JP2535468B2 - Benzopyran derivative, method for producing the same, and pharmaceutical composition containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel benzopyran derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. More specifically, the present invention relates to an acylamino group or a substituted urea group on an aromatic ring. The present invention relates to a benzopyran derivative and a pharmaceutically acceptable acid adduct thereof, a method for producing the same, and a pharmaceutical composition for antihyperlipidemia and antiarteriosclerosis based on the ACAT inhibitory action, which contains them as active ingredients.

BACKGROUND ART It is well known that arteriosclerosis is extremely important as a cause of various cardiovascular diseases.
Alternatively, active research is being conducted with the aim of reducing atherosclerosis. In particular, although a drug that lowers cholesterol in serum and arterial wall has been confirmed to be useful, an ideal drug having a clear clinical effect and few side effects has not been realized.

Recently, it has been revealed that the accumulation of cholesterol ester in the arterial wall is an important factor in the progression of arteriosclerosis. Therefore, reducing the amount of cholesterol in blood is effective in suppressing the progression and regression of arteriosclerosis.

Cholesterol in food is esterified in the small intestinal mucosa and then taken into the blood as chylomicrons. Acyl-CoA: Cholesterol Acyltransferas is involved in the production of cholesterol ester in the small intestinal mucosa and arterial wall.
It is known that e (ACAT) plays an important role. Therefore, it is considered that cholesterol absorption can be hindered by inhibiting ACAT in the small intestinal mucosa and suppressing esterification, and blood cholesterol level can be reduced.

Also, cholesterol is accumulated as cholesterol ester in the arterial wall. Therefore, inhibition of ACAT in the arterial wall is expected to effectively suppress the accumulation of cholesterol ester.

From the above, it is considered that the ACAT inhibitor becomes an effective drug for hyperlipidemia and arteriosclerosis by suppressing cholesterol absorption in the small intestine and cholesterol accumulation in the arterial wall.

Conventionally, as such an ACAT enzyme inhibitor, for example, a urea derivative (reference document; J. Med. Chem., 29, 1131 (1986), JP-A-63-317661, JP-A-1-93569, etc.)
And amide derivatives (reference; Japanese Patent Publication No. 63-54718),
JP-A-63-253060), but the structure is different from that of the compound of the present invention.

On the other hand, as a patent describing the benzopyran derivative, there is U.S. Pat.No. 4,415,741 and the like, but there is no specific disclosure about the compound of the present invention, and the benzopyran derivative has an ACAT inhibitory action so far. Not known at all. In addition, it has an antihyperlipidemic effect 6-
Acylaminochromanones (Reference: Japanese Patent Publication No. 60-1562)
No. 6, gazette and Japanese Patent Publication No. 60-35346 gazette) are known,
Its action is weaker than that of the compounds of the invention, and
It is not known to have an AT inhibitory effect. Furthermore, chromanes having a urea group on the aromatic ring (reference: J. Med. Che
m., vol. 13, p. 584 (1970)), 8-acylaminobenzopyrans having a leukotriene antagonistic action (references;
JP-A-61-50977, JP-A-61-126061, JP-A-61-143371, JP-A-62-230760, J. Me.
d. Chem., 31:84 (1988)), 8-acylaminochromans having a local anesthetic action (reference: Khim. Getrotsi).
kl. Soedin., 320 (1987)), but these are not known to have antihyperlipidemic action and ACAT inhibitory action.

DISCLOSURE OF THE INVENTION Accordingly, the present invention provides a novel benzopyran derivative having an ACAT enzyme inhibitory action and lowering blood cholesterol or arterial wall cholesterol and showing an excellent therapeutic effect, a method for producing the same, and a drug containing the same. The purpose is to

Other objects and advantages of the present invention will be apparent from the following description.

According to the invention, formula (I): [In the formula, one of X and Y is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group; and n is 0 or 1] and a pharmaceutically acceptable salt thereof. It

According to the invention, there is also formula (Ia): [In the formula, ^one of X ¹ and Y ¹ is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₆ lower alkyl group] in producing a benzopyran derivative represented by
Formula (II-a): (In the formula, ^one of X ¹ 'and Y ¹ ' is -N = C =
It is the same as X and Y except that it is O, and R ^{1 to} R ⁸ are as defined above. There is provided a process for the preparation of a benzopyran derivative of formula (Ia) and a pharmaceutically acceptable salt thereof, which comprises reacting with R ⁹ and R ¹⁰ as defined above.

Further in accordance with the present invention, formula (Ib): [In the formula, one of X ² and Y ² is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
Arylalkyl C ₁ -C ₁₉ alkyl group substituted through a nitrogen atom which may be substituted with a group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group or an unsubstituted or substituted C ₆ -C ₁₉ represents an arylalkyl group)
R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₆ lower alkyl group] in producing a benzopyran derivative represented by
Formula (II-b): (In the formula, X ² ′ and Y ² ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above). (wherein, R ⁹ is as defined above) wherein R ⁹ -N = C-O method for producing a benzopyran derivative and its pharmaceutically acceptable salts of formula (I-b), which comprises reacting a Will be provided.

According to the invention, further formula (Ic): [In the formula, one of X ³ and Y ³ is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₆ lower alkyl group] in producing a benzopyran derivative represented by
Formula (II-c): (In the formula, X ³ ′ and Y ³ ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above.) Preparation of a benzopyran derivative of formula (Ic) and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula R ⁹ COOH, wherein R ⁹ is as defined above, or a reactive derivative thereof. A method is provided.

