JP3318414B2 - Fused heterocyclic compound, method for producing the same and agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an excellent acyl-CoA:
Cholesterol acyltransferase (hereinafter "AC")
AT ") and / or blood cholesterol lowering.

[0002]

2. Description of the Related Art A phenyl group and -Y
-CONH-Ph [Y is-(CH ₂ ) _n- (n is 1 or 2
Or -NH-, and Ph represents a phenyl group.
Is substituted for the adjacent position.

(1) Journal of Indian Chemical Soy
ciety), Vol. 33, pp. 339-345 (issued in 1956).

[0004]

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(2) Journal of Indian Chemical Society, 53
Vol., Pp. 295-299 (issued in 1976)

[0006]

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A compound represented by the formula:

(3) Chemical abstract (Chemical abstract)
Abstract) Expressions described in Vol. 117, 48431c

[0009]

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Wherein R represents a chlorine atom or a methoxy group. (4) Pharmacoco, Edizione Scientifica, 34, 507-
Equations described on page 517 (issued in 1979)

[0011]

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Wherein R ⁰ , R ′, and R ″ are

[0013]

[Table 1]

(In the table, H is a hydrogen atom, Me is a methyl group,
MeO represents a methoxy group, iso-Pr represents an isopropyl group, and Cl represents a chlorine atom. ). ] Has been known. In these known documents, the document (3) also describes the antibacterial action of the compound. (1),
The literatures (2) and (4) describe only the synthesis of the compounds. The compounds described in the above-mentioned documents (1) to (4) have no reports on ACAT inhibitory action, blood cholesterol lowering action, or arteriosclerosis treating action.

The above compound is a side chain moiety -Y-CONH
Although the chemical structure of -Ph (hereinafter abbreviated as "side chain moiety [A]") is different, EP-512570-A1 has the formula

[0016]

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Wherein R ₁ is halo, NO ₂ , NH ₂ or aryl optionally substituted by lower alkylamino;
Alkoxy or acylamino; R ₂ ＨH, lower alkyl optionally substituted with alkyl, cycloalkyl or cyclo (lower) alkyl, cyclo (lower) alkenyl, heterocyclyl or (optionally substituted) aryl; R ₃ ＨH, aryl optionally substituted with lower alkyl, halo, NO ₂ , NH ₂ or alkylamino, R ₄ ＨH, aryl optionally substituted with halo, lower alkyl, alkoxy or halo, R ₅ = H, halo, lower alkyl, aryl, A = single bond or lower alkylene, X = O, S or NH, provided that when R ₂ is cycloalkyl, R ₃ is aryl,
R ₄ represents halo, lower alkoxy or aryl. ]
(A) represented by the formula: and its synthetic intermediate (b)
And it has been reported that (a) has an ACAT inhibitory action. The compound (a), the side chain moiety [A]
Of Y as -A-CH ₂ N <(A is a bond or lower alkylene) has a compound (b) side chain moiety [A]
Has hydrogen, optionally substituted alkyl or cycloalkyl in place of Ph, and
It has a different chemical structure from the compound described in (4).

[0018]

Under such circumstances, it has an excellent ACAT inhibitory effect, suppresses the absorption of cholesterol from the intestinal tract and the accumulation of cholesterol ester in the arterial wall in mammals, Of compounds useful as prophylactic and therapeutic agents for cerebral infarction, atherosclerosis and various diseases caused by them (eg, ischemic heart disease such as myocardial infarction and cerebral infarction, cerebrovascular disorder such as stroke) Was rare.

[0019]

The present inventors have made various studies on compounds having a fused 5-membered ring structure, and as a result, have found that
A phenyl group and -Y-CONH-Ph at the carbon atom of the heterocyclic portion of the condensed 5-membered heterocyclic ring comprising a 5-membered heterocyclic ring and a benzene ring
Wherein the symbols in the formula have the same meanings as described above, are compounds substituted at adjacent positions,

[0020]

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Wherein ring A and ring B are each a substituent
And the C ring has a substituent.
That the benzene ring, X is (a hydrocarbon group which may have a R is hydrogen atom or a substituent) (1) -NR-,
(2) —O— or (3) —S—, and Y is — (CH ₂ ) _n
-(N represents 1 or 2) or -NH-, and Ra represents ^a hydrogen atom or ^a hydrocarbon group which may have a substituent. However, if it has a C ring Gapa la position only substituent,
Ring B has a substituent at least in the ortho position. With the first time the synthesis of the compounds (I) or a salt thereof represented by], this novel compound monomer other powerful unexpectedly salts thereof A
It has been found that it exhibits a CAT inhibitory effect and is useful as a safe blood cholesterol lowering agent, a therapeutic agent for arteriosclerosis, and the like, and based on these, completed the present invention. That is, the present invention

(1) Compound (I) or a salt thereof, (2) ring A and ring B are each (i) a halogen atom,
(Ii) an optionally halogenated C _1-6 alkyl group,
(Iii) optionally halogenated C _1-6 alkoxy, (iv) hydroxyl, (v) amino, (vi) mono- or di-C _1-4 alkylamino and (vii) C
_1-3 1 to 4 substituents which may be a benzene ring substituted with a group selected from acyloxy groups, C ring is (i) halo
Gen atom, (ii) a C _1-6 A may be halogenated
Alkyl group, (iii) a C _1-6 A may be halogenated
Alkoxy group, (iv) hydroxyl group, (v) amino group,
(Vi) a mono- or di-C _1-4 alkylamino group, (vi
i) C _1-3 acyloxy group and (viii) carboxyl group
Benzene having 1 to 4 substituents selected from
Ring, X is (1) -NR- wherein R is (i) hydrogen atom or
(Ii) (a) a halogen atom, (b) C _3-6 cycloalkyl
(C) C _6-10 aryl group, (d) C _1-4 alkyl
, C _2-4 alkenyl, C _3-6 cycloalkyl or C
_6-10 aryl having one or two substituents
Good amino group, (c) hydroxyl group, (f) halogen
Of which may be C _1-4 alkoxy group, (g) C _1-4 A
A sil group, (h) a C _1-4 acyloxy group, (i) cyano
Group, protected by (j) C _1-4 alkyl or C _7-11 aralkyl.
Carboxyl group which may be protected, (k) carbamoy
Group, (l) mercapto group, (m) C _1-4 alkylthio
Group, (n) a sulfo group and (o) C _1-4 Al Kirusuruho
Having from 1 to 4 substituents selected from
Also a C _1-6 alkyl groups, C _2-6 alkenyl groups, C _3-8 Shi
A cycloalkyl group or a C _6-14 aryl group] (2) —O— or (3) —S—, Y is — (CH ₂ ) _n — (n represents 1 or 2) or —N
H- and ^Ra are (1) hydrogen atom or (2) (i) halogen
(Ii) C _3-6 cycloalkyl group, (iii) C _6-10
Aryl group, (iv) C _1-4 alkyl, C _2-4 alkenyl,
C _3-6 cycloalkyl or C _6-10 aryl is 1 or
An amino group optionally having two substituents;
A droxyl group, (vi) an optionally halogenated C
_1-4 alkoxy group, (vii) C _1-4 acyl group, (viii) C
_1-4 acyloxy group, (ix) cyano group, (x) C _1-4 Al
Kill or may be protected by C _7-11 aralkyl
Ruboxyl group, (xi) carbamoyl group, (xii) merca
(Xiii) C _1-4 alkylthio group, (xiv) sulfo
And (xv) C _1-4 alkylsulfonyl groups.
1 to 4 a C _1-6 aralkyl optionally having substituent
Alkyl , C _2-6 alkenyl, C _3-8 cycloalkyl
_Or (3) the ring A is (i) a halogen atom , (ii) an optionally halogenated C _1-4 alkyl group (iii), or a C _6-14 aryl group. The compound according to the above (1), which is a benzene ring optionally having 1 to 4 substituents selected from an optionally halogenated C _1-4 alkoxy group, (4) ring A is formula

[0023]

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Wherein A ¹ , A ² and A ³ are the same or different and are each independently a hydrogen atom , a halogen atom , an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _{1 -4 represents an} alkoxy group. The compound according to the above (1), which is an optionally substituted benzene ring represented by the formula:

(5) Ring B is selected from (i) halogen atom , (ii) optionally halogenated C _1-4 alkyl group and (iii) optionally halogenated C _1-4 alkoxy group. The compound according to the above (1), which is a benzene ring optionally having 1 to 4 substituents, and (6) a ring represented by the formula:

[0026]

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Wherein B ¹ , B ² and B ³ are the same or different and are each a hydrogen atom , a halogen atom , an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _{1 -4 represents an} alkoxy group. The compound according to the above (1), which is a benzene ring which may have a substituent represented by the following formula (7): (7) The compound according to the above (1), wherein the ring C is a benzene ring having two or more substituents. (8) ring C is (i) a halogen atom , (ii) optionally halogenated C _1-4 alkyl group, (iii) optionally halogenated C _1-4 alkoxy group, (iv) ) Amino group, (v) mono-
Or a benzene having 1 to 4 substituents selected from a di-C _1-4 alkylamino group, (vi) a C _1-3 acyloxy group, (vii) a carboxyl group and (viii) a hydroxyl group. A compound according to the above (1), which is

(9) When the ring C has the formula

[0029]

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[Wherein C ¹ , C ² and C ³ are the same or different and are a hydrogen atom , a halogen atom , an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _{1 -4} alkoxy group or di-C _1-4 alkylamino group. Benzene ring (however, unsubstituted
A compound according to the above (1), wherein the benzene ring is excluded) ;

[0031]

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[Wherein C ⁴ , C ⁵ and C ⁶ are the same or different and each represent a hydrogen atom or an optionally halogenated C
_{It represents a 1-4} alkyl group, a C _1-4 alkoxy group which may be halogenated, a C _1-3 acyloxy group or a hydroxyl group. (11) The compound according to the above (1), which is a benzene ring (excluding an unsubstituted benzene ring) represented by the formula (11), wherein the ring C may be (i) a halogen atom , or (ii) a halogenated atom . The compound according to the above (1), which is a benzene ring having 1 to 4 substituents selected from a C _1-4 alkyl group and (iii) an optionally halogenated C _1-4 alkoxy group,

(12) When X is -NR- (R is the above-mentioned (1)
(13) a compound according to the above (1) or (2), wherein R is a C _1-4 alkyl group; There -CH ₂ - in which the (1) the compound according (15) wherein Y is -NH- (1) compounds described, (16) said R ^a is a hydrogen atom (1) compound described (17) N- [2,6-bis (1-methylethyl) phenyl] -5-chloro-3- (2-methylphenyl) -2
-Benzofuranacetamide, 5-chloro-N- (2,
6-dimethoxyphenyl) -3- (2-methylphenyl) -2-benzofuranacetamide, N- [2,6-
Bis (1-methylethyl) phenyl] -5-chloro-3
-Phenyl-2-benzofuranacetamide, N-
[2,6-bis (1-methylethyl) phenyl] -N '
-[5-chloro-3- (2-methylphenyl) -2-benzofuryl] urea, 5-chloro-N- (2,6-diethoxyphenyl) -3- (2-methylphenyl) -2-
Benzofuranacetamide, N- [5-chloro-3-
(2-methylphenyl) -2-benzofuryl] -N'-
(2,6-dimethoxyphenyl) urea, N- [5-chloro-3- (2-methylphenyl) -2-benzofuryl] -N '-(2,6-diethoxyphenyl) urea,
N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-3- (2-trifluoromethylphenyl)
-2-benzofuranacetamide, 5-chloro-N-
(2,6-diethoxyphenyl) -3- (2-trifluoromethylphenyl) -2-benzofuranacetamide, N- [2,6-bis (1-methylethyl) phenyl] -N '-[5-chloro -3- (2-trifluoromethylphenyl) -2-benzofuryl] urea, N- [5
-Chloro-3- (2-trifluoromethylphenyl)-
2-benzofuryl] -N '-(2,6-diethoxyphenyl) urea or a salt thereof according to the above (1),

Equation (18)

[0035]

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[The symbols in the formula have the same meanings as described in the above (1). And a salt or a reactive derivative thereof represented by the formula

[0037]

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[The symbols in the formula have the same significance as described in the above (1). Characterized by reacting with a compound represented by the formula or a salt thereof,

[0039]

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[The symbols in the formula have the same meanings as described in the above (1). The method for producing a compound represented by the formula or a salt thereof,

Equation (19)

[0042]

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[The symbols in the formula have the same meanings as described in the above (1). And a salt thereof and a compound represented by the formula

[0044]

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[The symbols in the formula have the same meanings as described in the above (1). A compound represented by the formula:

[0046]

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[In the formula, Y 'represents -NH-, and other symbols have the same meanings as described in the above (1). Compound or preparation of a salt thereof], (20)

[0048]

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[ The symbols in the formula have the same meanings as described in the above 1.
You. ] A compound represented by or acyl -CoA a salt thereof: cholesterol acyltransferase inhibitors, to a hypocholesterolemic agent containing (21) A compound or its salt of (20) described.

