtaining the compound (XIII) by removing the protecting group R ⁴ of the carboxyl group of (XII). Various known methods depending on the type of R ⁴ in this reaction (XII) [Example, T.
W. Greene, Protective Groups in Organic Synthesis,
John Wiley & Sons, New York, 1981, p157-1
87]. For example, when the protecting group of (XII) is a lower alkyl group such as methyl, ethyl and the like, the reaction is carried out, for example, under the conditions according to the hydrolysis reaction described in the following ninth step.

In the eighth step, isoquinolone carboxylic acid (XII
In this step, I) is converted to an isocyanate (II ′). This step can be performed according to the method described in the second step. The ninth step is a step of converting the isocyanate group of (II ') to an amino group to obtain (IV'). This step is usually performed under hydrolysis conditions. This reaction is carried out, for example, in a solvent (eg, alcohols such as methanol, ethanol, propanol, butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, or a mixed solvent thereof), for example, sodium hydroxide, barium hydroxide, etc. The reaction is carried out under alkaline conditions using a hydroxide of an alkali or alkaline earth metal, or under acidic conditions using an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid and the like. The reaction temperature is usually about 0 ° C to 120 ° C, preferably about 15 ° C to 100 ° C. The reaction time is about 30 minutes to 36 hours, preferably,
About 1 hour to 20 hours. (IV ') can also be obtained by subjecting a compound of the present invention (I') wherein Y 'is O to hydrolysis conditions as described above.

The starting compound (VIII) in the above figure is, for example,
Known methods [e.g., P. Aeberli, P. Eden, J. H. Gogerty,
 W. J. Houlihan, and C. Penberthy, J, Med. Chem.,
18, 177 (1975)] or a method analogous thereto.
Can also be manufactured. In the above manufacturing method, Z⁰But
O and X is O or NR¹Explains only compounds of
Was performed, but Z⁰Wherein O is O and X is S;
Z⁰Is S and X is O, S or NR¹For compounds that are
However, it can be synthesized in the same manner as described above. Compound of the present invention
In the product (I) or a salt thereof, Z⁰Is H_TwoAnd X is
Raw material compound used for producing compound S
(II ″) or its salt, or (IV ″) or its salt
Is also a novel compound, for example, as shown in the following reaction (FIG. 2)
Industrially advantageous production by the method or a method equivalent thereto
can do.

[Reaction Diagram 2]

Embedded image [In the formula, A ring, B ring, R ³ and R ⁴ have the same meaning as described above, and L represents a halogen atom. In FIG. 2, a 2-methylbenzophenone derivative represented by the formula (XIV) is used as a starting material. The tenth step is a step for obtaining 2-halogenomethylbenzophenone (XV).
V) using known methods [eg, R. Faragher and TL G
ilchrist, J. Chem. Soc., Perkin I, 1976, p336] or a method analogous thereto.

The eleventh step is a step of reacting a halogen atom (eg, chlorine, bromine, iodine) which is a leaving group of (XV) with a thiol group to obtain (XVII). In this step, a thioglycolate represented by (XVI) is used as the thiol compound. The compound (XVI) may be used as it is, or may be subjected to the reaction as a salt, for example, an alkali metal salt such as lithium, sodium or potassium, or an alkaline earth metal salt such as calcium or magnesium. Good. Compound (XV) per mole of compound (XV)
1) to 10 mol, preferably 1 to 5 mol of I) or a salt thereof are reacted. Usually, the reaction is performed in a solvent. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile; ethers such as dimethoxyethane and tetrahydrofuran;
Dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like are preferably used. Addition of a base favors the reaction. Such bases include:
For example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide,
Triethylamine, diisopropylethylamine, pyridine and the like are preferred. In this reaction, instead of using a base, the compound (XVI) may be converted to, for example, an alkali metal salt or an alkaline earth metal salt as described above, and then reacted with the compound (XV). The amount of the base used varies depending on the compounds (XV) and (XVI) used, the type of the solvent, and other reaction conditions.
V) 1 to 10 mol, preferably 1 to 5 per 1 mol. The reaction temperature is about -50 ° C to 100 ° C, preferably-
It is performed in a range of 30 ° C to 80 ° C. The reaction time varies depending on the type of the compound (XV), the type of the compound (XVI) or a salt thereof, the reaction temperature and the like, but is preferably 1 to 72 hours, preferably 1 to 24 hours.

Compounds (XVII) to (XVIII) (step 12), (XVIII) to (XIX) (step 13) and (XI
From (X) to (XX) (14th step), (X) → (XI) (5th step), (XI) → (XII) (6th step)
Step) and (XII) → (XIII) (seventh step). In the twelfth step, the product (XIX), which is a dehydrated ring-closed product, may be obtained as a product depending on the type of (XVII), the type of base and solvent used, or the reaction temperature and reaction time. Compound (X
X) to (II ′) (15th step) and (II ″) to (I
V ″) (the sixteenth step) corresponds to (VIII) in reaction scheme 1 respectively.
→ (II ′) (second step) and (II ′) → (IV ′) (ninth step). In the above-described production method, only the compound in which Z ⁰ is H ₂ and X is S has been described. However, the compound in which Z ⁰ is H ₂ and X is O or NR ₁ is also produced in the same manner as the above production method. Can be synthesized. The compound obtained in each of the first to sixteenth steps is purified and collected by a purification method known per se, such as concentration, liquid conversion, phase transfer, solvent extraction, column chromatography, crystallization, or recrystallization. Alternatively, the mixture may be used in the next step reaction as it is.

