JP3014144B2 - Benzopyran derivatives, their production and pharmaceutical preparations containing them as active ingredients - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel benzopyran derivative, a method for producing the same,
More specifically, the present invention relates to a benzopyran derivative having an acylamino group or a substituted urea group on an aromatic ring, a pharmaceutically acceptable acid adduct thereof, and a method for producing the same. And pharmaceutical compositions containing them and their use as antihyperlipidemic agents.

Background Art It is well known that arteriosclerosis is extremely important as a factor of various cardiovascular diseases, and active research is being conducted with the aim of suppressing the progression of arteriosclerosis or regressing arteriosclerosis. . Particularly, although a drug that lowers cholesterol in serum or arterial wall has been found to be useful, an ideal drug with a clear clinical effect and few side effects has been realized.

On the other hand, it has been revealed that the accumulation of cholesterol ester in the arterial wall is an important factor in the development of arteriosclerosis.

In addition, acyl-coenzyme A-cholesterol acyltransferase Acyl-Co A Cholesterol Acylt is used for the production of cholesterol ester in the small intestinal mucosa and arterial wall.
It is known that ransferase (ACAT) plays an important role.

Conventionally, as such ACAT enzyme inhibitors, for example, urea derivatives (Reference: J. Med. Chem., Vol. 29, p. 1131 (1986), JP-A-63-316761, JP-A-1-93569, etc.)
And amide derivatives (Reference: JP-A-63-253060, etc.) have been reported.

On the other hand, reports on benzopyran derivatives include U.S. Pat.No. 4,415,741 and EP 48598.
No. 4, there is no specific disclosure of the compound of the present invention, and it is not known that such a benzopyran derivative has an ACAT inhibitory action. Also, 6-acylaminochromanones having an antihyperlipidemic action (references; Japanese Patent Publication No. 60-15626 and Japanese Patent Publication No. 60-35346) are known. Weaker than compounds and they are not known to have ACAT inhibitory action. Further, chromans having a urea group on an aromatic ring (references; J. Med. Chem., Vol. 13, p. 584 (1970)), 8-acylaminobenzopyrans having leukotriene antagonism and the like (references; JP-A-61-5097
No. 7, JP-A-61-260661, JP-A-61-143371
No., JP-A-62-230760, J. Med.Chem., Vol. 31,
84 (1988)), 8-acylaminochromans having local anesthetic action (Reference: Khim. Getrotsikl. Soedin., 320)
(1987)), but it is not known that these have an antihyperlipidemic action and an ACAT inhibitory action.

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide novel benzopyran derivatives, and to provide pharmaceutical compositions containing them as active ingredients and their antihyperlipidemic agents.

According to the present invention, formula (I) Wherein X is independently unsubstituted or substituted C ₇ -C ₂₀
Alkyl group, an unsubstituted or substituted C ₇ -C ₂₀ alkoxy group, an unsubstituted or substituted C ₇ -C ₂₀ acylamino group, unsubstituted or substituted C ₁₃ -C ₃₀ alkylamino group, an unsubstituted or substituted has been C ₈ -C ₂₀ alkyloxycarbonyl group, an unsubstituted or substituted C ₈ -C ₂₀ acyl group, unsubstituted or substituted C ₁₃ -C ₂₀ acyloxy group, unsubstituted or substituted C ₆ -C ₂₀ aryl groups,
Represents an unsubstituted or substituted C ₆ -C ₂₀ aryloxy group, wherein these substituents are a halogen atom, a hydroxyl group, an amino group, an alkoxy group or an aryloxy group; and Z is at the 8- or 5-position of the benzopyran ring. Substituted groups: R ¹ is independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group, an unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, a hydroxyl group, a nitro group A cyano group, an unsubstituted or substituted C ₁ -C ₆ lower acylamino group, an unsubstituted or substituted C ₁ -C ₁₂
Alkylamino group, an unsubstituted or substituted C ₁ -C ₇ lower alkyloxycarbonyl group, carboxyl group, C ₁ -C ₁₂ which are C ₁ -C ₇ lower acyl group, or an unsubstituted or substituted, which is unsubstituted or substituted Represents an acyloxy group, and these substituents are a halogen atom, a hydroxyl group or an amino group; R ^{2 to} R ⁷ each independently represent a hydrogen atom, a methyl group or an ethyl group, or R ² and R ³ together May represent an oxygen atom, and R ⁴ and R ⁶ together represent a carbon
R ⁶ and R ⁷ may together represent a carbon bond
R ⁸ may be a hydrogen atom, an unsubstituted C ₆ aryl group or an unsubstituted or halogen atom, a C ₁ -C ₁₄ alkyl group, an alkoxy group, an acylamino group, a monocyclic C ₅ -C ₇ carbocyclic ring; Or substituted with a dialkylamino group, an alkyloxycarbonyl group, an acyl group or an acyloxy group (these substituents are further substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C ₁ -C ₁₀
An alkoxy group, a C ₆ -C ₁₀ aryloxy group, or a C ₁ -C ₁₂ alkylamino group, which may be substituted) a C ₁₂ -C ₂₀ aryl group, unsubstituted, or substituted at other than 1-position with hexyl or decyl C ₅ -C ₂₀ cycloalkyl or cycloalkenyl group, or a group of the formula, (VII): (Wherein, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an unsubstituted or substituted C ₁ -C ₆ lower alkyl group, or R ¹⁰ and R ¹¹ together represent C ₃ -C ₇ may form a carbocyclic ring; R ¹² is a hydrogen atom, an unsubstituted or substituted C ₁ -C ₁₉ alkyl or alkenyl group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group, unsubstituted or substituted A C ₆ -C ₁₉ arylalkyl group, or a formula-
A group represented by AZB (where A is a C ₁ -C ₁₂ alkyl group, Z is an oxygen atom, a sulfur atom or a compound of the formula (VIII): (Wherein, R ¹³ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or R ¹³ may form a cyclic amine together with B, when forming the amine oxygen atom, a sulfur atom, or also to form a cyclic amine through a C ₁ -C ₆ lower alkyl group or a C ₆ -C ₁₉ arylalkyl nitrogen atom which may be substituted with a group B is unsubstituted or substituted C ₁ -C ₁₉
Represents an alkyl group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group or an unsubstituted or substituted C ₆ -C ₁₉ arylalkyl group), and a substituent which may be substituted on R ¹² and B Is a halogen atom, lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, cyano group,
Lower acylamino group, lower alkylamino group, lower alkyloxycarbonyl group, carboxyl group, lower acyl group or lower acyloxycarbonyl group), or formula (IX): Wherein R ¹⁴ is independently a substituted C ₁ -C ₁₄ alkyl group,
Substituted C ₁ -C ₁₄ alkoxy group, a substituted C ₁ -C ₁₄ acylamino group, substituted C ₁ -C ₁₄ alkylamino group,
Substituted C ₁ -C ₁₄ alkyloxycarbonyl group, substituted C ₁ -C ₁₄ acyl group, a substituted C ₁ -C ₁₄ acyloxy groups, these substituents are alkoxy of C ₁ -C ₁₃ group, C ₆ -C ₁₃ aryloxy group, C ₆ -C ₁₃ aryl group, an acylamino group of C ₁ ~C _13, C ₅ cyclic amino group -C _8, monoalkylamino group of C ₁ -C ₁₃ , an alkyl group of C ₁ -C ₁₃ dialkylamino group or a C ₂ -C _13, these are further each independently represent a halogen atom,
May be substituted with a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group; R ¹⁵ is independently a hydrogen atom, a halogen atom, an unsubstituted C _{1 to} C ₁₄ alkyl group, an unsubstituted C _{1 to} C
₁₄ alkoxy group, unsubstituted C ₁ -C ₁₄ acylamino group, unsubstituted C ₁ -C ₁₄ alkylamino group, unsubstituted C ₁ -C ₁₄ alkyloxycarbonyl group, unsubstituted C ₁ -C ₁₄ acyl group ,
Represents an unsubstituted C ₁ -C ₁₄ acyloxy group; p represents an integer of 1 to 5; q represents an integer of 0 to 4; p and q do not exceed 5 in total) R ⁹ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group;
And m is an integer of 0 to 3, n is an integer of 0 to 3,
o is 0 or 1, and m and n do not exceed 3 in total, but when n = 0, R ⁸ represents a group of the formula (IX);
= 1 to 3 and o = 0, at least one substitution position of X is the 6-position or 7-position of the benzopyran ring, and when o = 0 and the substitution position of X is the 5-position or 8-position, R ⁸ is the formula (VII)
Wherein the total number of carbon atoms of the groups R ¹⁰ , R ¹¹ and R ¹² in (VII) is 6 or more] and a pharmaceutically acceptable acid adduct thereof. .

