JPH08104688A - 2,4-thiazolidinedione derivative, its production and medicine composition containing the same - Google Patents

Abstract

PURPOSE: To obtain the new compound having an excellent hypoglycemic action and an excellent blood lipid-lowering action and useful as a diabete-treating agent, a hyperlipidemia-treating agent, a hypertension-treating agent, etc. CONSTITUTION: This compound is represented by formula I (R is hydrocarbon residue, heterocyclic group residue; n is 0,1 ; X is CH, N; Y is divalent hydrocarbon residue; R<1> , R<2> are H, halogen, etc.; L, M are H), e.g. 5-[3-methoxy-4-(5- methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl]-2,4-thiazolinedione. The compound is obtained e.g. by a method for condensing a compound of formula II with 2,4-thiazolinedione in the presence of a base such as a sodium alkoxide in a solvent such as methanol or by a method for hydrolyzing a compound of formula III in the presence of water and a mineral acid in a solvent such as methanol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazolidinedione derivative having a blood glucose and blood lipid lowering action, a method for producing the same, and a therapeutic agent for diabetes containing the same, which is used in the field of medicine. .

[0002]

2. Description of the Related Art Conventionally, various biguanide compounds and sulfonylurea compounds have been used as therapeutic agents for diabetes. However, biguanide compounds are rarely used at present because they cause lactic acidosis, and sulfonylurea compounds have a strong hypoglycemic effect, but often cause severe hypoglycemia, which requires caution in use. . Further, a thiazolidinedione derivative having a blood glucose and lipid lowering action without such drawbacks is known. For example, as a 2,4-thiazolidinedione derivative having a substituent at the 5-position,
JP-A-61-285372, JP-A-1-272573, JP-A-1-272574, JP-A-3-2173, JP-A-4
-66579, JP-A-4-69383, JP-A-6-15.
No. 7522 describes a 2,4-thiazolidinedione derivative having a benzyl or arylmethyl group substituted at the 5-position with a substituted aromatic ring or the like.

[0003]

DISCLOSURE OF THE INVENTION The present inventors
As a result of various studies on the thiazolidinedione derivative, as the 5-position substituent of the 2,4-thiazolidinedione derivative, for example, 2- (substituted phenyl or substituted pyridyl) ethyl group, 3- (substituted phenyl or substituted pyridyl)
A divalent linear or branched carbon chain having a substituted phenyl or substituted pyridyl at the terminal such as a propyl group, a 4- (substituted phenyl or substituted pyridyl) butyl group, or a 5- (substituted phenyl or substituted pyridyl) pentyl group. (In the case of a branched carbon chain, a part of the branched carbon chain and the substituent on the substituted phenyl group may combine to form a ring), a new derivative having a blood glucose and blood lipid lowering effect Found and completed the present invention.

[0004]

Means for Solving the Problems That is, the present invention provides (1) general formula (I):

[0005]

[Chemical 19]

[Wherein R represents a hydrocarbon residue or a heterocyclic residue which may be bonded via a carbon chain and may be substituted, n is 0 or 1 and X is CH or N. , Y each represents a divalent hydrocarbon residue. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and either R ¹ or R ² and a part of Y And may combine with each other to form a ring.

[0007]

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L and M each represent a hydrogen atom,
Alternatively, L and M may be bonded to each other to form one bond. ] The 2,4-thiazolidinedione derivative represented by these or its salt, (2) General formula (I-A1):

[0009]

[Chemical 21]

The 2,4-thiazolidinedione derivative or a salt thereof according to the above (1) represented by the above formula (3) n is 1,
Wherein R is a heterocyclic residue bonded via a carbon chain (1), wherein the 2,4-thiazolidinedione derivative or a salt thereof, (4) carbon chain -CH = CH- or -CH ₂
The 2,4-thiazolidinedione derivative or a salt thereof according to the above (3) which is CH ₂ —, (5) the heterocyclic residue has 1 to 3 oxygen atoms, sulfur atoms, and nitrogen atoms as ring-constituting atoms. The 2,4-thiazolidinedione derivative or a salt thereof according to (3) above, which is a 5- or 6-membered ring, (6) wherein the heterocyclic residue is of the formula

[0011]

[Chemical formula 22]

[In the formula, B ¹ is S, O or NR ⁴ (in the formula, R ⁴ represents a hydrogen atom, a lower alkyl group or an aralkyl group.)
B ² is a nitrogen atom or C—R ⁵ (R ⁵ is a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue), and R ³ is hydrogen. show atom or each optionally substituted hydrocarbon residue or heterocyclic residue, when R ³ and R ⁵ are replaced respectively to adjacent carbon atoms is bonded R ³ and R ⁵ are mutually It may form a condensed ring. ] The 2,4-thiazolidinedione derivative or salt thereof according to (3), which is an aromatic 5-membered ring residue represented by the formula (7):

[0013]

[Chemical formula 23]

[In the formula, R ⁵ and R ⁶ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon residue or a heterocyclic residue, and B represents an oxygen atom or a sulfur atom. ] 2,4- as described in the above (6), which is a group represented by
A thiazolidinedione derivative or a salt thereof, wherein (8) the heterocyclic residue is of the formula

[0015]

[Chemical formula 24]