[0044]

The compound (I) of the present invention or a salt thereof has excellent A
Although it has a CAT inhibitory effect, the results of its pharmacological tests are shown below. (1) Acyl-CoA: cholesterol transferase (ACAT) inhibitory activity [Experimental method] The enzyme sample ACAT was obtained from Heider et al., Journal of Lipid Research [Journal of Lipid].
id Research], Vol. 24, p. 1127 (1982), prepared from the microsomal fraction of the small intestinal mucosa of 6-week-old male Sprague-Dawley rats fasted for 20 hours. ACAT activity was determined by the method of Helgerud et al. (Journal of Research, Vol. 22, p. 271,
1981)) by calculating the amount of labeled cholesterol ester produced from [1- ¹⁴ C] oleoyl-CoA and endogenous cholesterol.

[Results] (1) [Table 1] shows the inhibition of the production of labeled cholesterol ester when 10 ^-6 M of a test compound (representative compound among the compounds obtained in Examples 1 to 31 below) was added. rate
(%) Is shown as an index of ACAT inhibitory action.

[Table 1] The 50% inhibitory concentration (IC ₅₀ ) of the compound of Example 15 was 1.
It was 3 × 10 ⁻⁸ M. Table 1 shows that compound (I) or a salt thereof has excellent ACAT inhibitory activity.

(2) Plasma Cholesterol-Lowering Effect in Cholesterol-Loaded Rats [Experimental Method] A 7-week-old male spray good gourd [Spragu
e Dawley] Rats were fed a 1% cholesterol diet (containing 0.5% cholic acid and 5% olive oil) for 3 days, grouped by plasma cholesterol levels (n = 5), and further supplemented with the same diet containing the test compound. They were bred for 4 days. Blood was collected between 8:30 and 10:00 am in a fed state and plasma cholesterol levels were measured enzymatically. The intake of the compound was calculated from the intake. [Results] [Table 2] shows the plasma cholesterol lowering effect of the test compound during cholesterol loading.

[Table 2] Test compound dose Plasma cholesterol (Example No.) (mg / kg / day ) (mg / dl) 対 照 Control group 0 191.0 ± 25.6 14 0.14 103.4 ± 23.7 * 150 .13 125.2 ± 22.6 * 数 値 Values are mean ± standard deviation * p <0.05 (control group Duncan's Multiplex Assay) This [Table 2] demonstrates that compound (I) or a salt thereof has an excellent plasma cholesterol lowering effect.

[0047]

The present invention will be further described in the following Reference Examples and Examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. May be changed. Elution in column chromatography in Reference Examples and Examples is TLC (Thin Layer Chromato
graphy, thin layer chromatography). In the TLC observation, 60F ₂₅₄ manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent in column chromatography as a developing solvent was
A UV detector was employed as a detection method. Silica gel for column chromatography is silica gel 60 manufactured by Merck.
(70-230 mesh) was used. Room temperature usually means 10 ° C to 35 ° C.

Reference Example 1 6-chloro-4-phenylisocoumarin-3-carboxylic acid 2-benzoyl-4-chlorobenzoic acid (2.60 g), acetone (60 ml), dimethylformamide (3 ml), potassium carbonate (1 .40 g) and diethyl bromomalonate (1.8
(5 ml) was stirred at room temperature for 16 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with water, dried (Na ₂ SO ₄ ) and evaporated to give the ester as a colorless oil. Acetic acid (40m
l) and hydrochloric acid (40 ml) were added, and the mixture was heated at 110 ° C for 3 hours.
The reaction solution was concentrated, water was added to the concentrate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (Na ₂ SO ₄ ), and evaporated to give the title compound as colorless crystals (2.70 g). Melting point 206-208 ° C (recrystallized from ethyl acetate-isopropyl ether) Elemental analysis calculated as C ₁₆ H ₉ O ₄ Cl Calculated C, 63.91; H, 3.02 Found C, 63.80; H, 2.95

Reference Example 2 6-Chloro-4-phenyl-1 (2H) -isoquinolinone-3-carboxylic acid Methanol (6 ml) of the compound obtained in Reference Example 1 (0.50 g)
Was stirred at room temperature for 7 hours adding _{5N-NH 3 / MeOH (8ml} ) was added. The solvent was distilled off, and water was added to the residue. The mixture was acidified with 1N HCl and extracted with ethyl acetate. The extract was washed with water, dried (Na ₂ SO ₄ ) and the solvent was distilled off to obtain the amide as a colorless oil.
4N-HCl-ethyl acetate (6 ml) was added to the oil, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, water and acetone were added to the residue, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration and washed sequentially with water, acetone and ether to give the title compound as colorless crystals (0.32 g). Melting point> 300 ° C (recrystallized from acetone-methanol) Elemental analysis Calculated for C ₁₆ H ₁₀ NO ₃ Cl C, 64.12; H, 3.36; N, 4.67 Found C, 64.03; H, 3.38; N, 4.67

Reference Example 3 6-Chloro-2-methyl-4-phenyl-1 (2H) -isoquinolinone-3-carboxylic acid The compound (3.01 g) obtained in Reference Example 1 was replaced with ammonia in Reference Example 2. The reaction was carried out in the same manner as in Reference Example 2 using methylamine to give the title compound (3.40 g). 248-250 ° C Reference Example 4 4- (4-Fluorophenyl) -2-methyl-1 (2H)-
Isoquinolinone-3-carboxylic acid Reference example 2 from 4- (4-fluorophenyl) isocoumarin-3-carboxylic acid (2.00 g) using methylamine
The title compound (1.73 g) was obtained by reaction and treatment in the same manner as in. 196-197 ° C