According to the present invention, there is also provided a pharmaceutical composition containing the benzopyran derivative and a pharmaceutically acceptable acid adduct thereof as an active ingredient, and an antihyperlipidemic agent thereof.

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies on benzopyran derivatives, and as a result, have found a novel benzopyran derivative having a substituted urea group or acylamino group on its aromatic ring. The present inventors have found that these novel compounds have an ACAT oxygen inhibitory effect, lower cholesterol in blood or arterial wall, and show an excellent therapeutic effect, and have reached the present invention.

In the above formula (I), X is independently an unsubstituted or substituted C ₇ -C ₂₀ alkyl group, an unsubstituted or substituted C ₇ -C ₂₀ alkoxy group, an unsubstituted or substituted C ₇ -C ₂₀ acylamino group, an unsubstituted or substituted C ₁₃ -C ₃₀ alkylamino group, unsubstituted or substituted C ₈ -C ₂₀ alkyloxycarbonyl group, an unsubstituted or substituted C ₈ -C ₂₀ acyl group, unsubstituted Or a substituted C ₁₃ -C ₂₀ acyloxy group, an unsubstituted or substituted C ₆ -C ₂₀ aryl group, or an unsubstituted or substituted C ₆ -C ₂₀ aryloxy group.

As the C ₇ -C ₂₀ alkyl group, C ₇ -C ₂₀ chain (linear or branched) or cyclic alkyl group (hereinafter, unless otherwise specified in the present invention, the alkyl group linear or Branched or cyclic alkyl groups), for example, heptyl, decyl, eicosyl,
Examples thereof include 2,2-dimethyloctyl and cyclohexylbutyl.

The C ₇ -C ₂₀ alkoxy group consisting of alkyl groups and oxy group of C ₇ -C ₂₀ are as alkoxy groups, for example heptyloxy, decyloxy, eicosyloxy, 2-methyl -
Examples include decyloxy and cyclopetylpropyloxy groups.

The C ₇ -C ₂₀ acylamino group consisting of acyl group and the amino group of the C ₇ -C ₂₀ are as acylamino group is, for example, octanoylamino, decanoylamino, 3,3-diethyl propanoyl amino group .

As the C ₁₃ -C ₃₀ alkylamino group, the same or different C ₁ -C ₁₅ mono- or dialkylamino group consisting of alkyl groups, such as octyl amino, N- decyl -N- methylamino, di-dodecyl amino group Can be mentioned.

C ₈ As the C ₈ -C ₂₀ alkyloxycarbonyl group
Alkoxy group and a carbonyl consisting group alkyloxycarbonyl group -C _20, can be, for example, heptyloxycarbonyl, decyloxycarbonyl, 2-ethyl-4-butyl-dodecyloxycarbonyl group.

The C ₈ -C ₂₀ alkyl group and consisting of a carbonyl acyl group of a hydrogen atom and C ₇ -C ₁₉ are as acyl groups, e.g. octanoyl, can be cited Pentadekairu, 3,3-diethyl hexanoyl group.

As the C ₁₃ -C ₂₀ acyloxy group, an acyl group and an acyloxy group consisting of oxy groups C ₁₃ -C _20, such as tri decanoyloxy, 2-methyl pentadecanoyl oxy, include cyclopentyl decanoyloxy group Can be.

Aryl groups of the C ₆ -C ₂₀ are as aryl groups such as phenyl, 2,4,6-trimethylphenyl, may be mentioned 4-decyl phenyl and the like.

As the C ₆ -C ₂₀ aryloxy group, an aryloxy group consisting of aryl and aryloxy groups of C ₆ -C _20, for example phenyloxy, 2,4,6-trimethylphenyl oxy,
Examples thereof include a 4-decylphenyloxy group.

Examples of the substituent of the substituted alkyl group, alkoxy group, acylamino group, alkylamino group, alkyloxycarbonyl group, acyl group, acyloxy group, aryl group and aryloxy group represented by X include a halogen atom, a hydroxyl group, an amino group, and the like. Groups, alkoxy groups, aryloxy groups, and the like. Examples of such a substituted alkyl group include, for example, a methoxydecyl group.

X is an unsubstituted or substituted C ₇
-C ₂₀ alkoxy group, an unsubstituted or substituted C ₁₃ -C
₃₀ alkylamino groups are preferred.

R ¹ is independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group, an unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, a hydroxyl group, a nitro group, a cyano group An unsubstituted or substituted C ₁ -C ₆ lower acylamino group, an unsubstituted or substituted C ₁ -C ₁₂ alkylamino group, an unsubstituted or substituted C ₁ -C ₇ lower alkyloxycarbonyl group, a carboxyl group Represents an unsubstituted or substituted C ₁ -C ₇ lower acyl group, or an unsubstituted or substituted C ₁ -C ₁₂ acyloxy group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.

As the C ₁ -C ₆ lower alkyl group, a linear (linear or branched) or cyclic lower alkyl group (hereinafter, when referred to as a lower alkyl group in the present invention, a linear or linear lower alkyl group unless otherwise specified) A branched chain or cyclic alkyl group), for example, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclohexyl and the like.

Examples of the C ₁ -C ₆ lower alkoxy group include an alkoxy group comprising a C ₁ -C ₆ lower alkyl group and an oxy group, such as methoxy, ethoxy, propoxy, and tert-butyloxy group.

The lower acylamino group of the C ₁ -C _6, a hydrogen atom and C ₁ -C ₆ lower acyl group and an acylamino group consisting of amino group is, for example, acetylamino, propanoylamino, a butanoylamino group .

Wherein C ₁ The alkylamino group -C _12, identical or different C ₁ -C ₁₂ alkyl group and mono- or dialkylamino group consisting of amino groups, for example methylamino,
Ethylamino, dimethylamino, diethylamino, N-
A butyl-N-methylamino group and the like can be mentioned.

As the lower alkyloxycarbonyl group of C ₁ -C _6, an alkyloxycarbonyl group consisting of an alkoxy group and a carbonyl group of C ₁ -C _6, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert
-Butyloxycarbonyl group and the like.

The C _{1 to} C ₇ lower acyl groups include a hydrogen atom and C ₁
-C ₆ alkyl groups and consisting of a carbonyl group acyl group, for example acetyl, propanoyl, butanoyl, and a benzoyl group.

Examples of the C ₁ -C ₁₂ acyloxy group include an acyloxy group consisting of a C ₁ -C ₁₂ acyl group and an oxy group, such as acetoxy, propanoyloxy, butanoyloxy, and benzoyloxy group.

Substituted lower alkyl group of the above R ^1, examples of the lower alkoxy group or a substituent such as a lower alkyloxycarbonyl group, such as halogen atom, there may be mentioned a hydroxyl group, an amino group or the like, for example such substituted Examples of the lower alkyl group include a trifluoromethyl group. Among them, R ¹ is preferably a hydrogen atom, a halogen atom, an unsubstituted or substituted lower alkyl group, or an unsubstituted or substituted lower alkoxy group.

R ^{2 to} R ⁷ independently represent a hydrogen atom, a methyl group or an ethyl group, and are preferably a hydrogen atom.

In the formula (I), R ⁸ is a hydrogen atom or an unsubstituted or substituted C ₆ -C ₂₀ aryl group, an unsubstituted or substituted C ₅ -C ₂₀ cycloalkyl or cycloalkenyl group other than 1-position, Or formula (VII): Represents a group represented by

Substituted C ₆ -C ₂₀ aryl group described above, a halogen atom, C ₁ -C ₁₄ alkyl group, an alkoxy group, an acylamino group, a mono- or dialkylamino group, an alkyloxycarbonyl group, with an acyl group or an acyloxy group such as Represents a substituted aromatic hydrocarbon group. These substituents also further halogen atom, a hydroxyl group, a nitro group, a cyano group, C ₁ -C ₁₀ alkoxy groups, C ₆ -C ₁₀ aryloxy group, may be substituted with C ₁ -C ₁₂ alkylamino group, etc. .

Among them, R ⁸ is preferably p-fluorophenyl, p-decylphenyl, p-methoxyphenyl, p-decyloxyphenyl, p-decylaminophenyl, p-decylmethylaminophenyl, 6- (p- (Chlorophenoxy) -hexyloxyphenyl, 6-butyloxy-hexyloxyphenyl and the like.

When representing an unsubstituted or substituted C ₁ -C ₂₀ cycloalkyl or cycloalkenyl group other than 1-position,
Preferably cyclopentyl, cyclohexyl, 1-cyclohexen-1-yl, 4-hexylcyclohexyl,
Or 4-decyloxycyclohexyl etc. can be mentioned.

R ₁₀ and R ₁₁ each independently represent a hydrogen atom or an unsubstituted or substituted C ₁ -C ₆ lower alkyl group,
Or R ₁₀ and R ₁₁ may form a carbocyclic ring of C ₃ -C ₇ together.