[In the formula, B represents an oxygen atom or a sulfur atom, R ⁷ and R ⁸ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon residue or a heterocyclic residue, or R ⁷ and R ⁸ may form a condensed ring attached. A group represented by] the (6), wherein the 2,4-thiazolidinedione derivative or a salt thereof, (9) B ¹ is NR ⁴
(Wherein R ⁴ represents a hydrogen atom, a lower alkyl group or an aralkyl group), and B ² is a nitrogen atom (6).
2,4-thiazolidinedione derivative or a salt thereof, (10) 2,4-thiazolidinedione derivative according to (1) above, wherein Y is a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms, or a salt thereof, (11) Y is -CH ₂ CH ₂
-The 2,4-thiazolidinedione derivative or a salt thereof according to (1), (12) the 2,4-thiazolidinedione derivative or a salt thereof according to (1), wherein L and M are each a hydrogen atom; 13) The 2,4-thiazolidinedione derivative or a salt thereof according to the above (1), wherein each of R ¹ and R ² is a hydrogen atom, (14) n is 1,
R represents a heterocyclic residue bonded through a carbon chain having 1 or 2 carbon atoms, Y represents a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms, and L and M each represent a hydrogen atom. Wherein R ¹ and R ² are each a hydrogen atom, and the 2,4-thiazolidinedione derivative or salt thereof according to (2) above, (15) Y is —CH ₂ CH ₂ — above.
4) the 2,4-thiazolidinedione derivative or salt thereof, (16) n is 1, R is a heterocyclic residue bonded through a carbon chain having 1 or 2 carbons, and Y is 1 to 1 carbon atoms. 4, each of which represents a divalent saturated aliphatic hydrocarbon residue, wherein L and M are each a hydrogen atom, R ¹ is a halogen atom, and R ² is a hydrogen atom. Thiazolidinedione derivative or salt thereof, (17) n is 1
R represents a heterocyclic residue bonded through a carbon chain having 1 or 2 carbon atoms, Y represents a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms, and L and M are respectively is a hydrogen atom, in which may a hydroxyl group R ¹ is substituted, the R ² is a hydrogen atom (2), wherein the 2,4-thiazolidinedione derivative or a salt thereof, is (18) n O,
R is a heterocyclic residue bonded via ethylene or vinylene, Y is a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms, L and M are each a hydrogen atom, and R ¹ , The 2,4-thiazolidinedione derivative or salt thereof according to the above (2), wherein each R ² is a hydrogen atom.
(19) 5- [3- [3-methoxy-4- (5-methyl-
2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (1)
2,4-thiazolidinedione derivative or a salt thereof, (20) 5- [3- [3-fluoro-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2. A 2,4-thiazolidinedione derivative or a salt thereof according to the above (1), which is 1,4-thiazolidinedione, (21) 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) ) Phenyl] Butyl]
A 2,4-thiazolidinedione derivative or a salt thereof according to (1) above, which is -2,4-thiazolidinedione;
2) 5- [3- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione, 2,4-thiazolidinedione derivative or salt thereof according to the above (1), (23) 5- [3
-[4- (5-methyl-2-naphthyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione derivative described in (1) above, or a salt thereof, (24) A pharmaceutical composition comprising the 2,4-thiazolidinedione derivative represented by the general formula (I) described in (I) above or a pharmaceutically acceptable salt thereof, (25) an insulin sensitivity enhancer (24) The pharmaceutical composition according to (24), which is a therapeutic agent for diabetes, (26) The pharmaceutical composition according to (24), (27) The pharmaceutical composition according to (24), which is a therapeutic agent for hyperlipidemia. (28) General formula (III):

[0017]

[Chemical 25]

[Wherein each symbol has the same meaning as defined above], which hydrolyzes an iminothiazolidinone compound represented by the general formula (I-B2):

[0019]

[Chemical formula 26]

[In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the 2, 4-thiazolidinedione derivative represented by these (29) General formula (I-B1):

[0021]

[Chemical 27]

[Wherein each symbol has the same meaning as defined above] to reduce the compound represented by the general formula (I-B2)
a):

[0023]

[Chemical 28]

[In the formula, R ′ represents a hydrocarbon residue or a heterocyclic residue which may be bonded via a saturated carbon chain and may be substituted, and Y ¹ represents a divalent saturated hydrocarbon residue. Shows the group
Either R ¹ or R ² and a part of Y ¹ may be bonded to each other to form a ring.

[0025]

[Chemical 29]

The other symbols have the same meanings as described above. ] The manufacturing method of the 2, 4-thiazolidinedione derivative represented by these, (30) General formula (V):

[0027]

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[Wherein each symbol is as defined above] and a compound represented by the general formula (VI): R "-CH ₂ -Q (VI) [wherein R" is a heterocyclic residue, Q represents a leaving group. ] The compound represented by general formula (I-D1) characterized by reacting with:

[0029]

[Chemical 31]

[In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the 2, 4-thiazolidinedione derivative represented by these is provided.

The compounds represented by the above general formula (I) include compounds represented by the following formula.

