JPH08311065A - Benzofuran derivative and medicinal composition containing the same - Google Patents

Abstract

PURPOSE: To obtain a new benzofuran derivative, having lowering actions on blood sugar and lipids and useful as a therapeutic agent for diabetes and hyperlipemia and an enhancer for insulin sensitivity. CONSTITUTION: This compound of formula I [ring A is a group capable of releasing a cation, with the proviso that a dotted underlined solid line is a single bond or a double bond; R<1> is a heterocyclic residue; R<2> is H, a halogen, a hydrocarbon residue, hydroxyl group or amino group; Y is a 1-8C bi- or a trivalent aliphatic hydrocarbon residue] or its salt, e.g. 5-[2-[6-(5-methyl2- phenyl-4-oxazolylmethoxy)-2-benzofuranyl]ethyl]-1H-tetrazole. The compound of formula I is obtained according to a well-known method. The compound of formula I in which the group of ring A is tetrazole is prepared by reacting, e.g. a nitrile derivative with an azide compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzofuran derivative having a blood glucose and blood lipid lowering activity and a therapeutic agent for diabetes comprising the same.

[0002]

2. Description of the Related Art Conventionally, various biguanide compounds and sulfonylurea compounds have been used as therapeutic agents for diabetes. However, since biguanide compounds cause lactic acidosis, they are rarely used at present.Although sulfonylurea compounds have a strong hypoglycemic effect, they often cause severe hypoglycemia and require caution in use. is there. In addition, tetrazole, 2,4-oxazolidinedione and 2,4-thiazolidinedione derivatives having blood glucose and lipid lowering actions without such drawbacks are known. The tetrazole derivative is described in, for example, Journal of Medicinal Chemistry, 35.
Vol. 944 (1992), U.S. Pat. No. 4,845,2.
No. 13 (1989), EP604, 983-A1 (19
93) and the like, 2,4-oxazolidinedione derivatives are described in, for example, JP-A-3-170478 and WO9202.
2,4-thiazolidinedione derivatives such as 520-A1 are disclosed in JP-A-61-85372 and JP-A-64-130.
88, JP-A-1-272573, JP-A1-272
574, JP-A-2-167225, JP-A-3-90.
078, JP-A-5-157522, JP-A-6-80
667, JP-A-5-213913, and JP-A-6-96.
No. 29, WO94222857, EP604, 983-A
1, JP-A-3-2173, JP-A-4-66579,
It is described in JP-A-4-69383 and the like.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found that tetrazole, 2,4-oxazolidinedione or 2,4-
As a result of various studies on various 5-membered heterocyclic derivatives such as thiazolidinedione, they have found that the novel derivatives each having a benzofuran ring on the 5-position substituent have blood glucose and lipid lowering effects, and completed the present invention.

[0004]

That is, the present invention provides a general formula

[Chemical 9] [In the formula,

[Chemical 10] Is a group capable of releasing a cation (however,

[Chemical 11] Represents a single bond or a double bond. ), R ¹ is a heterocyclic residue which may be bonded via a carbon chain and may be substituted, R ² is hydrogen, a halogen atom, an optionally substituted hydrocarbon residue, or a protected An optionally protected hydroxyl group or an optionally protected amino group, Y is 2 having 1 to 8 carbon atoms;
Each represents a monovalent or trivalent aliphatic hydrocarbon residue, and the benzene ring may be further substituted. ] The compound or its salt represented by this, and the pharmaceutical composition which contains the compound (benzofuran derivative) represented by General formula (I), or its pharmacologically acceptable salt as an active ingredient. It is a thing.

In the above general formula (I), a partial structural formula

[Chemical 12] The group capable of releasing a cation represented by is chemically (for example, a chemical reaction such as oxidation, reduction or hydrolysis).
Alternatively, it may be a group capable of releasing a cation or a group capable of converting into a cation under biological conditions, that is, under physiological conditions (for example, in-vivo reaction such as oxidation, reduction or hydrolysis by in-vivo enzyme). Examples of the group capable of releasing a cation include (1) a 5-membered heterocyclic group capable of releasing a cation, (2) a cyano group, (3) a carboxyl group, and (4)
In addition to C _2-7 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (5) C _7-11 aryloxycarbonyl group (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.), (6) carbon atom, for example 1 hetero atom such as nitrogen atom, sulfur atom, oxygen atom
5 to 6-membered heterocyclic-oxycarbonyl groups containing 4 to 4 (eg, pyridyloxycarbonyl, thienyloxycarbonyl, etc.), (7) sulfonic acid group, (8) C _1-4 alkyl group (eg, methyl, ethyl, Sulfamoyl group which may be mono-substituted with propyl, butyl, isobutyl, tert-butyl, etc., (9) phosphonic acid group, (10) di-C _1-4 alkoxyphosphoryl group (eg, dimethoxyphosphoryl, diethoxyphosphoryl) , Dipropoxyphosphoryl, etc.), (11) C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, etc.) which may be mono-substituted with carbamoyl group, (1
2) C _2-7 alkylsulfonylthiocarbamoyl group (eg, methylsulfonylthiocarbamoyl, ethylsulfonylthiocarbamoyl, etc.) and (13) trifluoromethanesulfonic acid amide group (—NHSO ₂ CF ₃ ) and the like.

The 5-membered heterocyclic group capable of releasing the above cation is a 5-membered heterocyclic group having 1 to 4 ring-constituting atoms selected from N, O and S, for example,

[Chemical 13] And the like.

The group capable of releasing a cation is preferably
It is a 5-membered heterocyclic group capable of releasing a cation. Among them, the formula

Embedded image The group represented by is more preferable. The group capable of releasing a cation is particularly preferably a group of the formula

[Chemical 15] Is a group represented by.

The heterocyclic residue represented by R ¹ which may be bonded via a carbon chain or may be substituted may be one directly bonded to —O— and may be bonded via a carbon chain. -
It may be bonded to O-, but is preferably bonded via a carbon chain. The carbon chain may be linear or branched and may be saturated or unsaturated. The carbon chain is preferably 2 having 1 to 8 carbon atoms.
A valent hydrocarbon group having 1 to 4 carbon atoms is more preferable. Heterocyclic residues include 5- or 6-membered rings or fused rings containing at least one nitrogen atom as ring-constituting atom. The heterocyclic residue is preferably an aromatic ring having an unsaturated bond, may have two or more nitrogen atoms as ring-constituting atoms, and, in addition to the nitrogen atom, an oxygen atom or a sulfur atom. May have a hetero atom. Specific examples of the heterocyclic residue include, for example, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl),
Triazolyl (1,2,3-triazol-4-yl,
1,2,4-triazol-3-yl), tetrazolyl,
Oxazolyl (2-oxazolyl, 4-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl)
And the like. These heterocyclic residues may have one or more substituents at any position on the ring, and examples of the substituent include a hydrocarbon residue, a heterocyclic group or an amino group. Further, it may have a substituent.

Examples of the hydrocarbon residue include an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue, an araliphatic hydrocarbon residue, and an aromatic hydrocarbon residue. Groups. Examples of the aliphatic hydrocarbon residue include an aliphatic hydrocarbon residue having 1 to 8 carbon atoms. Examples of such an aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl,
Saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms such as neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl (eg, alkyl group), preferably having 1 to 4 carbon atoms, and, for example, ethenyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3
-Hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-
Propinyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5- Hexynyl, 1-heptinyl, 1-octynyl and the like, unsaturated aliphatic hydrocarbon residue having 2 to 8 carbon atoms (eg, alkenyl group, alkadienyl group, alkynyl group, alkadiynyl group), preferably having 2 to 4 carbon atoms Is mentioned.

Examples of the alicyclic hydrocarbon residue include an alicyclic hydrocarbon residue having 3 to 7 carbon atoms. Examples of such alicyclic hydrocarbon residue include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
C3-C7 saturated alicyclic hydrocarbon residue such as cycloheptyl (eg, cycloalkyl group), preferably C5 or C6, and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl , 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3
-C5-C7 unsaturated alicyclic hydrocarbon residue such as cycloheptenyl and 2,4-cycloheptadienyl (eg, cycloalkenyl group, cycloalkadienyl group), preferably C5 or C6 There are things. The alicyclic-aliphatic hydrocarbon residue has 4 carbon atoms among those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded.
~ 9 are mentioned. Examples of such an alicyclic-aliphatic hydrocarbon residue include cyclopropylmethyl,
Cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptyl Examples thereof include ethyl. The aromatic-aliphatic hydrocarbon residue has, for example, 7 carbon atoms.
˜13 araliphatic hydrocarbon residues. Examples of such an araliphatic hydrocarbon residue include benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl and the like phenylalkyl having 7 to 9 carbon atoms, α- Naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-
Examples include naphthylalkyl having 11 to 13 carbon atoms such as naphthylethyl. Examples of the aromatic hydrocarbon residue include an aromatic hydrocarbon residue having 6 to 14 carbon atoms. As such an aromatic hydrocarbon residue, for example,
Examples thereof include phenyl and naphthyl (α-naphthyl, β-naphthyl).

The heterocyclic group is a 5- or 6-membered ring containing 1 to 3 atoms selected from N, O and S in addition to carbon as a ring-constituting atom, and is a group bonded via carbon. There are, for example, thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 4-).
Pyridyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrimidinyl ( 2-pyrimidinyl, 4-
Pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,
Unsaturated compounds such as 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (2-morpholinyl, 3-morpholinyl), tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl) and the like saturated ones.