According to the present invention, an AC containing the above-mentioned benzopyran derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
An AT inhibitor, antihyperlipidemic agent and antiarteriosclerotic agent composition are provided.

BEST MODE FOR CARRYING OUT THE INVENTION A benzopyran derivative of the formula (I) according to the present invention comprises a compound having a substituted urea group on the aromatic ring of n = 1 in the formula (I) and an aromatic compound of n = 0. The compound is roughly classified into a compound having a substituted acylamino group on the group ring, and each compound is represented by the formula (I) in which R ³ and R ⁴ are independently a hydrogen atom or unsubstituted or substituted C ₁ -C ₃ chroman derivatives and pharmaceutically acceptable salts thereof is a lower alkyl group, in formula (I), an oxygen atom and R ³ and R ⁴ together, R ⁵ and R ⁷ together carbon A chromanone derivative not representing a carbon bond and a pharmaceutically acceptable salt thereof, and in the formula (I), R ³ and R ⁴ together represent an oxygen atom, and R ⁵ and R ⁷ together And a chromone derivative that represents a carbon-carbon bond It is roughly classified into biological acceptable salts.

A first group of benzopyran derivatives according to the present invention are of formula (I-
It is represented by a).

[In the formula, ^one of X ¹ and Y ¹ is a formula: And the other represents the same substituent as R ¹ and R ² ] R ¹ and R ² in formula (Ia) are each independently,
Hydrogen atom, halogen atom, unsubstituted or substituted C ₁
To C ₆ lower alkyl group, unsubstituted or substituted C _{1 to} C ₆
A lower alkoxy group, a hydroxyl group, a nitro group, a cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkyl amino group, C ₁ -C ₇ lower alkyloxycarbonyl group, carboxyl group, C ₁ -C ₇ lower acyl group or a C ₁ -C ₇ lower acyloxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. The lower alkyl group means a C _{1 to} C ₆ chain (straight or branched) or cyclic alkyl group, and preferred specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, cyclopropyl, cyclohexyl and cyclopropylmethyl and the like. The lower alkoxy group means a group consisting of the C _{1 to} C ₆ lower alkyl group and an oxy group, and preferable specific examples thereof include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, Hexyloxy, cyclopropyloxy, cyclohexyloxy and cyclopropylmethoxy and the like. The lower alkylamino group is the same or different from the above C _1-
C ₆ means a mono- or dialkylamino group consisting of a lower alkyl group and an amino group, and preferable specific examples thereof include
Examples include methylamino, ethylamino, dimethylamino, diethylamino and N-butyl-N-methylamino. The lower alkoxycarbonyl group means the above C ₁ to
C ₆ means a group consisting of a lower alkoxy group and a carbonyl group, and preferable specific examples thereof include methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl and tert
-Butoxycarbonyl and the like. The lower acyl group means a group consisting of the C _{1 to} C ₆ lower alkyl group and a carbonyl group, and a preferable specific example thereof is acetyl,
Mention may be made of propionyl, butyryl, benzoyl and the like. The lower acylamino group means a group consisting of the C _{1 to} C ₇ lower acyl group and an amino group, and preferable specific examples thereof include acetylamino, propionylamino and benzoylamino. The lower acyloxy group means a group consisting of the C _{1 to} C ₇ lower acyl group and an oxy group, and preferable specific examples thereof include acetoxy, propionyloxy, butyryloxy and benzoyloxy. Further, as the substituent of the substituted lower alkyl group or lower alkoxy group,
Examples thereof include a halogen atom, a hydroxyl group and an amino group. Examples of such a substituted lower alkyl group include a trifluoromethyl group.

R ^{3 to} R ⁸ in formula (Ia) each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ together form an oxygen atom. ^May represent an atom, R ⁵ and R ⁷ may together represent a carbon-carbon bond, and R ⁷ and R ⁸ may together form a C ₅ -C ₇ carbocycle. Good. Preferable specific examples of the C ₁ -C ₃ lower alkyl group include methyl, ethyl, propyl and isopropyl.

R ⁹ in the formula (Ia) is a substituted C _{6 to} C ₂₀ aryl group, an unsubstituted or substituted C _{5 to} C ₂₀ cycloalkyl or cycloalkenyl group other than the 1-position, or a formula: Represents a group represented by. The substituted aryl group is
Halogen atom, C ₁ -C ₁₄ chain (straight or branched)
Or a cyclic alkyl group, a C ₁ -C ₁₄ alkoxy group, C ₁
To C ₁₄ acylamino group, C _{1 to} C ₁₄ mono- or dialkylamino group, C _{1 to} C ₁₄ alkyloxycarbonyl group, C
It means an aromatic hydrocarbon group substituted by a _{1 to} C ₁₄ acyl group or a C _{1 to} C ₁₄ acyloxy group, and preferred specific examples thereof include p-fluorophenyl, p-decylphenyl, and p-methoxy. Phenyl, p-isohexyloxyphenyl, p-decyloxyphenyl, p-butyrylaminophenyl, p- (N-butyl-N-methylaminophenyl, p-valeryloxyphenyl and m-heptanoylphenyl groups, etc. No substitution is possible
Preferable specific examples of the cycloalkyl or cycloalkenyl group substituted at other positions include cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclohexene-
1-yl, 4-hexylcyclohexyl, 4-decyloxycyclohexyl and the like can be mentioned.