In the above formula, ring A and ring B are each substituted
Represents a benzene ring which may have a group, and ring C is a substituent
Represents a benzene ring having Examples of such a substituent include a halogen atom (for example, fluorine, chlorine, bromine,
Iodine and the like, preferably, for example, chlorine and fluorine), an alkyl group which may be halogenated, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, an amino group, C _1-7 Acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.), mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, methylethylamino) , A methylpropylamino group, etc.), a C _1-3 acyloxy group (eg, formyloxy,
Acetoxy, propionyloxy group, etc.), hydroxyl group, cyano group, carboxyl group and the like.

The optionally halogenated alkyl group as a substituent on the benzene ring includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom (for example, fluorine, chlorine, Bromine and iodine (preferably, for example, chlorine, bromine, etc.) substituted with 1 to 5 or the like are used. For example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2-trifluoroethyl, pentafluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 2-
Trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5.5,5
-Trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexyl, 5-
Trifluoromethylpentyl and the like are widely used, preferably, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 2-
A linear or branched alkyl group having 1 to 4 carbon atoms such as trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl or the like; Those having 1 to 3 halogen atoms substituted are used. Examples of the optionally halogenated alkoxy group and the optionally halogenated alkylthio group which are substituents on the benzene ring include:
For example, an optionally halogenated alkoxy group or an optionally halogenated alkylthio group formed by bonding the alkyl group or the halogenated alkyl group to an oxygen atom and a sulfur atom, respectively, is used.

Examples of the optionally halogenated alkoxy group which is a substituent on the benzene ring include, for example, those having 1 carbon atom
To 6 linear or branched alkoxy groups, or those substituted with 1 to 5 halogen atoms as described above, such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy and the like are widely used, preferably, for example, methoxy, difluoromethoxy, trifluoromethoxy, Ethoxy, 2,2,2
A straight-chain or branched alkoxy group having 1 to 4 carbon atoms such as trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy or the like; Those having 1 to 3 halogen atoms substituted are used.

Examples of the alkylthio group which may be halogenated as a substituent on the benzene ring include, for example, a linear or branched alkylthio group having 1 to 6 carbon atoms or a group having 1 to 6 halogen atoms as described above. Those substituted with five or the like are used, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4
-Trifluorobutylthio, pentylthio, hexylthio and the like are generally used, and preferably, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
A linear or branched alkylthio group having 1 to 4 carbon atoms such as 4,4,4-trifluorobutylthio or a group obtained by substituting 1 to 3 halogen atoms as described above is used.

Preferred substituents for ring A, ring B and ring C are (i) a halogen atom , (ii) an optionally halogenated C _1-6 alkyl group, and (iii) a halogenated atom. C _1-6 alkoxy group, (iv) hydroxyl group, (v) amino group, (vi) mono- or di-C _1-4 alkylamino group or (vii) C _1-3 acyloxy group or the like may be used. Can be Each term used in (i) to (vii) has the same meaning as described above. The substituents on ring A, ring B and ring C may be substituted at any position on the ring, and when there are two or more substituents, they may be the same or different, and the number is 1 to 4 It may be. Also A
Ring, the carbon adjacent on the B ring or C ring - (CH ₂₎ l
- it may form a linked 5 to 7 membered ring with the group represented by (l 3 to an integer of 5), if such is included in the subject matter (I). Preferable examples of the ring A include, for example, a halogen atom (eg, fluorine, chlorine, bromine, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, trifluoromethyl, etc.) and halogenated _1-4 selected from C _1-4 alkoxy groups which may be _substituted (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.)
And preferably a benzene ring which may be substituted with one or two substituents. For example, the formula [A]

[0055]

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[Wherein A ¹ , A ² and A ³ are the same or different and are each a hydrogen atom , a halogen atom (for example, fluorine, chlorine, bromine, etc.), a C _1-4 alkyl group which may be halogenated ( For example, methyl, ethyl, isopropyl, trifluoromethyl, etc.) or optionally halogenated C
_1-4 alkoxy group (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.)]. More preferably, for example, in the formula [A], (1)
A ¹ , A ² and A ³ are both hydrogen atoms ; (2) A ¹ and A ² are both hydrogen atoms , and A ³ is a halogen atom , an optionally halogenated C _1-4 alkyl group or halogenated are unprotected C _1-4 alkoxy group, (3) a ¹ is a hydrogen atom, a ² and a ³ are identical or different, halogen atoms, optionally C _1-4 alkyl which may be halogenated group or a halogenated which may be C _1-4 alkoxy group, (4) a ² is a hydrogen atom, a ¹ and a ³ are identical or different and optionally C _1-4 alkyl which may be halogenated Or (5) a benzene ring which may have a substituent wherein A ¹ and A ² are both hydrogen atoms and A ³ is a halogen atom , and the like. Each term used in the above (1) to (5) has the same meaning as described above. More preferable examples of the ring A include, for example, in the above formula [A], (a) A ¹ , A ² and A ³ are both hydrogen atoms , (b) A ¹ and A ² are both hydrogen atoms , and A ³ Is a chlorine, methyl, ethyl, isopropyl, methoxy or trifluoromethyl group, (c) A ¹ is a hydrogen atom , A ² and A ³ are both methyl or methoxy groups, (d) A ² is a hydrogen atom , A ¹ and A ³ are both methyl groups. (E) A benzene ring or the like which may have a substituent wherein A ¹ and A ² are both hydrogen atoms and A ³ is chlorine is used.

[0057] Preferred examples of the ring B, for example, a halogen atom (e.g. fluorine, chlorine, bromine), optionally halogenated and C _1-4 alkyl groups (e.g. methyl, ethyl, isopropyl, trifluoromethyl, etc.) and halogenated which may be C _1-4 alkoxy group (e.g. methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.) 1 to 4 selected or al, is substituted preferably with one or two substituents A benzene ring,
More preferably, a benzene ring substituted at least in the ortho position is used. For example, the formula [B]

[0058]

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[Wherein B ¹ , B ² and B ³ are the same or different and are each a hydrogen atom , a halogen atom (for example, fluorine, chlorine, bromine, etc.), a C _1-4 alkyl group which may be halogenated ( For example, methyl, ethyl, isopropyl, trifluoromethyl, etc.) or optionally halogenated C
_1-4 alkoxy group (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.)] which may have a substituent. More preferably, for example, in the formula (B),

(1) B ¹ , B ² and B ³ are all hydrogen sources
Child, (2) B ¹ is a halogen atom, an optionally optionally C _1-4 alkyl group or halogenated optionally halogenated C
_1-4 alkoxy group, B ² and B ³ are both hydrogen atoms , (3) B ¹ is a hydrogen atom , and B ² and B ³ may be the same or different and may be halogenated C _{1- A 4-} alkoxy group, (4) a C _1-4 alkoxy group in which B ¹ , B ² and B ³ may be the same or different and may be halogenated. (5) a C _1- group in which B ¹ may be halogenated. ₄ alkyl groups, B ² and B ³ are both hydrogen atoms , or (6) B ¹ is a C _1-4 alkoxy group which may be halogenated, and B ² and B ³ are both hydrogen atoms A benzene ring which may have a substituent is used. the above
Each term used in (1) to (6) has the same meaning as described above. The even more preferred as a B ring, for example, in the formula (B), (a) B ^1, B ² and B ³ are both hydrogen atoms, (b) B ¹ is chlorine, fluorine, methyl, trifluoromethyl or a methoxy group B ² and B ³ are both hydrogen atoms
Child, (c) B ¹ is a hydrogen atom, B ² and B ³ are both methoxy ^{groups, (d) B 1, B} 2 and B ³ are both methoxy, are (e) B ¹ is a methyl group, B ² and B ³ are both hydrogen
An atom , or (f) a benzene ring or the like, which may have a substituent in which B ¹ is a methoxy group and B ² and B ³ are both hydrogen atoms , is used.

[0061] Preferable as the C ring, for example, a halogen atom (e.g. fluorine, chlorine, bromine), optionally halogenated and C _1-4 alkyl groups (e.g. methyl, ethyl, isopropyl, trifluoromethyl etc),
An optionally halogenated C _1-4 alkoxy group (eg, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.), a mono- or di-C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.), A benzene ring which may be substituted with 1 to 4, preferably 2 or 3 substituents selected from an amino group, a C _1-3 acyloxy group (for example, acetoxy and the like), a carboxyl group and a hydroxyl group (however, , Unsubstituted benzene ring
Is used ) . For example, the formula [C]

[0062]

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[Wherein C ¹ , C ² and C ³ are the same or different and are a hydrogen atom , a halogen atom (for example, fluorine, chlorine, bromine, etc.), an optionally halogenated C _1-4 alkyl group ( For example, methyl, ethyl, isopropyl, trifluoromethyl and the like), optionally halogenated C _1-4
Represents an alkoxy group (eg, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.) or a di-C _1-4 alkylamino group (eg, dimethylamino, etc.), or a formula [C ′]

[0064]

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[Wherein C ⁴ , C ⁵ and C ⁶ are the same or different and each represent a hydrogen atom or an optionally halogenated C
_1-4 alkyl group (for example, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl and the like), optionally halogenated C _1-4 alkoxy group (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy and the like) ), C _1-3 acyloxy group (for example, acetoxy)
Or a hydroxyl group], which may be a substituted benzene ring or the like (however, an unsubstituted benzene ring
Is used ) . More preferably, for example, in the above formulas [C] and [C '], (1) C ¹ , C ² and C ³ are the same or different and are each a halogen atom , an optionally halogenated C _1-4 alkyl group or a halogenated which may be C _1-4 alkoxy group, (2) C ¹ and C ² are identical or different, halogen atoms
A C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated, wherein C ³ is a hydrogen atom , and (3) C ¹ and C ³ are the same or different. Differently halogen sources
A C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated, wherein C ² is a hydrogen atom ,

(4) C ¹ and C ³ are hydrogen atoms ,
² is a halogen atom , (5) C ¹ and C ² are hydrogen atoms , and C ³ is a halogen atom.
Atoms or a halogenated which may be C _1-4 alkoxy group, (6) C ¹ and C ³ are hydrogen atom, C ² good C _1-4 alkoxy group which may be halogenated, (7) C ¹ and C ³ are hydrogen atoms , and C ^{2 is} di-C _1-4
An alkylamino group, (8) hydrogen atoms wherein C ⁴ , C ⁵ and C ⁶ are the same or different
Atom, an optionally halogenated C _1-4 alkyl group or halogenated which may be C _1-4 alkoxy group, (9) C ⁴ is a good C _1-4 alkyl group which may be halogenated C ⁵ and C ⁶ are hydrogen atoms , or (10) C ⁴ and C ⁶ are the same or different and may be halogenated C _1-4 alkyl groups, and C ⁵ is a hydrogen atom.
Substituted benzene ring such as a child is used. From (1) above
Each term used in (10) has the same meaning as described above.