The amino group may be substituted, and examples of the substituted amino group include N-monosubstituted amino group and N, N-disubstituted amino group. The “N-monosubstituted amino group” means an amino group having one substituent, and examples of the substituent include, for example, lower alkyl groups (eg, methyl, ethyl, propyl, butyl, isobutyl, tert. -Butyl and the like having 1 to 4 carbon atoms), cycloalkyl group (eg, cyclopentyl, cyclohexyl and the like having 3 to 7 carbon atoms), aryl group (eg, phenyl, naphthyl and the like having 6 to 14 carbon atoms), aromatic Group heterocyclic groups (eg, pyridyl, thienyl, furyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (eg, piperidinyl, pyrrolidinyl, morpholinyl, etc.), aralkyl groups (eg, benzyl, phenethyl, etc., 7 to 13 carbon atoms) ), An acyl group (eg, an alkanoyl group such as acetyl, propionyl, and the like having 1 to 6 carbon atoms), a carbamoyl group, an N-monosubstituted carboxylic acid group. Lubamoyl group (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (eg,
N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N, N-diethylcarbamoyl, etc.), lower alkoxycarbonyl group (eg, those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), Hydroxyl group, lower alkoxy group (eg, those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, butoxy), aralkyloxy group (eg, those having 7 to 13 carbon atoms such as benzyloxy, phenethyloxy, naphthylmethyloxy) And so on.

The "N, N-disubstituted amino group" means an amino group having two substituents, and one example of the substituent is a substituent in the above "N-monosubstituted amino group". And the other example is, for example,
Lower alkyl group (eg, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl), cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like having 3 carbon atoms) ~ 7), aryl groups (e.g., phenyl, naphthyl, etc., having 6 to 14 carbon atoms), aralkyl groups (e.g., benzyl, phenethyl, etc., having 7 to 13 carbon atoms), and the like. In addition, two substituents may combine with a nitrogen atom to form a cyclic amino group,
Examples of such a cyclic amino group include, for example, 1-azetidinyl, pyrrolidino, piperidino, morpholino, piperazino, and a lower alkyl group at the 4-position (eg, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl) and aralkyl. Groups (eg, those having 7 to 13 carbon atoms such as benzyl, phenethyl, naphthylmethyl), aryl groups (eg, phenyl, 4-
(C6-14 carbon atoms such as methylphenyl and naphthyl)
And the like.

The hydrocarbon residue and the heterocyclic group as the substituent on the heterocyclic residue, which may be bonded via a carbon chain and which may be substituted, represented by R ¹ are optional. It may have a substituent at the position. That is, when the hydrocarbon residue contains an alicyclic group (that is, the hydrocarbon residue is an aliphatic hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue or an araliphatic hydrocarbon residue). Case) or when the heterocyclic group is saturated, a lower alkyl group having 1 to 3 carbon atoms (eg, methyl, on the ring (including N atom))
It may have 1 to 3 ethyl, propyl, isopropyl). Further, when the hydrocarbon residue contains an aromatic hydrocarbon residue (that is, when the hydrocarbon residue is an araliphatic hydrocarbon residue or an aromatic hydrocarbon residue) or the heterocyclic group is unsaturated. When it is, it may have 1 to 4 substituents which are the same or different on the ring,
Examples of the substituent include halogen (eg, fluorine, chlorine, iodine, etc.), hydroxy group, cyano group, nitro group,
Trifluoromethyl group, lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like having 1 to 4 carbon atoms), lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl and the like, carbon number 1) ~ 4), a lower alkoxycarbonyl group (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc., having 2 to 4 carbon atoms, lower alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc., having 1 to 3 carbon atoms), lower alkylamino group (eg, methyl) And those having 1 to 4 carbon atoms such as amino, ethylamino and dimethylamino).

The heterocyclic residue represented by R ¹ which may be bonded via a carbon chain and which may be substituted has two or more hydrocarbon residues as its substituents, and When these hydrocarbon residues substitute each other in adjacent positions on the heterocycle, they may combine with each other to form a condensed ring. In this case, it means that the two hydrocarbon residues are linked to each other to form a saturated or unsaturated divalent chain hydrocarbon residue having 3 to 5 carbon atoms. Specific examples of the chain hydrocarbon residue include, for example, —CH ₂ C.
_{H 2 CH 2 -, - CH} 2 CH 2 CH 2 CH 2 -, - CH
_{2 CH 2 CH 2 CH 2 CH} 2 -, - CH = CHCH 2
-, -CH = CH-CH = CH-, -CH = CH-CH
_{= CH-CH 2 -, -} CH = CH-CH 2 CH 2 CH 2
-And the like.

The heterocyclic residue represented by R ¹ in the heterocyclic residue which may be bonded via a carbon chain and may be substituted is preferably a compound represented by the general formula:

Embedded image [In the formula, B ¹ is a sulfur atom, an oxygen atom or NR ⁴ [wherein R ⁴ is a hydrogen atom, a lower alkyl group or an aralkyl group. A group represented by], B ² is a nitrogen atom or C
-R ⁵ (R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group), R ³ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group. When it represents a ring group and R ³ and R ⁵ are respectively bonded to adjacent carbon atoms, R ³ and R ⁵ may be bonded to each other to form a condensed ring. ] Is represented.

Here, the lower alkyl group represented by R ⁴ is, for example, methyl or ethyl having 1 carbon atom.
~ 3 are mentioned. Examples of the aralkyl group represented by R ⁴ include those having 7 to 13 carbon atoms such as benzyl and phenethyl. In the optionally substituted hydrocarbon residue or heterocyclic group represented by R ³ and R ⁵ , the hydrocarbon residue, the heterocyclic group and their substituents are the substituents of the heterocyclic residue in R ¹ . The same as the above-mentioned hydrocarbon residue, heterocyclic group and substituents thereof can be mentioned. When R ³ and R ⁵ combine to form a condensed ring, the above-mentioned condensed ring formed when the heterocyclic group for R ¹ has two hydrocarbon residues as its substituents at positions adjacent to each other The same thing as what was done is mentioned. The heterocyclic residue is attached to the ring via a possible atom on the ring, but is preferably a group attached via the carbon atom adjacent to the nitrogen atom. For example, B ¹ is NR ⁴
In the case where B ² is C—R ⁵ , a group bonded via B ² is also a preferable example.

Among the heterocyclic groups represented by the above formula, particularly the general formula

[Chemical 17] [Wherein R ⁵ has the same meaning as above, and R ⁶ , R ⁷ and R ⁸
Are the same or different and represent hydrogen or a hydrocarbon residue or a heterocyclic group which may each be substituted, and R ⁷ and R ⁸ may combine to form a condensed ring. B represents an oxygen atom or a sulfur atom. ] Thiazolyl or oxazolyl represented by

In the optionally substituted hydrocarbon residue or heterocyclic group represented by R ⁶ , R ⁷ and R ⁸ , the hydrocarbon residue, the heterocyclic group and their substituents are the heterocyclic groups represented by R ¹ . Examples of the substituent of the ring residue include the same hydrocarbon residue, heterocyclic group and substituents as described above. R ⁷ and R ⁸ may form a condensed ring,
Examples of the condensed ring include the same as those described above as the condensed ring formed when the heterocyclic residue in R ¹ has two hydrocarbon residues at the positions adjacent to each other as the substituents. .

In the general formula (I), R ² represents hydrogen, a halogen atom, a hydrocarbon residue which may be substituted, a hydroxyl group which may be protected or an amino group which may be protected. Here, examples of the halogen atom include fluorine, chlorine, iodine and the like. Examples of the hydrocarbon residue and the substituent thereof in the optionally substituted hydrocarbon residue include the same as the above-mentioned hydrocarbon residue and the substituent thereof as the substituent of the heterocyclic residue in R ¹ . . Examples of the protecting group for an optionally protected hydroxyl group include (1) an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) , (2) aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), (3) aralkyl group having 7 to 13 carbon atoms (eg, benzyl, phenethyl, naphthylmethyl, etc.), (4) formyl, ( 5) an alkylcarbonyl group having 2 to 7 carbon atoms (eg, acetyl, propionyl, butyryl, valeryl etc.), (6) an aryloxycarbonyl group having 7 to 11 carbon atoms (eg, phenyloxycarbonyl, naphthyloxycarbonyl etc.), (7) 7 carbon atoms
To 11 arylcarbonyl groups (eg, benzoyl,
Naphthoyl, etc.), (8) aralkylcarbonyl group having 8 to 14 carbon atoms (eg, benzylcarbonyl, phenethylcarbonyl, etc.), (9) pyranyl or furanyl, and (10) tri-C _1-4 alkylsilyl group (eg, Trimethylsilyl, triethylsilyl, etc.) and the like. These protecting groups include, for example, a halogen atom (eg, chlorine, bromine, fluorine, etc.), an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl etc.), aryl having 6 to 14 carbon atoms (eg phenyl, naphthyl etc.), aralkyl having 7 to 13 carbon atoms (eg benzyl, phenethyl, naphthylmethyl etc.) and nitro group 1 It may have 4 to 4 substituents.