R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² are taken together to form a C _{3 to} C ₇ carbocycle. May be formed. The lower alkyl group has the same definition as the lower alkyl group for R ¹ , and its preferable specific examples include the same examples. R ¹³ is an unsubstituted or substituted C _{5 to} C ₁₉ chain or cyclic alkyl or alkenyl group, an unsubstituted or substituted C _{6 to} C ₁₉ aryl group, or an unsubstituted or substituted C _{6 to} C Represents ₁₉ arylalkyl groups. R
Preferred examples of R ⁹ when ¹³ is a C _{5 to} C ₁₉ alkyl group include hexyl, isohexyl, octyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosin, 1,1-dimethyl. Heptyl, 1,1-dimethylundecyl, 1,1,12,12
-Tetramethyltridecyl, 1-methyltridecyl, 1
-Decylcyclohexyl, 1-decylcyclopentyl,
1-dodecylcyclopropyl, 1-cyclohexyl-1
-Methylethyl, 1-ethyloctyl and the like. Specific examples of R ⁹ when R ¹³ is a C ₅ -C ₁₉ alkenyl group include hexenyl, 8-tridecenyl, 8
-Heptadecenyl, 9-octadecenyl, 8,11-heptadecadienyl, 1,1-dimethyl-8-nonenyl and cyclohexenylylmethyl. R ¹³ is C _{5 to} C
Preferred specific examples of R ⁹ when it is ₁₉ aryl group,
Benzyl, 1-phenylcyclopentyl, 1-phenylethyl, 1-methyl-1- (2-pyridyl) ethyl and the like can be mentioned. Specific examples of R ⁹ when R ¹³ is a C ₅ -C ₁₉ arylalkyl group include 2-phenylethyl, 8-phenyloctyl, 1,1-dimethyl-11-phenylundecyl, 1-benzyl. Cyclopentyl, (1
-Phenylcyclopentyl) methyl, 1,1-dimethyl-
4- (1-methyl-1,2,3,4-tetrahydroquinoline-
6-yl) butyl, 1,1-dimethyl-7-pyridylheptyl, 2,2-diphenylethyl and the like.
Further, R ¹³ is a group represented by the formula -AZB (in the formula,
A is an alkyl group of C ₁ -C _12, Z is an oxygen atom, a sulfur atom or the formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C It represents the ₆ -C ₁₉ aryl group or an unsubstituted or substituted C ₆ -C ₁₉ group represented arylalkyl represents a group). The lower alkyl group and the lower acyl group for R ¹⁴ have the same definition as the lower alkyl group and the lower acyl group for R ¹ , and the preferred examples thereof are also the same. Preferable specific examples of R ¹⁴ together with B to form a cyclic amine include 1-pyrrolidinyl, piperidino, morpholino, thiolphorino, and 4-methyl-1-.
Examples thereof include piperazinyl and 4-benzyl-1-piperazinyl. The alkyl group for B has the same definition as the lower alkyl group for R ¹ or the alkyl group for R ¹³ , and the preferred examples thereof are also the same. The aryl group and arylalkyl group for B have the same definition as the aryl group and arylalkyl group for R ¹³ , and preferred examples thereof are also the same. Specific preferred examples of R ⁹ when R ¹³ is a group represented by the formula —A—Z—B include 6-isobutoxyhexyl, 6-p-clophenoxyhexyl, and 5-p-dimethylaminophenoxy. Pentyl, 5-isohexyloxy-1,1-dimethylpentyl, 7-isohexyloxy-1,1-dimethylheptyl, 7-isobutoxy-1,1-dimethylheptyl, 7-neopentyloxy-1,1-dimethyl Heptyl, 5-p-chlorophenoxy-1,1-dimethylpentyl, 6-p-chlorophenoxy-1,1-dimethylhexyl, 7-p-chlorophenoxy-1,1-dimethylheptyl, 1,1-dimethyl- 7-p-tolyloxyheptyl,
5- (p-tert-butylphenoxypentyl, 1,1-dimethyl-6-p-dimethylaminophenoxyhexyl,
1,1-dimethyl-7-p-dimethylaminophenoxyheptyl, 7-isopropylamino-1,1-dimethylheptyl, 7-benzylamino-1,1-dimethylheptyl,
7- (N-benzyl-N-methylamino) -1,1-dimethylheptyl, 7- (N-p-chlorobenzyl-N-methylamino) -1,1-dimethylheptyl, 7- (N-p
-Chlorophenyl-N-methylamino) -1,1-dimethylheptyl, 1,1-dimethyl-7-piperidinoheptyl, 1,1-dimethyl-7- (4-methyl-1-piperazinyl) heptyl, 7- (4-benzyl-1-piperazinyl) -1,1-dimethylheptyl, 5- (4-benzyl-
1-piperazinyl) -1,1-dimethylpentyl and 6
-(P-chlorophenylthio) -1,1-dimethylhexyl and the like can be mentioned. Further, each group of R ¹³ is a single or plural halogen atom, lower alkyl group, lower alkoxy group, hydroxy group, nitro group, cyano group, lower acylamino group, lower alkylamino group, lower alkyloxycarbonyl group, carboxyl group. It may be substituted with a group, a lower acyl group or a lower acyloxycarbonyl group. The definition of these substituents is the same as the definition in R ¹ , and its preferable specific examples include the same examples. Preferable specific examples of R ⁹ including R ¹³ substituted by these substituents include 10-ethoxycarbonyldecyl, 2- (p-nitrophenyl) ethyl, 7-p-chlorophenyl-1,1.
-Dimethylheptyl, 4-p-isobutylphenyl-1,
1-dimethylbutyl, 1- (3-benzoylpropyl)
Cyclopentyl, 4-p-diethylaminophenyl-1,
1-dimethylbutyl, 6-p-ethoxyphenyl-1,1-
Examples thereof include dimethylhexyl, (1-m-cyanophenylcyclopentyl) methyl, (1-p-dimethylaminophenylcyclopentyl) methyl and (1-p-methoxyphenylcyclopentyl) menyl.