As the C ₁ -C ₆ lower alkyl groups such as methyl,
Ethyl, propyl, isopropyl, pentyl, neopentyl, hexyl, cyclohexyl, cyclopropylmethyl groups and the like.

R ¹² is a hydrogen atom, an unsubstituted or substituted C ₁ -C ₁₉ alkyl or alkenyl group, an unsubstituted or substituted
C ₆ -C ₁₉ aryl group, or unsubstituted or substituted C ₆
It represents a -C ₁₃ arylalkyl group. Preferred examples of R ⁸ when R ¹² is a C _{1 to} C ₁₉ alkyl group include methyl, ethyl, propyl, isobutyl, hexyl, isohexyl, octyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl. , Nonadecyl, eicosyl, 1,1-dimethylheptyl, 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. Preferred examples of R ⁸ when R ¹² is a C ₂ -C ₁₉ alkenyl group include propenyl, isopentenyl, hexenyl, 8-tridecenyl, 8-heptadecenyl, 9-octadecenyl, 8,11
-Heptadecadienyl, 1,1-dimethyl-8-nonenyl and cyclohexenylmethyl and the like. R ¹²
Preferred specific examples of R ⁸ when but a C ₆ -C ₁₉ aryl group, benzyl, 1-phenyl cyclopentyl, 1-
Phenylethyl and 1-methyl-1- (2-pyridyl) ethyl and the like. Preferable specific examples of R ⁸ when R ¹² is a C ₆ -C ₁₉ arylalkyl group include an arylalkyl group comprising an aromatic ring hydrocarbon and an alkyl group, for example, 2-phenylethyl, 8-phenyloctyl , 1,1-dimethyl-11-phenylundecyl, 1-benzylcyclopentyl, (1-phenylcyclopentyl) methyl, 2,2-diphenylethyl and the like. Further, R ¹² is a group represented by the formula —A—Z—B (where A is a C ₁ -C ₁₂ alkyl group, Z is an oxygen atom, a sulfur atom or a formula (VIII): (Wherein, R ¹³ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or R ¹³ may form a cyclic amine together with B, when forming the amine oxygen atom, a sulfur atom, or also to form a cyclic amine through a C ₁ -C ₆ lower alkyl group or a C ₆ -C ₁₉ arylalkyl nitrogen atom which may be substituted with a group B is unsubstituted or substituted C ₆ -C ₁₉
Alkyl group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group, or an unsubstituted or substituted C ₆ -C ₁₉ arylalkyl represents a group) a group represented by. The lower alkyl group and the lower acyl group for R ¹³ have the same definition as the lower alkyl group and the lower acyl group for R ¹ , and preferred examples thereof are also the same.

Preferred examples of the case where R ¹³ forms a cyclic amine together with B include 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 4-methyl-1-piperazinyl and 4-benzyl-1-piperazinyl. Is mentioned. The alkyl group for B has the same definition as the lower alkyl group for R ¹ or the alkyl group for R ¹² , and preferred examples thereof include the same examples.

The aryl group and arylalkyl group in B are R
^The same definitions as those of the aryl group and the arylalkyl group in ¹² are given, and preferable specific examples thereof include the same examples.
When R ¹² is a group represented by the formula -AZB, preferred specific examples of R ⁸ include 6-isobutoxyhexyl and 6-isobutoxyhexyl.
p-chlorophenoxyhexyl, 5-p-dimethylaminophenoxypentyl, 5-isohexyloxy-1,1
-Dimethylpentyl, 7-isohexyloxy-1,1-
Dimethylheptyl, 7-isobutoxy-1,1-dimethylheptyl, 7-neopentyloxy-1,1-dimethylheptyl, 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-dimethyl Heptyl, 7- (N-benzyl-N-methylamino) -1,1
-Dimethylheptyl, 7- (N-p-chlorobenzyl-
N-methylamino) -1,1-dimethylheptyl, 7-
(Np-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, Examples include 1-dimethylheptyl, 5- (4-benzyl-1-piperazinyl) -1,1-dimethylpentyl and 6- (p-chlorophenylthio) -1,1-dimethylhexyl. Further, each group of R ¹² is one or more of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a cyano group, a lower acylamino group, a lower alkylamino group, a lower alkyloxycarbonyl group, and a carboxyl group. Group, lower acyl group or lower acyloxycarbonyl group. The definitions of these substituents are the same as defined in R ^1, the preferred embodiment also include the same examples. Preferred specific examples of R ⁸ including R ¹² 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-dimethylhexyl, (1-m-cyanophenylcyclopentyl) methyl, (1-p-dimethylaminophenylcyclopentyl) methyl and (1 -P-
Methoxyphenylcyclopentyl) methyl and the like.

R ⁹ in the above formula (I) represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group. The lower alkyl group has the same definition as the lower alkyl group for R ¹ , and preferred examples thereof include the same examples.

In the above formula (I), R ⁸ is a group represented by the formula (IX): Represents a group represented by

R ¹⁴ is substituted independently C ₁ -C ₁₄ alkyl group, a substituted C ₁ -C ₁₄ alkoxy group, a substituted C ₁ -C ₁₄ acylamino group, substituted C ₁ -C ₁₄ alkylamino group, substituted C ₁ -C ₁₄ alkyloxycarbonyl group C ₁ to, substituted
-C ₁₄ acyl group, a substituted C ₁ -C ₁₄ acyloxy group.

These alkyl groups, alkoxy groups, acylamino groups,
The definition of the alkylamino group, the alkyloxycarbonyl group, the acyl group and the acyloxy group is the same as the definition of each group in the above R ¹ except that the carbon atoms include those having a long carbon number of C _{1 to} C ₁₄ , and the following R ¹⁵ Are similarly defined.

Substituent of such these substituted C ₁ -C ₁₄ alkyl group, a halogen atom, C ₁ -C ₁₃ alkoxy groups, C ₆ -C ₁₃ aryloxy group, C ₁ -C ₁₃ aryl group, C ₁ -C ₁₃ acylamino group, C ₅ -C ₈ cyclic amino groups, C ₁ -C ₁₃ mono- or dialkylamino group, C ₂ -C ₁₃ alkyloxycarbonyl group, C ₁ -C ₁₃ acyl group, C ₁ -C ₁₄ acyloxy group, Examples include a hydroxyl group, an amino group, a nitro group, a cyano group, and a carboxyl group. Further, these substituents such as C ₁ -C ₁₃ alkyl groups may be repeatedly substituted with the above-mentioned substituents.

Examples of the substituted C ₁ -C ₁₄ alkyl group include trifluoromethyl, 6-methoxyhexyl, 4-chlorophenoxymethyl, and 2- (4-methoxymethoxyphenyl) ethyl.

Examples of the substituted C ₁ -C ₁₄ alkoxy group include chloromethoxy, 6-methoxyhexyloxy, 6- (4
-Chlorophenoxy) hexyloxy, 2- (4-methoxymethoxyphenyl) ethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy and the like.

Examples of the substituted C ₁ -C ₁₄ acylamino group include chloroacetylamino, 6-methoxyhexanoylamino, 4-chlorobenzoylamino, and 4-methoxyphenylacetylamino.

As the substituted C ₁ -C ₁₄ alkylamino group, mono- or dialkylamino groups consisting of the same or different C ₁ -C ₁₄ substituted alkyl groups, for example, chloromethylamino, 4-chlorobenzylmethylamino, di ( 6-
Methoxyhexyl) amino, di (4-t-butyloxyphenylethyl) amino group and the like.

Examples of the substituted C ₁ -C ₁₄ alkyloxycarbonyl group include chloromethoxycarbonyl, 6-methoxyhexyloxycarbonyl, 6- (4-chlorophenoxy) hexyloxycarbonyl, and 2- (4-methoxymethoxyphenyl) ethoxycarbonyl And the like.

Examples of the substituted C ₁ -C ₁₄ acyl group include chloroacetyl, 6-methoxyhexanoyl, 4-chlorobenzoyl, and 4-methoxyphenylacetyl group.

Examples of the substituted C ₁ -C ₁₄ acyloxy group include chloroacetyloxy, 6-methoxyhexanoyloxy, 4-chlorobenzoyloxy, 4-methoxyphenylacetyloxy and the like. Among them, R ¹⁰ is preferably a substituted C ₁ -C ₁₄ alkoxy group or a substituted C ₁ -C ₁₄ alkylamino group.

R ¹⁵ is independently a hydrogen atom, a halogen atom, unsubstituted C ₁ -C
₁₄ alkyl group, unsubstituted C ₁ -C ₁₄ alkoxy group, unsubstituted C ₁ -C ₁₄ acylamino group, unsubstituted C ₁ -C ₁₄ alkylamino group, unsubstituted C ₁ -C ₁₄ alkyloxycarbonyl group Represents an unsubstituted C ₁ -C ₁₄ acyl group or an unsubstituted C ₁ -C ₁₄ acyloxy group. As the halogen atom, a fluorine atom,
Examples thereof include a chlorine atom and a bromine atom.