Examples of the protecting group for the amino group which may be protected include (1) formyl and (2) carbon number 2
To 7 alkylcarbonyl groups (eg, acetyl, propionyl, butyryl, valeryl, etc.), (3) arylcarbonyl groups having 7 to 11 carbon atoms (eg, benzoyl, naphthoyl, etc.), (4) alkyl groups having 2 to 7 carbon atoms Oxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (5) Aryloxycarbonyl group having 7 to 11 carbon atoms (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.), (6) C8 to 1 carbon
And the aralkylcarbonyl group of 4 (eg, benzylcarbonyl, phenethylcarbonyl, etc.), (7) trityl group, and (8) phthaloyl group. These protecting groups include, for example, a halogen atom (eg, chlorine, bromine, fluorine, etc.), an alkylcarbonyl group having 2 to 7 carbon atoms (eg, acetyl, propionyl, butyryl, etc.) at a substitutable position.
Valeryl etc.) and a nitro group may have 1 to 3 substituents. In the general formula (I), R
² is particularly preferably hydrogen.

Divalent or trivalent carbon atom represented by Y having 1 to 8 carbon atoms
The valent aliphatic hydrocarbon residue may be linear or branched, may be saturated or unsaturated, and is preferably one having 1 to 7 carbon atoms. Examples of the divalent aliphatic hydrocarbon residue, for _{example, -CH 2 -, - CH (} C
_{H 3) -, - (CH} 2) 2 -, - CH (C 2 H 5) -, -
_{(CH 2) 3 -, -} (CH 2) 4 -, - (CH 2) 5 -, -
_{(CH 2) 6 -, -} (CH 2) 7 - saturated ones, such as, for example, -CH = CH -, - C (CH 3) = CH -, - CH
_{= CH-CH 2 -, -} C (C 2 H 5) = CH -, - CH 2 -
_{CH = CH-CH 2 -,} - CH 2 -CH 2 -CH = CH-
_{CH 2 -, - CH = CH} -CH = CH-CH 2 -, - CH
It may be unsaturated such as ═CH—CH═CH—CH═CH—CH ₂ —. Specific examples of the trivalent aliphatic hydrocarbon residue, for example, -CH =, - C (CH 3) =, - C
_{H 2 CH =, - C (} C 2 H 5) =, - (CH 2) 2 -CH
_{=, - (CH 2) 3} -CH =, - (CH 2) 4 CH =, -
_{(CH 2) 5 -CH =,} - (CH 2) 6 -CH = saturated ones, such as, for example, -CH = CH-CH =, - CH (C 2
_{H 5) -CH =, - CH} 2 -CH = CH-CH =, - CH
_{2 -CH 2 -CH = CH-CH} =, - CH = CH-CH =
CH-CH =, -CH = CH-CH = CH-CH = CH
It may be unsaturated such as -CH =. Of these, saturated ones having 2 to 5 carbon atoms are more preferable, and —CH ₂ CH ₂ C is preferable.
H ₂ - is most preferred.

In the general formula (I), the benzene ring in the benzofuran ring may be substituted with 1 to 3 substituents. Examples of such a substituent include halogen (eg, fluorine, chlorine, iodine, etc.), hydroxy group, cyano group, nitro group, trifluoromethyl group, lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, Butoxy or the like having 1 to 4 carbon atoms, lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl or the like having 1 to 4 carbon atoms), lower alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxy) Carbonyl, etc., having 2 to 4 carbon atoms, lower alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc., having 1 to 3 carbon atoms)
And lower alkylamino groups (having 1 to 4 carbon atoms such as methylamino, ethylamino and dimethylamino). The benzene ring in the benzofuran ring is preferably unsubstituted.

In the general formula (I), Y and R ² are bonded to the 2 or 3 position of the benzofuran ring, and R ¹ -O is bonded to the 4, 5, 6 or 7 position of the benzofuran ring.
R ¹ -O is preferably bonded to the 6-position of the benzofuran ring, and Y is preferably bonded to the 2-position of the benzofuran ring.

As a preferred example of the compound represented by the general formula (I), for example, R ¹ is bonded through a methylene group,
The oxazole group optionally substituted with phenyl and / or methyl has a partial structural formula

Embedded image R ² represents hydrogen, Y represents a divalent or trivalent aliphatic hydrocarbon residue having 1 to 4 carbon atoms, R ¹ —O is at the 6-position of the benzofuran ring, and Y is at the 2-position of the benzofuran ring. Compounds that bind are included.

Preferred specific examples of the compound represented by the general formula (I) include 5- [2- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-
Benzofuranyl] ethyl] -1H-tetrazole, 5-
[3- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl]-
1H-tetrazole, 5- [4- [6- (5-methyl-
2-Phenyl-4-oxazolylmethoxy) -2-benzofuranyl] butyl] -1H-tetrazole, 5- [6
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranylmethylidene] -2,4-thiazolidinedione, 5- [6- (5-methyl-2-phenyl-4- Oxazolylmethoxy) -2-benzofuranylmethyl] -2,4-thiazolidinedione, 5- [3-
[6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -2,4
-Thiazolidinedione, 5- [6- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) -2-benzofuranylmethyl] -2,4-oxazolidinedione, 5-
[3- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl]-
2,4-oxazolidinedione or 5- [3- [5-
(5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -1H-tetrazole and the like, among which 5- [3- [6- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
2-Benzofuranyl] propyl] -1H-tetrazole is particularly preferred.

The salt of the compound represented by the general formula (I) of the present invention (hereinafter referred to as compound (I)) is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base or an organic base. , A salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,
Examples thereof include salts with succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc. Is mentioned. Among these salts, sodium salt and potassium salt are most preferable.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof has a low toxicity, a blood glucose and blood lipid lowering action and an insulin sensitivity enhancing action, and as it is or a pharmacologically known method. Mixed with an acceptable carrier, excipient, bulking agent, etc., to give a mammal (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig,
It can be used as a therapeutic agent for diabetes, an insulin sensitivity enhancer, a therapeutic agent for hyperlipidemia or an antihypertensive agent for monkeys and the like). The compound (I) of the present invention has low toxicity. For example, when the compound of Example 7 is orally administered to a mouse at a rate of 15 mg / kg per day for 4 days, there is no change in body weight and liver weight from the control. I was not able to admit. The method of administration is usually used orally as tablets, capsules (including soft capsules and microcapsules), powders, granules, etc., but in some cases parenterally as injections, suppositories, pellets, etc. it can. Dosage is 0.05-1 per day when orally administered to adults
It is 0 mg / kg, and it is desirable to administer this amount once to three times a day. The compound (I) of the present invention is blended with a pharmaceutically acceptable carrier, and is orally or parenterally as a solid preparation such as tablets, capsules, granules and powders; or a liquid preparation such as syrups and injections. Can be administered to.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances which are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations, It is added as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like. In addition, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can be used, if necessary. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include, for example, starch, carboxymethyl cellulose,
Examples include carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of the solubilizing agent include, for example,
Polyethylene glycol, propylene glycol, D-
Examples thereof include mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as glyceryl monostearate; Examples thereof include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like.

The method for producing the compound (I) of the present invention will be described below. Compound (I) can be produced by a method known per se, for example, the method shown below or a method analogous thereto. (1) Method for synthesizing compound (IA) whose cation-releasing group is tetrazole

[Chemical 19] [Each symbol in the formula has the same meaning as described above. ]

The compound (IA) in which the group capable of releasing a cation is tetrazole is produced by reacting the nitrile derivative (II) with an azide compound. Compound (II)
To the compound (IA) is described in, for example, the Journal of American Chemical Society (Journal
of American Chemical Society), 80, 3908 (1958), by reaction with ammonium chloride and sodium azide in N, N-dimethylformamide. The amount of ammonium chloride and sodium azide used is 1 per mol of compound (II).
-7 mol, preferably 1-5 mol, 50 ° C-18
It is carried out at 0 ° C. for 1 to 50 hours. In addition, compound (II)
From compound to compound (IA)
Organic Chemistry (Journal of Organic Che
mistry), 56, 2395 (1991), the compound (II) is reacted with trimethyltin azide or tributyltin azide and then treated with an acid. The compound (I-
A) and salts thereof can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(2) The group capable of releasing a cation is 2,4-
Method for synthesizing compound (IB) which is oxazolidinedione

Embedded image [In the formula, Y ¹ represents a bond or a divalent aliphatic hydrocarbon residue, and other symbols have the same meanings as described above. ]

The aliphatic hydrocarbon residue represented by Y ¹ is Y
Among the divalent or trivalent aliphatic hydrocarbon residues having 1 to 8 carbon atoms represented by, are divalent ones having 1 to 7 carbon atoms. Compound (I-B1) is produced by condensation of aldehyde compound (III) and 2,4-oxazolidinedione. This reaction is carried out in a solvent in the presence of a base. As the solvent, methanol, ethanol, propanol,
Alcohols such as isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, isopropyl ether,
Ethers such as tetrahydrofuran; N, N-dimethylformamide, dimethylsulfoxide, acetic acid and mixed solvents thereof can be mentioned. Examples of the base include sodium alkoxide (eg, sodium methoxide, sodium ethoxide, etc.); potassium carbonate, sodium carbonate,
Alkali metal salts such as sodium acetate; metal hydrides such as sodium hydride; secondary amines such as piperidine, piperazine, pyrrolidine, morpholine, diethylamine and diisopropylamine. The amount of 2,4-oxazolidinedione used is 1 with respect to compound (III).
It is -10 molar equivalents, preferably 1-5 molar equivalents. The amount of the base used is 0.01 to 5 relative to compound (III).
It is a molar equivalent, preferably 0.05 to 2 molar equivalents. This reaction is carried out at 0 to 180 ° C., preferably 50 to 130 ° C.
It takes 5 to 30 hours. The compound (I-B1) thus obtained can be obtained by a known separation and purification means, for example,
It can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Further, regarding the double bond at the 5-position of 2,4-oxazolidinedione ring, (E) form And may be obtained as a mixture of the (Z) form.