Reference Example 5 4- (2-methylphenyl) -2,6,7-trimethyl-1
(2H) -isoquinolinone-3-carboxylic acid step 1 N- [4,5-dimethyl-2- (2-methylbenzoyl) benzoyl] -N-methylglycine ethyl ester 4,5-dimethyl-2- (2-methyl Benzoyl) benzoic acid (705 mg), 1-hydroxybenzotriazole (49
0 mg), 1,3-dicyclohexylcarbodiimide (660
mg) and tetrahydrofuran (20 ml) was stirred at room temperature for 1 hour. The precipitated crystals were separated by filtration, and N-methylglycine ethyl ester hydrochloride (600 mg) and triethylamine (0.55 ml) were added to the filtrate, followed by stirring at room temperature for 16 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed successively with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and water, and dried (MgSO ₄ ).
Thereafter, the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-ethyl acetate = 3: 1).
→→ 1: 1) gave the title compound as a yellow oil (880 mg)
Was obtained as IR νmax (Neat) cm ^-1 : 1740, 1640, 1600, 1550, 14
40, 1400, 1300 NMR (200 MHz, CDCl ₃ ) ppm: 1.31 (3H, t, J = 7H
z), 2.23 (1H, s), 2.25 (2H, s), 2.28 (1H, s), 2.34 (2H,
s), 2.39 (3H, s), 2.95 (2H, s), 3.04 (1H, s), 3.96 (0.67
H, s), 4.19 (1.33H, s), 4.23 (2H, q, J = 7Hz), 7.14-7.46
(5H, m)

Step 2 4- (2-methylphenyl) -2,6,7-trimethyl-1
(2H) -Isoquinolinone-3-carboxylic acid ethyl ester 1,8-diazabicyclo [5.4.0] undec-7-ene (0.5 ml) was added to a solution of the compound (858 mg) obtained in Step 1 in toluene (15 ml). Was added and the mixture was heated under reflux for 9 hours. The solvent was distilled off, and ethyl acetate was added to the residue. This mixture is mixed with water,
Wash sequentially with 10% aqueous potassium hydrogen sulfate and water, and dry (Mg
After SO ₄ ), the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-ethyl acetate =
3: 1 → 1: 1) to give the title compound as colorless crystals. 126-128 ° C (recrystallized from ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.89 (3H, t, J = 7H
z), 2.09 (3H, s), 2.25 (3H, s), 2.40 (3H, s), 3.61 (3H,
s), 3.98 (2H, q, J = 7 Hz), 6.73 (1H, s), 7.11-7.39 (4H,
m), 8.27 (1H, s)

Step 3 4- (2-methylphenyl) -2,6,7-trimethyl-1
(2H) -isoquinolinone-3-carboxylic acid The compound obtained in Step 2 (87 mg), 1N-NaOH (1.5 ml).
And a mixture of ethanol (5 ml) was heated at reflux for 27 hours. After adding water to this mixture and washing with ethyl ether,
The mixture was acidified with 10% aqueous potassium hydrogen sulfate and extracted with ethyl acetate. The extract was washed with saline, dried (MgSO ₄ ),
The solvent was distilled off to obtain the title compound as colorless crystals (60 mg). 298-299 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.11 (3H, s), 2.24
(3H, s), 2.39 (3H, s), 3.67 (3H, s), 6.68 (1H, s), 7.14-
Reaction and treatment were conducted in the same manner as in Reference Example 1 using 7.43 (4H, m), 8.25 (1H, s) 2-benzoylbenzoic acids to obtain the compound of Reference Example 6-7. Reference Example 6 7-chloro-4-phenylisocoumarin-3-carboxylic acid, melting point 220-221 ° C Reference Example 7 4- (4-fluorophenyl) -6-methylisocoumarin-3-carboxylic acid, melting point 198-199 ° C

Reference Example 8 3-Amino-6-chloro-4-phenylisocoumarin The compound (1.0 g) obtained in Example 2 was diluted with dichloromethane (50 g).
trifluoroacetic acid (4 ml) was added to the solution at room temperature for 30 minutes.
Stir for a minute. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate and brine, dried (Na ₂ SO ₄ ) and evaporated to give the title compound as yellow crystals (710 mg). Melting point: 216-217 ° C (recrystallized from ethyl acetate-isopropyl ether) Elemental analysis: calculated as C ₁₅ H ₁₀ NO ₂ Cl · １ ／ H ₂ O C, 65.23; H, 3.83; N, 5.07 found C, 65.20 H, 3.97; N, 4.96 Reference Example 9 3-amino-6-chloro-2-methyl-4-phenyl-
1 (2H) -isoquinolinone Reference Example 8 was performed using the compound (0.61 g) obtained in Example 5.
The reaction and treatment were carried out in the same manner as in the above, to give the title compound as yellow crystals (0.4).
2g). Melting point 181-183 ° C (recrystallized from ethyl acetate-isopropyl ether) Elemental analysis Calculated for C ₁₆ H ₁₃ N ₂ OCl Calculated C, 67.49; H, 4.60; N, 9.84 Found C, 67.34; H, 4.69; N , 9.77

Reference Example 10 6-Fluoro-4- (4-fluorophenyl) isocoumarin-3-carboxylic acid Instead of 2-benzoyl-4-chlorobenzoic acid in Reference Example 1, 4-fluoro-2- (4-fluoro ) Reaction and treatment with benzoylbenzoic acid in the same manner as in Reference Example 1 gave the title compound as colorless crystals. Melting point 202-205 ° C Reference Example 11 4- (2-methoxyphenyl) -2-methyl-1 (2
H) -Isoquinolinone-3-carboxylic acid Reaction from 4- (2-methoxyphenyl) isocoumarin-3-carboxylic acid (1.50 g) in the same manner as in Reference Example 2 using methylamine instead of ammonia in Reference Example 2. After treatment, the title compound was obtained as colorless crystals (1.34 g). 205-207 ° C