[0067] as more preferable as the C ring,
For example, in the above formulas [C] and [C '], (a) C ¹ , C ² and C ³ are each a fluorine, chlorine, methyl, trifluoromethyl, methoxy or ethoxy group, and (b) C ¹ and C ² are Both are fluorine, chlorine, methyl, isopropyl, trifluoromethyl, methoxy or ethoxy and C ³ is a hydrogen atom , and (c) C ¹ and C ³ are both fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, An ethoxy or isopropoxy group wherein C ² is a hydrogen atom , (d) C ¹ is an isopropyl group, C ² is a hydrogen atom and C ³ is a methyl group, (e) C ¹ and C ³ are hydrogen atoms and C ² is chlorine, (f) C ⁴ is N, N-dimethylamino group at C ⁵ and C ⁶ are hydrogen atoms, (g) C ⁴ and C ⁶ are the C ⁵ hydrogen atoms N, N-dimethylamino group, (h) C ⁴ and C ⁶ are both methyl or isopropyl C ⁵ is an acetoxy group, or (i) C ⁴ and C ⁶ are both methyl, isopropyl or
tert- butyl C ⁵ hydroxyl groups in group, a (j) C ² is fluorine or chlorine, are hydrogen atoms C ¹ and C ^3, are hydrogen atom (k) C ¹ and C ^3, C ² is Fluorine, chlorine, a methoxy group, (l) C ¹ and C ³ are hydrogen atoms , C ² is a methoxy or isopropoxy group, (m) C ¹ and C ³ are hydrogen atoms , and C ² is N, N A dimethylamino group, (n) C ⁴ , C ⁵ and C ⁶ are the same or different and fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, (o) C ⁴ is methyl , Ethyl, isopropyl or trifluoromethyl, C ⁵ and C ⁶ are hydrogen atoms , or (p) C ⁴ and C ⁶ are the same or different and are methyl, ethyl, isopropyl, trifluoromethyl, and C ⁵ is substituted is hydrogen atom Benzene ring or the like is used. In the above formula, X represents -NR- (R represents a hydrogen atom or a hydrocarbon group which may have a substituent), -O- or -S-, preferably -NR- or -O-. -Is commonly used.

In the above formula, R and Ra represent ^a hydrogen atom or ^a hydrocarbon group which may have a substituent. Examples of such a hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group. As the alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms is used, and preferably, for example, methyl, ethyl, propyl, isopropyl, butyl,
1 carbon atoms such as isobutyl, sec-butyl, tert-butyl, etc.
To 4 linear or branched alkyl groups are used. As the alkenyl group, an alkenyl group having 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl and sec-butenyl is used, and preferably, an alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl and isopropenyl is used. Alkenyl group is used. The alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, Al key alkenyl group having 2 to 6 carbon atoms such as sec- butynyl is used, preferably, for example, ethynyl, propynyl, carbon atoms such as isopropenyl 2 To 4 alkynyl groups are used.
Examples of the cycloalkyl group include C.sub.4 such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
_{A 3-8} cycloalkyl group is used, and preferably, a C _3-6 cycloalkyl group such as cyclopropyl and cyclobutyl is used. As the aryl group, an aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, and phenanthryl is used, and an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl is preferably used.

Examples of the substituent of the hydrocarbon group which may have ^a substituent of R and Ra include (i) a halogen atom ,
(ii) cycloalkyl group, (iii) aryl group, (iv) amino group optionally having alkyl, alkenyl, cycloalkyl or / and aryl group as a substituent, (v) hydroxyl group, (vi) halogen Optionally substituted alkoxy group, (vii) acyl group, (viii) acyloxy group, (ix)
A cyano group, (x) a carboxyl group which may be protected,
(xi) a carbamoyl group, (xii) a mercapto group, (xiii) an alkylthio group, (xiv) a sulfo group, and (xv) an alkylsulfonyl group. These substituents may be the same or different and may be substituted with 1 to 4, preferably 1 or 2. In the substituent of the hydrocarbon group represented by R and R ^a, fluorine as the halogen atom such as chlorine, bromine, iodine is used, preferably fluorine, chlorine or the like is used. As the cycloalkyl group, for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is used.
As the aryl group, for example, a C _6-10 aryl group such as phenyl and naphthyl is used. In an amino group which may have one or two alkyl, alkenyl, cycloalkyl or / and aryl groups as substituents,
As the alkyl group, for example, a C _1-4 alkyl group such as methyl, ethyl, propyl, and isopropyl is used, and as the alkenyl group, for example, a C _2-4 alkenyl group such as ethenyl, propenyl, isopropenyl, and butenyl is used. As the cycloalkyl group, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is used, and as the aryl group, a C _6-10 aryl group such as phenyl and naphthyl is used. Preferred examples of the amino group include an amino group, methylamino, ethylamino, dimethylamino,
A mono- or di-C _1-4 alkylamino group such as a diethylamino group is used. Examples of the optionally halogenated alkoxy group include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-
Trifluoroethoxy, propoxy, isopropoxy,
A C _1-4 alkoxy group such as butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy or a halogen atom (eg, fluorine, chlorine, etc.) of 1 to 3;
One that has been replaced is used. As the acyl group, a C _1-4 acyl group such as formyl, acetyl, propionyl, butyryl, and isobutyryl is used. As the acyloxy group, a C _1-4 acyloxy group such as formyloxy, acetyloxy, propionyloxy, butyryloxy, and isobutyryloxy group is used. As the protecting group for the carboxyl group which may be protected, a C _1-4 alkyl group such as methyl, ethyl and tert-butyl group, a C _7-11 aralkyl group such as benzyl and the like are used. As the alkylthio group, for example, a C _1-4 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like is used. As the alkylsulfonyl group,
For example, C _1-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and butylsulfonyl groups are used.

Preferred examples of the substituent of the hydrocarbon group which may have ^a substituent of R and Ra include, for example,
(i) a halogen atom , (ii) a cycloalkyl group, (iii) an aryl group, (iv) alkyl, alkenyl, cycloalkyl, an amino group which may have an aryl group as a substituent,
(v) hydroxyl group, (vi) optionally halogenated alkoxy group, (vii) acyl group, (viii) acyloxy group, (ix) cyano group, (x) optionally protected carboxyl group, xi) a carbamoyl group or the like is used [from (i)
The terms in (xi) are as defined above.] More preferably, for example, (a) a C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (b) a C _6-10 aryl group (eg, phenyl, naphthyl, etc.), (c) An amino group, (d) a mono- or di-C _1-4 alkylamino group (for example, methylamino,
Ethylamino, dimethylamino, diethylamino, etc.),
(d) A carboxyl group which may be protected with a C _1-4 alkyl group or a benzyl group (for example, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.) and the like are used.

Preferred examples of R and R ^a include (1) a hydrogen atom, (2) a C _3-6 cycloalkyl group,
_6-10 aryl group, mono- or di-C _1-4 alkylamino group, hydroxyl group, carboxyl group which may be protected by C _1-4 alkyl group and the like,
_{A 1-6} alkyl group or (3) C _3-8 cycloalkyl group is used, and more preferably, for example, a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t
ert-butyl, cyclopropyl, cyclopropylmethyl, benzyl, 2,2-dimethylaminoethyl, 2,2-
Diethylaminoethyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and the like are used. Particularly preferred examples of R include, for example, a hydrogen atom and a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.). More preferably, R is a C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl and the like, and R ^a is a hydrogen atom and the like. In the above formula, n represents 1 or 2. In particular, n is 1
Is preferred.

Y represents-(CH ₂ ) _n- (n represents 1 or 2) or -NH-, and preferably -CH ₂ -or -NH- is widely used. Preferred examples of each symbol definitive in compound (I) are shown below. (1) -i; A ring is a halogen atom (for example, fluorine,
Chlorine, bromine, etc.) and optionally halogenated C
It is a benzene ring which may be substituted with one or two substituents selected from _1-4 alkyl groups (for example, methyl, ethyl, isopropyl, trifluoromethyl and the like). (1) -ii; ring A is a group represented by the formula

[0073]

Embedded image

[Wherein A ⁴ represents a halogen atom (for example, fluorine, chlorine, etc.)] ]. (2) -i; ring B is optionally halogenated C
_{Selected from 1-4} alkyl groups (eg, methyl, ethyl, isopropyl, trifluoromethyl, etc.) and optionally halogenated C _1-4 alkoxy groups (eg, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.) A benzene ring which may be substituted with one or two substituents.

(2) -ii; ring B is a group represented by the formula

[0076]

Embedded image

[Wherein B ⁴ is an optionally halogenated C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, trifluoromethyl, etc.) or a C _1-4 alkoxy group (eg, methoxy, ethoxy) , Isopropoxy, etc.)]. (3) -i; wherein the ring C is a halogen atom (eg, fluorine, chlorine, etc.), a C _1-4 alkyl group which may be halogenated (eg, methyl, ethyl, isopropyl, trifluoromethyl, etc.) and A benzene ring which may be substituted with 1 to 3 substituents selected from an optionally halogenated C _1-4 alkoxy group (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy, etc.) . (3) -ii; C ring, wherein

[0078]

Embedded image

[Wherein C ⁷ and C ⁸ each represent C _1-4
An alkyl group (eg, methyl, ethyl, isopropyl, etc.) or a C _1-4 alkoxy group (eg, methoxy, ethoxy, isopropoxy, etc.); C ⁹ and C ¹⁰ are each a halogen atom (eg, fluorine, chlorine, etc.); C ¹¹ ,
C ¹² and C ¹³ each represent a halogen atom (eg, fluorine, chlorine, etc.) or a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, etc.). ] It is a benzene ring represented by these.

(4) -i; X is -NR'- (R 'represents a C _1-4 alkyl group such as methyl, ethyl and isopropyl) or -O-. (4) -ii; X is -NR'- (R 'represents a C _1-4 alkyl group such as methyl, ethyl and isopropyl). (4) -iii; X is -O-. (5) -i; Y is _{-CH 2 -, - CH 2 CH} 2 - or -
NH-. (5) -ii; Y is -CH ₂ - is. (5) -iii; Y is -NH-. (6) -i; ^Ra is a hydrogen atom . Preferred combinations are shown below.

[0081]

[Table 2]

The fused 5-membered heterocyclic compound represented by the formula (I) or a salt thereof can be produced, for example, by the following method. Namely: a compound obtained by reacting a carboxylic acid represented by the general formula (II) or a salt thereof or a reactive derivative thereof with an amine represented by the general formula (III) or a salt thereof
(I) or a salt thereof is produced. A compound (I) or a salt thereof is produced by reacting an amine represented by the general formula (IV) or a salt thereof with a compound represented by the general formula (V ) or a salt thereof. Hereinafter, the method will be described in detail.

Method: The reaction between the carboxylic acid represented by the general formula (II) or a salt thereof or a reactive derivative thereof and the compound (III) or a salt thereof is an amide bond or urea bond formation reaction. Will be implemented. For example, compound (II) or a salt thereof (for example, a salt with an alkali metal such as sodium, potassium or magnesium, or an alkaline earth metal, etc.) and compound (III) or a salt thereof (for example, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid, or Methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, salts with organic acids such as maleic acid, etc.), the reaction is usually carried out using an appropriate condensing agent, or (II) or its Preferably, the salt is once introduced into its reactive derivative (III) or reacted with its salt. Examples of such a condensing agent include dicyclohexylcarbodiimide, 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide and the like are used. When these condensing agents are used, usually, a solvent (for example, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, dichloromethane, 1,2-dichloroethane, benzene, toluene, N,
Ethers such as N-dimethylformamide and dimethylsulfoxide, esters, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides and the like). This reaction may promote the reaction in the presence of a base,
About -10 ° C to 100 ° C, preferably about 0 ° C to 6 ° C
The reaction is performed at 0 ° C. The reaction time is generally 1 to 96 hours, preferably 1 to 72 hours. (III) or a salt thereof and a condensing agent are used in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the (II) or a salt thereof. As the base, for example, alkylamines such as triethylamine, and cyclic amines such as N-methylmorpholine and pyridine are used.
It is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of I) or a salt thereof.