R ¹⁰ in formula (Ia) represents a hydrogen atom or a C ₁ -C ₈ lower alkyl group. The lower alkyl group has the same definition as the lower alkyl group for R ¹ , and its preferable specific examples include the same examples.

This compound has the formula (II-a): (In the formula, ^one of X ¹ 'and Y ¹ ' is -N = C =
It is the same as X and Y except that it is O, and R ^{1 to} R ⁸ are as defined above, and a compound represented by the formula (benzopyranyl isocyanate) is represented by the formula It is prepared by reacting with an amine represented by the formula: wherein R ⁹ and R ¹⁰ are as defined above.

The benzopyranyl isocyanate represented by the above formula (II-a) can be produced according to a conventionally known method. For example, it can be obtained by a Hofmann decomposition reaction of a corresponding carboxylic acid amide, a thermal decomposition reaction of a carboxylic acid azide, or a reaction of a corresponding amine with phosgene or a homologous reagent thereof.

The above amines can be produced according to a conventionally known method.

The production method provided by the present invention is carried out by reacting 1 equivalent of benzopyranyl isocyanate represented by the above formula (II-a) with 0.2 to 5 equivalents of the above amines without solvent or in the presence of a solvent. can do. The reaction temperature is -20 to 150 ° C, preferably room temperature to 100 ° C, and the reaction time is usually 72 hours or less. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, aprotic polar solvents such as ethyl acetate, dimethylformamide and dimethyl sulfoxide. Is used.

After completion of the reaction, usual separation and purification operations, that is, extraction,
The desired benzopyran derivative represented by the above formula (Ia) can be isolated by performing recrystallization, chromatography or the like. In addition, they can be converted into pharmaceutically acceptable salts by conventional methods.

The second benzopyran derivative according to the present invention has the formula (I-
It is represented by b).

[In the formula, one of X ² and Y ² is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
In represents a group represented by; R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group].

In the formula (Ib), each group of R ^{1 to} R ⁸ and its associated R ^{9 to} R ¹⁴ , A, Z and B represent the same definition as each group in the formula (Ia), The same example can be given as a specific example.

This benzopyran derivative has the formula (II-b): (In the formula, X ² ′ and Y ² ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above) ( Benzopyranylamines) with isocyanates of the formula R ⁹ —N═C—O, where R ⁹ is as defined above.

The benzopyranylamine represented by the above formula (II-b) can be produced according to a conventionally known method. Further, the above-mentioned isocyanates can also be produced according to a conventionally known method.

The production method according to the present invention comprises 1 equivalent of benzopyranylamine represented by the above formula (II-b) and the above isocyanates.
It can be carried out by reacting 0.2 to 5 equivalents in the absence or presence of a solvent. The reaction temperature is -20 to 150 ° C, preferably room temperature to 100 ° C, and the reaction time is usually 72 hours or less. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, aprotons such as dimethylformamide and dimethylsulfoxide. A polar solvent or the like is used.

After completion of the reaction, usual separation and purification operations, that is, extraction,
The desired benzopyran derivative represented by the above formula (Ib) can be isolated by performing recrystallization, chromatography or the like. In addition, they can be converted into pharmaceutically acceptable salts by conventional methods.

The third benzopyran derivative according to the present invention has the formula (I-
It is represented by c).

[In the formula, one of X ³ and Y ³ is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷
May together represent a carbon-carbon bond, R ⁷ and
R ⁸ may be taken together to form a C ₅ -C ₇ carbocycle; R ⁹ is a substituted C ₆ -C ₂₀ aryl group, unsubstituted or substituted at positions other than 1 -C _{5. 20} cycloalkyl or cycloalkenyl groups, or a formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
Represents a group represented by.

In the formula (I-c), each group of R ^{1 to} R ⁸ and its associated R ^{9 to} R ¹⁴ , A, Z and B represent the same definition as each group in the formula (Ia), The same example can be given as a specific example.

The compound (I-c) has the formula (II-c): (In the formula, X ³ ′ and Y ³ ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above.) Is prepared by reacting with R ⁹ COOH, where R ⁹ is as defined above, or a reactive derivative thereof.

The compound represented by the above formula (II-c) can be produced according to a conventionally known method as described above. The carboxylic acids or their reactive derivatives can also be produced according to conventionally known methods.

The production method provided by the present invention includes, for example, the above formula (II-
1 equivalent of benzopyranylamine represented by c) and 1 to 5 equivalents of the above-mentioned carboxylic acids, for example, 1 to 2 equivalents of dicyclohexylcarbodiimide and basic amines such as triethylamine, pyridine, 0.1 to 1.5 equivalents of 4-dimethylaminopyridine. It can be carried out by reacting and in the presence of a solvent.

The reaction temperature is −20 to 150 ° C., preferably room temperature to 100 ° C., and the reaction time is usually 72 hours or less.