Reference Example 12 4- (3,5-Di-tert-butyl-4-hydroxyphenyl) -2-methyl-1 (2H) -isoquinolinone-3-
Carboxylic acid Step 1 N- [2- (3,5-di-t-butyl-4-hydroxybenzoyl) benzoyl] -N-methylglycine ethyl ester 2- (3,5-di-t-butyl-4-hydroxy Oxalyl chloride (1.56 ml) and dimethylformamide (catalytic amount) were added to a solution of (benzoyl) benzoic acid (2.88 g) in anhydrous tetrahydrofuran (80 ml), and the mixture was stirred for 30 minutes. To this mixture was added triethylamine (1.15 ml).
After stirring at 50 ° C. for 2 hours, the solvent was distilled off. To the residue were added anhydrous tetrahydrofuran (100 ml), sarcosine ethyl ester hydrochloride (3.75 g) and triethylamine (4.48 ml), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid, aqueous sodium carbonate and water, dried (Na ₂ SO ₄ ) and evaporated to give the title compound as colorless crystals (2.0 g). 98-99 ° C (recrystallized from ethyl acetate-isopropyl ether)

Step 2 4- (3,5-Di-tert-butyl-4-hydroxyphenyl) -2-methyl-1 (2H) -isoquinolinone-3-
Carboxylic acid ethyl ester To a solution of the compound obtained in Step 1 (1.85 g) in dimethylformamide (20 ml) was added sodium hydride (60% oil) (0.30 g) and chloromethyl methyl ether (1.
60 ml) and stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off to obtain the methoxymethyl ether compound of the compound obtained in Step 1 as an oil. To this oil was added anhydrous toluene (100 ml) and 1,1
8-Diazabicyclo [5.4.0] undec-7-ene (1.5 ml) was added, and the mixture was stirred at 110 ° C for 4 hours.
Ethyl acetate was added to the reaction solution, washed successively with water, dilute hydrochloric acid and water, and dried (Na ₂ SO ₄ ).
(3,5-Di-t-butyl-4-methoxymethoxyphenyl) -3,4-dihydro-4-hydroxy-2-methyl-1 (2H) -isoquinolinone-3-carboxylic acid ethyl ester (single colorless crystals ) Was obtained. Toluene (100
ml) and p-toluenesulfonic acid hydrate (1.0 g) were added, and the mixture was heated under reflux for 1 hour. Ethyl acetate was added to the mixture, washed successively with water, aqueous sodium hydrogen carbonate and water, dried (Na ₂ SO ₄ ), and the solvent was distilled off to obtain the title compound as pale yellow crystals (1.60 g). Melting point: 225-227 ° C (recrystallized from acetone-isopropyl ether) Elemental analysis: calculated for C ₂₇ H ₃₃ NO ₄ C, 74.45; H, 7.64; N, 3.22 found C, 74.42; H, 7.42; N, 2.99

Step 3 4- (3,5-Di-tert-butyl-4-hydroxyphenyl) -2-methyl-1 (2H) -isoquinolinone-3-
Carboxylic acid To the compound (1.60 g) obtained in Step 2 was added ethanol (35 m
l), H ₂ O (7 ml) and potassium hydroxide (1.60)
g) was added and the mixture was heated under reflux for 24 hours. After evaporating the solvent, the residue was acidified by adding diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (Na ₂ SO ₄ ), and evaporated to give the title compound as colorless crystals (1.33 g). Melting point> 300 ° C. (recrystallized from acetone-isopropyl ether) Elemental analysis: calculated as C ₂₅ H ₂₉ NO ₄ .H ₂ O C, 70.57; H, 7.34; N, 3.29 Found C, 70.71; H, 7.60; N, 3.40

Reference Example 13 4-Phenyl-1H-2-benzothiopyran-3-carboxylic acid Step 1 2-bromomethylbenzophenone 2-methylbenzophenone (9.8 g), N-bromosuccinimide (8.9 g), peroxide Benzoyl (0.5
g), carbon tetrachloride (150 ml) under light irradiation
Heated to reflux for an hour. After cooling, the insolubles were removed by filtration and the filtrate was concentrated to give the title compound quantitatively as an oil. NMR (200 MHz, CDCl ₃ ) ppm: 4.70 (2H, s), 7.26-
7.65 (7H, m), 7.75-7.85 (2H, m) Step 2 2-benzoylbenzylthioacetic acid ethyl ester To a solution of the compound obtained in Step 1 in dichloromethane (100 ml) is ethyl thioglycolic acid ester (6.0 g) and triethylamine. (8.4 ml), stirred at room temperature for 1.5 hours, washed with water and dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (9: 1) to give the title compound as an oil (11.0 g). NMR (200 MHz, CDCl ₃ ) ppm: 1.24 (3H, t, J = 7 Hz),
3.04 (2H, s), 4.03 (2H, s), 4.12 (2H, q, J = 7Hz), 7.27-7.6
6 (7H, m), 7.78-7.82 (2H, m)