[0032]

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[In the formula, each symbol has the same meaning as described above. ] Considering the strength and toxicity of the compound, the general formula
Among the compounds represented by (I-A1), (I-A2) and (I-A3), the compounds represented by (I-A1) and (I-A2) are preferable, and the compounds represented by (I-A1) Is particularly preferable. In the above general formula (I), when L and M are bonded to each other to form one bond, the general formula (I) is represented by the general formula (I-B1):

[0034]

[Chemical 33]

[In the formula, each symbol has the same meaning as described above. When each of L and M represents a hydrogen atom, the general formula (I) is represented by the general formula (I-B2):

[0036]

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[In the formula, each symbol has the same meaning as described above. ] Means The compound represented by the general formula (I-B1) has a double bond at the 5-position of the 2,4-thiazolidinedione ring in (E) form and (Z) form. The general formula (I-
The compound represented by B2) includes (R) and (S) optically active isomers due to the asymmetric carbon at the 5-position of the 2,4-thiazolidinedione ring. The compound represented by the general formula (I-B2) is an optical isomer of these (R) and (S) isomers,
And racemic.

Among the compounds represented by the general formulas (I-B1) and (I-B2), the compound represented by the general formula (I-B2) is preferable. In the above general formula (I), when one or both of R ¹ and R ² is a hydrocarbon residue, one of the hydrocarbon residues and a part of Y are bonded to each other to form a ring. May be. When R ¹ is bonded to a part of Y, specific examples thereof include compounds represented by the following general formula.

[0039]

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[Wherein Y'represents a divalent hydrocarbon residue,
Other symbols have the same meanings as above. ] Among the above compounds (I-C1) to (I-C4), (I-C2)
Compounds represented by and (I-C4) are preferred.

In the general formula (I), the heterocyclic residue which may be bonded via the carbon chain represented by R is a heterocyclic residue directly bonded to-(O) n-. Alternatively, a heterocyclic residue may be bonded to-(O) n- via a carbon chain, but a compound bonded via a carbon chain is preferable.
The carbon chain is preferably one having 1 to 8 carbon atoms, which may be linear or branched, and may be saturated or unsaturated. Specific examples of the carbon chain include those similar to the divalent hydrocarbon residue represented by Y described later. The carbon chain is preferably ethylene (-CH ₂ C
H ₂ -) or vinylene (-CH = CH-). The heterocyclic residue is preferably 1) a 5- or 6-membered ring or a condensed ring, and 2) a heterocyclic residue having at least one nitrogen atom as a ring-constituting atom (nitrogen-containing heterocyclic residue).
And 3) the ring is preferably an aromatic ring having an unsaturated bond, and 4) the ring may have two or more nitrogen atoms as ring-constituting atoms, and in addition to nitrogen, an oxygen atom,
It may have a hetero atom such as a sulfur atom 5)
It may have a substituent at any position on the ring. Specific examples of the heterocyclic residue include, for example, pyrrolyl (eg, 2-pyrrolyl), pyrazolyl (eg, 3-pyrazolyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl), triazolyl (eg, 1,2 , 3-triazol-4-yl, 1,
2,4-triazol-3-yl), tetrazolyl, oxazolyl (eg, 2-oxazolyl, 4-oxazolyl),
Thiazolyl (eg, 2-thiazolyl, 4-thiazolyl) and the like can be mentioned. These heterocyclic residues may have one or more substituents at any position on the ring, and examples of the substituents include a hydrocarbon residue, a heterocyclic group or an amino group. Further, it may have a substituent.

The hydrocarbon residue as a substituent of the heterocyclic residue in R includes an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue, and an araliphatic. A hydrocarbon residue and an aromatic hydrocarbon residue are mentioned. Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, Saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms such as 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-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, Three
-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 residues having 2 to 8 carbon atoms (eg, alkenyl group, alkynyl group), preferably those having 2 to 4 carbon atoms. Examples of the alicyclic hydrocarbon residue include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cycloheptyl (eg, cycloalkyl group), preferably having 5 or 6 carbon atoms, and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl , 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3
Examples thereof include unsaturated cycloaliphatic hydrocarbon residues having 5 to 7 carbon atoms (eg, cycloalkenyl group) such as -cycloheptenyl and 2,4-cycloheptadienyl, preferably those having 5 or 6 carbon atoms. As the alicyclic-aliphatic hydrocarbon residue, those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded (eg, cycloalkyl-alkyl group, cycloalkenyl-alkyl group), Having 4 to 9 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl,
Cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3
-Cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like. Examples of the 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-naphthylethyl and the like The naphthylalkyl of 11-13 is mentioned. Examples of the aromatic hydrocarbon residue include phenyl and naphthyl (α-naphthyl, β-naphthyl).

The heterocyclic group as a substituent of the heterocyclic residue in R includes N, O, S other than carbon as atoms constituting the ring.
It is a group that is a 5- or 6-membered ring containing 1 to 3 selected from the group bonded via carbon, and specific examples thereof include thienyl (eg, 2-thienyl, 3-thienyl), furyl (eg, , 2-furyl, 3-furyl), pyridyl (eg, 2-
Pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl
(Example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),
Unsaturated pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, etc.), Piperidinyl (eg, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl), pyrrolidinyl
Examples thereof include saturated ones (eg, 2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (eg, 2-morpholinyl, 3-morpholinyl), tetrahydrofuryl (eg, 2-tetrahydrofuryl, 3-tetrahydrofuryl).