[0035]

[Chemical 21] [In the formula, R ¹ 'is a heterocyclic residue which may be bonded via a saturated carbon chain and may be substituted, and Y ² is a bond or a divalent saturated aliphatic hydrocarbon residue. And other symbols have the same meanings as above. ]

The saturated aliphatic hydrocarbon residue represented by Y ² is a saturated divalent aliphatic hydrocarbon residue represented by Y ¹ and having 1 to 7 carbon atoms. The heterocyclic residue which may be bonded via a saturated carbon chain represented by R ¹ ′ and which may be substituted may be bonded via a carbon chain represented by R ¹ . Among the optionally substituted heterocyclic residues, those in which the carbon chain is saturated. By subjecting compound (I-B1) to a reduction reaction, compound (I-
B2) can be produced. This reduction reaction is performed according to a conventional method in a solvent in the presence of a catalyst, in a hydrogen atmosphere at 1 to 150 atm. As the solvent, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; benzene, toluene,
Aromatic hydrocarbons such as xylene; diethyl ether,
Ethers such as isopropyl ether and tetrahydrofuran; chloroform, dichloromethane, 1,1,2,2
Halogenated hydrocarbons such as tetrachloroethane; ethyl acetate, acetic acid, N, N-dimethylformamide and mixed solvents thereof. As a catalyst, a metal such as a nickel compound, a transition metal catalyst such as palladium, platinum, or rhodium can be advantageously used. The reaction temperature is 0 to 100 ° C, preferably 10 to 80 ° C, and the reaction time is 0.5 to 50 hours. The compound (I-B2) thus obtained can be isolated and purified by known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography or the like.

(3) The group capable of releasing a cation is 2,4-
Method for synthesizing compound (IC) which is thiazolidinedione

[Chemical formula 22] [Each symbol in the formula has the same meaning as described above. ]

The compound (I-C1) is produced by condensation of the aldehyde compound (III) and 2,4-thiazolidinedione. This reaction is carried out in the same manner as Method B. . The compound (I-C1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. . Compound (I-C1) is 2,4
-Regarding the double bond at the 5-position of the thiazolidinedione ring, (E)
It may be obtained as a mixture of the body and the (Z) body.

[0039]

[Chemical formula 23] [Each symbol in the formula has the same meaning as described above. ]

This method is carried out in the same manner as the method C. The compound (I-C2) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

(4) Method for synthesizing compound (ID) in which the group capable of releasing a cation is 2-thioxothiazolidin-4-one

[Chemical formula 24] [Each symbol in the formula has the same meaning as described above. ]

In this method, 2-thioxothiazolidine-4 is prepared by condensation of aldehyde compound (III) and rhodamine.
The -one derivative (I-D1) is prepared. This reaction is carried out in the same manner as Method B. The compound (I-D1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (I-D1) may be obtained as a mixture of the (E) form and the (Z) form with respect to the double bond at the 5-position of the 2-thioxothiazolidin-4-one ring.

[0043]

[Chemical 25] [Each symbol in the formula has the same meaning as described above. ]

In this method, the compound (ID
Compound (I-D2) is produced by reducing 1). This reaction is carried out in the same manner as in Method C. The compound (I-D2) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

(5) The group capable of releasing a cation is 2,4-
Method for synthesizing compound (IE) which is imidazolidinedione

[Chemical formula 26] [Each symbol in the formula has the same meaning as described above. ]

In this method, a 2,4-imidazolidinedione derivative (I-E1) is produced by condensation of an aldehyde compound (III) and hydantoin. This reaction is carried out in the same manner as Method B. The compound (I-
E1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (I-
E1) relates to the double bond at the 5-position of the 2,4-imidazolidinedione ring, and may be obtained as a mixture of the (E) form and the (Z) form.

[0047]

[Chemical 27] [Each symbol in the formula has the same meaning as described above. ]

In this method, the compound (IE) obtained by Method H was used.
Compound (I-E2) is produced by reducing 1). This reaction is carried out in the same manner as in Method C. The compound (I-E2) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

(6) The groups capable of releasing cations are 1, 2,
A compound which is 4-oxadiazol-5-one (I-
F) synthesis method

[Chemical 28] [Each symbol in the formula has the same meaning as described above. ]

In this method, the nitrile derivative (II) is converted to an amidoxime form (IV) and then cyclized to obtain an oxadiazol-5-one form (IF).
The reaction of the compound (II) to the amidoxime compound (IV) is carried out in an ordinary organic solvent using 2 to 10 mol of hydroxylamine per 1 mol of the compound (II). Such solvents include amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), alcohols (eg, methanol, ethanol, etc.), ethers ( (Eg, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.) and the like. When an inorganic acid salt (eg, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.) or an organic acid salt (eg, hydroxylamine oxalate, etc.) is used as the hydroxylamine, a suitable base (eg, potassium carbonate, sodium carbonate,
Sodium hydroxide, triethylamine, sodium methoxide, sodium ethoxide, sodium hydride, etc.) are allowed to coexist in an equivalent amount and the reaction is performed at 20 to 120 ° C. for about 1 to 24 hours. The amidoxime derivative (IV) thus obtained can be used in the usual coexistence with chlorocarbonic acid ester (eg, methyl chlorocarbonate, ethyl chlorocarbonate, etc.) (eg, triethylamine, pyridine, potassium carbonate, sodium carbonate, etc.). An O-acyl derivative is obtained by reacting in a solvent (eg, chloroform, dichloromethane, dioxane, tetrahydrofuran, acetonitrile, pyridine, etc.). The reaction is usually the amidoxime form (IV) 1
2 to 5 mol of chlorocarbonic acid ester and 2
It is carried out in a solvent in the presence of ˜5 mol of base. Reaction temperature is 0
The reaction time is about 1 to 10 hours.

The reaction of the O-acyl amidoxime compound thus obtained to the ring-closed compound (IF) is carried out by heating in a usual solvent. As such a solvent,
Examples thereof include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, etc.). The reaction is carried out by adding the O-acylamidoxime form in a solvent to
It is performed by heating for 10 hours. The compound (IF) thus obtained is separated by known means of separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography or the like.

(7) The groups capable of releasing cations are 1, 2,
A compound which is 4-oxadiazole-5-thione (I-
Method G)

[Chemical 29] [Each symbol in the formula has the same meaning as described above. ]

In this method, the compound (I-
F) obtained as a synthetic intermediate (A).
V) is ring-closed to produce a thioketone body (IG). The reaction from the amidoxime form (IV) to the thioketone form (IG) is carried out by the amidoxime form (IV)
It is carried out in an organic solvent using 1 to 1 mol of 1,1'-thiocarbonyldiimidazole per mol. Examples of such a solvent include ethers (eg, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, etc.), acetonitrile, acetone and the like.
As the base, amines (eg, pyridine, triethylamine, 2,6-dimethylpyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4. 0] -7-undecene etc.) and the like. This reaction is preferably carried out in a solvent at −30 ° C. to 30 ° C. for about 0.5 to 10 hours. The compound (IG) thus obtained can be separated by known means of separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

(8) The groups capable of releasing cations are 1, 2,
Method for synthesizing compound (I-H) which is 3,5-oxathiadiazole-2-oxide

Embedded image [Each symbol in the formula has the same meaning as described above. ]

This method is the same as compound (I-
F) obtained as a synthetic intermediate (A).
The 1,2,3,5-oxathiadiazole-2-oxide (I-H) is obtained by ring closure of V). The reaction from the amidoxime form (IV) to the 1,2,3,5-oxathiadiazole-2-oxide form (I-H) is carried out by reacting the amidoxime form (IV) in an organic solvent (eg, dioxane, tetrahydrofuran, dichloromethane, chloroform). Etc.) and a base (eg, pyridine, triethylamine, etc.) in the presence of thionyl chloride to react with compound (I-
H) is produced. This reaction is carried out in the amidoxime form (IV) 1
In a solvent in the presence of about 1 to 3 mol of base, based on mol.
It is desirable to add about 2 to 10 mol of thionyl chloride at 30 ° C to 30 ° C and perform the treatment for 0.5 to 10 hours. The compound (I-H) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

(9) The groups capable of releasing a cation are 1, 2,
Synthesis of compound (II) which is 4-oxadiazolidine-3,5-dione

[Chemical 31] [In the formula (VII), A ¹ and A ² are the same or different and each represents a halogen atom, an alkoxy group, an aralkyloxy group or an aryloxy group, and the other symbols have the same meanings as described above. ]