Step 3 4-Phenyl-1H-2-benzothiopyran-3-carboxylic acid ethyl ester Potassium tert-butoxy (7.14 g) in tetrahydrofuran (80 ml) was added to a solution of the compound (1
0.0g) in tetrahydrofuran (30 ml) was added dropwise. After stirring at room temperature for 40 minutes, the solvent was distilled off to about 1/2, H ₂ O was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residual oil was crystallized from isopropyl ether-hexane to give the title compound as pale yellow crystals (0.75g). 89-90 ° C (recrystallized from ethanol) Elemental analysis Calculated for C ₁₈ H ₁₆ O ₂ S Calculated C, 72.94; H, 5.44 Found C, 72.93; H, 5.55 The aqueous layer is acidic with 2N HCl. And extracted with ethyl acetate. The extract is washed with water, dried (MgSO ₄ ), and the solvent is distilled off.
-Phenyl-1H-2-benzothiopyran-3-carboxylic acid was obtained as colorless crystals (3.5 g). Melting point: 155-156 ° C (recrystallized from ethanol) Elemental analysis: Calculated for C ₁₆ H ₁₂ O ₂ S: C, 71.62; H, 4.51 Found C, 71.58; H, 4.47 Step 4 4-phenyl-1H-2- Benzothiopyran-3-carboxylic acid Ethyl carboxylate obtained in Step 3 (592 mg),
A mixture of 2N NaOH (3ml), ethanol (2ml), dioxane (6ml) was heated at 80 ° C for 1 hour. Water was added and the mixture was made acidic with 2N HCl and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was crystallized from isopropyl ether-hexane to give the title compound as colorless crystals. 155-156 ° C. This compound was identical to the carboxylic acid obtained in step 3.

Reference Example 14 4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-carboxylic acid Step 1 2- (2-methoxybenzoyl) benzylthioacetic acid ethyl ester Using 2-methoxy-2'-methylbenzophenone hand,
When the reaction and treatment were carried out in the same manner as in Steps 1 and 2 of Reference Example 13, the title compound was obtained as an oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.25 (3 H, t, J = 8 Hz),
3.10 (2H, s), 3.67 (3H, s), 4.16 (2H, s), 4.16 (2H, q, J = 8H
z), 6.94-7.06 (2H, m), 7.20-7.53 (6H, m) Step 2 4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-carboxylic acid ethyl ester diisopropylamine (2.1 ml) Was added dropwise to a solution of n-butyllithium in tetrahydrofuran (20 ml) at -78 ° C (1.6 mmol / ml, 8.5 ml). After the mixture was stirred at -78 ° C for 30 minutes, a solution of the compound obtained in Step 1 (1.4 g) in tetrahydrofuran (5 ml) was added dropwise. Stir at -78 ° C for further 30 minutes 2N-H
Cl was added and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), and the solvent was distilled off.
4-Dihydro-4-hydroxy-4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-carboxylic acid ethyl ester was obtained as an oil. The oily substance was dissolved in benzene and p-toluenesulfonic acid monohydrate (0.7
7 g) and heated to reflux with a Dean-Stark device.
Was. After 30 minutes, add water and extract with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1) to give the title compound as colorless crystals (0.7).
7 g). 86-87 ° C (recrystallized from ethanol) Elemental analysis calculated as C ₁₉ H ₁₈ O ₃ S Calculated C, 69.91; H, 5.56 Found C, 70.00; H, 5.69

Step 3 4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-carboxylic acid Using the compound obtained in Step 2, react and treat in the same manner as in Step 4 of Reference Example 13 to obtain the title compound as colorless crystals Was obtained as Melting point 190-192 ° C Elemental analysis calculated for C ₁₇ H ₁₄ O ₃ S C, 68.44; H, 4.73 found C, 68.48; H, 4.81 Example 1 N- (6-chloro-4-phenylisocoumarin- 3-yl) -N '-(2,4-difluorophenyl) urea 6-chloro-4-phenylisocoumarin-3-carboxylic acid (1.50 g), diphenylphosphoryl azide (DPPA)
(1.41 ml) and triethylamine (0.71 ml) were added dropwise with stirring at room temperature to a mixture of benzene (50 ml). The mixture was stirred at room temperature for 1 hour and under reflux for 30 minutes, and 2,4-difluoroaniline (0.80 ml) was added, followed by refluxing for 2 hours. After cooling, the reaction solution was washed successively with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, and dried (Na ₂ S
O ₄ ) and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-acetone = 4:
By subjecting to 1), the title compound was obtained as colorless crystals (0.90 g). Melting point: 196-197 ° C (recrystallized from ethyl acetate-isopropyl ether) Elemental analysis: calculated as C ₂₂ H ₁₃ N ₂ O ₃ ClF ₂ C, 61.91; H, 3.07; N, 6.56 found C, 62.03; H, 3.20; N, 6.44

Example 2 t-butyl N- (6-chloro-4-phenylisocoumarin-3-yl) carbamate 6-chloro-4-phenylisocoumarin-3-carboxylic acid (2.50 g), t-butanol (30 ml), DPPA (2.
A mixture of 35 ml) and triethylamine (1.18 ml) was stirred at room temperature for 1 hour and then refluxed for 1 hour. The reaction solution was concentrated, and ethyl acetate was added to the concentrate. The mixture was washed successively with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried (Na ₂ SO ₄ ) and evaporated to give the title compound as colorless crystals (1.52 g). Melting point: 183-184 ° C (recrystallized from ethyl acetate-isopropyl ether) Elemental analysis: calculated as C ₂₀ H ₁₈ NO ₄ Cl C, 64.61; H, 4.88; N, 3.77 found C, 64.36; H, 5.12; N , 3.60