The amino group as a substituent of the heterocyclic residue in R may be substituted, and examples of the substituted amino group include N-mono-substituted amino group and N, N-di-substituted amino group. . The N-mono-substituted amino group means an amino group having one substituent, and examples of the substituent include, for example, a lower alkyl group (eg, methyl, ethyl, propyl, butyl, i-butyl, t-group). -Butyl and other carbon atoms 1
~ 4), cycloalkyl groups (eg, cyclopentyl,
C3 to C7 such as cyclohexyl), aryl group
(Eg, phenyl, naphthyl, etc.), aromatic heterocyclic group (eg, pyridyl, thienyl, furyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (eg, piperidinyl, pyrrolidinyl, morpholinyl, etc.), aralkyl group (eg. , Benzyl,
Phenethyl etc.), acyl group (eg athicel, propionyl etc.), carbamoyl group, N-monosubstituted carbamoyl 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, Methoxy, ethoxy, propoxy, butoxy, etc. having 1 to 4 carbon atoms), aralkyloxy group
(Eg, benzyloxy, phenethyloxy, naphthylmethyloxy, etc.) and the like.

The N, N-disubstituted amino group means an amino group having two substituents, and one example of the substituents is the substituent in the above-mentioned "N-monosubstituted amino group". Similar examples are mentioned, and the other examples include, for example, a lower alkyl group, a cycloalkyl group, an aryl group, an aralkyl group and the like. Further, two substituents may combine with a nitrogen atom to form a cyclic amino group, and examples of such a cyclic amino group include, for example, 1-azetidinyl, pyrrolidino, piperidino, morpholino, piperazino and 4-position. Lower alkyl groups (eg, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl), aralkyl groups (eg, benzyl, phenethyl, naphthylmethyl, etc.), aryl groups
(Eg, phenyl, 4-methylphenyl, naphthyl, etc.) and the like.

The hydrocarbon residue or the heterocyclic group as a substituent on the heterocyclic residue which may be bonded via the carbon chain represented by R has a substituent at any position. May be. When the hydrocarbon residue contains an alicyclic group or when the heterocyclic group is saturated, a lower alkyl group having 1 to 3 carbon atoms (eg, methyl group) is present on the ring (including N atom). ,
It may have 1 to 3 ethyl, propyl, isopropyl). When the hydrocarbon residue contains an aromatic hydrocarbon residue or when the heterocyclic group is unsaturated, it has 1 to 4 substituents which are the same or different on the ring. The substituent may be, for example, halogen (fluorine, chlorine, iodine), hydroxy, cyano, nitro,
Trifluoromethyl, lower alkoxy (eg, methoxy,
Ethoxy, propoxy, isopropoxy, butoxy etc. having 1 to 4 carbon atoms), lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl etc. having 1 to 4 carbon atoms)
4), lower alkoxycarbonyl (eg, those having 2 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl), lower alkylthio (eg, those having 1 to 3 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, etc. ), A lower alkylamino group (having 1 carbon atom such as methylamino, ethylamino, dimethylamino, etc.
~ 4)) and the like.

The heterocyclic residue, which may be bonded via the carbon chain represented by R, has two or more hydrocarbon residues as its substituents, and these hydrocarbon residues are heterocyclic rings with each other. When substituting at the adjacent position above, they may be joined together to form a fused 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-like hydrocarbon residue, for example, _{-CH 2 CH 2 CH 2 -,} - CH 2 CH 2 CH 2 C
_{H 2 -, - CH 2 CH} 2 CH 2 CH 2 CH 2 -, - CH = CHC
_{H 2 -, - CH = CH} -CH = CH -, - CH = CH-C
_{H = CH-CH 2 -,} - CH = CH-CH 2 CH 2 CH 2 -
And the like. Among the heterocyclic residues in the heterocyclic residue which may be bonded via the carbon chain represented by R, the general formula

[0048]

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(Wherein B ¹ is a sulfur atom, an oxygen atom or NR ⁴ [wherein R ⁴ is a hydrogen atom, a lower alkyl group (eg, those having 1 to 3 carbon atoms such as methyl or ethyl)] or an aralkyl group (eg, , Benzyl, phenethyl, etc.). A group represented by], B ² represents a nitrogen atom or C-R ⁵ (R ⁵ is a hydrogen atom or each optionally substituted hydrocarbon residue or heterocyclic group.). R ³ represents a hydrogen atom or an optionally substituted hydrocarbon residue or heterocyclic group, and when R ³ and R ⁵ are respectively bonded to adjacent carbon atoms, R ³ and R ⁵ are mutually It may combine with each other to form a condensed ring. } Is preferable. R ³ , R ⁵
The hydrocarbon residue represented by, the heterocyclic group, and the substituents of these groups are the hydrocarbon residue and the heterocyclic group described above as the substituents of the heterocyclic residue which may be bonded via the carbon chain represented by R. It is the same as the ring group and the substituents of those groups. The heterocyclic residue is attached via a possible atom on the ring, preferably a group attached via the carbon atom adjacent to the nitrogen atom. For example, when B ¹ is NR ⁴ and 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

[0050]

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[In the formula, R ⁵ has the same meaning as described above, and R ⁶ and R
⁷ and R ⁸ are the same or different and each represents hydrogen or a hydrocarbon residue or a heterocyclic group which may be substituted, and R ⁷ and R ⁸ may combine to form a condensed ring.
B represents an oxygen atom or a sulfur atom. ] The thiazolyl or oxazolyl shown by these is preferable. R ⁶ , R ⁷ , R
^The hydrocarbon residue represented by ⁸ and the heterocyclic group and their substituents are the above-mentioned hydrocarbon residue, It is similar to the ring residue and the substituents thereof. This R ⁷ , R ⁸
May form a condensed ring, and in this case as well, similar to those described as the condensed ring formed when the heterocyclic residue has two hydrocarbon residues as the substituents at positions adjacent to each other. Is.