Examples of the reactive derivative (II) include acid halides (eg, chloride, bromide, etc.), acid anhydrides, mixed acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, and isobutyl carbonates). An active ester (e.g., an ester with hydroxysuccinimide, an ester with 1-hydroxybenzotriazole,
Esters with N-hydroxy-5-norbornene-2,3-dicarboximide, esters with p-nitrophenol, esters with 8-oxyquinoline, and the like. When reacting the compound (III) or a salt thereof with the reactive derivative of (II), a solvent (eg, chloroform, dichloromethane, 1,2-dichloroethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dimethoxyethane, ethyl acetate, benzene) , Toluene, pyridine, halogenated hydrocarbons such as N, N-dimethylformamide, ethers, esters, hydrocarbons, amides, etc.). This reaction may promote the reaction in the presence of a base. The reaction temperature is usually about -10 ° C to 120 ° C, preferably about 0 ° C to 100 ° C. The reaction time is generally 1 to 48 hours, preferably 1 to 24 hours.
Time. The amount of (III) or a salt thereof to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the reactive derivative of (II). Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, sodium carbonate, potassium carbonate and the like. Alkali metal carbonates, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, etc. are used.
The amount is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of (II) or a reactive derivative thereof. Also,
When a water-immiscible solvent is used in this reaction, water may be added to the reaction system and the reaction may be performed in a two-phase system.

Further, in the present method, when Y of the compound (II) is -NH-, a corresponding isocyanate ([II-2] described later) is preferably used as a derivative of the reactivity. A reaction using these isocyanates and the compound (III) or a salt thereof produces a urea derivative.
In this reaction, compound (III) itself may be used as a solvent, but the reaction can also be performed in another solvent. Such other solvent may be any solvent as long as it does not hinder the reaction, for example, ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) ), Esters (eg, methyl acetate,
Ethyl acetate and the like, amides (eg, N, N-dimethylformamide and the like), sulfoxides (eg, dimethyl sulfoxide and the like) and the like are preferably used. When compound (III) is used in the form of a salt, the reaction can be significantly advanced by adding a desalting agent, if necessary. in this case,
As the desalting agent, for example, tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine, and aromatic amines such as pyridine, picoline and N, N-dimethylaniline are preferably used. The amount of the desalting agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the salt of (III). The reaction temperature is usually -10C to 180C, preferably 0C to 1C.
20 ° C. The reaction time is generally 15 minutes to 40 hours, preferably 30 minutes to 20 hours. The amount of (III) or a salt thereof used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of (II) or a salt thereof.

Method: This method is a method for preparing compound (IV) which is an amine derivative or a salt thereof (eg, a salt with a mineral acid such as hydrochloric acid or sulfuric acid, or methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaral A salt with an organic acid such as an acid or maleic acid) and a compound (V) which is an isocyanate derivative to produce a urea derivative. This method can be carried out in the same manner as the above-mentioned method based on the reaction between (II-2), (II-3) and (III). When the compound (I) or a salt thereof produced by the above method or the above includes a lower alkoxy group in the benzene ring in the A ring, B ring , C ring , R and R ^a group, if necessary, By reacting with boron tribromide or the like, it can be converted to a hydroxyl group. This reaction is usually carried out in a solvent (e.g., dichloromethane, chloroform, carbon tetrachloride,
Benzene, halogenated hydrocarbons such as toluene, hydrocarbons, etc.) about -20 ° C. a stone 80 ° C. in, preferably carried out at about 0 ℃ to 30 ° C., the amount of boron tribromide is lower alkoxy It is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents per one. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours. Further, the compound (I) or a salt thereof produced by the above method or the method may be a ring A, ring B, ring C , R,
When the benzene ring in the group represented by R ^a contains a hydroxyl group, it can be converted to an alkoxy or acyloxy group by performing an alkylation or acylation reaction, if necessary. The alkylation reaction is
In a solvent (eg, alcohols such as methanol, ethanol, and propanol, ethers such as dimethoxyethane, dioxane, and tetrahydrofuran, ketones such as acetone, and amides such as N, N-dimethylformamide), a base (eg, trimethylamine) , Triethylamine, N-methylmorpholine, pyridine, picoline, N,
An organic base such as N-dimethylaniline, potassium carbonate,
In the presence of sodium carbonate, potassium hydroxide, an inorganic base such as sodium hydroxide), an optionally substituted alkane halide (e.g., chloride, bromide, iodide, etc.), sulfate or sulfonate
(E.g., methanesulfonate, p-toluenesulfonate,
The reaction is performed by reacting an alkylating agent such as benzenesulfonate). The reaction temperature is usually -10C to 100C, preferably about 0C to 80C.
The amount of the alkylating agent to be used is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

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

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

The starting compounds (II) and (IV) used to produce the compound (I) of the present invention or a salt thereof, or a salt thereof are industrially advantageous, for example, by the method shown in the following figure or a method analogous thereto. Can be manufactured.

[0090]

Embedded image

(Wherein the ring B ′ may have a substituent.
A benzene ring, R ^b is a carboxyl-protecting group, and other symbols are as defined above. Further, the substituent on the B ′ ring is
It has the same meaning as the substituent of ring B described above. )

Compounds of the formulas (IX) and (II-1) wherein X is --O-- can be obtained from (VI) (X ＝ O) by chaterdia (JN Cha
tterjea) et al. Journal of Indian Chemical Soceit
y), Vol. 45, pp. 171-177 (issued in 1968) (steps 1 to 4) or a method analogous thereto. In (IX) and (II-1), X is -NR
Compounds-and -S- can also be produced by a method analogous thereto. Further, in (II-1), X is -N
The compound represented by R- is a known method using phenylhydrazines and γ-phenylacetoacetates as starting materials [UM Teotino, Gazzetta Chimica Italiana, 1853-1].
862 (issued in 1959)] or a method analogous thereto.

In the fifth step, the carboxyl group of (IX) is converted into an isocyanate group (II-2) [This compound corresponds to the compound of formula (II) wherein Y is -NH-. And a method of converting (IX) into an isocyanate form as an acid azide form. Although various methods are known in the literature, any method can be applied to (IX). For example, an azidating agent (for example, diphenylphosphoryl azide (hereinafter abbreviated as DPPA) and the like) and (I
By reacting with (X), the acid azide of (IX) can be produced. This reaction is usually performed in a solvent inert to the reaction.
(Examples, ethers such as ethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, methyl acetate, esters such as ethyl acetate, acetone, 2-butanone and the like Ketones, aromatic amines such as pyridine, amides such as N, N-dimethylformamide, etc.). Base
The reaction may proceed in the presence of (eg, trimethylamine, triethylamine, N-methylmorpholine, etc.). The reaction time is generally about 5 minutes to 12 hours, preferably about 1 hour.
0 minutes to 6 hours. Reaction temperature is usually about -10 ° C
To 150 ° C, preferably about -5 ° C to 120 ° C. The amount of azidating agent (eg, DPPA) used is
It is 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, relative to (IX).

The produced acid azide can be isolated and purified by a means known per se. However, the reaction solution is generally heated without isolation to convert it into the isocyanate (II-2). In this conversion reaction, it is preferable to use the same solvent as that used for the azidation, usually about 20 ° C to 200 ° C,
It is preferably carried out by heating to about 30 ° C to 150 ° C. The reaction time is usually about 5 minutes to 10 hours,
Preferably about 5 minutes to 6 hours. The obtained compound (II-2) can be isolated by a means known per se, or can be used as a raw material for producing a compound (I ′) in which Y ′ is —NH— without isolation. .

The seventh step is a step of converting the acetic acid derivative (II-1) to the isocyanate derivative (II-3). This step can be performed according to the method described in the fifth step. Sixth
And the eighth step converts the isocyanate groups of (II-2) and (II-3) into amino groups, and converts them into (IV-1) and (IV), respectively.
-2). This step is usually performed under hydrolysis conditions. In this reaction, for example, a solvent (eg, alcohols such as methanol, ethanol, propanol, butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, or a mixed solvent thereof)
For example, the reaction is performed under alkaline conditions using a hydroxide of an alkali or alkaline earth metal such as sodium hydroxide or barium hydroxide, or under acidic conditions using an inorganic acid such as hydrochloric acid, hydrobromic acid , sulfuric acid , or the like. . The reaction temperature is usually about 0 ° C to 120 ° C, preferably about 15 ° C to 100 ° C. The reaction time is about 30 minutes to 36 hours, preferably about 1 hour to 20 hours. Compounds in which X is -NR- among the compounds (IV-1) can be prepared, for example, by a known method [e.g. G. Winter
s) et al., Pharmacoco, Edizione Scientifica 34, 507
517 (issued in 1979)] or a method based thereon. Also, EP-A1-
The compound described in 512570 can be industrially advantageously produced by using the compound (IV-2) in the present invention. For example, (IV-1) and (V) can be converted to the above (IV) It can be easily produced by reacting in the same manner as in the reaction of (V).

In the above-mentioned methods for producing the target substance and the starting material, when the starting compound contains a reactive group such as an amino group, a hydroxyl group or a carboxyl group as a substituent, a protecting group may be added according to a conventional method, if necessary. Can be used as a raw material. The introduced protecting group is removed by subjecting it to a deprotection reaction according to a conventional method after completion of the reaction, if necessary, to obtain the desired compound (I ′) or a synthetic intermediate thereof or a salt thereof. it can. As such a protecting group, for example, those used in the field of peptides and the like are appropriately adopted. Among them, as the protecting group for an amino group, for example, formyl, chloroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p- Preferred are methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trityl and the like. Examples of the hydroxyl-protecting group include chloroacetyl, benzyl, p-
Nitrobenzyl, methylthiomethyl, methoxymethyl,
Trimethylsilyl, tert-butyldimethylsilyl, 2-
Tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyl and the like are used. Examples of the carboxyl protecting group include benzyl, benzhydryl,
Trityl, p-methoxybenzyl, p-nitrobenzyl, tertiary butyl, allyl and the like are used.

In the above-mentioned production method, when an amino group or a carboxyl group is contained in the raw material compound or the synthetic intermediate, etc., if necessary, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrogen bromide, etc.) may be used according to a conventional method. Acids, etc.), organic acids (eg, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, calcium, magnesium, etc.) A salt with an alkaline earth metal, aluminum or ammonium, or an organic base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine). Can also You. Further, the compound obtained in each of the above steps may be purified by a known means such as concentration, liquid conversion,
Phase transfer, solvent extraction, column chromatography, crystallization,
It may be purified and collected by recrystallization or the like, or may be used as a mixture in the next step reaction.

Compound (I) or a pharmaceutically acceptable salt thereof (for example, a salt with an inorganic or organic base or a salt with an inorganic or organic acid described above) is an excellent acyl-CoA:
It has an inhibitory action on cholesterol acyltransferase (ACAT), and has low acute toxicity and toxicity due to continuous administration, and is safe as a drug. ACAT is an enzyme involved in the esterification of cholesterol to higher fatty acids in cells. It is absorbed as an ester of cholesterol in the intestinal tract and accumulates as an ester of cholesterol in peripheral organs and cells (eg, arterial walls, macrophages, etc.). It is known to play an important role. Therefore, the ACAT inhibitory substance inhibits the absorption of dietary cholesterol from the intestinal tract, suppresses a rise in blood cholesterol level, suppresses the accumulation of intracellular cholesterol ester in atherosclerotic lesions, and prevents the progression of atherosclerosis. Can be. Therefore, the compound (I) of the present invention, which has an excellent ACAT inhibitory activity, or a salt thereof can be used for producing high cholesterol in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, horses, cows, sheep, monkeys, humans, etc.). It is useful as a safe prophylactic / therapeutic agent for blood disease, atherosclerosis and diseases caused by these diseases (for example, ischemic heart disease such as myocardial infarction and cerebrovascular disorder such as cerebral infarction and stroke).