The C ₁ -C ₁₄ alkyl unsubstituted, for example methyl, ethyl, isopropyl, cyclohexyl, decyl,
Examples thereof include a tetradecyl group.

Examples of the unsubstituted C ₁ -C ₁₄ alkoxy group include a methoxy, ethoxy, isopropoxy, cyclohexyloxy, decyloxy, tetradecyloxy group and the like.

Examples of the unsubstituted C ₁ -C ₁₄ acylamino group include acetylamino, propanoylamino, isobutanoylamino, cyclohexylcarbonylamino, decanoylamino, and tetradecanoylamino groups.

The unsubstituted C ₁ -C ₁₄ alkylamino group, the same or different unsubstituted C ₁ -C ₁₄ alkyl group consisting of mono- or dialkylamino group, for example methylamino, ethylamino, diisopropylamino, methylcyclohexylamino, decylamino And the like.

The C ₁ -C ₁₄ alkyloxycarbonyl group unsubstituted such as methoxycarbonyl, ethoxycarbonyl,
Examples include isopropoxycarbonyl, cyclohexyloxycarbonyl, decyloxycarbonyl, and tetradecyloxycarbonyl groups.

Examples of the unsubstituted C ₁ -C ₁₄ acyl group include acetyl, propanoyl, isobutanoyl, decanoyl, cyclohexylacetyl and the like.

The C ₁ -C ₁₄ acyloxy group of unsubstituted, and examples thereof include acetyloxy, propanoyloxy, iso-butanoyloxy, decanoyloxy, cyclohexyl acetyl group or the like.

Among them, R ¹⁵ is preferably a hydrogen atom, a halogen atom, an unsubstituted C ₁ -C ₁₄ alkyl group or an unsubstituted alkoxy group.

p represents an integer of 1 to 5, q represents an integer of 0 to 4,
p and q do not exceed 5 in total.

R ⁹ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group. C ₁
The -C ₆ lower alkyl group include methyl, ethyl, isopropyl, cyclopentylmethyl group and the like.

In the above formula (I), m represents 0 to 3, and n represents 0 to 3. Further, m and n do not exceed 3 in total.

In the above formula (I), o represents 0 or 1. When o is 0, it represents an acylamino group, and when o is 1, it represents a mono- or di-substituted urea group.

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

According to the present invention, preferred examples of the benzopyran derivative represented by the formula (I) include the following compounds. Further, the compound of the present invention includes all its optical isomers when it has an asymmetric carbon in its structural formula.

A preferred specific example when n is not 0 is (101) N- (7-decyloxy-4-chromanone-
8-yl) -2,2-dimethylpropanamide (Example 1)
(102) N- (7-decyloxy-4-chromanone-
8-yl) -4-chlorobenzoylamide (see Example 2) (103) N- (7-decyloxy-4-chromanone-
8-yl) acetamide (see Example 3) (104) N- (7-decyloxy-4-chromanone-
8-yl) -2,2-dimethyldodecaneamide (Example 4
(105) 8- (4-chlorophenoxy) -N- (7-
(Decyloxy-4-chroman-8-yl) -2,2-dimethyloctanamide (see Example 5) (106) 4-decyloxy-N- (7-decyloxy-4-chroman-8-yl) benzamide (Example 6
(107) 4- (6- (4-Chlorophenoxy) hexyloxy) -N- (7-decyloxy-4-chroman-8-yl) benzamide (see Example 7) (108) N- (7- Decyloxy-4-oxo-4H-
1-benzopyran-8-yl) -2,2-dimethylpropanamide (see Example 8) (109) N- (7- (4- (4-methoxyphenyl)
(Butoxy) -4-chromanon-8-yl) -2,2-dimethylpropanamide (see Example 9) (110) N- (7- (6-phenylhexyloxy)
-4-chroman-8-yl) -2,2-dimethylpropanamide (Compound 110) (126) 1-2,2-dimethylpropyl-3- (7-decyloxy-4-chromanon-8-yl) urea (Example
Preferred examples of the above formula (I) when n is 0 or 1 to 3 and R ⁸ is the formula (IX) include: (201) N- (7-methoxy-4-chromanone-8) −
Yl) -4- (6- (4-Chlorophenoxy) hexyloxy) benzoylamide (see Example 11) (202) N- (7-methoxy-4-chromanone-8-
Yl) -4- (4-chlorobenzyloxy) benzoylamide (see Example 12) (203) N- (7-methoxy-4-chromanone-8-
Yl) -4- (6- (2-Methylpropyloxy) hexyloxy) benzoylamide (see Example 13) (204) N- (7-methoxy-4-chromanone-8-
Yl) -4- (6-Propoxyhexyloxy) benzoylamide (see Example 14) (205) N- (7-methoxy-4-chromanone-8-
Yl) -4- (3-Dimethylamino) propoxybenzoylamide (see Example 15) (206) N- (7-methoxy-4-chromanone-8-
Yl) -4- (2-piperidino) ethyloxybenzoylamide (see Example 16) As the compound represented by the formula (I) of the present invention, the substituents on the benzopyran ring in the compounds of the specific examples (101) to (220) are the same, and the benzopyran ring is
R ² and R ³ are each independently a hydrogen atom or a benzopyran derivative which is an unsubstituted or substituted C ₁ to C ₁₀ alkyl group, such as a chroman derivative, wherein R ² and R ³ together represent an oxygen atom, Benzopyran derivatives wherein ⁴ and R ⁶ together do not represent a carbon-carbon bond, such as chromanone derivatives, and R ² and R ³ together represent an oxygen atom, and R ⁴
And R ⁶ together represent a benzopyran derivative which represents a carbon bond, for example, those having a mother nucleus of any benzopyran ring selected from 4-oxobenzopyran derivatives. Among these chroman, chromanone, and 4-oxobenzopyran derivatives, the mother nucleus is preferably a chromanone derivative.

In addition, as shown in the specific examples, in the formula (I) of the present invention, in the above three kinds of mother nuclei, in each case, o is 1, and in that case, R ⁹ is a hydrogen atom. Certain benzopyran derivatives, benzopyran derivatives wherein o is 0, and pharmaceutically acceptable acid adducts thereof can be mentioned as preferred.

Further, regarding the substituent of the benzopyran ring in the formula (I), the substitution position of the group Z is the 8-position or 5-position of the benzopyran ring.
Or a pharmaceutically acceptable acid adduct thereof, and the group Z is substituted at the 8-position of the benzopyran ring, and a substituent other than a hydrogen atom is located at the 7-position. Preferred benzopyran derivatives and pharmaceutically acceptable acid adducts thereof can be mentioned. Also, a benzopyran derivative in which the substituent at the 7-position of the benzopyran ring is an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or an unsubstituted or substituted C ₁ -C ₂₀ alkoxy group, and pharmaceutically acceptable derivatives thereof Acid adduct,
Above all, the substituent at the 7-position of the benzopyran ring is an unsubstituted or substituted C ₁ -C ₂₀ alkoxy group, or the substituent at the 7-position of the benzopyran ring is a group X and the group Z has 7 or less carbon atoms. Certain benzopyran derivatives and pharmaceutically acceptable acid adducts thereof are also preferred.
Still further, in the above formula (I), n is 0 and Z is a group represented by the above formula (IX).
Above all, a benzopyran derivative in which the substitution position of the group Z is the 8-position of the benzopyran ring.

In particular, a benzopyran derivative in which the group Z is located at the 8-position of the benzopyran ring and a substituent other than a hydrogen atom is located at the 7-position, and a pharmaceutically acceptable acid adduct thereof are also preferred compounds.

When the substituent of the benzopyran ring in the compound of the formula (I) of the present invention is the preferable one as described above, the benzopyran ring includes the chroman, chromanon,
And 4-oxobenzopyran derivatives, among them, chromanone derivatives are preferred.

According to the present invention, the following formula (II) [Wherein, R ^{1 to} R ⁷ , X, m, n are the same as the definitions of R ^{1 to} R ⁷ , X, m, n in the formula (I), respectively]. Luisocyanate and the following formula (III) [Wherein, R ⁸ and R ⁹ each represent R ⁸ in the formula (I).
And R ⁹ are the same as those defined above) to obtain a benzopyran derivative wherein o is 1 in the above formula (I) and a pharmaceutically acceptable acid adduct thereof. A manufacturing method can be provided.

The 1-benzopyranyl isocyanate represented by the above formula (II) can be produced according to a conventionally known method. For example, it can be obtained by a method for decomposing a corresponding carboxylic acid amide by Hoffman decomposition, a thermal decomposition reaction of a carboxylic acid azide, or a reaction of a corresponding amine with phosgene or a homologous reagent thereof. The amines represented by the above formula (III) can be produced according to a conventionally known method.