In the general formula (I), the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R is the same as the above-mentioned hydrocarbon residue in the heterocyclic residue. Can be mentioned. Further, examples of the substituent include the same as the above-mentioned substituents in the hydrocarbon residue or the heterocyclic residue. R is preferably a heterocyclic group which may be bonded via a carbon chain. The ring having X as its constituent atom is a benzene ring when X is CH and a pyridine ring when X is N. CH is preferably CH. n represents 0 or 1, and when n is 0, it means that R is directly bonded to a benzene ring or a pyridine ring, and when n is 1, it is bonded through one oxygen atom. Means that.
n is preferably 1. In the general formula (I), R ¹ and R ²
The halogen atom represented by, the optionally substituted hydroxyl group, and the hydrocarbon residue in the optionally substituted hydrocarbon residue are a heterocyclic group which may be bonded via a carbon chain represented by R. The thing mentioned as the substituent in a ring group is mentioned.

The divalent hydrocarbon residue represented by Y may be either aliphatic or aromatic, but is preferably aliphatic. The divalent hydrocarbon residue may be linear or branched and may be saturated or unsaturated, but is preferably one having 1 to 7 carbon atoms. Specific examples thereof include _{-CH 2 -, - CH (CH} 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 -
CH = CH -, - C ( CH 3) = CH -, - CH = CH-C
_{H 2 -, - C (C} 2 H 5) = CH -, - CH 2 -CH = CH-C
_{H 2 -, - CH 2 -CH} 2 -CH = CH-CH 2 -, - CH =
_{CH-CH = CH-CH 2} -, - CH = CH-CH = CH
-CH = CH-CH ₂ - may be of unsaturated such.
Among them, saturated ones having 1 to 4 carbon atoms are more preferable, and -C
H ₂ CH ₂ - is most preferred. In the formula (I-C5), Y'means one having 1 to 5 carbon atoms in the definition of Y. Examples of the divalent aromatic hydrocarbon residue represented by Y include phenylene and naphthylene, and phenylene is preferable.

Preferred specific examples of the compound represented by the formula (I) include the following compounds. 5- [3- [3-
Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (Example 9), 5- [3- [3-fluoro-
4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (Example 10), 5- [3- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) phenyl] butyl] -2,4-thiazolidinedione (Example 14), 5-
[3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (Example 18), and 5- [3- [4- (5 −
Methyl-2-naphthyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (Example 22).

The salt of compound (I) of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a base. Examples thereof include salts with acidic or acidic amino acids. 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. Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic salts include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. To be Among these salts, sodium salt and potassium salt are most preferable.

The compound (I) of the present invention (that is, the compound represented by the formula (I); hereinafter, compounds represented by other formulas may be abbreviated in the same manner) or a pharmaceutically acceptable compound thereof. Oxalate has a low toxicity and has a blood glucose and blood lipid lowering action and an insulin sensitivity enhancing action, and is used as it is or in a mixture with a pharmacologically acceptable carrier, excipient, bulking agent and the like known per se, in a mammal ( (Eg, human, mouse, rat, cat, dog, rabbit, cow, pig, sheep, monkey, etc.), it can be used as a therapeutic agent for diabetes and a hypotensive agent. The compound (I) of the present invention has low toxicity. For example, when the compound of Example 14 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 relative to the control. I couldn't do it.
The method of administration is usually used orally as tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, but in some cases parenterally as injections, suppositories, pellets and the like. The dosage is 0.0 when administered orally to an adult (body weight of about 50 kg) per day.
It is 5 to 10 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 as 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. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Suitable 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, 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 polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, and the like; for example, polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Hydrophilic polymers such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Preferable examples of the isotonicity 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. Preferred examples of the soothing agent 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 production method of the compound (I) of the present invention is described below.

Method A

[Chemical 38]

[Wherein each symbol has the same meaning as defined above] Compound (I-B1) is produced by condensation of compound (II) and 2,4-thiazolidinedione. This reaction is carried out in a solvent in the presence of a base. As the solvent, methanol, ethanol, propanol, isopropanol, 2
-Alcohols such as methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide and acetic acid. Examples of the base include sodium alkoxide (eg, sodium methoxide, sodium ethoxide, etc.), potassium carbonate,
Secondary amines such as sodium carbonate, sodium hydride, sodium acetate, piperidine, piperazine, pyrrolidine, morpholine, diethylamine and diisopropylamine are used. The amount of 2,4-thiazolidinedione used is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (II). The amount of the base used is the compound (I
0.01-5 molar equivalents relative to I), preferably 0.05
~ 2 molar equivalents. This reaction is carried out at 0 to 150 ° C., preferably 20 to 100 ° C. for 0.5 to 30 hours.
Compound (I-B1) produced by this method 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. Also, regarding the double bond at the 5-position of the 2,4-thiazolidinedione ring, it may be obtained as a mixture of the (E) form and the (Z) form.