The compound (I) or a salt thereof includes those exhibiting an action of inhibiting the formation of lipid peroxide (antioxidant action) (for example, in formula (I) , ring A, ring B and ring C ) . At least one of which is a benzene ring substituted with an amino group or a hydroxyl group which may be substituted with a C _1-4 alkyl group). It is known that peroxidation of lipids in a living body is closely related to arteriosclerosis and the development of ischemic diseases in the brain and cardiovascular system. Therefore, the compound (I) or a salt thereof having both an ACAT inhibitory action and an antioxidant action can prevent and treat various vascular lesions caused by both blood cholesterol and lipid peroxide, and thus is useful as a pharmaceutical. High usefulness.

When the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as the above-mentioned medicament, an appropriate pharmacologically acceptable carrier or excipient (eg, starch, lactose, sucrose) , Calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin,
Polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, etc.), disintegrants (eg, carboxymethylcellulose calcium, talc, etc.), diluents (eg, physiological saline, etc.), etc. Powders, fine granules, granules,
Although it can be administered orally or parenterally in the form of tablets, capsules or injections, it is more preferably administered orally when used for the purpose of inhibiting cholesterol absorption. The dose varies depending on the type of compound (I) or a salt thereof, the route of administration, symptoms, age of the patient, and the like. For example, when administered orally to an adult hypercholesterolemia patient, the daily dose is 1 kg of body weight About 0.0 per
05 to 50 mg, preferably about 0.05 to 10 m
g, more preferably about 0.2 to 4 mg, and
It is preferable to administer the drug in 1 to 3 times a day.

[0101]

(Experimental method)

Enzyme specimen ACAT was published by Heidel et al. In Journal of Lipid Research.
h], Vol. 24, p. 1127 (1982), prepared from a microsomal fraction of the small intestinal mucosa of a 6-week-old male Sprague-Dawley rat fasted for 20 hours. ACAT activity was determined according to the method of Helgerud et al. (Journal of Lipid Research, Vol. 22, p. 271, 1981).
^[1-14 C] were calculated by measuring the production amount of labeled cholesterol ester from oleoyl -CoA and endogenous cholesterol.

[0102] [Results] The test compounds in Table 3 labeled cholesterol ester formation inhibitory rate when the added 10 ^-6 M (following Examples 1 to representative compounds among the compounds obtained in 24) (% )
Is shown as an index of ACAT inhibitory action.

[0103]

[Table 3]

Table 3 shows that compound (I) or a salt thereof has an excellent ACAT inhibitory action.

(2) Blood high cholesterol-lowering effect (cholesterol-lowering effect) [Experimental method] Seven ICR mice (each divided into two groups of three) of 6
High cholesterol-cholate-containing feed was ingested for one day for high cholesterol blood. The test compound was administered orally during the last two days, half of the total dose was administered on day 6, and the other half on day 7. After fasting overnight (16 hours after the last administration), the animals were sacrificed, the sera of the animals of each of the two groups were collected, and the cholesterol level and the heparin precipitated lipoprotein (HPL) level were measured. Both cholesterol and HPL levels were measured using an automatic analyzer, the former being CHOD-PA by enzymatic method.
P method, the latter being turbidimetric (Shurr et al.) [CE Dau
Hen, Atherosclerosis Drug Discovery, Plenum Publish
ing, New York, pp. 215-229 & 231-249.
Page 1976). [Table 4] shows the reduction rate (%) of cholesterol and HPL as compared with each control group. 〔result〕

[0106]

[Table 4]

From Table 4, it is clear that compound (I ) or a salt thereof exhibits an excellent blood high cholesterol lowering effect. (Po indicates oral administration)

[0108]

The present invention will be further described in the following Reference Examples and Examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. May be changed. Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise specified. In the TLC observation, 60 F ₂₅₄ manufactured by Merck was used as a TLC plate, the solvent used as an eluent in column chromatography as a developing solvent was used as a detection method, and ULC was used as a detection method.
A V detector was employed. Silica gel for column chromatography is silica gel 60 (70-230) manufactured by Merck.
Mesh). Room temperature usually means about 10 ° C to 35 ° C. Sodium sulfate or magnesium sulfate was used for drying the extract. Abbreviations in the examples and reference examples mean the following. DMF: dimethylformamide,
THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, Hz: hertz, J: coupling constant, m: multiplet, q: quartet, t: triplet,
d: doublet, s: singlet, b: broad, like:
Approximation

Example 1 N- [2,6-bis (1-methylethyl) phenyl]-
5-Chloro-3- (2-methylphenyl) -2-benzofuranacetamide Chloride into a solution of 5-chloro-3- (2-methylphenyl) benzofuran-2-acetic acid (3.00 g) in anhydrous THF (30 ml). Oxalyl (1.30 ml) and DMF (1 drop)
Was added at room temperature, and the mixture was stirred for 0.5 hour. Evaporate the solvent,
The residue was dissolved in dichloromethane (10ml). This solution was added to a solution of 2,6-diisopropylaniline (2.50 ml) and triethylamine (3.00 ml) in dichloromethane (30 ml) and stirred at room temperature for 1 hour. The solvent was distilled off, and ethyl acetate was added to the residue.
After washing with water, aqueous sodium hydrogen carbonate and water in that order and drying, the solvent is distilled off to give the title compound as colorless crystals (1.86).
g). 260-261 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.11 (6H, d, J = 7.0H)
z), 1.12 (6H, d, J = 6.8Hz), 2.22 (3H, s), 2.96 (2H, m), 3.
79 (1H, d, J = 16Hz), 3.89 (1H, d, J = 16Hz), 6.90-7.50 (11H,
m) Elemental analysis: C ₂₉ H ₃₀ NO ₂ Cl Calculated: C, 75.72; H, 6.57; N, 3.04 Found: C, 75.71; H, 6.66; N, 3.17 Starting in Examples 2-5 below. Using benzofuran-2-acetic acid and aniline corresponding to each example compound as raw materials, the target compound was obtained in the same manner as in example 1.

Example 2 5-chloro-N- (2,6-dimethoxyphenyl) -3
-(2-Methylphenyl) -2-benzofuranacetamide Melting point 185-187 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.21 (3H, s), 3.75 (8
H, s like), 6.54 (2H, d, J = 8.4Hz), 6.81 (1H, bs), 7.10-
7.50 (8H, m) Elemental analysis C ₂₅ H ₂₂ NO ₄ Calculated C as Cl, 68.89; H, 5.09; N, 3.21 Found C, 69.00; H, 5.35; N, 3.49

Example 3 5-chloro-3- (2-methylphenyl) -N- (2,
4,6-Trimethylphenyl) -2-benzofuranacetamide Melting point: 222-224 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 2.10 (6H, s), 2.21 (3
H, s), 2.24 (3H, s), 3.81 (2H, d, J = 3.2Hz), 6.86 (2H, s),
6.95 (1H, bs), 7.20-7.50 (7H, m) Elemental analysis _{C 26 H 24 NO 2 Cl ·} 0.2H 2 O Calculated C, 74.08; H, 5.83; N, 3.32 Found C, 73.97 H, 5.81; N, 3.26

Example 4 N- [2,6-bis (1-methylethyl) phenyl]-
5-Chloro-3-phenyl-2-benzofuranacetamide Melting point 260-262 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.10 (12H, d, J = 6.8H)
z), 2.94 (2H, m ), 4.03 (2H, s), 6.90-7.70 (12H, m) Elemental analysis C ₂₈ H ₂₈ NO ₂ Calculated C as Cl, 75.41; H, 6.33; N, 3.14 Found Value C, 75.13; H, 6.39; N, 3.22

Example 5 5-Chloro-N- (2,6-dimethoxyphenyl) -3
-Phenyl-2-benzofuranacetamide Melting point 253-254.5 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.77 (6H, s), 3.95 (2
H, s), 6.55 (2H, d, J = 8.4Hz), 6.87 (1H, bs), 7.10-7.70 (9
H, m) Elemental analysis calculated as C ₂₄ H ₂₀ NO ₄ Cl Calculated C, 68.33; H, 4.78; N, 3.32 Found C, 68.14; H, 4.91; N, 3.38

Example 6 N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-1-methyl-3-phenyl-2-indoleacetamide 5-chloro-1-methyl-3-phenylindole-2
Oxalyl chloride (0.10 ml) and DMF (1 drop) were added to a solution of acetic acid (150 mg) in anhydrous THF (5 ml) at room temperature and stirred for 0.5 hours. The solvent was distilled off, and the residue was dissolved in dichloromethane (3 ml). This solution was
The solution was added to a solution of diisopropylaniline (0.15 ml) and triethylamine (0.40 ml) in dichloromethane (5 ml) and stirred at room temperature for 1 hour. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, dried and evaporated to give the title compound as colorless crystals (74 mg). . 279-280 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.01 (12H, d, J = 7.0H)
z), 2.70 (2H, m), 3.87 (3H, s), 4.10 (2H, s), 6.54 (1H, b
s), 7.05-7.65 (11H, m ) Elemental analysis C ₂₉ H ₃₁ N ₂ Calculated as OCl C, 75.88; H, 6.81 ; N, 6.10 Found C, 75.74; H, 6.61; N, 5.92 The following In Examples 7 to 10, the target compound was obtained in the same manner as in Example 6, except that indole-2-acetic acid and aniline corresponding to each example compound were used as starting materials.

Example 7 N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-1-methyl-3- (2-methylphenyl)
-2-indoleacetamide melting point 266-267 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.02 (12H, t like, J =
6.8Hz), 2.17 (3H, s), 2.70 (2H, m), 3.78 (1H, d, J = 16Hz),
3.88 (3H, s), 3.91 (1H, d, J = 16Hz), 6.54 (1H, bs), 7.05-7.40
(10H, m) Elemental analysis _{C 30 H 33 N 2 OCl ·} 0.2H 2 O Calculated C, 75.59; H, 7.06; N, 5.88 Found C, 75.70; H, 7.04; N, 5.75

Example 8 5-Chloro-N- (2,6-dimethoxyphenyl) -1
-Methyl-3- (2-methylphenyl) -2-indoleacetamide Melting point 191-193 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) pp
m: 2.18 (3H, s), 3.75 (6H, s), 3.78 (2H, bs), 3.87 (3H, s
s), 6.51 (1H, bs), 6.53 (2H, d, J = 8.4Hz), 7.10-7.40 (8H,
m) Elemental analysis C ₂₆ H ₂₅ N ₂ O ₃ Calculated C as Cl, 69.56; H, 5.61; N, 6.24 Found C, 69.35; H, 5.64; N, 6.23

Example 9 N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-3- (2-methoxyphenyl) -1-methyl-2-indoleacetamide Melting point 270-273 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.80-1.10 (12H, m),
2.63 (2H, m), 3.62 (3H, s), 3.84 (5H, s like), 7.00-7.50
(11H, m) Elemental analysis calculated as C ₃₀ H ₃₃ N ₂ O ₂ Cl Calculated C, 73.68; H, 6.80; N, 5.73 Found C, 73.54; H, 6.88; N, 5.60

Example 10 5-chloro-N- (2,6-dimethoxyphenyl) -3
-(2-methoxyphenyl) -1-methyl-2-indoleacetamide Melting point 160 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.74 (9H, s), 3.85 (5
H, s like), 6.53 ( 2H, d, J = 8.4Hz), 6.95-7.45 (9H, m) Elemental analysis C ₂₆ H ₂₅ N ₂ O ₄ Calculated C as Cl, 67.17; H, 5.42; N , 6.03 found C, 67.14; H, 5.59; N, 5.78.