The halogen atom represented by A ¹ and A ² includes, for example, chlorine, bromine, iodine and the like, and the alkoxy group includes a lower alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy and the like having 1 carbon atom). ~ 4 things)
However, as the aralkyloxy group, those having 7 to 13 carbon atoms such as a benzyloxy group, and as the aryloxy group,
Examples include phenoxy groups having 6 to 14 carbon atoms. In this method, aldehyde (III) is treated with an alcohol such as methanol and ethanol, an organic solvent such as aromatic hydrocarbons such as benzene, toluene, and xylene, or a solvent inert to the reaction such as water or a mixed solvent thereof. If necessary, in the presence of a catalyst such as sodium acetate or p-toluenesulfonic acid, optionally using an azeotropic dehydrator or dehydrating agent, to react with hydroxylamine or a salt thereof,
Compound (V) is produced by reducing the resulting Schiff base with a reducing agent commonly used for reductive amination, such as borane-pyridine complex and sodium borohydride. Then, the compound (V) is treated with an alkali cyanate in an organic solvent inert to the reaction such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran or a mixed solvent thereof, if necessary in the presence of an acid catalyst such as hydrochloric acid. Compound (VI) is produced by reacting a metal. Then, the compound (VI) is reacted with a carbonyl compound represented by the general formula (VII) to give the compound (II).
Can be manufactured. This reaction is carried out in an organic solvent (eg,
Dioxane, tetrahydrofuran, ether, dimethoxyethane, methanol, ethanol, 2-methoxyethanol, dimethylsulfoxide, etc.), compound (VI) 1
It is desirable to use about 1 to 3 mol of the compound (VII) per mol, preferably at 0 ° C. to 150 ° C. in the presence of a base (sodium hydroxide, potassium hydroxide, etc.).
The compound (II) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

(10) Method for synthesizing compound (II) wherein cation-releasing group is cyano group

Embedded image [In the formula, R ⁹ represents a lower alkyl group, and q represents 0, 1 or 2
And other symbols have the same meanings as above. ]

The lower alkyl group represented by R ⁹ includes
Examples thereof include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. In this method, first, an aldehyde derivative (III-1) is reacted with a cyanomethylphosphonate derivative (VIII) to produce an unsaturated nitrile derivative (II-1). Compound (II
The reaction of I-1) with compound (VIII) is carried out in the presence of a base in an appropriate solvent according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform, dichloromethane and 1,2-dichloroethane. And halogenated hydrocarbons such as; N, N-dimethylformamide, dimethylsulfoxide, and mixed solvents thereof.
Examples of the base include potassium hydroxide, sodium hydroxide,
Alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate; pyridine, triethylamine, N,
Examples include amines such as N-dimethylaniline; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide, potassium t-butoxide, and the like. -1) About 1 to 5 mol is preferable with respect to 1 mol. The amount of the compound (VIII) used is the compound (III-
1) 1 to 5 mol, preferably 1 to 3 mol per mol. This reaction is generally carried out at -50 ° C to 150 ° C, preferably -10 to 100 ° C. Reaction time is 0.5-3
0 hours. Then, the compound (II-1) is subjected to catalytic reduction to produce the compound (II-2). This reduction reaction is carried out in the same manner as method C. The nitrile compounds (II-1) and (II-
2) is a known separation and purification means, for example, concentration, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

[0060]

[Chemical 33] [In the formula, n represents an integer of 1 to 6, W represents a halogen atom, and other symbols have the same meanings as described above. ]

Examples of the halogen atom represented by W include chlorine, bromine, iodine and the like. In this method, first, an aldehyde derivative (III-2) is condensed with a phosphonium salt (IX) to produce a compound (II-3). This reaction is carried out in the presence of a base in an appropriate solvent according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform, dichloromethane and 1,2-dichloroethane. And halogenated hydrocarbons such as N; N-dimethylformamide, dimethylsulfoxide, and mixed solvents thereof. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine and N, N-dimethylaniline; sodium hydride and potassium hydride. Metal hydride; sodium ethoxide, sodium methoxide, potassium t-butoxide, etc., and the amount of these bases to be used is preferably about 1 to 5 mol relative to compound (III-2). The amount of compound (IX) to be used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (III-2).
This reaction is generally -50 ° C to 150 ° C, preferably -1.
It is carried out at 0 to 100 ° C. The reaction time is 0.5 to 30 hours. Then, the compound (II-4) is produced by subjecting the compound (II-3) to catalytic reduction. This reduction reaction is carried out in the same manner as method C. The nitrile compounds (II-3) and (II-4) thus produced can be separated and purified by known means such as concentration, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

[0062]

Embedded image [Wherein R ¹⁰ is a lower alkyl group and p is 0, 1 or 2
, Q represents a leaving group, and other symbols have the same meanings as above. ]

Examples of the lower alkyl group represented by R ¹⁰ include those exemplified as the lower alkyl group represented by R ⁹ . Examples of the leaving group represented by Q include halogen atoms such as chlorine, bromine, and iodine, as well as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and the like. In this method, first, an aldehyde derivative (III-2) is condensed with a compound (X) to produce an unsaturated ester derivative (XI). This reaction consists of compound (III-1) of method N and compound (VII).
It is carried out in the same manner as the reaction of I). Then, the compound (X
I) is catalytically reduced to produce a saturated ester derivative (XII). This reduction reaction is carried out in the same manner as method C. Then, the compound (XII) is subjected to a reduction reaction to produce an alcohol derivative (XIII). This reduction reaction can be performed by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, etc. are used. That is, this reaction is carried out by treating the compound (XII) with a reducing agent. As the reducing agent, sodium borohydride,
Alkali metal borohydride such as lithium borohydride,
Examples thereof include metal hydrogen complex compounds such as lithium aluminum hydride and borane compounds. This reaction is carried out in a solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform, dichloromethane and 1,2-dichloroethane. Halogenated hydrocarbons such as N; N-dimethylformamide, dimethylsulfoxide, and mixed solvents thereof are appropriately selected and used according to the type of reducing agent. The reaction temperature is usually -50 ° C to 150 ° C.
C., preferably -10 to 100.degree. The reaction time is 0.5 to 30 hours.

Then, the compound (XIII) is reacted with a halogenating agent or a sulfonylating agent to produce (XIV). As the halogenating agent, hydrochloric acid, thionyl chloride,
Phosphorus tribromide and the like are preferably used, in which case a compound (XIV) in which Q is chlorine or bromine is produced. This reaction is performed using an appropriate inert solvent (for example, benzene, toluene,
Xylene, chloroform, dichloromethane etc.) or using an excess halogenating agent as a solvent at -10 to 80 ° C. The amount of the halogenating agent used is the compound (XII
I) It is 1 to 20 mol per 1 mol. As the sulfonylating agent, methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride and the like are preferably used, and Q is methanesulfonyloxy,
A compound (XIV) represented by p-toluenesulfonyloxy and benzenesulfonyloxy is produced. This reaction is carried out in a suitable inert solvent (for example, benzene, toluene, xylene, diethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, etc.) and a base (for example, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,
(For example, potassium carbonate) at -10 to 30 ° C. The amounts of the sulfonylating agent and the base used are the compound (X
III) 1 to 2 mol per 1 mol, respectively. Compound (XIV) in which Q is iodine by reacting 1 to 2 mol of sodium iodide or potassium iodide with 1 mol of compound (XIV) in which Q is chlorine, bromine or sulfonyloxy produced as described above ) Can also be manufactured. In this case, the reaction is carried out in a solvent such as acetone, 2-butanone, methanol or ethanol at 20 to 80 ° C.
Done in.

Next, the compound (II-5) is produced by reacting the compound (XIV) with potassium cyanide or sodium cyanide. The reaction is usually a solvent (for example, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, methanol, ethanol, chloroform, dichloromethane, acetone, 2-butanone,
N, N-dimethylformamide, dimethylsulfoxide, etc.) at 0 to 100 ° C., and the amount of potassium cyanide or sodium cyanide used is that of compound (XIV) 1
It is 1 to 5 mol per mol. The nitrile compound (II-5) thus produced can be isolated and purified by a known separation and purification means such as concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
The compound (II) described above is also used as a raw material compound in the above-mentioned Method A and Method J.

(11) Compounds (XI) and (XI) in which the group capable of releasing a cation is an alkoxycarbonyl group.
Method of Synthesizing I) Compounds (XI) and (XII) can be produced according to Method P described above. Compounds (XI) and (XII) thus produced can be isolated and purified by known means such as concentration, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography or the like.

(12) Method for synthesizing compound in which cation-releasing group is carboxyl group The cation-releasing group is carboxyl group by hydrolyzing the compound (II), (XI) or (XII). The compounds that are groups can be prepared. Hydrolysis is usually carried out by contacting with a base or an acid in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol and propanol; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; N, N-dimethylformamide and a mixed solvent thereof. As the base, potassium hydroxide,
Alkali metal salts such as sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate are used.
The amount of the base used is about 1 to 3 mol based on 1 mol of the raw material compound. As the acid, inorganic acids such as hydrochloric acid and hydrobromic acid, and organic acids such as p-toluenesulfonic acid are used.
The amount of the acid used is 1 mol to a large excess amount with respect to 1 mol of the raw material compound. When using an acid, a large excess of acid may be used as a solvent. The reaction temperature is usually -50 ° C to 150 ° C.
C., preferably -10.degree. C. to 100.degree. The reaction time is about 0.5 to 30 hours. The compound thus produced can be isolated and purified by a known separation and purification means such as concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The above-mentioned B method, D method, F method, H method, M method,
The aldehyde derivative (III) used as a raw material compound for Method N, Method O and Method P can be produced, for example, by the following Method Q or Method R.