Method B

[Chemical Formula 39]

[In the formula, each symbol has the same meaning as described above. The compound (I-B2) is produced by hydrolyzing the compound (III). Hydrolysis of compound (III) is usually carried out in a suitable solvent in the presence of water and a mineral acid. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and 2-methoxyethanol, dimethyl sulfoxide, sulfolane, and mixed solvents thereof. Examples of the mineral acid include hydrochloric acid, hydrobromic acid, sulfuric acid and the like, and the amount thereof used is 0.1 to 20 molar equivalents, preferably 0.2 to 10 molar equivalents, relative to compound (III). The amount of water added is usually in large excess with respect to compound (III). The reaction temperature is usually 20 to 150 ° C, preferably 50 to 120 ° C,
The reaction time is 0.5 to 50 hours. The 2,4-thiazolidinedione derivative (I-B2) thus obtained is 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. be able to.

Method C

[Chemical 40]

[In the formula, R ′ represents a hydrocarbon residue or a heterocyclic residue which may be bonded via a saturated carbon chain and may be substituted, and Y ¹ represents a divalent saturated aliphatic carbon group. It represents a hydrogen residue and may be bonded to either R ¹ or R ² to form a ring.

Embedded image Other symbols have the same meanings as above. ]

The linear or branched divalent saturated aliphatic hydrocarbon residue having 1 to 7 carbon atoms represented by Y ¹ is a saturated divalent aliphatic hydrocarbon residue represented by Y. It is a thing.
The optionally substituted hydrocarbon residue represented by R ′ is
The hydrocarbon residue represented by R has a saturated carbon chain. The heterocyclic residue which may be bonded via a saturated carbon chain represented by R ′ is a heterocyclic residue which may be bonded via a carbon chain represented by R and whose carbon chain is saturated Is. The compound (I-B2a) can be produced by subjecting the compound (I-B1) to a reduction reaction. 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, methanol, ethanol, propanol, isopropanol, 2
-Alcohols such as methoxyethanol, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, etc. Halogenated hydrocarbons, ethyl acetate, acetic acid, N, N-dimethylformamide, or a mixed solvent 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 2,4-thiazolidinedione derivative (I-B2a) thus obtained can be isolated and purified by known separation and purification means, for example, concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method D

Embedded image

[In the formula, D is lower alkoxy, lower alkylthio or lower acyloxy, and other symbols have the same meanings as described above. Examples of the lower alkoxy group represented by D include those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, and examples of the lower alkylthio group include carbon groups such as methylthio, ethylthio, propylthio, isopropylthio and butylthio. The lower acyloxy having 1 to 4 carbon atoms includes those having 1 to 4 carbon atoms such as acetyloxy and propionyloxy. Two D's may combine with each other to form ethylenedioxy, propylenedioxy, dithiotrimethylene and the like. That is, -CH (D) ₂ of formula (IV) means a protected aldehyde group. Compound (IV) is condensed with 2,4-thiazolidinedione to give compound (IB
1) is manufactured. This condensation reaction is carried out by the compound (I
It is carried out similarly to the reaction of I) with 2,4-thiazolidinedione.

Method E

[Chemical 43]

[In the formula, Q is a leaving group, and other symbols are as defined above. Examples of the leaving group represented by Q include a halogen atom (chlorine, bromine, iodine), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and the like. Compound (V) and compound (VI) are condensed to produce compound (I-D1). 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, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane, ketones such as acetone and 2-butanone, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and these A mixed solvent may be used. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N, N-dimethylaniline, metal hydrogen such as sodium hydride and potassium hydride. Compound, sodium ethoxide, sodium methoxide, potassium t-butoxide and the like. The amount of these bases used is preferably about 1 to 5 molar equivalents relative to compound (V). This reaction is usually -50 ° C to 150 ° C.
It is preferably carried out at about -10 ° C to 100 ° C. The reaction time is 0.5 to 30 hours. The 2,4-thiazolidinedione derivative (I-D1) thus obtained is 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. can do. The raw material (II) of Method A is produced, for example, by Method F.

Method F

[Chemical 44]

[Wherein R ⁹ and R ¹⁰ are the same or different and each represents a lower alkyl group, R ¹¹ represents a hydrogen atom or a lower alkyl group, q represents 0, 1 or 2, and other symbols are the same as defined above. It is significant. ] The lower alkyl group represented by R ⁹ , R ¹⁰ and R ¹¹ includes, for example, methyl, ethyl, propyl,
Examples thereof include those having 1 to 4 carbon atoms such as isopropyl and butyl. In this method, first, a carbonyl derivative (VII) is reacted with a phosphonoacetic acid derivative or an ω-phosphonocarboxylic acid derivative (VIII) to give an unsaturated ester derivative (IX).
To manufacture. The reaction of (VII) and (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, N, N-dimethylformamide, dimethyl sulfoxide and chloroform, Examples thereof include dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and a mixed solvent thereof.
Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, pyridine, triethylamine, N,
Examples thereof 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. The amount of these bases used is compound (V
About 1 to 5 molar equivalents relative to III) are preferred. The amount of compound (VIII) used is 1 to 5 with respect to compound (VII).
The molar equivalent is preferably about 1 to 3 molar equivalents. This reaction is generally -50 ° C to 150 ° C, preferably about -10 ° C to
It is carried out at 100 ° C. The reaction time is 0.5 to 30 hours.