Example 11 N- [2,6-bis (1-methylethyl) phenyl]-
N '-[5-chloro-3- (2-methylphenyl) -2
-Benzofuryl] urea 5-chloro-3- (2-methylphenyl) benzofuran-2-carboxylic acid (300 mg) in anhydrous benzene (10
ml) to the suspension was added diphenylphosphoryl azide (0.33m
l) and triethylamine (0.16 ml) were added, and the mixture was stirred at room temperature for 15 minutes, and then heated under reflux for 1 hour. This reaction solution (5-chloro-3-phenylbenzofuran-2-
2,6-Diisopropylaniline (0.3 ml) was added to the mixture (containing isocyanate), and the mixture was stirred under reflux for 0.5 hour. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, dried and evaporated to give the title compound as colorless crystals (2
17 mg). Melting point 240-240.5 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.9-1.30 (12H, m),
2.10 (1.5H, s), 2.29 (1.5H, s), 3.09 (2H, m), 6.00 (0.5H,
bs), 6.11 (0.5H, bs), 6.79 (0.5H, s), 7.06 (0.5H, bs),
7.10-7.40 (10H, m) Elemental analysis calculated as C ₂₈ H ₂₉ N ₂ O ₂ Cl Calculated C, 72.95; H, 6.34; N, 6.08 Found C, 73.01; H, 6.32; N, 5.78

Example 12 N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,4-difluorophenyl) urea When 2,4-difluoroaniline is used in place of 2,6-diisopropylaniline of Example 11, the title compound is colorless when reacted in the same manner as in Example 11. Obtained as crystals. 230 ° C. (decomposition) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.24 (3H, s), 6.75-
6.90 (3H, m), 6.95-7.50 (7H, m), 7.85 (1H, bs), 7.90-8.1
0 (1H, m) Elemental analysis _{C 22 H 15 N 2 O 2} ClF 2 · 0.3H 2 O Calculated C, 63.18; H, 3.76; N, 6.70 Found C, 63.19; H, 3.88; N , 6.62

Example 13 N- [5-chloro-3- (2-methylphenyl) -2-
Benzofurylmethyl] -N '-(2,4-difluorophenyl) urea Diphenylphosphoryl azide was added to a suspension of 5-chloro-3- (2-methylphenyl) benzofuran-2-acetic acid (300 mg) in anhydrous benzene (10 ml). (0.33 ml) and triethylamine (0.16 ml) were added, and the mixture was stirred at room temperature for 15 minutes, and then heated under reflux for 1 hour. 2,4-Difluoroaniline (0.30 ml) was added to the reaction mixture containing {2- [5-chloro-3- (2-methylphenyl) benzofuryl] methyl isocyanate}, and the mixture was stirred for 0.5 hour under reflux with heating. Was. The solvent was distilled off, ethyl acetate was added to the residue, and water, diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate,
After washing with water and drying, the solvent was distilled off. The residue was separated and purified by column chromatography using silica gel (30 g) (hexane-ethyl acetate = 3: 1) to give the title compound as colorless crystals (63 mg). 178-180 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 2.12 (3H, s), 4.44 (2
H, s like), 5.49 (1H, bs), 6.65-6.80 (3H, m), 7.10-7.35
(7H, m), 7.70-7.90 ( 1H, m) Elemental analysis _{C 23 H 17 N 2 O 2} ClF Calculated C as _{2, 64.72; H, 4.01;} N, 6.56 Found C, 64.46; H, 4.36 N, 6.32

Example 14 N- [5-Chloro-1-methyl-3-phenyl-2-indolylmethyl] -N '-(3-isopropoxyphenyl) urea 5-Chloro-3- ( 2-methylphenyl)
When 5-chloro-3-phenylbenzofuran-2-acetic acid is used instead of benzofuran-2-acetic acid and 3-isopropoxyaniline is used instead of 2,4-difluoroaniline, the reaction is carried out in the same manner as in Example 13 to give the title. The compound was obtained as colorless crystals. 218-220 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.30 (6H, d, J = 6 Hz),
3.18 (3H, s), 4.49 (1H, m), 4.71 (2H, s), 4.8 (1H, b), 6.2
(1H, b), 6.60-6.70 (2H, m), 6.84-6.86 (1H, m), 7.12-7.5
. 1 (8H, m), 7.58 (1H, d, J = 2Hz) Elemental analysis C ₂₆ H ₂₆ N ₃ O ₂ Calculated C as Cl, 69.71; H, 5.85; N, 9.38 Found: C, 69.61; H, 5.82; N, 9.37.

Example 15 5-Chloro-N- (2,6-diethoxyphenyl) -3
-(2-methoxyphenyl) -1-methyl-2-indoleacetamide using 5-chloro-3- (2-methoxyphenyl) -1-methylindole-2-acetic acid and 2,6-diethoxyaniline The reaction was carried out in the same manner as in Example 6 to obtain the title compound as colorless crystals. 180-183 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.25 (4H, t, J = 6.8H)
z), 1.39 (2H, t, J = 6.9Hz), 3.73 (3H, s), 3.86 (3H, s), 3.96
(2.7H, q, J = 6.8Hz), 4.08 (1.3H, q, J = 6.9Hz), 6.49 (1.3H, d,
J = 8.4Hz), 6.58 (0.7H, d, J = 8.6Hz), 6.90-7.50 (9H, m)

Example 16 5-Chloro-N- (2,6-diethoxyphenyl) -3
-(2-Methylphenyl) -2-benzofuranacetamide When 2,6-diethoxyaniline is used in place of 2,6-diisopropylaniline of Example 1 and reacted in the same manner as in Example 1, the title compound is obtained. Obtained as colorless crystals. 145-147 ° C (recrystallized from ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.28 (5H, t, J = 7.0H)
z), 1,39 (1H, t, J = 7.0Hz), 2.20 (3H, s), 3.75 (2H, bs),
3.98 (3.3H, q, J = 7.0Hz), 4.08 (0.7H, q, J = 7.0Hz), 6.51
(1.7H, d, J = 8.4Hz), 6.58 (0.3H, d, J = 8.4Hz), 6.87 (1H, b
s), 7.04-7.47 (8H, m)

Example 17 5-chloro-3- (2-methylphenyl) -N- (2,
(4,6-trifluorophenyl) -2-benzofuranacetamide The reaction was conducted in the same manner as in Example 1 except that 2,4,6-trifluoroaniline was used instead of 2,6-diisopropylaniline in Example 1. The title compound was obtained as colorless crystals. 193-194 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.20 (3H, s), 3.82 (2
(H, d, J = 1.8Hz), 6.65-6.80 (2H, m), 6.98 (1H, bs), 7.23-7.51
(7H, m) Example 11 was repeated using 2,4,6-trifluoroaniline, 2,6-dimethoxyaniline and 2,6-diethoxyaniline instead of 2,6-diisopropylaniline of Example 11. When the reaction was carried out in the same manner as in
8, 19 and 20 compounds were obtained.

Example 18 N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,4,6-trifluorophenyl) urea Melting point 224-226 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.27 (3H, s), 6.70 (2
(H, t, J = 8.0Hz), 7.15-7.44 (7H, m), 7.73 (1H, s), 8.46 (1H, s)

Example 19 N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,6-dimethoxyphenyl) urea Melting point 254-256 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.24 (3H, s), 3.69 (6
H, s), 6.52 (1H, bs), 6.56 (2H, d, J = 8.4Hz), 7.12-7.43 (1
0H, m)

Example 20 N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,6-diethoxyphenyl) urea Melting point 210-212 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.28 (6H, t, J = 7.0H)
z), 2.21 (3H, s), 3.96 (4H, q, J = 7.0Hz), 6.53 (1H, s), 6.
55 (2H, d, J = 8.0Hz), 6.95 (1H, bt), 7.07-7.44 (8H, m)

In Examples 21 and 22, 5-chloro-3- (2-trifluoromethylphenyl) -benzofuran-2-acetic acid (Reference Example 9) and aniline (2,6-diisopropylaniline and 2,6-diphenylaniline) were used. The reaction was carried out in the same manner as in Example 1 using diethoxyaniline) to obtain the desired compound. Example 21 N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-3- (2-trifluoromethylphenyl)
-2-Benzofuranacetamide Melting point 233-234 ° C (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.13 (12H, dd, J = 6.8,
3.2Hz), 2.90-3.08 (2H, m), 3.79 (2H, dd, J = 24.0,16.4Hz),
6.96-7.04 (2H, m), 7.12-7.48 (6H, m), 7.56-7.69 (2H, m), 7.
88 (1H, dd, J = 6.6,2.0Hz) Calculated elemental analysis _{C 29 H 27 NO 2 ClF 3} C, 67.77; H, 5.29; N, 2.73 Found C, 67. 61; H, 5.29; N, 2.56

Example 22 5-Chloro-N- (2,6-diethoxyphenyl) -3
-(2-trifluoromethylphenyl) -2-benzofuranacetamide Melting point 133.6-134.2 ° C (recrystallized from hexane-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.26 (6H, t, J = 7.0Hz),
3.57-3.90 (2H, m), 3.98 (4H, q, J = 7.0Hz), 6.52 (2H, d, J = 8.4
Hz), 6.71 (1H, s), 6.90 (1H, bs), 7.06-7.28 (3H, m), 7.38-7.
52 (2H, m), 7.52-7.68 (2H, m), 7.84 (1H, dd, J = 7.2,1.8Hz) Calculated elemental analysis _{C 27 H 23 NO 4 ClF 3} C, 62.61; H , 4.48; N, 2.70 found C, 62.22; H, 4.43; N, 2.56.

In Examples 23 and 24, 5-chloro-3- (2-trifluoromethylphenyl) -benzofuran-2-carboxylic acid (Reference Example 8) and aniline (2,6
-Diisopropylaniline and 2,6-diethoxyaniline) to give the target compound in the same manner as in Example 11. Example 23 N- [2,6-bis (1-methylethyl) phenyl]-
N '-[5-Chloro-3- (2-trifluoromethylphenyl) -2-benzofuranyl] urea Melting point 223.6-224 ° C (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 0.69-1.36 (12H, m), 2.
80-3.44 (2H, m), 5.90,6.20 (tocal 1H, each bs), 6.54,7.0
0-7.95 (tocal 11H, bs and m ) calcd C as elemental analysis _{C 28 H 26 N 2 O 2} ClF 3, 65.31; H, 5.09; N, 5.44 Found C, 64. 93; H, 5.09; N, 5.30

Example 24 N- [5-Chloro-3- (2-trifluoromethylphenyl) -2-benzofuryl] -N '-(2,6-diethoxyphenyl) urea Melting point: 184-185 ° C (ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.27 (6H, t, J = 7.0 Hz),
3.90-4.04 (4H, m), 6.40 (1H, bs), 6.56 (2H, d, J = 8.4Hz), 7.0
6-7.24 (4H, m), 7.38 (1H, d, J = 9.0Hz), 7.47-7.71 (3H, m), 7.
80 (1H, d, J = 6.6 Hz) Elemental analysis value Calculated as C ₂₆ H ₂₂ N ₂ O ₄ ClF ₃ Calculated C, 60.18; H, 4.27; N, 5.40 Found C, 60. 16; H, 4.38; N, 5.36

Reference Example 1 5-chloro-3-phenylbenzofuran-2-carboxylic acid Step 1 4-chloro-2-benzoylphenol (1.95 g)
To a DMF (30 ml) solution was added sodium hydride (60% oil) (400 mg), and the mixture was stirred at room temperature for 30 minutes. Then, bromoacetic acid methyl ester (1.0 ml) was added, and the mixture was stirred for 2 hours under ice-water cooling. The reaction solution was concentrated, ethyl acetate was added to the residue, washed with water and dried, and the solvent was distilled off. The residue was separated and purified by column chromatography (hexane-ethyl acetate = 3: 1) using silica gel (40 g) to give methyl 4-chloro-2-benzoylphenoxyacetic acid as colorless crystals (2.21 g). . Melting point 71-72 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.70 (3H, s), 4.
54 (2H, s), 6.81 (1H, d like, J = 9.2Hz), 7.35-7.60 (5H,
m), 7.85 (2H, d like, 7.0Hz) Elemental analysis C ₁₆ H ₁₃ O ₄ Calculated C as Cl, 63.06; H, 4.30 Found C, 63.04; H, 4.27

Step 2 Toluene (40 ml) of the compound (2.1 g) obtained in Step 1
Add 1,8-diazabicyclo [5.4.0] undec-
7-ene (2.1 ml) was added, and the mixture was stirred under reflux for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off to give methyl 5-chloro-3-phenylbenzofuran-2-carboxylate as colorless crystals (1.32)
g). 103-105 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.88 (3H, s), 7.
30-7.65 (8H, m) Elemental analysis _{C 16 H 11 O 3 Cl ·} 0.3H 2 O Calculated C, 65.79; H, 4.00 Found C, 65.88; H, 4. 15 Step 3 Compound (1.2 g) obtained in Step 2 in methanol (20 m
l) and 2N-NaOH in a mixture of THF (20 ml).
(5.0 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, water was added to the concentrate, and the mixture was washed with ethyl acetate. The aqueous layer was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (0.69 g). 247-248 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 7.35-7.60 (8H,
m) Elemental analysis: calculated as C ₁₅ H ₉ O ₃ Cl, calculated C, 66.07; H, 3.33, found C, 65.77; H, 3.17.