Example 3 N- [6-chloro-1,2-dihydro-2-methyl-4
-Phenyl-1-oxoisoquinolin-3-yl]-
N '-(2,4-difluorophenyl) urea 6-chloro-4-phenylisocoumarin-3 of Example 1
6-chloro-2-methyl-4- instead of carboxylic acid
When the reaction and treatment were carried out in the same manner as in Example 1 using phenyl-1 (2H) -isoquinolinone-3-carboxylic acid, the title compound was obtained as colorless crystals. Melting point> 300 ° C. Elemental analysis value calculated as C ₂₃ H ₁₆ N ₃ O ₂ ClF ₂ calculated value C, 62.81; H, 3.67; N, 9.55 found value C, 62.82; H, 3.57; N, 9.46 Example 4 N- [ 6-chloro-1,2-dihydro-2-methyl-4-
Phenyl-1-oxoisoquinolin-3-yl] -N '
-(3-methylphenyl) urea 6-chloro-4-phenylisocoumarin-3 of Example 1
6-chloro-2-methyl-4- instead of carboxylic acid
When phenyl-1 (2H) -isoquinolinone-3-carboxylic acid was used and the reaction and treatment were carried out in the same manner as in Example 1 using 3-methylaniline instead of 2,4-difluoroaniline, the title compound was obtained as colorless crystals. Was done. Melting point> 300 ° C Elemental analysis calculated for C ₂₄ H ₂₀ N ₃ O ₂ Cl Calculated C, 68.98; H, 4.82; N, 10.06 Found C, 68.87; H, 4.94; N, 9.84

Example 5 t-butyl N- (6-chloro-1,2-dihydro-2-
Methyl-4-phenyl-1-oxoisoquinoline-3-
Il) carbamate 6-chloro-4-phenylisocoumarin-3 of Example 2
6-chloro-2-methyl-4- instead of carboxylic acid
When the reaction and treatment were carried out in the same manner as in Example 2 using phenyl-1 (2H) -isoquinolinone-3-carboxylic acid, the title compound was obtained as colorless crystals. Melting point 217-218 ° C Elemental analysis calculated as C ₂₁ H ₂₁ N ₂ O ₃ Cl Calculated C, 65.54; H, 5.50; N, 7.28 Found C, 68.87; H, 4.94; N, 7.06 Same as in Example 3. According to the method, 4-phenyl-1 (2H)
When the reaction was carried out using -isoquinolinone-3-carboxylic acids, the compound of Example 6-8 was obtained.

Example 6 N- (6-chloro-1,2-dihydro-4-phenyl-1
-Oxoisoquinolin-3-yl) -N '-(2,4-difluorophenyl) urea Melting point> 300 ° C Example 7 N- [1,2-dihydro-4- (4-fluorophenyl)-
2-methyl-1-oxoisoquinolin-3-yl]-
N '-(2,4-difluorophenyl) urea Melting point> 300 DEG C. Example 8 N- [1,2-dihydro-4- (2-methylphenyl)-
2,6,7-trimethyl-1-oxoisoquinoline-3-
Yl] -N '-(2,4-difluorophenyl) urea Melting point: 252-254 ° C. In the same manner as in Example 1, 4-phenylisocoumarin-3-carboxylic acid was used to react with DPPA and then reacted with amines. The reaction yielded the compounds of Examples 9-20.

Example 9 N- (7-Chloro-4-phenylisocoumarin-3-yl) -N '-(2,4-difluorophenyl) urea Melting point 194-195 ° C. Example 10 N- [4- ( 4-Fluorophenyl) -6-methylisocoumarin-3-yl] -N '-(2,4-difluorophenyl) urea Melting point 246-248 ° C Example 11 N- [4- (4-fluorophenyl) isocoumarin- 3-
Yl] -N '-(2,4-difluorophenyl) urea Melting point 204-205 ° C

Example 12 N- (4-phenylisocoumarin-3-yl) -N'-
(2,4-Difluorophenyl) urea Melting point 194-195 ° C Example 13 N- (6-Chloro-4-phenylisocoumarin-3-yl) -N '-(4-acetoxy-3,5-dimethylphenyl) Urea Melting point 218-219 ° C Example 14 N- [4- (2-methoxyphenyl) isocoumarin-3
-Yl] -N '-(4-acetoxy-3,5-dimethylphenyl) urea Melting point 224-225 ° C

Example 15 N- [4- (2-methoxyphenyl) isocoumarin-3
-Yl] -N '-(2,4-difluorophenyl) urea Melting point 213-215 ° C Example 16 N- [6-Fluoro-4- (4-fluorophenyl) isocoumarin-3-yl] -N'-( 2,4-difluorophenyl) urea Melting point 191-193 ° C Example 17 N- [6-Fluoro-4- (4-fluorophenyl) isocoumarin-3-yl] -N '-(4-acetoxy-
3,5-dimethylphenyl) urea melting point 233-234 ° C

Example 18 N- (4-phenylisocoumarin-3-yl) -N'-
(4-acetoxy-3,5-dimethylphenyl) urea Melting point 223-225 ° C Example 19 N- [4- (2-methoxyphenyl) isocoumarin-3
-Yl] -N'-cyclohexylurea Melting point 217-219 ° C Example 20 N- [4- (2-methoxyphenyl) isocoumarin-3
-Yl] -N'-ethoxycarbonylmethylurea Melting point 155-157 ° C

Example 21 Benzyl N- [4- (2-methoxyphenyl) isocoumarin-3-yl] carbamate 4- (2-methoxyphenyl) isocoumarin-3-carboxylic acid (148 mg), dry benzene (8 ml), DPPA
(0.143 ml) and triethylamine (0.071 m)
The mixture obtained in l) was stirred at room temperature for 1 hour and then heated to reflux for 30 minutes. This mixture was added to benzyl alcohol (0.1
5 ml) and refluxed for 4 hours. After cooling, the reaction solution was
The extract was washed successively with dilute hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried (Na ₂ SO ₄ ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-acetone = 3: 1) to give the title compound as colorless crystals (50%).
mg). 144-146 ° C (recrystallized from ethyl acetate-ethyl ether) Elemental analysis Calculated for C ₂₄ H ₁₉ NO ₅ C, 71.81; H, 4.77; N, 3.49 Found C, 71.64; H, 4.52; N, 3.57