The production method provided by the present invention comprises, for example, the step of adding 1 equivalent of 1-benzopyranyl isocyanate represented by the above formula (II) and 0.2 to 5 equivalents of the amines represented by the above formula (III) without solvent or It can be carried out by reacting in the presence of a solvent. The reaction temperature ranges from -20 to 150 ° C, preferably from room temperature to 100 ° C, and the reaction time is usually within 72 hours. 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, and aprotic polar solvents such as ethyl acetate, dimethylformamide, and dimethyl sulfoxide. Is used.

After completion of the reaction, the usual separation and purification operations, ie, extraction,
By performing recrystallization, chromatography and the like, the target benzopyran derivative represented by the above formula (I) can be isolated. They can be converted into pharmaceutically acceptable acid adducts by a conventional method.

According to the present invention, there is also provided a compound of formula (IV) Wherein R ^{1 to} R ⁷ and X, m, n are the same as defined for R ^{1 to} R ⁷ and X, m, n in the formula (I), respectively. And an isocyanate represented by the following formula (V): O = C = NR ⁸ (V) wherein R ⁸ is the same as the definition of R ⁸ in the formula (I). By doing so, it is possible to provide a method for producing a benzopyran derivative in which o = 1 and R ⁹ = H in the formula (I), that is, a benzopyran derivative having a substituted urea group and an acid adduct.

1-Benzopyranylamine represented by the above formula (IV) can be prepared by a conventionally known method [Reference: J. Indian Chem. Soc., 37
, P. 217 (1960)].
The isocyanates represented by the above formula (V) can be produced according to a conventionally known method.

The production method provided by the present invention is, for example, a method comprising adding 1 equivalent of 1-benzopyranylamine represented by the above formula (IV) and 0.2 to 5 equivalents of isocyanates represented by the above formula (V) in the absence of a solvent or a solvent. It can be carried out by reacting in the presence.

The reaction temperature ranges from -20 to 150 ° C, preferably from room temperature to 100 ° C, and the reaction time is usually within 72 hours. As a 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, esters such as ethyl acetate, and aprotic compounds such as dimethylformamide and dimethyl sulfoxide. A polar solvent or the like is used.

After completion of the reaction, the usual separation and purification operations, ie, extraction,
By performing recrystallization, chromatography, or the like, the desired chromone derivative represented by the above formula (I) can be isolated. They can be converted into pharmaceutically acceptable acid adducts by a conventional method.

1-benzo-pyranyl amines with the following formula ^{(VI) R 8 -COOH ... (} VI) wherein represented by further above formula according to the present invention (IV), R R ⁸ is in the formula (I) ⁸ Is the same as the definition of the above), by reacting with a carboxylic acid or a reactive derivative thereof represented by the formula (I), the benzopyran derivative in which o = 0 in the above formula (I), that is, a benzopyran derivative having an acylamino group and acid addition A method for producing a body can be provided. The 1-benzopyranylamine represented by the above formula (IV) can be produced according to a conventionally known method as described above.

The carboxylic acids represented by the above formula (VI) or reactive derivatives thereof can be produced according to a conventionally known method.

The production method provided by the present invention comprises, for example, a method of condensing 1 equivalent of 1-benzopyranylamine represented by the above formula (IV) and 1 to 5 equivalents of carboxylic acids represented by the above formula (V),
For example, 1 to 2 equivalents of dicyclohexylcarbodiimide and a basic amine such as triethylamine, pyridine,
The reaction can be carried out by reacting 0.1 to 1.5 equivalents of dimethylaminopyridine in the presence of a solvent.

The reaction temperature ranges from -20 to 150 ° C, preferably from room temperature to 100 ° C, and the reaction time is usually within 72 hours.

Alternatively, 1 equivalent of 1-benzopyranylamine represented by the above formula (IV) and a reactive derivative of a carboxylic acid represented by the above formula (VI), for example, 1 to 5 equivalents of a corresponding carboxylic acid chloride or acid anhydride are used. Can be carried out in the presence of a solvent.

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 a 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 dimethyl sulfoxide are used. . In this case, basic amines such as triethylamine, pyridine, 4-dimethylaminopyridine and the like may be added in an amount of 0.1 to 1.5 equivalents.

After completion of the reaction, the usual separation and purification operations, ie, extraction,
By performing recrystallization, chromatography and the like, the target benzopyran derivative represented by the above formula (I) can be isolated. They can be converted into pharmaceutically acceptable acid adducts by a conventional method.

The benzopyran derivative and the pharmaceutically acceptable acid adduct thereof provided by the present invention have an ACAT enzyme inhibitory effect and have an excellent pharmacological effect of lowering total cholesterol and LDL in blood, liver and artery wall. Having. Therefore, it is useful for suppressing the progress of hyperlipidemia such as arteriosclerosis and for regression.

The benzopyran derivative and the pharmaceutically acceptable acid adduct thereof provided by the present invention can be administered orally or parenterally.

Oral dosage forms include, for example, tablets, powders, granules,
Capsules and the like. To make a dosage form,
Excipients such as lactose, starch, microcrystalline cellulose,
It can be formed by a usual method using a binder such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone, and a disintegrant such as sodium alkinate, sodium hydrogencarbonate and sodium laurate. Powders and granules can be formed by the same method. Capsules are formed by filling powders, granules and the like into capsules such as gelatin.

As parenteral preparations, for example, transdermal preparations such as suppositories and patches,
Injections and the like can be mentioned.

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

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Example 1 N- (7-decyloxy-4-chroman-8-yl)
Synthesis of 2,2-dimethylpropanamide (Compound 101) 8-amino-7-decyloxy-4-chromanone 2.17
g of 1,2-dichloroethane in 20 ml of triethylamine.
14 ml were added, and 0.84 ml of trimethylacetyl chloride was added little by little. The mixture was stirred at room temperature for 20 hours.

After the reaction, extraction was performed with dichloromethane. After drying, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain 2.09 g of the desired title compound.