REFERENCE EXAMPLE 2 5-Chloro-3-phenylbenzofuran-2-acetic acid Step 1 Oxalyl chloride (0.06 g) was added to a solution of 5-chloro-3-phenylbenzofuran-2-carboxylic acid (0.66 g) in anhydrous THF (15 ml). .30 ml) and DMF (1 drop) were added at room temperature and stirred for 0.5 hour. The solvent was distilled off and the residue (containing the acid chloride) was dissolved in anhydrous THF (10 ml). To this solution was added a solution of diazomethane in ethyl ether (N
-Nitrosomethylurea) was added, and the mixture was stirred at room temperature for 0.5 hour. The solvent was distilled off, the residue (including the diazoketone) was dissolved in methanol (20 ml), and the mixture was stirred at 50 ° C. while heating, and silver oxide (Ag ₂ O) was added.
(0.20 g) was added in small portions. This mixture was stirred under reflux for 3 hours, and then filtered using Celite.
The solvent was distilled off from the filtrate. Silica gel (30 g)
Separation and purification by column chromatography using hexane (hexane-ethyl acetate = 5: 1) gave 5-chloro-3-phenylbenzofuran-2-acetic acid methyl ester as a pale yellow oil (0.44 g). ^{[1 H-NMR (200MHz, CDCl} 3) ppm: 3.76 (3
H, s), 3.87 (2H, s), 7.20-7.30 (1H, m), 7.35-7.60 (7H,
m)]. Step 2 The compound (0.44 g) obtained in Step 1 was treated with methanol (10 m
l) 1N-NaOH (2 ml) was added to the solution and stirred at room temperature for 2 hours. Concentrate the reaction solution, add water to the concentrate,
Washed with ethyl acetate. The aqueous layer was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (0.25 g). Melting point 194-195 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.91 (2H, s), 7.
20-7.60 (8H, m) Elemental analysis C ₁₆ H ₁₁ O ₃ Calculated C as Cl, 67.03; H, 3.87 Found C, 67.09; H, 3.76

Reference Example 3 5-Chloro-3- (2-methylphenyl) benzofuran-2-carboxylic acid Instead of 4-chloro-2-benzoylphenol in Reference Example 1, 4-chloro-2- (2-methylbenzoyl) ) Steps 1 to 3 of Reference Example 1 using phenol
The reaction was carried out in substantially the same manner as to give the title compound. The compound names and physicochemical data obtained in each step are shown. Step 1 4-Chloro-2- (2-methylbenzoyl) phenoxyacetic acid methyl ester Melting point 81-83 ° C (ether-
Recrystallization from hexane) NMR (200 MHz, CDCl ₃ ) ppm: 2.53 (3H, s), 3.
70 (3H, s), 4.47 (2H, s), 6.79 (1H, d, J = 8.4Hz), 7.10-7.45
(6H, m) Elemental analysis C ₁₇ H ₁₅ O ₄ Calculated C as Cl, 64.06; H, 4.74 Found C, 64.08; H, 4.69 Step 2 5-chloro-3- (2-Methylphenyl) benzofuran-2-carboxylic acid methyl ester pale yellow oil NMR (200 MHz, CDCl ₃ ) ppm: 2.16 (3H, s), 3.
82 (3H, s), 7.20-7.60 (7H, m) Step 3 (title compound) Melting point 212-214 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 2.16 (3H, s) , 7.
20-7.60 (7H, m), 9.00 (1H, bs) Elemental analysis C ₁₆ H ₁₁ O ₃ Calculated C as Cl, 67.03; H, 3.87 Found C, 66.86; H, 3 .93

Reference Example 4 5-Chloro-3- (2-methylphenyl) benzofuran-2-acetic acid 5-chloro-3-phenylbenzofuran-2 of Reference Example 2
The title compound was obtained by reacting in the same manner as in Steps 1 and 2 of Reference Example 2 using 5 -chloro-3- (2-methylphenyl) benzofuran-2-carboxylic acid instead of -carboxylic acid. The compound names and physicochemical data obtained in each step are shown. Step 1 5-chloro-3- (2-methylphenyl) benzofuran-2-acetic acid methyl ester pale yellow oil NMR (200 MHz, CDCl ₃ ) ppm: 2.18 (3H, s), 3.
69 (5H, s like), 7.19-7.45 (7H, m) Step 2 (title compound) Melting point 135-136 ° C (recrystallized from ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 2.17 (3H, s) , 3.
73 (2H, s), 7.20-7.45 (7H, m) Elemental analysis C ₁₇ H ₁₃ O ₃ Calculated C as Cl, 67.89; H, 4.36 Found C, 67.85; H, 4 .39

Reference Example 5 5-chloro-1-methyl-3-phenylindole-2
-Acetic acid step 1 γ-phenylacetoacetic acid ethyl ester (2.88 g)
Sodium acetate (1.83 g) and 1- (4-chlorophenyl) were added to a mixture of acetic acid (30 ml) and water (10 ml).
Prepared by reducing -1-methylhydrazine hydrochloride {4-chloro-N-methyl-N-nitrosoaniline in acetic acid-water using zinc powder [melting point 171-174 ° C; NMR (20
_{0MHz, DMSO-d 6) ppm} : 3.14 (3H, s), 7.20 (2H, d,
(J = 9 Hz), 7.29 (2H, d, J = 9 Hz)]｝ (2.73 g), and the mixture was stirred at room temperature for 15 minutes and then at 110 ° C. for 20 minutes. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with water, diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, dried, and the solvent was distilled off. The residue was purified by column chromatography on silica gel (30 g) (hexane-ethyl acetate = 4: 1) to give 5-chloro-1-methyl-3.
-Phenylindole-2-acetic acid ethyl ester was obtained as an oil (4.34 g). [NMR (200
MHz, CDCl ₃ ) ppm: 1.29 (3H, t, J = 7 Hz), 3.76 (3H, s),
3.86 (2H, s), 4.24 (2H, q, J = 7Hz), 7.17-7.62 (8H, m)].

Step 2 The compound obtained in Step 1 (4.20 g) and ethanol (70 m
A mixture of l) and NaOH (20 ml) was stirred at room temperature for 14 hours. The reaction solution was concentrated, water was added to the concentrate, and the mixture was washed with ethyl acetate. The aqueous layer was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as pale yellow crystals (2.73 g). 141-142 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (3H, s), 3.9
3 (2H, s), 7.24-7.61 (8H, m) Elemental analysis C ₁₇ H ₁₄ NO ₂ Calculated C as Cl, 68.12; H, 4.71; N, 4.67 Found C, 68 .01; H, 4.69; N, 4.55

Reference Example 6 5-chloro-1-methyl-3- (2-methylphenyl)
Indole-2-acetic acid step 1 Instead of ethyl γ-phenylacetoacetate,
(2-methylphenyl) acetoacetic acid ethyl ester ｛2
-Methylphenylacetic acid was prepared by subjecting it to a carbon enrichment reaction using N, N-carbonylimidazole and magnesium ethylmalonate in THF [NMR (200 MHz, C
DCl ₃ ) ppm: 1.26 (3H, t, J = 7 Hz), 2.25 (3H, s), 3.43 (2
H, s), 3.85 (2H, s), 4.17 (2H, q, J = 7Hz), 7.11-7.20 (4H
z)] The reaction was carried out in the same manner as in Step 1 of Reference Example 5 using｝ to give 5-
Chloro-1-methyl-3- (2-methylphenyl) indole-2-acetic acid ethyl ester was obtained as an oil [NMR (200 MHz, CDCl ₃ ) ppm: 1.22 (3H,
t, J = 7Hz), 2.12 (3H, s), 3.67,3.68 (each 1H, s), 3.76 (3H, s
s), 4.14 (2H, q, J = 7 Hz), 7.15-7.35 (7H, m)]. Step 2 The compound obtained in Step 1 was subjected to a hydrolysis reaction in the same manner as in Step 2 of Reference Example 5 to give the title compound as pale yellow crystals. 154.5-155.5 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.11 (3H, s), 3.7
3,3.74 (each 1H, s), 3.76 (3H, s), 7.15-7.31 (7H, m) Elemental analysis C ₁₈ H ₁₆ NO ₂ Calculated as Cl C, 68.90; H, 5.14 ; N, 4.46 found C, 68.96; H, 5.14; N, 4.39.

Reference Example 7 5-chloro-3- (2-methoxyphenyl) -1-methylindole-2-acetic acid Step 1 γ-phenylacetoacetic acid
(2-methoxyphenyl) acetoacetic acid ethyl ester {Prepared by subjecting 2-methoxyphenylacetic acid to a carbon enrichment reaction using N, N-carbonylimidazole and magnesium ethylmalonate in THF [NMR (200M
Hz, CDCl ₃ ) ppm: 1.26 (3H, t, J = 7 Hz), 3.45 (2H,
s), 3.78 (2H, s), 3.82 (3H, s), 4.17 (2H, q, J = 7Hz), 6.87
-7.32 (4H, m)]} to give 5-chloro-3- (2-methoxyphenyl)-
1-Methylindole-2-acetic acid ethyl ester was obtained as pale yellow crystals. 94-95 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 1.26 (3H, t, J = 7.
0Hz), 3.74 (3H, s), 3.76 (3H, s), 4.19 (2H, q, J = 7.0H
z), 6.95-7.45 (7H, m ) Elemental analysis C ₂₀ H ₂₀ NO ₃ Calculated C as Cl, 67.13; H, 5.63; N, 3.91 Found C, 67.20; H , 5.58; N, 3.94 Step 2 The compound obtained in Step 1 was subjected to a hydrolysis reaction in the same manner as in Step 2 of Reference Example 5 to give the title compound as colorless crystals. 153-154 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.73 (3H, s), 3.7
6 (3H, s), 3.78 (2H, s), 7.00-7.45 (7H, m) Elemental analysis C ₁₈ H ₁₆ NO ₃ Calculated C as Cl, 65.56; H, 4.89; N, 4 .25 found C, 65.62; H, 4.98; N, 4.22.