Embedded image [Each symbol in the formula has the same meaning as described above. ]

In this method, first, an unsaturated ester derivative (XI) is subjected to a reduction reaction to give an alcohol derivative (XV).
To manufacture. This reduction reaction is carried out by the compound (XI
It is carried out in the same manner as the reduction reaction of I), but it is advantageously carried out by using diisobutylaluminum hydride as the reducing agent. Then, the compound (XV) is subjected to an oxidation reaction to produce an unsaturated aldehyde derivative (III-3). This oxidation reaction can be carried out by a method known per se. For example, oxidation with manganese dioxide, oxidation with chromic acid, oxidation with dimethyl sulfoxide, etc. are used. That is, this reaction is carried out by treating the compound (XV) with an oxidizing agent. Although manganese dioxide, chromic anhydride, etc. are used as the oxidizing agent, the use of manganese dioxide is advantageous. This reaction is carried out in a solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; N, N-dimethylformamide, dimethyl sulfoxide and a mixed solvent thereof are appropriately selected and used according to the kind of the oxidizing agent. The reaction temperature is usually -50 ° C to 150 ° C.
C., preferably -10 to 100.degree. The reaction time is 0.5 to 30 hours. The aldehyde derivative (III-3) thus obtained is a known separation and purification means,
For example, it can be isolated and purified by concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0070]

Embedded image [Each symbol in the formula has the same meaning as described above. ]

This method is carried out in the same manner as the Q method. That is, the reduction reaction of compound (XVI) is the same as the reduction reaction of compound (XI) in Method Q, and
The oxidation reaction of I) can be made into the compound (III-1) in the same manner as the oxidation reaction of the compound (XV) in the Q method. The aldehyde derivative thus obtained (III
-1) can be isolated and purified by known separation and purification means, for example, concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (XVI) for Method R is, for example,
It can be manufactured by the following method.

Embedded image [In the formula, T represents a lower alkyl group, an aralkyl group and an acyl group, and other symbols have the same meanings as described above. ]

Examples of the lower alkyl group represented by T include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, and examples of the aralkyl group include benzyl and diphenylmethyl. , Trityl and the like having 7 to 19 carbon atoms, and as the acyl group, carbonyl group is bonded to lower alkyl having 1 to 4 carbon atoms or aromatic hydrocarbon having 6 to 14 carbon atoms such as acetyl, propionyl and benzoyl. The ones that have been done are listed.
In this method, first, the compound (XVIII) having a hydroxyl group substituted with the protecting group T and the compound (XIX) are condensed to produce the compound (XX). This reaction is carried out in the presence of a base in an appropriate solvent according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform, dichloromethane and 1,2-dichloroethane. And halogenated hydrocarbons such as N; N-dimethylformamide, dimethylsulfoxide, and mixed solvents thereof. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine and N, N-dimethylaniline; sodium hydride, potassium hydride and the like. Metal hydrides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, and the like.
It is preferably about 1 to 5 mol per mol. Compound (XI
The amount of X) used is 1 with respect to 1 mol of the compound (XVIII).
-5 mol, preferably 1-3 mol. This reaction is generally carried out at -20 ° C to 180 ° C, preferably 0 to 120 ° C. The reaction time is 0.5 to 30 hours.

Then, the compound (XX) is intramolecularly condensed to produce the compound (XXI). This reaction is
It is carried out in an appropriate solvent in the presence of a base according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform, dichloromethane and 1,2-dichloroethane. Halogenated hydrocarbons such as; ethyl acetate, pyridine, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, acetic acid, acetic anhydride, and mixed solvents thereof. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ Amines such as 5,4,0] -7-undecene; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide, potassium t-butoxide, and the like. Use of these bases The amount is preferably about 1 to 5 mol with respect to 1 mol of the compound (XX). This reaction is usually -2.
It is carried out at 0 ° C to 180 ° C, preferably 0 to 120 ° C.
The reaction time is 0.5 to 30 hours.

Then, the compound (XXI) is deprotected to produce the compound (XXII). This reaction is appropriately performed according to a conventional method depending on the type of the protecting group T. Then, the compound (X
XII) is condensed with compound (XXIII) to give compound (X
VI) is produced. This reaction is carried out in the same manner as the reaction between compound (XXIII) and compound (XIX). The compound (XVI) thus produced can be isolated and purified by known means such as concentration, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography or the like.

[0076]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to experimental examples, examples and reference examples.

【Example】

Experimental Example Blood glucose and blood lipid lowering action in mice The test compound was added to powder feed (CE-2, CLEA Japan, Inc.) in an amount of 0.
A mixture of 005% was given to KKA ^y mice (9 to 14 weeks old) freely for 4 days. During this time, water was given freely. Blood was collected from the orbital vein and plasma was used to analyze glucose and triglyceride by the enzyme method iatrochem-
GLU (A) kit (Yatron) and Iatro-M
It was quantified using the A701TG kit (Yatron).
The value of each drug-administered group was expressed as a reduction rate (%) with respect to the drug-non-administered group, and is shown in Table 1.

[0077]

[Table 1] ───────────────────────── Compounds Blood glucose lowering action Lipid lowering action (Example number) (%) (%) ─── ────────────────────── 2 61 92 6 6 0 27 7 38 38 26 8 61 70 70 ──────────────── ─────────

As described above, the compound (I) of the present invention and its salt have excellent blood glucose and blood lipid lowering actions,
It is useful as a drug such as a therapeutic agent for diabetes, an insulin sensitivity enhancer, a therapeutic agent for hyperlipidemia, and a therapeutic agent for hypertension.

Example 1 2- (2-Cyanoethyl) -6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran (1.20 g), sodium azide (1.09 g), ammonium chloride (0.90 g) and N, N-dimethylformamide (30 ml) at 130-140 ° C.
Stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO
After ₄ ), the solvent was distilled off and the residue was subjected to silica gel column chromatography. From the portion eluted with methanol-chloroform (5:95, v / v), 5- [2-
[6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] ethyl] -1H-tetrazole (1.05 g, 78%) was obtained. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 177-178 [deg.] C. Calculated elemental analysis _{C 22 H 19 N 5 O 3} : C, 65.83; H, 4.77; N, 17.45 Found: C, 65.57; H, 4.97 ; N, 17 .44

Example 2 In the same manner as in Example 1, 5- [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -1H-tetrazole was added. Obtained. Yield 58%. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 139-140 [deg.] C.

Example 3 In the same manner as in Example 1, 5- [4- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] butyl] -1H-tetrazole was added. Obtained.
Yield 55%. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 114-11
5 ° C.

Example 4 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofurancarbaldehyde (1.2
0 g) 2,4-thiazolidinedione (0.465
g), piperidine (0.12 g) and ethanol (4
(0 ml) was heated under reflux for 2 hours. After cooling, precipitated 5- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranylmethylidene] -2,4-thiazolidinedione crystal (1.46
g, 94%). Recrystallized from chloroform-ethanol. Yellow prism crystal. Melting point 272-273 [deg.] C. Elemental analysis _{C 23 H 16 N 2 O 5} S · 1 / 4H 2 O Calculated: C, 63.22; H, 3.81 ; N, 6.41 Found: C, 63.16; H, 3.62; N, 6.31

Example 5 5- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranylmethylidene]-
A mixture of 2,4-thiazolidinedione (0.80 g), palladium-carbon (5%, 1.60 g) and tetrahydrofuran (250 ml) was added at room temperature, 3.2 kgf / c.
Catalytic reduction was carried out at a hydrogen pressure of m ² for 8 hours. The catalyst was filtered off, and the filtrate was further catalytically reduced for 16 hours under the same conditions. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-chloroform (1: 5, v / v), 5- [6-
Crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranylmethyl] -2,4-thiazolidinedione (0.305 g, 38%) were obtained. Recrystallized from dichloromethane-methanol. Yellow needles. Melting point 179-180 [deg.] C. Elemental analysis _{C 23 H 18 N 2 O 5} S Calculated: C, 63.58; H, 4.18 ; N, 6.45 Found: C, 63.51; H, 3.96 ; N, 6.52

Example 6 (E) -3- [6- (5-methyl-2-phenyl-4-
A mixture of oxazolylmethoxy) -2-benzofuranyl] acrolein (1.00 g), 2,4-thiazolidinedione (0.49 g), piperidine (0.24 g) and acetic acid (20 ml) was heated under reflux for 2 hours. . The reaction mixture was concentrated under reduced pressure to precipitate crystals (0.79 g).
Was collected by filtration. Tetrahydrofuran (200m)
1) dissolved in palladium-carbon (5%, 1.60 g)
Was added and catalytic reduction was carried out at a hydrogen pressure of 3.2 kgf / cm ² for 8 hours. The catalyst was filtered off, and the filtrate was further catalytically reduced for 8 hours under the same conditions. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
From the portion eluted with ethyl acetate-chloroform (1: 9, v / v), 5- [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] Crystals of -2,4-thiazolidinedione (0.34g, 26%) were obtained. Recrystallized from dichloromethane-methanol. Yellow prism crystal. Melting point 167
~ 168 ° C. Elemental analysis value Calculated as C ₂₅ H ₂₂ N ₂ O ₅ S: C, 64.92; H, 4.79; N, 6.06 Measured value: C, 64.63; H, 4.85; N, 5.95

Example 7 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofurancarbaldehyde (1.7
0 g) 2,4-oxazolidinedione (1.55
A mixture of g), pyrrolidine (0.365 g) and ethanol (40 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water and the precipitated crystals were collected by filtration. The crystals were dissolved in tetrahydrofuran (100 ml), palladium-carbon (0.40 g) was added, and catalytic reduction was performed at room temperature and 1 atm. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the portion eluted with methanol-chloroform (2:98, v / v), 5- [6- (5-methyl-2-phenyl-
4-Oxazolylmethoxy) -2-benzofuranylmethyl] -2,4-oxazolidinedione crystal (0.14
g, 6.6%). Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 172-173
° C. Elemental analysis C ₂₃ H ₁₈ N ₂ O ₆ Calculated: C, 66.03; H, 4.34 ; N, 6.70 Found: C, 65.95; H, 4.31 ; N, 6 .71

Example 8 In the same manner as in Example 7, 5- [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -2,4- Crystals of oxazolidinedione were obtained. Yield 25%. Recrystallized from dichloromethane-methanol. Pale yellow prism crystal. Melting point 1
59-160 ° C.