Alternatively, by reacting 1 equivalent of benzopyranylamine represented by the above formula (II-c) with a reactive derivative of the above carboxylic acid, for example, 1 to 5 equivalents of a corresponding carboxylic acid chloride or acid anhydride in the presence of a solvent. It can be carried out.

The reaction temperature is in the range of -20 to 150 ° C, preferably -10 to 100 ° C, and the reaction time is usually 72 hours or less.

As the reaction solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, and aprotic polar solvents such as dimethylformamide and dimethylsulfoxide are used. . In this case, basic amines such as triethylamine, pyridine, 4-dimethylaminopyridine and the like are added in an amount of 0.1 to 1.5.
You may add an equivalent amount.

After completion of the reaction, usual separation and purification operations, that is, extraction,
The desired benzopyran derivative represented by the above formula (Ic) can be isolated by performing recrystallization, chromatography or the like.

According to the present invention, the compound of the present invention may have a basic group in its molecule, and may be an acid adduct at this time, and examples of such an acid include hydrochloric acid, hydrobromic acid and sulfuric acid. Examples thereof include mineral acids such as phosphoric acid and carbonic acid, organic acids such as citric acid, malic acid, oxalic acid, tartaric acid, fumaric acid, and methanesulfonic acid.

Specific preferred examples of the benzopyran derivative represented by the general formula [I] according to the present invention include compounds having each substituent shown in the following table. In addition, G in the table
Is the formula: Represents When the compound of the present invention has an asymmetric carbon in the structural formula, it includes all optical isomers thereof.

INDUSTRIAL APPLICABILITY The novel benzopyran derivative and pharmaceutically acceptable salt thereof provided by the present invention have an ACAT enzyme inhibitory action and an excellent pharmacological action to reduce total cholesterol and LDL in blood, liver and arterial wall. It is useful for suppressing the progression of hyperlipidemia and arteriosclerosis and for regression.

The benzopyran derivative and the pharmaceutically acceptable salt thereof according to the present invention can be mixed with a pharmacologically unfriendly carrier to give a pharmaceutical composition, and the content of the active ingredient in the pharmaceutical composition is particularly Although not limited, it is usually 5 to 70% by weight.

The benzopyran derivative and the pharmaceutically acceptable salt thereof provided by the present invention can be administered orally.

Examples of the dosage form of oral agents include tablets, powders, granules, capsules and the like.

To form a dosage form, for example, an excipient such as lactose, starch, crystalline cellulose, a binder such as carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, and the like, and a disintegrating agent such as sodium alginate, sodium hydrogen carbonate, and sodium laurate. And can be molded by a usual method. Powders and granules can be formed by the same method. Capsules are powders,
It is molded by filling granules and the like into capsules such as gelatin. Examples of parenteral agents include suppositories, transdermal agents such as patches, injections and the like.

The dose of the benzopyran derivative and the pharmaceutically acceptable salt thereof provided by the present invention varies depending on the degree of disease, age of the patient, sex, etc., but is usually 1 to 500 mg / adult per adult.

In the compound names described in the present specification,
Chroman represents 3,4-dihydro-2H-benzopyran,
4-chromanone is 3,4-dihydro-4-oxo-2H-1.
-Benzopyran, 4-chromanonyl represents 3,4-dihydro-4-oxo-2H-1-benzopyranyl and chromone represents 4-oxo-4H-1 benzopyran.

EXAMPLES Hereinafter, the present invention will be described more specifically according to examples, but it goes without saying that the present invention is not limited to the following examples.

Reference Example 1 Synthesis of 7-methoxy-4,4-dimethylchroman-8-ylisocyanate 400 mg of 7-methoxy-4,4-dimethylchroman-8-carboxylic acid was dissolved in dry benzene, and oxalyl was stirred at room temperature. 1.2 ml of chloride was added little by little. After the vigorous bubbling subsided, the mixture was heated to 60 ° C. and reacted for 1.5 hours. Excess oxalyl chloride and benzene were distilled off under reduced pressure to obtain an acid chloride (yellowish brown liquid).

165 mg of sodium azide was dried under reduced pressure and dissolved in 6 ml of dimethyl sulfoxide. While stirring, a solution of the acid chloride obtained above in 1.5 ml of dimethyl sulfoxide was added dropwise. 30
After stirring for minutes, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution,
It was dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 346 mg of a brown viscous liquid. This liquid was dissolved in 5 ml of o-dichlorobenzene and reacted at 155 ° C for 30 minutes. Evaporation of o-dichlorobenzene under reduced pressure gave 309 mg of the desired title compound.

Physical property value IR (neat) 3000,2060,2270 (NCO), 1605,1590,1490,143
5,1290,1250,1190,1095,790 cm ^-1 . Reference Example 2 Synthesis of 7-methyl-4-chromanone-8-yl isocyanate 8-amino-7-methyl-4-chromanone 180 mg, triphosgene 103 mg, tetrachloride Triethylamine (0.15 ml) was added to a mixture of carbon (8 ml) with stirring at room temperature, and the mixture was refluxed.6.
The reaction was carried out for 5 hours. After cooling to room temperature, ether was added and insoluble materials were removed by filtration. The filtrate was concentrated to obtain 195 mg of the desired title compound.

Reference Example 3 7-methoxy-4-oxo-4H-1-benzopyran-8
Synthesis of -ylisocyanate By using 194 mg of 8-amino-7-methoxychromone and by the same production method as in Reference Example 2, 122 m of the target compound was obtained.
got g.