Then, the compound (IX) is subjected to a reduction reaction to produce an alcohol derivative (X). 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 compound (IX) with a reducing agent. As a reducing agent, an alkali metal borohydride
(Eg, sodium borohydride, lithium borohydride, etc.), metal hydrogen complex compounds such as lithium aluminum hydride, diborane and the like can be mentioned, but it is advantageously carried out by using diisobutylaluminum hydride. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, chloroform,
Carbon tetrachloride, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2 -Alcohols such as methoxyethanol, amides such as N, N-dimethylformamide, and mixed solvents thereof are appropriately selected and used according to the type of reducing agent. The reaction temperature is -20 ° C to 150 ° C, particularly preferably 0 ° C to 100 ° C, and the reaction time is about 1 to 24 hours.

Then, the compound (X) is subjected to an oxidation reaction to produce an unsaturated carbonyl derivative (II-1). 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 (X) 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 an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane. Ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, or a mixed solvent thereof are appropriately selected and used depending on the kind of the oxidizing agent. Reaction temperature is -20 ℃
~ 150 ° C, particularly 0 ° C to 100 ° C is suitable, and the reaction time is about 1 to 24 hours. Then, the compound (II
The compound (II-2) is produced by subjecting -1) to a reduction reaction. This reduction reaction is carried out in the same manner as in method C.

Aldehyde derivative thus obtained
(II-1) and (II-2) 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. F
The raw material compound (VII) of the method is, for example, chemical and
Pharmaceutical & Buretin (Chemical & P
harmaceutical Bulletin), 39, 1440 (19)
1990), JP-A-4-225978, JP-A-61-85.
372, JP-A-61-271287, JP-A-63-13
9182, JP-A-3-170478, WO911949.
6-A1, EP-428312-A, JP-A-1-299.
289 and JP-A-63-230689. A part of the aldehyde derivative (VII-1) can also be synthesized by the G method, for example.

Method G

Embedded image

[In the formula, Q ′ represents a halogen atom, and other symbols have the same meanings as described above. Examples of the halogen atom represented by Q ′ include chlorine, bromine and iodine.
In this method, the compound (XI) is treated with butyllithium, sec.-butyllithium, t.-butyllithium, methyllithium, phenyllithium, phenylmagnesium bromide, etc., and then reacted with N, N-dimethylformamide to give compound (XI). VII-1) is produced. The raw material (XI) for Method G can be produced, for example, by Method H.

Method H

Embedded image

[In the formula, 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 and iodine.
In this method, phosphonium salt (XII) and aldehyde derivative
Compound (XI-1) is produced by condensing (XIII). This condensation reaction is carried out by compound (VII) and compound (VI) in Method G.
It is carried out in the same manner as the reaction of II). A part of the intermediate (IX) in Method F is also produced, for example, by Method I.

Method I

[Chemical 47]

[In the formula, each symbol has the same meaning as described above. This reaction is carried out in the presence of a base in a suitable solvent. 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, ethyl acetate,
Acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof can be mentioned. Examples of the base include alkali metal hydroxides (such as sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (such as magnesium hydroxide and calcium hydroxide), and alkali metal carbonates (such as sodium carbonate). , Potassium carbonate, etc., alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate etc.), alkali metal acetates (eg sodium acetate, potassium acetate) Etc.), trialkylamine (eg, trimethylamine, triethylamine, etc.), picoline, N
-Methylpyrrolidine, N-methylmorpholine, 1,5-
Such as diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2.2.2] non-5-ene, 1,8-diazabicyclo [5,4,0] -7-undecene. An organic base is mentioned. The amount of these bases used is preferably about 1 to 5 molar equivalents relative to compound (XV). This reaction is usually -20
C. to 150.degree. C., preferably about -10.degree. C. to 100.degree.

The raw material compound (XIV) of Method I can be synthesized by, for example, Chemical & Pharmaceutical Bulletin,
Volume 30, Pages 3563 (1982); Chemical and
Pharmaceutical & Buretin (Chemical & P
harmaceutical Bulletin), 30, 30580 (19)
1982); Chemical & Pharmaceutical Bulleti (Chemical & Pharmaceutical Bulleti)
n), 32, 2267 (1984); Arzneimitel-Forsung / Drug Research (Arzneimi
ttel-Forschung / Drug Research), 40, 37
Page (1190); Journal of Medicinal Chemistry,
35, 2617 (1992), JP-A-61-267
580, JP-A-61-286376, JP-A-61-85
372, Japanese Examined Patent Publication No. 2-307979, JP-A-62-5981.
Etc. Compound (III) used in Method B
Is manufactured by the J method, for example.