Example 9 In the same manner as in Example 1, 5- [3- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -1H-tetrazole was added. Obtained. Yield 82%. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 136-137
° C.

Example 10 6-sodium hydride (60%, oily, 0.20 g)
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carbaldehyde (1.50
g) and diethyl cyanomethylphosphonate (0.88
A solution of g) in N, N-dimethylformamide (30 ml) was gradually added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and neutralized with 2N hydrochloric acid, and then ethyl acetate (2
(00 ml). The ethyl acetate layer was washed with water and dried (M
gSO ₄ ) then palladium-carbon (5%, 0.70 g)
Was added and catalytically reduced at room temperature and 1 atm. The catalyst is filtered off,
After concentrating the filtrate, the residue was subjected to silica gel column chromatography. Ethyl acetate-chloroform (2: 9
8, (v / v), a crystal of 2- (2-cyanoethyl) -6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran (1.34 g, 8).
3%). Recrystallized from dichloromethane-hexane. Colorless prism crystals. Melting point 92-93 [deg.] C.

Example 11 Sodium hydride (60%, oily, 0.20 g) was added to 3-
Cyanopropyltriphenylphosphonium bromide (2.07 g) in N, N-dimethylformamide (30
(ml) solution was gradually added at room temperature and stirred for 1 hour. 6
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carbaldehyde (1.40
g) was added, and the mixture was stirred at 70 to 80 ° C for 2 hours. The reaction mixture was poured into ice water and neutralized with 2N hydrochloric acid, and then ethyl acetate (2
(00 ml). The ethyl acetate layer was washed with water and dried (M
After gSO ₄ ) the solvent was evaporated and the residue was subjected to silica gel column chromatography. An oily material was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, v / v).
This was dissolved in tetrahydrofuran (40 ml), palladium-carbon (5%, 0.70 g) was added, and catalytic reduction was performed at room temperature and 1 atm. The catalyst was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 3, v / v), 2- (4-cyanobutyl) -6- (5-methyl-
Crystals of 2-phenyl-4-oxazolylmethoxy) benzofuran (0.97 g, 60%) were obtained. Recrystallized from diethyl ether-hexane. Colorless prism crystals. Melting point 87-88 [deg.] C.

Example 12 Sodium hydride (60%, oily, 0.72 g) 6-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carbaldehyde (6.00
g) and triethyl phosphonoacetate (4.04 g)
Was gradually added to a solution of N, N-dimethylformamide (100 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and precipitated (E) -ethyl 3- [6-
Crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] acrylate were obtained. Recrystallization from dichloromethane-ethanol gave colorless prism crystals (7.03 g, 97%). Melting point 141
~ 142 ° C.

Example 13 3- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propanol (0.88 g), methanesulfonyl chloride (0.335)
g), triethylamine (0.295 g) and dichloromethane (30 ml) were stirred at room temperature for 14 hours. The reaction mixture was washed with 2N hydrochloric acid and dried (MgS
After O ₄ ) the solvent was distilled off. The residue was dissolved in N, N-dimethylformamide (30 ml), potassium cyanide (0.24 g) was added, and the mixture was stirred at 90-100 ° C for 4 hr. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (MgS
After O ₄ ), the solvent was evaporated and the residue was subjected to silica gel column chromatography. From a portion eluted with ethyl acetate-hexane (1: 4, v / v), 2- (3-cyanopropyl) -6- (5-methyl-2-phenyl-4)
Crystals of -oxazolylmethoxy) benzofuran were obtained.
Recrystallization from ethyl acetate-hexane gave colorless prism crystals (0.65 g, 72%). Melting point 94-95 [deg.] C.

Example 14 In the same manner as in Example 12, 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-
Carboxaldehyde was reacted with triethylphosphonoacetate to obtain (E) -ethyl 3- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] acrylate. Yield 93%. Recrystallized from acetone-isopropyl ether. Colorless needles. Melting point 120-121 ° C.

Example 15 In the same manner as in Example 13, 3- [5- (5-methyl-2)
After the mesylation of -phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propanol, sodium cyanide was reacted to give 2- (3-cyanopropyl) -5-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzofuran was obtained. Yield 80%. Recrystallized from acetone-isopropyl ether. Colorless prism crystals.
Melting point 114-115 [deg.] C.

Formulation Example 1 Formulation Example of Tablet (1) 5- [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -1H-tetrazole (implementation) Compound of Example 2) 10 g (2) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose calcium 44 g (5) Magnesium stearate 1 g 1000 tablets 120 g (1), (2), (3) total amount and 30 g (4) is kneaded with water, vacuum dried, and then granulated. 1 at the end of this granulation
By mixing 4 g of (4) and 1 g of (5) and making tablets with a tableting machine, 1000 tablets containing 10 mg of (1) per tablet are produced.

Formulation Example 2 Formulation Example of Tablets (1) 5- [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -2,4-oxazolidine Dione (Compound of Example 8) 30 g (2) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose calcium 44 g (5) Magnesium stearate 1 g 1000 tablets 140 g (1), (2), (3) total amount And 30 g of (4) are kneaded with water, vacuum dried, and then granulated. 1 at the end of this granulation
By mixing 4 g of (4) and 1 g of (5) and tableting with a tableting machine, 1000 tablets containing (1) 30 mg per tablet are produced.

Reference Example 1 4-Methoxysalicylaldehyde (21.0 g), methyl bromoacetate (22.2 g), potassium carbonate (22.9)
g) and N, N-dimethylformamide (150 m
The mixture of l) was stirred at 90-100 ° C for 1 hour. The reaction mixture was poured into ice water, and precipitated crystals of methyl 2-formyl-5-methoxyphenoxyacetate (27.
7 g, 90%) was collected by filtration. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 109
~ 110 ° C.

Reference Example 2 Methyl 2-formyl-5-methoxyphenoxyacetate (27.7 g) 1,8-diazabicyclo [5,4,
A mixture of 0] -7-undecene (40.8 g) and toluene (200 ml) was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, 6N hydrochloric acid was added to the residue,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, 10% hydrochloric acid-methanol (30 ml) was added to the residue, and the mixture was heated at 70 to 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (Mg
After SO ₄ ) the solvent was evaporated and the residue was subjected to silica gel column chromatography. From the portion eluted with chloroform-hexane (1: 2, v / v), methyl 6-
Methoxybenzofuran-2-carboxylate (14.
3 g, 57%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 97-
98 ° C.

Reference Example 3 Boron tribromide (24.9 g) was added dropwise to a solution of methyl 6-methoxybenzofuran-2-carboxylate (18.6 g) in dichloromethane (200 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 day. . The reaction mixture was poured into ice water and ethyl acetate (300 ml) was added. The organic layer is washed with water and dried (M
After gSO ₄ ), the solvent was distilled off, 10% hydrochloric acid-methanol (60 ml) was added to the residue, and the mixture was heated at 70 to 80 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals of methyl 6-hydroxybenzofuran-2-carboxylate (10.75 g) were collected by filtration using diethyl ether-isopropyl ether (2: 1, v / v). The filtrate was concentrated and the residue was subjected to silica gel column chromatography. Diethyl ether-hexane (1: 2,
From the portion eluted with v / v), methyl 6-hydroxybenzofuran-2-carboxylate (1.75 g) was obtained. Total yield 73%. Recrystallized from diethyl ether-isopropyl ether. Colorless prism crystals. Melting point 1
76-177 ° C.

Reference Example 4 Methyl 6-hydroxybenzofuran-2-carboxylate (1.75 g), 4-chloromethyl-5-methyl-2-phenyloxazole (2.00 g), potassium carbonate (1.51 g) and N. A mixture of N-dimethylformamide (40 ml) was stirred at 80 to 90 ° C for 1 hour. The reaction mixture was poured into ice water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (Mg
After SO ₄ ) the solvent was evaporated and the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-chloroform (1:99, v / v), methyl was added.
Crystals of 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carboxylate (3.00 g, 91%) were obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 125-126 [deg.] C.

Reference Example 5 Lithium aluminum hydride (0.285 g) was added to methyl 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carboxylate (2.
70 g) in tetrahydrofuran (40 ml) solution at 0 ° C
Then, the mixture was gradually added and stirred for 1 hour. After carefully adding 1N hydrochloric acid to the reaction mixture, water (300 ml) was further added and the precipitated crystal of 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-methanol was collected by filtration. Recrystallized from chloroform-methanol. A colorless prism crystal (2.17 g, 87%) was obtained. 202-203 ° C.

Reference Example 6 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-methanol (21.0
g), active manganese dioxide (52.0 g) and tetrahydrofuran (800 ml) were stirred at 60 to 65 ° C for 6 hours. The insoluble material was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography.
From the portion eluted with ethyl acetate-chloroform (2:98, v / v), 6- (5-methyl-2-phenyl-4-) was used.
Crystals of oxazolylmethoxy) benzofuran-2-carbaldehyde (14.3 g, 69%) were obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 137-138 [deg.] C.