Example 1 1-dodecyl-3- (7-methyl-4-chromanone-8
-Ill) Urea (113) 95 mg of dodecylamine was added to a solution of 100 mg of 7-methyl-4-chromanon-8-yl isocyanate in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the target compound was recrystallized from ethyl acetate.
Obtained 150 mg.

Physical property value ¹ H NMR (CDCl ₃ ) δ (ppm): 0,88 (t, J = 6.6Hz, 3H), 1.
15-1.36 (m, 20H), 2.34 (s, 3H), 2.79 (t, J = 6.4Hz, 2
H), 3.22 (t, J = 6.2Hz, 2H), 4.55 (t, J = 6.4Hz, 2H), 5.
67 (br.s, 1H), 6.92 (d, J = 7.9Hz, 1H), 7.74 (d, J = 7.9
Hz, 1H). mp161-165 ° C Example 2 N- (7-methoxy-4-chromanon-8-yl) -2,
2-Dimethyldodecane amide (219) A solution of 98 mg of 8-amino-7-methoxy-4-chromanone and 0.07 ml of triethylamine in 2 ml of dichloromethane was added 2,2-
127 mg of dimethyldodecanoic acid chloride was added, and the mixture was stirred at room temperature for 12 hours. Add 15 ml of 2N hydrochloric acid and add ethyl acetate (25 ml x
Extracted in 2). The extract was washed with 25 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (3: 2 = hexane / ethyl acetate) to give the desired title compound (198 m)
got g.

Physical property value ¹ H NMR (CDCl ₃ ) δ (ppm): 0,88 (t, J = 5.3Hz), 1.03
-1.70 (m, 18H), 1.30 (s, 6H), 2.77 (t, J = 6.6Hz, 2
H), 3.88 (s, 3H), 4.53 (t, J = 6.6Hz, 2H), 6.64 (d, J =
8.8Hz, 1H), 6.74 (br.s, 1H), 7.84 (d, J = 8.8Hz, 1H). mp130-131 ° C. Examples 3-54 Synthesis of Benzopyran Derivatives The compounds of the present invention were synthesized according to the method of Example 1 or Example 2 using the corresponding starting materials and reactants. The physical property values are shown in Table 1. The compound numbers in Table 1 represent the numbers given to the compounds listed as the above-mentioned preferred specific examples.

Example 55 N- (7-methoxy-4-chromanon-8-yl) -2,
2-Dimethyl-8-p-dimethylaminophenoxyoctanamide (246) N- (7-methoxy-4-chromanon-8-yl)-
2,2-Dimethyl-8-bromooctanamide (252) 150m
g of acetonitrile (5 ml) in p-nitrophenol
49 mg and potassium carbonate 49 mg were added, and the mixture was heated under reflux for 15 hours.
10 ml of water was added to the reaction solution, which was made alkaline with a 2N NaOH aqueous solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give N- (7-methoxy-4-chromanone-
8-yl) -2,2-dimethyl-8-p-nitrophenoxyoctanamide was obtained. This was dissolved in 10 ml of ethyl acetate, 50 mg of Pd-C (10%) was added, and the mixture was stirred under hydrogen. Pd
The catalyst was filtered off and the solvent was distilled off to give N-
(7-Methoxy-4-chromanon-8-yl) -2,2-
Dimethyl-8-p-aminophenoxyoctanamide was obtained. This was dissolved in 10 ml of ethanol and 50 mg of PtO ₂ and
500 mg of 37% formaldehyde aqueous solution was added, and the mixture was stirred under hydrogen at room temperature for 15 hours. After removing the catalyst by filtration and concentrating,
Purification by silica gel chromatography (1: 1 = ethyl acetate / hexane) gave 34 mg of the desired title compound. Ethanol in which HCl gas was dissolved was added, and the solvent was distilled off to obtain a hydrochloride.

Physical property value ¹ H NMR (CDCl ₃ ) δ (ppm): 1.2-1.9 (m, 10H), 1.30
(S, 6H), 2.82 (t, J = 6Hz, 2H), 3.86 (s, 3H), 3.89 (t,
J = 6Hz, 2H), 4.50 (t, J = 6Hz, 2H), 6.62 (d, J = 9Hz, 1
H), 6.7-6.9 (m, 5H), 7.83 (d, J = 9Hz, 1H). Example 56 Measurement of ACAT Enzyme Inhibitory Activity (Measurement of ACAT Enzyme Inhibitory Activity of Rabbit Small Intestinal Mucosa Microsomes) Preparation of rabbit small intestinal mucosa microsomes and measurement of ACAT enzyme activity were carried out by the method of Salone and Field [Reference; Biochemica e
Biophysica, 712, p. 557 (1982)] with some modifications.

Rabbit small intestine mucosa was homogenized using 40 mM phosphate buffer containing 30 mM EDTA, 50 mM KCl, 0.1 M sucrose, pH 7.4 (buffer A), and centrifuged at 10,000 xg at 4 ° C for 30 minutes to obtain a supernatant. Got The supernatant was further centrifuged at 105,000 xg at 4 ° C for 1 hour to obtain a precipitate. The precipitate was resuspended in buffer A to give a microsome fraction.

A buffer solution A containing 43 μM bovine serum albumin and 0.5 mg / ml microsome fraction was used to obtain a dimethylsulfoxide solution of each concentration of the test compound at 1% v / v, and the mixture was heated at 37 ° C. for 5 minutes.