Example 22 t-butyl N- [4- (2-methoxyphenyl) isocoumarin-3-yl] carbamate 6-chloro-4-phenylisocoumarin-3 of Example 2
-4- (2-methoxyphenyl) instead of carboxylic acid
The reaction and treatment in the same manner as in Example 2 using isocoumarin-3-carboxylic acid gave the title compound as colorless crystals. 203-205 ° C (recrystallized from acetone-ethyl ether) Elemental analysis Calculated for C ₂₁ H ₂₁ NO ₅ C, 68.65; H, 5.76; N, 3.81 Found C, 68.42; H, 5.48; N, 3.83 Example 23 N- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,2-dihydro-2-methyl-1-oxoisoquinolin-3-yl] -N '-(2 The reaction and treatment were carried out in the same manner as in Example 3 using the isoquinoline-3-carboxylic acid obtained in Reference Example 12 to give the title compound as colorless crystals. 230-232 ° C

Example 24 N- [4- (2-methoxyphenyl) -1,2-dihydro-2-methyl-1-oxoisoquinolin-3-yl]
-N '-(2,4-difluorophenyl) urea When the reaction and treatment were carried out in the same manner as in Example 3 using the isoquinoline-3-carboxylic acid obtained in Reference Example 11, the title compound was obtained as colorless crystals. Melting point 207-209 [deg.] C Example 25 N- [4- (2-methoxyphenyl) -1,2-dihydro-2-methyl-1-oxoisoquinolin-3-yl]
-N'-ethoxycarbonylmethylurea 6-chloro-4-phenylisocoumarin-3 of Example 1
-Reaction and treatment in the same manner as in Example 1 using the compound obtained in Reference Example 11 instead of carboxylic acid and using glycine ethyl ester instead of 2,4-difluoroaniline give the title compound as colorless crystals. Was. 128-130 ° C

Example 26 N- (4-acetoxy-3,5-dimethylphenyl)-
N '-(4-phenyl-1H-2-benzothiopyran-
3-yl) urea 4-phenyl-1H-2-benzothiopyran-3-carboxylic acid (Reference Example 13) (268 mg), DPPA (330)
mg) and benzene (5 ml) were added dropwise with triethylamine (0.14 ml), and refluxed at room temperature for 30 minutes.
Stir for 0 minutes. Then, 4-acetoxy-3,5-dimethylaniline hydrochloride (258 mg) and triethylamine (0.17 ml) were added, and the mixture was further heated under reflux for 20 minutes, washed with water and dried (MgSO ₄ ), and the solvent was distilled off. The residue was treated with ether to give the title compound as colorless crystals (280 m
g). Melting point: 206-208 ° C (recrystallized from ethanol-dichloromethane) Elemental analysis: calculated as C ₂₆ H ₂₄ N ₂ O ₃ C, 70.25; H, 5.44; N, 6.30 Found: C, 69.93; H, 5.21; N, 6.11

Example 27 N- (4-acetoxy-3,5-dimethylphenyl)-
N '-[4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-yl] urea Using the compound obtained in Reference Example 14, the reaction and treatment were carried out in the same manner as in Example 26 to give the title compound. Was. Melting point: 248-249 ° C (recrystallized from acetone) Elemental analysis: calculated for C ₂₇ H ₂₆ N ₂ O ₄ C, 68.33; H, 5.52; N, 5.90 found: C, 68.38; H, 5.34; N, 5.98 Example 28 N- (4-N, N-dimethylaminophenyl) -N'-
[4- (2-methoxyphenyl) -1H-2-benzothiopyran-3-yl] urea Instead of 4-phenyl-1H-2-benzothiopyran-3-carboxylic acid of Example 26, 4- (2-methoxyphenyl) Using -1H-2-benzothiopyran-3-carboxylic acid and 4-N, N-dimethylaminoaniline instead of 4-acetoxy-3,5-dimethylaniline, the reaction and treatment were conducted in the same manner as in Example 26. The title compound was obtained. 229-230 ° C (recrystallized from acetone) Elemental analysis Calculated for C ₂₅ H ₂₅ N ₃ O ₂ S Calculated C, 69.58; H, 5.84; N, 9.74 Found C, 69.69; H, 5.80; N, 9.74

Example 29 N- (4-hydroxy-3,5-dimethylphenyl)-
N '-(4-phenyl-1H-2-benzothiopyran-
3-yl) urea 2N NaOH was added to a solution of the compound obtained in Example 26 (80 mg) in methanol-tetrahydrofuran (1: 1, 3 ml).
(1 ml) was added and stirred at room temperature for 15 minutes. Add water 2
Acidified with NHCl and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and acetone was added to the extract to give the title compound as colorless crystals (32 mg). Melting point 227-228 ° C Elemental analysis calculated for C ₂₄ H ₂₂ N ₂ O ₂ S Calculated C, 71.62; H, 5.51; N, 6.96 Found C, 71.37; H, 5.53; N, 7.04 Example 30 N- ( 4-N, N-dimethylaminophenyl) -N'-
(6-chloro-4-phenylisocoumarin-3-yl)
Urea Instead of 2,4-difluoroaniline of Example 1, 4
Example 1 using -N, N-dimethylaminoaniline
The reaction and treatment were conducted in the same manner as in the above to give the title compound as colorless crystals. Melting point 210-212 ° C (recrystallized from acetone-ethyl ether) Example 31 N- (4-N, N-dimethylaminophenyl) -N'-
[4- (2-Methoxyphenyl) isocoumarin-3-yl] urea 6-chloro-4-phenylisocoumarin-3 of Example 1
-As in Example 1, using 4- (2-methoxyphenyl) isocoumarin-3-carboxylic acid instead of carboxylic acid and 4-N, N-dimethylaniline instead of 2,4-difluoroaniline The title compound was obtained as colorless crystals. 229-231 ° C (recrystallized from acetone)

[0077]

The present invention provides a novel A having an excellent effect.
A CAT inhibitor can be provided.