Reference Example 7 (E) -Ethyl 3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] acrylate (1.30 g) in tetrahydrofuran (50 ml) solution. Palladium-carbon (5%, 0.70
g) was added and catalytically reduced at room temperature and 1 atm. The catalyst was filtered off, sodium borohydride (0.61 g) was added to the filtrate, and methanol (10 ml) was added dropwise under reflux. After heating under reflux for 1 hour, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. Wash the ethyl acetate layer with water,
After drying (MgSO ₄ ), the solvent was evaporated and the residue was subjected to silica gel column chromatography. Ethyl acetate-
From the part eluted with chloroform (1: 5, v / v),
3- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propanol was obtained as an oil (0.90 g, 77%). NMR (δ ppm, CDCl ₃ ): 1.42 (1H,
brs), 1.9-2.1 (2H, m), 2.44.
(3H, s), 2.86 (2H, t, J = 7.5H
z), 3.74 (2H, t, J = 6.5Hz),
5.02 (2H, s), 6.34 (1H, s),
6.92 (1H, dd, J = 8.5, 2Hz), 7.
11 (1H, d, J = 2Hz), 7.35 (1H,
d, J = 8.5 Hz), 7.4-7.5 (3H,
m), 7.95-8.1 (2H, m)

Reference Example 8 Toluene solution of diisobutylaluminum hydride (1
M, 39 ml) to (E) -ethyl 3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2.
-Benzofuranyl] acrylate (5.23 g) was added dropwise to a solution of dichloromethane (200 ml) at 0 ° C. After stirring for 5 hours, the reaction mixture was added with methanol (3 ml)-
Water (10 ml) was added carefully. The insoluble material was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography. Ethyl acetate-chloroform (1: 5, v
/ V), the (E) -3- [6- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
Crystals of 2-benzofuranyl] -2-propen-1-ol (3.90 g, 83%) were obtained. Recrystallized from acetone-hexane. Colorless prism crystals. Melting point 143-14
4 ° C.

Reference Example 9 (E) -3- [6- (5-methyl-2-phenyl-4-)
Oxazolylmethoxy) -2-benzofuranyl] -2-
Propen-1-ol (3.85 g), active manganese dioxide (8.00 g) and dichloromethane (150 m).
The mixture of l) was stirred at room temperature for 2 hours. After the insoluble matter was filtered off, the filtrate was concentrated to give crystals of (E) -3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] acrolein (3.40 g). , 89
%) Was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 132-133
° C.

Reference Example 10 In the same manner as in Reference Example 1, methyl 2-formyl-4-methoxyphenoxyacetate was obtained by the reaction of 5-methoxysalicylaldehyde and methyl bromoacetate. Yield 86%. Recrystallized from acetone-hexane. Colorless prism crystals. Melting point 74-75 [deg.] C.

Reference Example 11 In the same manner as in Reference Example 2, methyl 5-methoxybenzofuran-2-carboxylate was obtained from methyl 2-formyl-4-methoxyphenoxyacetate. yield
71%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 78-79 [deg.] C.

Reference Example 12 In the same manner as in Reference Example 3, methyl 5-hydroxybenzofuran-2-carboxylate was obtained from methyl 5-methoxybenzofuran-2-carboxylate. yield
89%. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 172-173 [deg.] C.

Reference Example 13 Methyl 5-hydroxybenzofuran-2-carboxylate and 4-chloromethyl-5 were prepared in the same manner as in Reference Example 4.
-Methyl-2-phenyloxazole was reacted to give methyl 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carboxylate. Yield 87%. Recrystallized from acetone-ethyl acetate. Colorless prism crystals. Melting point 177-178 [deg.] C.

Reference Example 14 In the same manner as in Reference Example 5, methyl 5- (5-methyl-2)
Reduction of -phenyl-4-oxazolylmethoxy) benzofuran-2-carboxylate gave 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-methanol. Yield 79%. Recrystallized from acetone-methanol. Colorless prism crystals. Melting point
162-163 ° C.

Reference Example 15 In the same manner as in Reference Example 6, 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-methanol was oxidized to give 5- (5-methyl-2). -Phenyl-4-oxazolylmethoxy) benzofuran-2-carbaldehyde was obtained. Yield 42%. Recrystallized from acetone-methanol. Pale yellow prism crystal. Melting point 137
~ 138 ° C.

Reference Example 16 In the same manner as in Example 11, (E) -ethyl 3- [5-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] acrylate is reduced with diisobutylaluminum hydride to give (E) -3- [5-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] -2-propen-1-ol was obtained. Yield 90%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 145-146 [deg.] C.

Reference Example 17 (E) -3- [5- (5-methyl-2-phenyl-4-)
Oxazolylmethoxy) -2-benzofuranyl] -2-
A solution of propen-1-ol (2.00 g) in tetrahydrofuran (100 ml) was added with palladium-carbon (5%,
0.30 g) was added, and catalytic reduction was performed at room temperature and 1 atm. The catalyst was filtered off, the filtrate was concentrated and 3- [5- (5-methyl-
2-Phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propanol was obtained. Yield 93%. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 101-102 [deg.] C.

[0113]

The compound (I) of the present invention or a salt thereof comprises
It has excellent blood glucose and blood lipid lowering effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 417/14 263 C07D 417/14 263 // (C07D 413/14 257: 04 263: 32 307: 79) (C07D 413/14 263: 32 263: 44 307: 79) (C07D 417/14 263: 32 277: 34 307: 79)

Claims (19)

[Claims] 1. A general formula: [In the formula, Is a group capable of releasing a cation (provided that Represents a single bond or a double bond. ), R ¹ is a heterocyclic residue which may be bonded via a carbon chain and may be substituted, R ² is hydrogen, a halogen atom, an optionally substituted hydrocarbon residue, or a protected An optionally protected hydroxyl group or an optionally protected amino group, Y is 2 having 1 to 8 carbon atoms;
Each represents a monovalent or trivalent aliphatic hydrocarbon residue, and the benzene ring may be further substituted. Or a salt thereof. 2. The compound or a salt thereof according to claim 1, wherein the group capable of releasing a cation is a 5-membered heterocyclic group capable of releasing a cation. 3. The compound according to claim 2, wherein the 5-membered heterocyclic group capable of releasing a cation is a 5-membered heterocyclic group having 1 to 4 ring atoms selected from N, O and S. Or its salt. 4. A partial structural formula: The compound or salt thereof according to claim 1, which is 5. A partial structural formula: The compound or salt thereof according to claim 1, which is 6. A partial structural formula: The compound or salt thereof according to claim 1, which is 7. The compound according to claim 7, wherein R ¹ is an optionally substituted heterocyclic residue bonded via a carbon chain, or a salt thereof. 8. The compound or salt thereof according to claim 7, wherein the carbon chain has 1 to 8 carbon atoms. 9. The compound or its salt according to claim 1, wherein the heterocyclic residue is a 5- or 6-membered ring or a condensed ring containing at least one nitrogen atom as a ring-constituting atom. 10. A heterocyclic residue is represented by: [Wherein B ¹ is a sulfur atom, an oxygen atom or NR ⁴ (provided that R ⁴ is a hydrogen atom, a lower alkyl group or an aralkyl group), and B ² is a nitrogen atom or C).
-R ⁵ (R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group), R ³ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group. When it represents a ring group and R ³ and R ⁵ are respectively bonded to adjacent carbon atoms, R ³ and R ⁵ may be bonded to each other to form a condensed ring. ] The compound or its salt of Claim 7 shown by these. 11. A heterocyclic group represented by R ³ or R ⁵ is a 5- or 6-membered ring containing 1 to 3 atoms selected from N, O and S in addition to carbon as a ring-constituting atom. Item 10
The described compound or a salt thereof. 12. The compound according to claim 1, wherein R ² is hydrogen, or a salt thereof. 13. The compound or a salt thereof according to claim 1, wherein Y is —CH ₂ CH ₂ CH ₂ —. 14. An oxazole group in which R ¹ is bonded through a methylene group and which may be substituted with phenyl and / or methyl has a partial structural formula: R ² represents hydrogen, Y represents a divalent or trivalent aliphatic hydrocarbon residue having 1 to 4 carbon atoms, R ¹ —O is at the 6-position of the benzofuran ring, and Y is at the 2-position of the benzofuran ring. The compound according to claim 1, which binds, or a salt thereof. 15. 5- [2- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] ethyl] -1H-tetrazole, 5- [3- [6
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -1H-tetrazole, 5- [4- [6- (5-methyl-2-phenyl-4-oxazoli) Lumethoxy) -2-benzofuranyl] butyl] -1H-tetrazole, 5- [6- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
2-Benzofuranylmethylidene] -2,4-thiazolidinedione, 5- [6- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) -2-benzofuranylmethyl] -2,4-thiazolidinedione, 5- [3- [6-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -2,4-thiazolidinedione, 5- [6- (5-methyl-2-phenyl-4-oxazolyl Methoxy) -2-benzofuranylmethyl] -2,4-oxazolidinedione, 5- [3-
[6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -2-benzofuranyl] propyl] -2,4
-Oxazolidinedione or 5- [3- [5- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
The compound according to claim 1, which is 2-benzofuranyl] propyl] -1H-tetrazole, or a salt thereof. 16. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 17. The pharmaceutical composition according to claim 16, which is a therapeutic agent for diabetes. 18. The method according to claim 1, which is an insulin sensitivity enhancer.
6. The pharmaceutical composition according to 6. 19. The pharmaceutical composition according to claim 16, which is a therapeutic agent for hyperlipidemia.