Then containing ^[1-14 C] oleoyl CoA (3.7kB), 4
After adding 0 μM oleoyl CoA and heating at 37 ℃ for 10 minutes,
Chloroform containing 10 mg / ml cholesteryl oleate /
The reaction was stopped by adding methanol (2/1).

0.111 kB [ ³ H] cholesteryl oleate and 1 N hydrochloric acid were added and stirred, and then cholesteryl oleate extracted in the chloroform layer was separated by thin layer chromatography, and its injection activity was measured to be the ACAT activity. Table 2 shows the results.

The LD ₅₀ of each test compound was 2 g or more / kg (mouse).

Example 57: Measurement of serum cholesterol change rate Male Wistar rats weighing 200 g were fed with normal diet (CE-
(2, CLEA Japan, Inc.) was freely ingested and preliminarily reared for 7 days.

Then a diet enriched with cholesterol and fat (2
% Cholesterol, 1% cholic acid, 20% casein, 45%
Granulated sugar, 12% coconut oil, 4% KC floc, 1
% Mixed vitamins, 7% mixed minerals and 8% dry fish powder, manufactured by CLEA Japan, Inc. were freely ingested and raised for 3 days. During the cholesterol loading period, the test compound of the present invention was orally administered to the test animals at an oral dose of 10 mg / kg body weight.
It was administered once a day for 3 days. Subject animals received vehicle only.

Test animals were fasted 8 hours after the last dose and fasted 16
After a period of time, the test animals were sacrificed. Serum cholesterol levels were measured for each animal.

The results are shown in Table 3 as the serum cholesterol change rate (%) compared with the control.

Serum cholesterol change rate (%) = {(A−B) / B} × 100 (wherein A: test compound administration group total serum cholesterol amount,
B: Control group serum total cholesterol) Example 58: Production of tablet A tablet containing 30 mg of the compound of Example 1 was produced according to the following formulation.

Compound of Example 1 30 mg Lactose 87 mg Starch 30 mg Magnesium stearate 3 mg Industrial applicability According to the present invention, novel benzopyran derivatives such as new chroman derivatives, chromanone derivatives, chromone derivatives and their pharmaceutically acceptable A salt is provided, and these benzopyran derivatives are useful as an ACAT inhibitor, an antihyperlipidemic agent and an antiarteriosclerotic agent composition as described above.

Front Page Continuation (72) Inventor Tsutomu Mochizuki 5-20-2 Tamahei, Hino-shi, Tokyo Teijin Hino Dormitory 214 (72) Inventor Hiroshi Tanabe 3-18-4 Tamahei, Hino-shi, Tokyo 231 Teijin Tama Apartment 231 (72) Inventor Mikio Ota 3-18-4 Tamadaira, Hino City, Tokyo 113-18 Teijin Tama Apartment 113 (72) Hisao Yamaguchi 2-2-12 Asahigaoka, Hino City, Tokyo (56) Reference Japanese Patent Laid-Open No. 51- 108069 (JP, A) JP-A-51-141874 (JP, A) Khim. Geterotsikl. Soedin. , [3] (1987) P. 320-344 Bill. Chim. Farm. , 114 [5] (1975) P. 294-298

Claims (17)