Physical Properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.82 (d, J = 8.9 Hz, 1H), 6.79 (s, 1H), 6.61 (d, J = 8.
9Hz, 1H), 4.54 (t, J = 6.6Hz, 2H), 4.03 (t, J = 6.6Hz, 2
H), 2.77 (t, J = 6.6Hz, 2H), 1.77 (tt, J = 6.6Hz, 2H),
1.26-1.43 (m, 14H), 1.34 (s, 9H), 0.88 (t, J = 6.6Hz,
3H) mp 156-158 ° C Example 2 N- (7-decyloxy-4-chroman-8-yl)
Synthesis of 4-chlorobenzoylamide (Compound 102) Using 51.4 mg of 8-amino-decyloxy-4-chromanone, the title compound of interest 50.9 mg was obtained in the same manner as in Example 1.
mg was obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.88 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.47
(D, J = 8.6Hz, 2H), 7.21 (s, 1H), 6.68 (d, J = 8.9Hz, 1
H), 4.55 (t, J = 6.3 Hz, 2H), 4.07 (t, J = 6.6 Hz, 2H), 2.
80 (t, J = 6.3 Hz, 2H), 1.75 (tt, J = 6.6 Hz, 2H), 1.21-
1.37 (m, 14H), 0.88 (t, J = 6.6 Hz, 3H) Melting point 155-157 ° C Example 3 N- (7-decyloxy-4-chromanon-8-yl)
Synthesis of acetamide (compound 103) 8-amino-7-decyloxy-4-chromanone 404m
g, and in the same manner as in Example 1, the desired title compound 3
38 mg were obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.85 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.55
(T, J = 6.6Hz, 2H), 4.05 (t, J = 6.6Hz, 2H), 2.78 (t, J
= 6.6Hz, 2H), 2.17 (br, 3H), 1.79 (tt, J = 6.6,6.6Hz, 4
H), 1.11-1.50 (m, 14H), 0.88 (t, J = 6.6 Hz, 3H). IR (KBr) 3246,2914,2851,1680,1655,1535,1445,1381,1292c
m ^-1 . Melting point 151.5-152.5 ° C Example 4 N- (7-decyloxy-4-chromanon-8-yl)
Synthesis of -2,2-dimethyldodecaneamide (Compound 104) 8-amino-7-decyloxy-4-chromanone 100m
Using g, in the same manner as in Example 1, the desired title compound 1
54 mg were obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.82 (d, J = 9.9 Hz, 1H), 6.76 (s, 1H), 6.61 (d, J = 9.
9Hz, 1H), 4.52 (t, J = 6.3Hz, 2H), 4.02 (t, J = 6.3Hz, 2
H), 2.77 (t, J = 6.4 Hz, 2H), 1.7-1.8 (m, 2H), 1.0-1.
7 (m, 38H), 0.88 (t, J = 5.3Hz, 6H). Example 5 Synthesis of 8- (4-chlorophenoxy) -N- (7-decyloxy-4-chroman-8-yl) -2,2-dimethyloctaneamide (Compound 105) 8-amino-7-decyloxy-4-chromanone 100m
Using g, in the same manner as in Example 1, the desired title compound 1
78 mg were obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.82 (d, J = 9.9 Hz, 1H), 7.21 (d, J = 9.9 Hz, 2H), 6.76
(S, 1H), 6.80 (d, J = 9.9Hz, 1H), 6.62 (d, J = 9.9Hz, 1
H), 4.52 (t, J = 6.3 Hz, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.
91 (t, J = 6.6Hz, 2H), 2.76 (t, J = 6.3Hz, 2H), 1.3-1.9
(M, 32H), 0.88 (t, J = 6.4Hz, 3H). Example 6 Synthesis of 4-decyloxy-N- (7-decyloxy-4-chroman-8-yl) benzamide (Compound 106) 8-amino-7-decyloxy-4-chromanone 224m
g, and in the same manner as in Example 1, the desired title compound 3
49 mg were obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.88 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.9 Hz, 1H), 6.96
(D, J = 8.6Hz, 2H), 6.67 (d, J = 8.9Hz, 1H), 4.55 (t, J
= 6.1Hz, 2H), 4.06 (t, J = 6.3Hz, 2H), 4.02 (t, J = 6.4H
z, 2H), 2.79 (t, J = 6.3Hz, 2H), 1.66-1.86 (m, 4H), 1.
22-1.46 (m, 28H), 0.85-0.90 (m, 6H). IR (KBr) 3252,2920,2853,1701,1651,1605,1435,1292,1254,111
1cm ^-1 . Melting point 106.2-107.2 ° C Example 7 4- (6- (4-chlorophenoxy) hexyloxy)
Synthesis of -N- (7-decyloxy-4-chroman-8-yl) benzamide (Compound 107) 76 mg of 8-amino-7-decyloxy-4-chromanone
And using the title compound 73 in the same manner as in Example 1
mg was obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.88 (d, J = 8.9 Hz, 2H), 7.23 (s, 1H), 7.22 (d, J = 8.
9Hz, 2H), 6.92 (d, J = 8.9Hz, 2H), 6.90 (d, J = 8.3Hz, 1
H), 6.81 (d, J = 8.9Hz, 2H), 6.49 (d, J = 8.3Hz, 1H), 4.
17 (t, J = 4.9Hz, 2H), 4.01 (t, J = 6.6Hz, 2H), 3.93 (t, J
J = 6.6Hz, 2H), 3.79 (s, 3H), 2.75 (t, J = 6.3Hz, 2H),
1.96 (tt, J = 6.3Hz, 4.9Hz, 2H), 1.78-1.86 (m, 4H), 1.
51-1.57 (m, 4H). Example 8 Synthesis of N- (7-decyloxy-4-oxo-4H-1-benzopyran-8-yl) -2,2-dimethylpropanamide (Compound 108) Using 301 mg of 8-amino-7-decyloxychromone, 200 mg of the desired title compound was obtained in the same manner as in Example 1.
I got

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 8.10 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.01
(D, J = 8.9Hz, 1H), 6.99 (br, 1H), 6.26 (d, J = 6.3Hz, 1
H), 4.10 (t, J = 6.3 Hz, 2H), 1.82 (tt, J = 6.3, 6.3 Hz, 2
H), 1.38 (s, 9H), 1.15-1.56 (m, 14H), 0.89 (t, J = 6.
6Hz, 3H). IR (KBr) 3281,2924,2855,1664,1528,1441,1406,1304,1254,108
6,804 cm ^-1 . Melting point 108.5-109.0 ° C Example 9 N- (7- (4- (4-methoxyphenyl) butoxy)
Synthesis of -4-chroman-8-yl) -2,2-dimethylpropanamide (Compound 109) Using 45 mg of 8-amino-7- (4- (4-methoxyphenyl) butoxy) chromanone, 34 mg of the title compound was obtained in the same manner as in Example 1.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.83 (d, J = 8.9 Hz, 1H), 6.82 (s, 4H), 6.77 (br.s, 1
H), 6.63 (d, J = 8.9Hz, 1H), 4.54 (t, J = 6.3Hz, 2H), 4.
12 (t, J = 5.6Hz, 2H), 3.96 (t, J = 5.6Hz, 2H), 3.77 (s,
3H), 2.78 (t, J = 6.3Hz, 2H), 1.86-2.06 (m, 4H), 1.33
(S, 9H). Melting point 119-121 ° C Example 10 Synthesis of N- (7- (6-phenylhexyloxy) -4-chroman-8-yl) -2,2-dimethylpropanamide (Compound 110) Using 163 mg of 8-amino-7- (6-phenylhexyloxy) chromanone, 195 mg of the desired title compound was obtained in the same manner as in Example 1.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.82 (d, J = 8.9 Hz, 1H), 7.15-7.30 (m, 5H), 6.60
(D, J = 8.9Hz, 1H), 4.53 (t, J = 6.3Hz, 2H), 4.02 (t, J
= 6.3Hz, 2H), 2.77 (t, J = 6.3Hz, 2H), 2.61 (t, J = 7.6H
z, 2H), 1.77 (tt, J = 6.6and6.3Hz, 2H), 1.64 (tt, J = 7.
6and7.3Hz, 2H), 1.22-1.57 (m, 4H), 1.33 (s, 9H). Melting point 140 DEG-141 DEG C. Example 11 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(6- (4-chlorophenoxy) hexyloxy) benzoylamide (Compound 201) To 9.10 g of 6- (4-chlorophenoxy) hexyloxybenzoic acid was added 100 ml of thionyl chloride, and the mixture was stirred under reflux for 2 hours. Excess thionyl chloride was distilled off under reduced pressure, and 100 ml
It was dissolved in 1,2-trichloroethane.

5.04 g of 7-methoxy-8-amino-4-chromanone,
2.64 g of triethylamine, 50 ml of 1,1,2-trichloroethane
The solution was added little by little and stirred at room temperature for 72 hours.

After the reaction, extraction was performed with dichloromethane. After drying, the organic solvent was distilled off. The precipitated solid was recrystallized from 750 ml of ethyl acetate to obtain 9.67 g of the title compound.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.89 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 8.9 Hz, 1H), 7.22
(D, J = 8.9Hz, 2H), 7.21 (s, 1H), 6.96 (d, J = 8.9Hz, 2
H), 6.82 (d, J = 8.9 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 4.
55 (t, J = 6.6Hz, 2H), 4.04 (t, J = 6.6Hz, 2H), 3.95 (t, J
J = 6.6Hz, 2H), 3.90 (s, 3H), 2.79 (t, J = 6.6Hz, 2H),
1.79-1.85 (m, 4H), 1.54-1.57 (m, 4H). 163-164 ° C.

Example 12 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(4-chlorobenzyloxy) benzoylamide (Compound 202) N- (7-methoxy-4-chroman-8-yl)-
53 mg of 4-hydroxybenzoylamide in acetonitrile
Dissolve in 2 ml and add 35 mg of potassium carbonate.

While stirring the mixture at room temperature, 50 μL of 4-chlorobenzyl chloride was added and reacted under reflux for 6 hours.

After the reaction, potassium carbonate was removed, and the product was purified by column chromatography to obtain 64 mg of the title compound (87%). Physical properties ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 7.90 (d, 2H, J = 8.7Hz), 7.89 (d, 1H, J = 9.1Hz), 7.38
(S, 4H), 7.24 (brs.1H), 7.03 (d, 2H, J = 8.7Hz), 6.69
(D, 1H, J = 9.1Hz), 5.11 (s, 2H), 4.55 (t, 2H, J = 6.4H
z), 3.90 (s, 3H), 2.79 (t, 2H, J = 6.4 Hz). mp 91-92 ° C.

Example 13 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(6- (2-methylpropyloxy) hexyloxy) benzoylamide (Compound 203) Using 6- (2-methylpropoxy) hexyl bromide, N- (7-methoxy-4-chroman-8-yl) -4-hydroxybenzoylamide was obtained in the same manner as in Example 12.
Reaction with 60 mg afforded 69.6 mg of the title compound. Yield 77% Physical property value ¹ H-NMR (CDCl ₃ ) δ / ppm 0.90 (d, 6H, J = 7 Hz), 1.4-1.9 (m, 9H), 2.79 (t, 2H,
J = 7Hz), 3.17 (d, 2H, J = 7Hz), 3.42 (t, 2H, J = 7Hz),
3.90 (s, 3H), 4.03 (t, 2H, J = 7Hz), 4.55 (t, 2H, J = 7H
z). 6.69 (d, 1H, J = 8 Hz), 6.95 (d, 2H, J = 8 Hz), 7.2 (b
s, 1H), 7.88 (d, 3H, J = 8 Hz). Mp 148-150 ° C. Example 14 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(6-propoxyhexyloxy) benzoylamide (Compound 204) Example 12 using 6-propoxyhexyl bromide
Was reacted with 64 mg of N- (7-methoxy-4-chroman-8-yl) -4-hydroxybenzoylamide to obtain 6.4 mg of the title compound.