Reference Example 8 5-chloro-3- (2-trifluoromethylphenyl)
Benzofuran-2-carboxylic acid In place of 4-chloro-2-benzoylphenol in Reference Example 1, 4-chloro-2- (2-trifluoromethylbenzoyl) phenol [2-bromo-4-chloro- (2-
(Methoxyethoxy) methoxybenzene and ortho- (trifluoromethyl) benzaldehyde as starting materials: Melting point: 71-72 ° C. (recrystallized from hexane-isopropyl ether)] The title compound was obtained by the reaction according to the above method. The compound names and physicochemical constants obtained in each step are shown below. Step 1 4-Chloro-2- (2-trifluoromethylbenzoyl) phenoxyacetic acid methyl ester Melting point 133-134 ° C (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 3.67 (3H, s), 4.3
7 (2H, s), 6.76 (1H, d, J = 8.8Hz), 7.38-7.50 (2H, m), 7.51-
7.60 (2H, m), 7.70-7.80 (2H, m) Step 2 5-chloro-3- (2-trifluoromethylphenyl)
Benzofuran-2-carboxylic acid methyl ester Melting point 104-106 ° C (recrystallized from hexane) NMR (200 MHz, CDCl ₃ ) ppm: 3.77 (3H, s), 7.2
6 (1H, s), 7.36 (1H, d, J = 6.6Hz), 7.45 (1H, dd, J = 9.0,2.2H
z), 7.55-7.72 (3H, m), 7.85 (1H, dd, J = 6.8, 2.0 Hz) Step 3 (title compound) Melting point 205-208 ° C. (recrystallized from hexane) NMR (200 MHz, CDCl ₃ ) ppm ： 7.26 (1H, s), 7.3
6 (2H, dd, J = 6.2,2.2Hz), 7.47 (1H, dd, J = 9.0,2.0Hz), 7.53-
7.71 (3H, m), 7.84 (1H, dd, J = 6.8,2.4Hz) Calculated elemental analysis _{C 16 H 8 O 3 ClF 3} C, 56.41; H, 2.37 Found C, 56 .22; H, 2.35

Reference Example 9 5-chloro-3- (2-trifluoromethylphenyl)
Benzofuran-2-acetic acid 5-chloro-3-phenylbenzofuran-2 of Reference Example 2
When the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 using 5-chloro-3- (2-trifluoromethylphenyl) benzofuran-2-carboxylic acid instead of -carboxylic acid, the title compound was obtained. Was. The compound names and physicochemical constants obtained in each step are shown below. Step 1 5-chloro-3- (2-trifluoromethylphenyl)
Benzofuran-2-acetic acid methyl ester pale yellow oil NMR (200 MHz, CDCl ₃ ) ppm: 3.69 (3H, s), 3.7
7 (2H, s), 7.13 (1H, d, J = 2.2Hz), 7.26 (1H, dd, J = 8.8,2.0H
z), 7.32-7.70 (4H, m), 7.83 (1H, dd, J = 7.2, 2.0 Hz) Step 2 (title compound) pale yellow oil NMR (200 MHz, CDCl ₃ ) ppm: 3.68 (2H, dd, J = 27.6,
17.0Hz), 7.14 (1H, d, J = 2.0Hz), 7.26 (1H, dd, J = 9.2,2.0H
z), 7.32-7.66 (4H, m), 7.84 (1H, dd, J = 6.8,2.2Hz)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 3/06 A61P 3/06 9/10 9/10 C07D 209/24 C07D 209/24 209/40 209/40 307/79 307 / 79 307/82 307/82 333/60 333/60 333/66 333/66 (56) References JP-A-50-70360 (JP, A) JP-A-60-67480 (JP, A) JP-A Sho 49-87661 (JP, A) JP-A-51-1458 (JP, A) JP-A-1-213276 (JP, A) JP-B-46-14899 (JP, B1) US Pat. No. 4,137,311 (US, A) J . Indian Chem. SoC. , (1976), 53 (3), p. 295-9 Tetrahedron Let t. , (1975), (44), p. 3877-8 Tetrahedron Let t. , (1970), (5), p. 395-9 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 209/18 C07D 209/24 C07D 209/40 C07D 307/79 C07D 307/82 C07D 333/60 C07D 333/66 CA (STN ) REGISTRY (STN)

Claims (21)

(57) [Claims] (1) Formula (1) [Wherein, A ring and B ring each represent a benzene ring which may have a substituent, C ring represents a benzene ring having a substituent, and X represents (1) -NR- (R represents a hydrogen atom or a substituted indicates a hydrocarbon group which may have a group), (2) -O- or (3) -S-, Y is - (CH _{2) n} - (n is 1 or 2) or - In NH-, Ra represents ^a hydrogen atom or ^a hydrocarbon group which may have a substituent. Where C
When the ring has a substituent only at the para position, ring B has a substituent at least at the ortho position. Or a salt thereof. 2. The ring A and the ring B are each (i) a halogen atom, (ii) a C _1-6 alkyl group which may be halogenated, and (iii) a C _1-6 alkoxy which may be halogenated. Group, (iv) hydroxyl group, (v) amino group, (v
i) a mono- or di-C _1-4 alkylamino group and (vi
i) a benzene ring optionally having 1 to 4 substituents selected from a C _1-3 acyloxy group, a C ring having (i) a halogen atom, and (ii) an optionally halogenated C _{1 -6} alkyl group, (iii) optionally halogenated C _1-6 alkoxy group, (iv) hydroxyl group,
(V) an amino group, (vi) a mono- or di-C _1-4 alkylamino group, (vii) a C _1-3 acyloxy group and (viii)
A benzene ring having 1 to 4 substituents selected from a carboxyl group, X is (1) -NR- [R is (i) a hydrogen atom or (ii)
(A) a halogen atom, (b) a C _3-6 cycloalkyl group,
(C) C _6-10 aryl group, (d) C _1-4 alkyl, C _2-4
An amino group optionally having one or two substituents of alkenyl, C _3-6 cycloalkyl or C _6-10 aryl, (e) a hydroxyl group, (f) optionally halogenated C _{1- 4} alkoxy group, (g) C _1-4 acyl group,
(H) C _1-4 acyloxy group, (i) cyano group, (j)
A carboxyl group which may be protected with a C _1-4 alkyl or C _7-11 aralkyl, (k) a carbamoyl group,
(L) mercapto group, (m) C _1-4 alkylthio group,
(N) a C _1-6 alkyl group , a C _2-6 alkenyl group which may have 1 to 4 substituents selected from a sulfo group and (o) a C _1-4 alkylsulfonyl group , C _{3 -8} cycloalkyl group or C _6-14 aryl group] (2) —O— or (3) —S—, Y is — (CH ₂ ) _n — (n represents 1 or 2) or —N
H- and ^Ra are (1) hydrogen atom or (2) (i) halogen atom, (ii) C _3-6 cycloalkyl group, (iii) C _6-10 aryl group, (iv) C _1-4 alkyl , _C2-4 alkenyl, C
_{1-6 of 3-6} cycloalkyl or C _6-10 aryl
An amino group which may have an individual substituent, (v) a hydroxyl group, and (vi) an optionally halogenated C _1-4.
Alkoxy group, (vii) C _1-4 acyl group, (viii) C _1-4
Acyloxy group, (ix) cyano group, (x) carboxyl group optionally protected by C _1-4 alkyl or C _7-11 aralkyl, (xi) carbamoyl group, (xii) mercapto group, (xiii) C ₁ 1 selected from a _-4 alkylthio group, a (xiv) sulfo group and a (xv) _C1-4 alkylsulfonyl group
C _1-6 alkyl _optionally having 4 to 4 substituents
Group, C _2-6 alkenyl, C _3-8 compound of claim 1, wherein a cycloalkyl group or a C _6-14 aryl group. 3. The ring A is selected from (i) a halogen atom, (ii) an optionally halogenated C _1-4 alkyl group and (iii) an optionally halogenated C _1-4 alkoxy group. The compound according to claim 1, which is a benzene ring optionally having 1 to 4 substituents. (4) ring A has the formula: Wherein A ¹ , A ² and A ³ are the same or different and are each independently a hydrogen atom , a halogen atom, an optionally halogenated C
_1-4 alkyl group or optionally halogenated C _1-4
Shows an alkoxy group. The compound according to claim 1, which is a benzene ring represented by the formula: 5. The ring B is selected from (i) a halogen atom , (ii) an optionally halogenated C _1-4 alkyl group and (iii) an optionally halogenated C _1-4 alkoxy group. The compound according to claim 1, which is a benzene ring optionally having 1 to 4 substituents. (6) ring B is a compound of the formula [In the formula, B ¹ , B ² and B ³ are the same or different and are each independently a hydrogen atom, a halogen atom, an optionally halogenated C
_1-4 alkyl group or optionally halogenated C _1-4
Shows an alkoxy group. The compound according to claim 1, which is a benzene ring represented by the formula: 7. The compound according to claim 1, wherein the ring C is a benzene ring having two or more substituents. 8. The ring C is (i) a halogen atom, (ii) an optionally halogenated C _1-4 alkyl group, (iii) an optionally halogenated C _1-4 alkoxy group, (iv) A) an amino group, (v) a mono- or di-C _1-4 alkylamino group,
The compound according to claim 1, which is a benzene ring having 1 to 4 substituents selected from (vi) a C _1-3 acyloxy group, (vii) a carboxyl group and (viii) a hydroxyl group. 9. The ring C is of the formula: [In the formula, C ¹ , C ² and C ³ are the same or different and are each independently a hydrogen atom, a halogen atom, an optionally halogenated C
_{A 1-4} alkyl group, a C _1-4 alkoxy group which may be halogenated, or a di-C _1-4 alkylamino group. ]
The compound according to claim 1, which is a benzene ring represented by the following formula (however, excluding an unsubstituted benzene ring). (10) the ring (C) has the formula: [Wherein, C ⁴ , C ⁵ and C ⁶ are the same or different and are a hydrogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group,
C _{1-3 represents an} acyloxy group or a hydroxyl group. ]
The compound according to claim 1, which is a benzene ring represented by the following formula (however, excluding an unsubstituted benzene ring). 11. The method according to claim 11, wherein the ring C is (i) a halogen atom, (ii) an optionally halogenated C _1-4 alkyl group and (iii)
The compound according to claim 1, which is a benzene ring having 1 to 4 substituents selected from an optionally halogenated _C1-4 alkoxy group. 12. The compound according to claim 1, wherein X is -NR- (R has the same meaning as defined in claim 1) or -O-. 13. The compound according to claim 1, wherein R is a C _1-4 alkyl group. 14. The compound according to claim 1, wherein Y is --CH _2- . 15. The compound according to claim 1, wherein Y is -NH-. 16. The compound according to claim 1, wherein ^Ra is a hydrogen atom. 17. N- [2,6-bis (1-methylethyl) phenyl] -5-chloro-3- (2-methylphenyl) -2-benzofuranacetamide, 5-chloro-N- (2,6 -Dimethoxyphenyl) -3
-(2-methylphenyl) -2-benzofuranacetamide, N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-3-phenyl-2-benzofuranacetamide, N- [2,6-bis (1-methylethyl) phenyl]-
N '-[5-chloro-3- (2-methylphenyl) -2
-Benzofuryl] urea, 5-chloro-N- (2,6-diethoxyphenyl) -3
-(2-methylphenyl) -2-benzofuranacetamide, N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,6-dimethoxyphenyl) urea, N- [5-chloro-3- (2-methylphenyl) -2-
Benzofuryl] -N '-(2,6-diethoxyphenyl) urea, N- [2,6-bis (1-methylethyl) phenyl]-
5-chloro-3- (2-trifluoromethylphenyl)
-2-benzofuranacetamide, 5-chloro-N- (2,6-diethoxyphenyl) -3
-(2-trifluoromethylphenyl) -2-benzofuranacetamide, N- [2,6-bis (1-methylethyl) phenyl]-
N '-[5-chloro-3- (2-trifluoromethylphenyl) -2-benzofuryl] urea; N- [5-chloro-3- (2-trifluoromethylphenyl) -2-benzofuryl] -N' The compound according to claim 1, which is-(2,6-diethoxyphenyl) urea or a salt thereof. 18. The formula: 6] [The symbols in the formula are as defined in claim 1. And a salt or a reactive derivative thereof represented by the formula : [The symbols in the formula are as defined in claim 1. Wherein the compound or the reaction of a salt thereof], formula embedded image [The symbols in the formula are as defined in claim 1. ] Or a salt thereof. (19) a compound represented by the formula : [The symbols in the formula are as defined in claim 1. And a salt thereof, and a compound represented by the formula : [The symbols in the formula are as defined in claim 1. Wherein the compound is represented by the following formula : [Wherein, Y 'represents -NH-, and other symbols have the same meanings as in claim 1]. ] Or a salt thereof. 20. formula: 12] [The symbols in the formula are as defined in claim 1. An acyl-CoA: cholesterol acyltransferase inhibitor comprising the compound represented by the formula: or a salt thereof. 21. A formula: 13] [The symbols in the formula are as defined in claim 1. ] The blood cholesterol lowering agent containing the compound represented by these, or its salt.