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/10 A61P 9/10 101 101 C07D 311/76 C07D 311/76 335/06 335/06 (56) References JP-A-2-6457 (JP, A) Special Table Hei 5-506844 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 217/24 A61K 31/365 A61K 31/38 A61K 31/47 A61P 3 / 06 A61P 9/10 A61P 9/10 101 C07D 311/76 C07D 335/06 CA (STN) EPAT (QUESTEL) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. A compound of the general formula [Wherein the A ring and the B ring may be a benzene ring which may have a substituent, X represents O, S or NR ¹ (R ¹ represents a hydrogen atom or an alkyl group), Y represents NH, O or (CH ₂ ) _n (n represents an integer of 0 to 2), and R ² represents a substituent. Shows a hydrocarbon group which may have a group. ] The heterocyclic amine derivative represented by these, or its salt. 2. A compound of the general formula [Wherein the A ring and the B ring are benzene rings which may have a substituent, Z is O or S, X is O, S or NR
¹ (R ¹ represents a hydrogen atom or an alkyl group);
H, O or (CH ₂ ) _n (n represents an integer of 0 to 2)
And R ² represents a hydrocarbon group which may have a substituent. ] The heterocyclic amine derivative represented by these, or its salt. 3. A ring and a B ring each being (1) a halogen atom
(2) substituted with 1 to 5 halogen atoms
A linear or branched C _1-6 alkyl group which may be
(3) Even when substituted with 1 to 5 halogen atoms
Good linear or branched C _1-6 alkoxy groups, (4)
A straight line which may be substituted with 1 to 5 halogen atoms.
A chain or branched C _1-6 alkylthio group, (5) C _1-7
Acylamino group, (6) C _1-3 acyloxy group and
(7) 1 to 1 selected from the group consisting of hydroxyl groups
Represents a benzene ring which may be substituted with 4 substituents
Or adjacent carbons on the ring A or ring B are of the formula
-(CH ₂ ) l- (l is an integer of 3 to 5)
May form a 5- to 7-membered ring together with the radical
A compound according to claim 1. 4. The method according to claim ^{1, wherein} the alkyl group of R ¹ is linear or branched.
C _1-6 alkyl group, C _3-6 cycloalkyl group or C _3-6
2. A cycloalkyl-C _1-4 alkyl group.
Compound. 5. R ² is (i) a halogen atom and (ii) 1 is not present.
Straight chain, which may be substituted with 5 halogen atoms
_{Or a} branched C _1-6 alkyl group, (iii) 1 to 5
Linear or branched, which may be substituted by halogen atoms
C _1-6 alkoxy group, (iv) 1 to 5 halogen
Linear or branched C which may be substituted with
_1-6 alkylthio group, (v) C _1-7 acylamino group, (v
i) C _1-3 acyloxy group and (vii) hydroxyl group
Substituted with 1 to 5 substituents selected from the group consisting of
May be, (1) linear or branched C _1-8 al
Kill group, (2) C _3-8 cycloalkyl group, (3) C _3-8 Shi
A cycloalkyl -C _1-4 alkyl group, (4) C _6-10 aryl
Or (5) a C _7-16 aralkyl group.
Listed compound. Wherein R ² is (i) a halogen atom, (ii) C _1-4 A
Alkyl group, (iii) C _1-4 alkoxy group, (iv) hydroxy
A sil group, (v) a C _1-3 acyloxy group and (vi)
Is an amino which may be substituted by two C _1-4 alkyl groups.
1 to 5 substituents selected from the group consisting of
2. The compound according to claim 1, which is an optionally substituted phenyl group.
Compound. 7. A compound of the general formula [The symbols in the formula are as defined in claim 1.] Or a salt thereof, and a general formula R ² —Y′—H wherein Y ′ is NH or O, and R ² has the same meaning as described in claim 1. A compound represented by the general formula: [Wherein, Y ′ has the same meaning as described above, and the other symbols have the same meanings as in claim 1. The method for producing a heterocyclic amine derivative or a salt thereof represented by the formula: 8. A compound of the general formula [The symbols in the formula are as defined in claim 1.] Or a salt thereof and a general formula R ² —Y—CO ₂ H [wherein the symbols have the same meanings as in claim 1]. And a salt thereof or a reactive derivative thereof. [The symbols in the formula are as defined in claim 1.] The method for producing a heterocyclic amine derivative or a salt thereof represented by the formula: 9. A compound of the general formula [R ⁵ is H ₂ or ＣC ＝ O, and the other symbols are as defined in claim 1. ] The heterocyclic amine derivative represented by these, or its salt. 10. A compound of the general formula [The symbols in the formula are as defined in claim 1. Wherein the heterocyclic amine derivative represented by the formula or a salt thereof is hydrolyzed. [The symbols in the formula are as defined in claim 1. And a salt thereof. 11. A compound of the general formula [The symbols in the formula are as defined in claim 1. An acyl CoA: cholesterol transferase inhibitor comprising a heterocyclic amine derivative represented by the formula: 12. Hypercholesterolemia, arteriosclerosis, illness
Claimed as a preventive / therapeutic agent for ischemic heart disease or cerebrovascular disease
Item 12. An inhibitor according to Item 11.