Physical Properties ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 0.92 (t, 3H, J = 7 Hz), 1.3-1.9 (m, 10H), 2.79 (t, 2
H, J = 7Hz), 3.37 (t, 2H, J = 7Hz), 3.43 (t, 2H, J = 7H)
z), 3.90 (s, 3H), 4.04 (t, 2H, J = 7 Hz), 4.55 (t, 2H, J
= 7Hz), 6.69 (d, 1H, J = 9Hz), 6.95 (d, 2H, J = 9Hz), 7.
21 (bs, 1H), 7.88 (d, 3H, J = 9 Hz). Example 15 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(3-dimethylamino) propoxybenzoylamide (Compound 205) Using 3-chloro-N, N-dimethylpropylamine,
Reaction with 74 mg of N- (7-methoxy-4-chroman-8-yl) -4-hydroxybenzoylamide as in Example 12 gave 24 mg of the title compound.

Physical Properties ¹ H-NMR (CDCl ₃ , TMS) δ / ppm 7.87-7.89 (m, 3H), 7.21 (brs, 1H), 6.97 (d, 2H, J =
9.1Hz), 6.69 (d, 1H, J = 8.7Hz), 4.55 (t, 2H, J = 6.4H)
z), 4.09 (t, 2H, J = 6.4 Hz), 3.90 (s, 3H), 2.79 (t, 2H,
J = 6.4Hz), 2.46 (t, 2H, J = 7.2Hz), 2.26 (s, 6H), 1.99
(Tt, 2H, J = 6.4Hz, 7.2Hz). Melting point 148-149 DEG C. Example 16 N- (7-methoxy-4-chroman-8-yl) -4
Synthesis of-(2-piperidino) ethyloxybenzoylimide (Compound 206) Example using N- (2-chloroethyl) piperidine
N- (7-methoxy-4-chromanone-8-
Reaction with 50 mg of yl) -4-hydroxybenzoylamide gave 24 mg of the title compound.

Physical property values ¹ H-NMR (CDCl ₃ , TMS) δ (ppm) 7.87-7.90 (m, 3H), 7.21 (brs, 1H), 6.98 (d, 2H, J =
9.1Hz), 6.69 (d, 1H, J = 9.1Hz), 4.55 (t, 2H, J = 6.4H)
z), 4.18 (t, 2H, J = 6.1 Hz), 3.90 (s, 3H), 2.82 (t, 2H,
J = 6.1Hz), 2.79 (t, 2H, J = 6.4Hz), 2.54 (br, 4H), 1.6
0-1.63 (m, 4H) 1.46 (br, 2H). Reference Example 1 Synthesis of 7-decyloxy-4-chroman-8-yl-isocyanate 8-amino-7-decyloxy-4-chromanone 318 m
0.14 ml of triethylamine was added to a solution of g and triphosgene (162 mg) in carbon tetrachloride (8 ml), and the mixture was stirred under reflux for 3 hours. After cooling to room temperature, ether was added and insolubles were removed by filtration.
The filtrate is concentrated under reduced pressure to give the title compound of interest
369 mg were obtained.

Example 17 Synthesis of 1-2,2-dimethylpropyl-3- (7-decyloxy-4-chroman-8-yl) urea (Compound 126) 30 mg of t-butylamine was added to a solution of 106 mg of 7-decyloxy-4-chroman-8-yl-isocyanate in ethyl acetate. After stirring at room temperature, the solvent is distilled off and column chromatography (silica gel, hexane / ethyl acetate)
1: 2) to give the desired title compound 119
mg was obtained.

Physical properties ¹ H-NMR (CDCl ₃ ) δ / ppm 7.79 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H), 5.58
(Br.s, 1H), 4.73 (br.s, 1H), 4.57 (t, J = 6.3Hz, 2H),
4.07 (t, J = 6.6Hz, 2H), 2.78 (t, J = 6.3Hz, 2H), 1.82
(Tt, J = 6.9and6.6Hz, 2H), 1.35 (s, 9H), 1.20-1.52
(M, 14H), 0.88 (t, J = 6.9Hz, 3H). Example 18 Measurement of ACAT Enzyme Inhibitory Activity (Measurement of ACAT Enzyme Inhibitory Activity of Rabbit Small Intestinal Mucosal Microsomes) Preparation of rabbit small intestinal mucosal microsomes and measurement of ACAT enzyme activity were carried out by the method of Salone and Field [Reference: Biochemica e
t Biophysica, vol. 712, p. 557 (1982)].

Rabbit small intestinal mucosa was homogenized using 40 mM phosphate buffer containing 30 mM EDTA, 50 mM KCl, and 1.0 M sucrose, pH 7.4 (buffer A), and centrifuged at 10,000 xg at 4 ° C for 30 minutes to obtain a supernatant. I got The supernatant was further centrifuged at 105,000 × g at 4 ° C. for 1 hour to obtain a precipitate. The precipitate was resuspended in buffer A to give the microsomal fraction.

Each concentration of the test compound (Examples 1, 3 to 5) was added to buffer A containing 43 µM bovine serum albumin and 0.5 mg / ml microsomal fraction.
And the compound obtained in 7-14) in 1% v / v and heated at 37 ° C. for 5 minutes.

Then containing ^[1-14 C] oleoyl CoA (3.7 kBq),
After adding 43 μM oleoyl CoA and heating at 37 ° C. for 10 minutes, the reaction was stopped by adding chloroform / methanol (2/1) containing 10 mg / ml cholesteryl oleate.

After adding and stirring 0.13 kBq of [ ³ H] cholesteryl oleate and 1N hydrochloric acid, cholesteryl oleate extracted into the chloroform layer was separated by thin layer chromatography, and the radioactivity was measured to determine the ACAT activity. Table 1 shows the results.

Example 19 Measurement of Serum Cholesterol Change Rate Male Wistar rats weighing 200 g were fed normal diet (CD-
2, made by Nippon Clea Co., Ltd.) and preliminarily reared for 7 days.

Then a cholesterol and fat enriched diet (2
% Cholesterol, 1% cholic acid, 20% casein, 45%
Granulated sugar, 12% coconut oil, 4% KC flock, 1
% Mixed vitamins, 7% mixed minerals and 8% dried fish powder, manufactured by CLEA Japan, Inc.), and bred for 3 days. 0.3mg / kg body weight during this cholesterol loading period
The test compound of the present invention (the compound obtained in Examples 1 and 11) was administered to the test animal once a day for 3 days at an oral dose of. Control animals received vehicle only.

Eight hours after the last dose, the test animals were fasted and fasted for 16 hours.
After hours, the test animals were sacrificed. Serum cholesterol levels were measured for each animal.

The results are shown in Table 2 as the percentage change in serum cholesterol (%) in comparison with the control.

Serum cholesterol change rate (%) = {(AB) / B} × 100 (where A: total amount of serum cholesterol in the test compound administration group,
B: control group serum total cholesterol) Example 20 Preparation of Tablet A tablet containing 30 mg of the compound of Example 1 was prepared according to the following formulation.

Example 1 Compound 30 mg Lactose 87 mg Starch 30 mg Magnesium stearate 3 mg According to the present invention, as described above, a novel benzopyran derivative can be obtained, and a drug for anti-atherosclerosis and anti-hyperlipidemia can be obtained. it can.