(57) [Claims] 1. Formula (I): [In the formula, one of X and Y is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and
R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷ may together represent a carbon-carbon bond, R ⁷ and R ⁸
C ₅ -C ₇ may form a carbocyclic ring together is; C ₆ -C ₂₀ aryl group R ⁹ is substituted, unsubstituted or 1
Cycloalkyl or cycloalkenyl group of C ₅ -C ₂₀ substituted with non-position, or the formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group; and n is 0 or 1] and a pharmaceutically acceptable salt thereof. 2. A benzopyran derivative according to claim 1, wherein n = 1 in the formula (I), and a pharmaceutically acceptable salt thereof. 3. In the formula (I), R ³ and R ⁴ are each independently a hydrogen atom or an unsubstituted or substituted C ₁ -C ₃ lower alkyl group, and the benzopyran derivative and the pharmaceutical thereof. Acceptable salt. 4. In the formula (I), R ³ and R ⁴ together represent an oxygen atom, and R ⁵ and R ⁷ together do not represent a carbon-carbon bond. Benzopyran derivative and a pharmaceutically acceptable salt thereof. 5. In the formula (I), R ³ and R ⁴ together represent an oxygen atom, and R ⁵ and R ⁷ together represent a carbon-
The benzopyran derivative according to claim 2, which represents a carbon bond, and a pharmaceutically acceptable salt thereof. 6. A benzopyran derivative according to claim 1, wherein n = 0 in the formula (I), and a pharmaceutically acceptable salt thereof. 7. A benzopyran derivative according to claim 6, wherein R ³ and R ⁴ in formula (I) are each independently a hydrogen atom or an unsubstituted or substituted C ₁ -C ₃ lower alkyl group, and a pharmaceutical composition thereof. Acceptable salt. 8. R ^{9 of} formula (I) is of the formula In the above formula, at least one of R ¹¹ and R ¹² is C _{1 to} C _6.
The benzopyran derivative according to claim ₇ , which is a lower alkyl group, or R ¹¹ and R ¹² together form a C ₃ -C ₇ carbocycle, and a pharmaceutically acceptable salt thereof. 9. In the formula (I), R ³ and R ⁴ together represent an oxygen atom, and R ⁵ and R ⁷ together do not represent a carbon-carbon bond. Benzopyran derivative and a pharmaceutically acceptable salt thereof. 10. R ^{9 of} formula (I) is of the formula In the above formula, at least one of R ¹¹ and R ¹² is C _{1 to} C _6.
The benzopyran derivative according to claim 9 which is a lower alkyl group or R ¹¹ and R ¹² together form a C ₃ -C ₇ carbocycle, and a pharmaceutically acceptable salt thereof. 11. A compound according to claim 6, wherein in the formula (I), R ³ and R ⁴ together represent an oxygen atom, and R ⁵ and R ⁷ together represent a carbon-carbon bond. Benzopyran derivatives and pharmaceutically acceptable salts thereof. 12. R ^{9 of} formula (I) is of the formula In the above formula, at least one of R ¹¹ and R ¹² is C _{1 to} C _6.
The benzopyran derivative according to claim ¹¹ , which is a lower alkyl group or R ¹¹ and R ¹² together form a C ₃ -C ₇ carbocycle, and a pharmaceutically acceptable salt thereof. 13. Formula (Ia): [In the formula, ^one of X ¹ and Y ¹ is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and
R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷ may together represent a carbon-carbon bond, R ⁷ and R ⁸
C ₅ -C ₇ may form a carbocyclic ring together is; C ₆ -C ₂₀ aryl group R ⁹ is substituted, unsubstituted or 1
Cycloalkyl or cycloalkenyl group of C ₅ -C ₂₀ substituted with non-position, or the formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₆ lower alkyl group] in producing a benzopyran derivative represented by
Formula (II-a): (In the formula, ^one of X ¹ 'and Y ¹ ' is -N = C =
It is the same as X and Y except that it is O, and R ^{1 to} R ⁸ are as defined above. A method for producing a benzopyran derivative of the formula (Ia) and a pharmaceutically acceptable salt thereof, which comprises reacting the compound with R ⁹ and R ¹⁰ as defined above. 14. Formula (Ib): [In the formula, one of X ² and Y ² is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and
R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷ may together represent a carbon-carbon bond, R ⁷ and R ⁸
C ₅ -C ₇ may form a carbocyclic ring together is; C ₆ -C ₂₀ aryl group R ⁹ is substituted, unsubstituted or 1
Cycloalkyl or cycloalkenyl group of C ₅ -C ₂₀ substituted with non-position, or the formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
In the production of a benzopyran derivative represented by the following formula (II-b): (In the formula, X ² ′ and Y ² ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above). (wherein, R ⁹ is as defined above) wherein R ⁹ -N = C-O method for producing a benzopyran derivative and its pharmaceutically acceptable salts of formula (I-b), which comprises reacting a . 15. Formula (I-c): [In the formula, one of X ³ and Y ³ is a formula: Are shown and the other represents the same substituent as R ¹ and R ^2; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, hydroxyl group, nitro group, cyano group, C ₁ -C ₆ lower acylamino group, C ₁ -C ₁₂ lower alkylamino group, C ₁ -C ₇ lower alkyl oxycarbonyl group, a carboxyl group, C ₁ -C ₇
Represents a lower acyl group or a C _{1 to} C ₇ lower acyloxy group; R ^{3 to} R ⁸ each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₃ lower alkyl group, or R ³ and
R ⁴ may together represent an oxygen atom, R ⁵ and R ⁷ may together represent a carbon-carbon bond, R ⁷ and R ⁸
C ₅ -C ₇ may form a carbocyclic ring together is; C ₆ -C ₂₀ aryl group R ⁹ is substituted, unsubstituted or 1
Cycloalkyl or cycloalkenyl group of C ₅ -C ₂₀ substituted with non-position, or the formula: (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom or an unsubstituted or substituted C _{1 to} C ₆ lower alkyl group, or R ¹¹ and R ¹² together form C _{3 to} C 6. ₇ carbocycles may be formed; R ¹³ is an unsubstituted or substituted C ₅ -C
₁₉ chain or cyclic alkyl or alkenyl groups, unsubstituted or substituted C _{6 to} C ₁₉ aryl groups, unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl groups, or formula -AZ- A group represented by B (wherein A is C _{1 to} C ₁₂
Is an alkyl group, Z is an oxygen atom, a sulfur atom or a formula: (In the formula, R ¹⁴ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or may form a cyclic amine together with B, and in this case, Oxygen atom,
Sulfur atom or C _{1 to} C ₆ lower alkyl group or C _{6 to} C ₁₉
A cyclic amine may be formed via a nitrogen atom which may be substituted with an arylalkyl group); B is an unsubstituted or substituted C _{1 to} C ₁₉ alkyl group, an unsubstituted or substituted C Represents a _{6 to} C ₁₉ aryl group or an unsubstituted or substituted C _{6 to} C ₁₉ arylalkyl group).
In producing a benzopyran derivative represented by the formula (II-c): (In the formula, X ³ ′ and Y ³ ′ are the same as X and Y except that one of them is —NH ₂ , and R ^{1 to} R ⁸ are as defined above.) Preparation of a benzopyran derivative of formula (Ic) and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula R ⁹ COOH, wherein R ⁹ is as defined above, or a reactive derivative thereof. Method. 16. A benzopyran derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
ACAT inhibitor. 17. An antihyperlipidemic agent comprising the benzopyran derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An anti-atherosclerotic agent comprising the benzopyran derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.