Continued on the front page (72) Inventor Tsutomu Mochizuki 5-20-2 Tamadaira, Hino-shi, Tokyo Teijin Hino Dormitory (72) Inventor Hiroshi Tanabe 3-18-4-231, Tamadaira, Hino-shi, Tokyo (72) Invention Mikio Ota 3-18-4-113 Tamadaira, Hino City, Tokyo (72) Inventor Masatoshi Kano 3-2-5 Tamadaira, Hino City, Tokyo Heights 201 Obama 201 (72) Inventor Hisao Yamaguchi 2 Asahigaoka, Hino City, Tokyo JP-A-4-182467 (JP, A) JP-A-2-49778 (JP, A) JP-A-3-95144 (JP, A) JP-A-62-53981 (JP) , A) Patent 2535468 (JP, B2) Phytochemistry, 5 [6] (1966), pp. 139-146. 1153-1158 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/00-311/96 REGISTRY (STN) CA (STN)

Claims (12)

(57) [Claims] (1) Formula (I) Wherein X is independently unsubstituted or substituted C ₇ -C ₂₀
Alkyl group, an unsubstituted or substituted C ₇ -C ₂₀ alkoxy group, an unsubstituted or substituted C ₇ -C ₂₀ acylamino group, unsubstituted or substituted C ₁₃ -C ₃₀ alkylamino group, an unsubstituted or substituted has been C ₈ -C ₂₀ alkyloxycarbonyl group, an unsubstituted or substituted C ₈ -C ₂₀ acyl group, unsubstituted or substituted C ₁₃ -C ₂₀ acyloxy group, unsubstituted or substituted C ₆ -C ₂₀ aryl groups,
Represents an unsubstituted or substituted C ₆ -C ₂₀ aryloxy group, wherein these substituents are a halogen atom, a hydroxyl group, an amino group, an alkoxy group or an aryloxy group; and Z is at the 8- or 5-position of the benzopyran ring. Substituted groups: R ¹ is independently a hydrogen atom, a halogen atom, an unsubstituted or substituted C ₁ -C ₆ lower alkyl group, an unsubstituted or substituted C ₁ -C ₆ lower alkoxy group, a hydroxyl group, a nitro group , Cyano group, unsubstituted or substituted C ₁ -C ₆ lower acylamino group, unsubstituted or substituted C ₁ -C ₁₂ alkylamino group, unsubstituted or substituted C ₁ -C ₇ lower alkyloxycarbonyl group represents a carboxyl group, an unsubstituted or substituted C ₁ -C ₇ lower acyl group or an unsubstituted or substituted C ₁ -C ₁₂ acyloxy groups, these substituents is a halogen atom, a hydroxyl group or an amino group; R ^{2 to} R ⁷ each independently represent a hydrogen atom, a methyl group or an ethyl group, or R ² and R ³ may together represent an oxygen atom, and R ⁴ and R ⁶ together Carbon-carbon May represent case, R ⁶ and R ⁷ taken together C ₅
May form a carbocyclic ring -C _7; R ⁸ is a hydrogen atom or an unsubstituted, unsubstituted C ₆ aryl group or a halogen atom, C ₁ -C ₁₄ alkyl group, an alkoxy group,
Substituted with an acylamino group, a mono- or dialkylamino group, an alkyloxycarbonyl group, an acyl group or an acyloxy group (these substituents are further substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C ₁ -C ₁₀ alkoxy group) , C ₆ -C ₁₀ aryloxy group, optionally substituted with C ₁ -C ₁₂ alkylamino group) C ₁₂ -C ₂₀ aryl group,
Unsubstituted or hexyl or decyl in C ₅ -C ₂₀ cycloalkyl or cycloalkenyl group substituted with other than 1-position or the formula, (VII): (Wherein, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an unsubstituted or substituted C ₁ -C ₆ lower alkyl group, or R ¹⁰ and R ¹¹ together represent C ₃ -C ₇ may form a carbocyclic ring; R ¹² is a hydrogen atom, an unsubstituted or substituted C ₁ -C ₁₉ alkyl or alkenyl group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group, unsubstituted or substituted A C ₆ -C ₁₉ arylalkyl group, or a formula-
A group represented by AZB (where A is a C ₁ -C ₁₂ alkyl group, Z is an oxygen atom, a sulfur atom or a compound of the formula (VIII): (Wherein, R ¹³ represents a hydrogen atom, a C ₁ -C ₆ lower alkyl group or a C ₁ -C ₆ lower acyl group, or R ¹³ may form a cyclic amine together with B, when forming the amine oxygen atom, a sulfur atom, or also to form a cyclic amine through a C ₁ -C ₆ lower alkyl group or a C ₆ -C ₁₉ arylalkyl nitrogen atom which may be substituted with a group B is unsubstituted or substituted C ₁ -C ₁₉
Represents an alkyl group, an unsubstituted or substituted C ₆ -C ₁₉ aryl group or an unsubstituted or substituted C ₆ -C ₁₉ arylalkyl group), and a substituent which may be substituted on R ¹² and B Is a halogen atom, lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, cyano group,
Lower acylamino group, lower alkylamino group, lower alkyloxycarbonyl group, carboxyl group, lower acyl group or lower acyloxycarbonyl group), or formula (IX): Wherein R ¹⁴ is independently a substituted C ₁ -C ₁₄ alkyl group,
Substituted C ₁ -C ₁₄ alkoxy group, a substituted C ₁ -C ₁₄ acylamino group, substituted C ₁ -C ₁₄ alkylamino group,
Substituted C ₁ -C ₁₄ alkyloxycarbonyl group, substituted C ₁ -C ₁₄ acyl group, a substituted C ₁ -C ₁₄ acyloxy groups, these substituents are alkoxy of C ₁ -C ₁₃ group, C ₆ -C ₁₃ aryloxy group, C ₆ -C ₁₃ aryl group, an acylamino group of C ₁ ~C _13, C ₅ cyclic amino group -C _8, monoalkylamino group of C ₁ -C ₁₃ , an alkyl group of C ₁ -C ₁₃ dialkylamino group or a C ₂ -C _13, these are further each independently represent a halogen atom,
May be substituted with a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group; R ¹⁵ is independently a hydrogen atom, a halogen atom, an unsubstituted C _{1 to} C ₁₄ alkyl group, an unsubstituted C _{1 to} C
₁₄ alkoxy group, unsubstituted C ₁ -C ₁₄ acylamino group, unsubstituted C ₁ -C ₁₄ alkylamino group, unsubstituted C ₁ -C ₁₄ alkyloxycarbonyl group, unsubstituted C ₁ -C ₁₄ acyl group ,
Represents an unsubstituted C ₁ -C ₁₄ acyloxy group; p represents an integer of 1 to 5; q represents an integer of 0 to 4; p and q do not exceed 5 in total) R ⁹ represents a hydrogen atom or a C ₁ -C ₆ lower alkyl group; and m is an integer from 0 to 3; n is an integer from 0 to 3;
Is 0 or 1, and m and n do not exceed 3 in total, but when n = 0, R ⁸ represents a group of the formula (IX), and n =
When o = 0 at 1 to 3, at least one substitution position of X is the 6-position or 7-position of the benzopyran ring, and when o = 0, X
When the substitution position of is in the 5- or 8-position, R ⁸ represents a group of the formula (VII) and the total number of carbon atoms of the groups R ¹⁰ , R ¹¹ and R ^{12 in} the (VII) is 6 or more. A benzopyran derivative represented and a pharmaceutically acceptable acid adduct thereof. 2. The benzopyran derivative and the pharmaceutically acceptable acid adduct thereof according to claim 1, wherein the substitution position of the group Z is the 8-position of the benzopyran ring. 3. The benzopyran derivative and the pharmaceutically acceptable acid thereof according to claim 2, wherein the group Z is substituted at the 8-position of the benzopyran ring, and a substituent other than a hydrogen atom is present at the 7-position. Adduct. 4. The benzopyran ring in which the substituent at the 7-position is unsubstituted
C ₁ -C ₂₀ alkyl group or an unsubstituted C ₁ -C ₂₀ benzopyran derivative according to claim 3 is an alkoxy group and pharmaceutically acceptable acid adduct. 5. A benzopyran ring wherein the substituent at the 7-position is unsubstituted.
C ₁ -C ₂₀ benzopyran derivative according to claim 4 is an alkoxy group and pharmaceutically acceptable acid adduct. 6. The substituent at the 7-position of the benzopyran ring is a group X,
4. The benzopyran derivative and the pharmaceutically acceptable acid adduct thereof according to claim 3, wherein the group Z has 7 or less carbon atoms. 7. In the above formula (I), n is 0 and Z
Is a group represented by the above formula (IX), and the substitution position of the group Z is the 8-position of the benzopyran ring, and the benzopyran derivative and a pharmaceutically acceptable acid adduct thereof according to claim 1. 8. The group Z is located at the 8-position of the benzopyran ring,
8. The benzopyran derivative and the pharmaceutically acceptable acid adduct thereof according to claim 7, wherein a substituent other than a hydrogen atom is present at the position. 9. A pharmaceutical composition having a cholesterol-lowering effect comprising an effective amount of the benzopyran derivative according to claim 1 or a pharmaceutically acceptable acid adduct thereof and a pharmaceutically acceptable carrier. . 10. An ACAT inhibitor comprising the benzopyran derivative according to claim 1 or a pharmaceutically acceptable acid adduct thereof as an active ingredient. 11. An anti-atherosclerotic agent comprising the benzopyran derivative according to claim 1 or a pharmaceutically acceptable acid adduct thereof as an active ingredient. 12. An antihyperlipidemic agent comprising the benzopyran derivative according to claim 1 or a pharmaceutically acceptable acid adduct thereof as an active ingredient.