J method

Embedded image

[In the formula, each symbol has the same meaning as described above. ] By reacting compound (XV) with thiourea,
(III) is produced. This reaction is usually alcohol
(Eg, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), dimethyl sulfoxide, N, N-dimethylformamide, sulfolane and the like. The reaction temperature is generally 20 ° C to 180 ° C, preferably 50 ° C.
C to 150C. The amount of thiourea used is compound (XV)
To 1 to 2 molar equivalents. In this reaction, hydrogen halide is produced as a by-product as the reaction progresses. To capture this, a deoxidizing agent such as sodium acetate or potassium acetate may be added to carry out the reaction. The deoxidizing agent is usually used in 1 to 1.5 molar equivalents relative to compound (XV). Compound (III) is produced by such a reaction and can be isolated if desired. However, compound (III) may be immediately introduced into the acid hydrolysis step of the present invention without isolation. The raw material (IV) of the method D and the raw material (II) of the method A are also produced, for example, by the method K.

K method

[Chemical 49]

[In the formula, m represents an integer of 1 to 6, and other symbols have the same meanings as described above. In this method, first, the compound (VI
Compound (IV-1) is produced by condensing I) with compound (XVI). This condensation reaction is performed by the compound (VII) in Method F.
And compound (VIII). Then, the compound (IV-1) is subjected to a reduction reaction to give the compound (IV-
2) This reduction reaction is carried out by the compound (IB
It is carried out in the same manner as the catalytic reduction reaction of 1). Compound (IV
-2) can be further deprotected by treatment with an acid in a water-containing solvent to give an aldehyde derivative (II-3). Examples of the solvent include alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran and dioxane, acetonitrile, acetone, 2-butanone, a mixed solvent of acetic acid and water. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and p-toluenesulfonic acid.
The raw material (XV) of the J method is produced, for example, by the L method.

L method

Embedded image

[In the formula, each symbol has the same meaning as described above. ] Compound (XVI) is reacted with a halogenating agent to give Compound (XV)
To manufacture. As the halogenating agent, hydrochloric acid, thionyl chloride, phosphorus tribromide and the like are preferably used. In this case, the compound (XV) in which Q ′ is chlorine or bromine is produced. This reaction is performed in an appropriate inert solvent (for example, benzene,
Toluene, xylene, chloroform, dichloromethane, etc.) or using an excess halogenating agent as a solvent-1
It is carried out at 0 to 80 ° C. The amount of halogenating agent used is compound
It is 1 to 20 molar equivalents relative to (XVI). Compounds (X) in which Q'generated as described above is chlorine or bromine
1) to 1) sodium iodide or potassium iodide
Compound in which Q'is iodine when reacted at 1.5 molar equivalents
(XV) can also be produced. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol or ethanol at a reaction temperature of 20 to 80 ° C.
The raw material (XVI) of the L method is produced, for example, by the M method.

Method M

[Chemical 51]

[Wherein Y ² is a bond or a divalent aliphatic hydrocarbon residue having 1 to 6 carbon atoms, Y ³ is a bond or a divalent saturated aliphatic hydrocarbon having 1 to 6 carbon atoms] Represents a residue, and other symbols have the same meanings as described above. ] The divalent aliphatic hydrocarbon residue having 1 to 6 carbon atoms represented by Y ² is 2 represented by Y
A valent aliphatic hydrocarbon residue having 1 to 6 carbon atoms. Y 2 divalent saturated aliphatic hydrocarbon residue represented by ³ Y ²
The saturated one is shown in.

In this method, compound (II-4) is condensed with pyruvic acid to produce compound (XVII). Compound (II
-4) and the condensation reaction of pyruvic acid are the compounds in Method A.
The reaction is carried out in a hydrous alcohol in the presence of a base similar to the reaction of (II) with 2,4-thiazolidinedione. Then, the compound (XVII) was subjected to an esterification reaction to give the compound (XVI).
II) is produced. This esterification reaction can be carried out by a method known per se, for example, a method of directly reacting the compound (XVII) with an alcohol (R ¹⁰ OH) in the presence of an acid or esterification or the reactivity of the compound (XVII). Derivatives such as acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides or mixed acid anhydrides (e.g., anhydrides with dimethyl carbonate, anhydrides with diethyl carbonate, anhydrides with diisobutyl carbonate, etc.) Alcohol (R ¹⁰ OH)
And the like are appropriately used. Then the compound
Compound (XIX) is produced by subjecting (XVIII) to a catalytic reduction reaction. This catalytic reduction reaction is carried out in the same manner as in Method C. Then, the compound (XIX) was subjected to a reduction reaction to give the compound (XVI).
-1) is manufactured. This reduction reaction can be carried out by a method known per se. For example, reduction with metal hydride,
Reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used. That is, this reaction is carried out by treating compound (XIX) with a reducing agent. As the reducing agent, an alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), a metal hydride complex compound such as lithium aluminum hydride, a metal hydride such as sodium hydride, an organic tin compound (hydrogen (Triphenyltin fluoride, etc.), nickel compounds, metals such as zinc compounds and metal salts, catalytic reducing agents using transition metal catalysts such as palladium, platinum, rhodium, and hydrogen, and diborane, and the like. It is advantageously performed by using an alkali metal (eg, sodium borohydride, lithium borohydride, etc.). This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane. Ethers such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2
-Alcohols such as methoxyethanol, amides such as N, N-dimethylformamide, and mixed solvents thereof are appropriately selected and used according to the kind of the reducing agent. The reaction temperature is -20 ° C to 150 ° C, especially 0 ° C to 10 ° C.
0 degreeC is suitable and reaction time is about 1 to 24 hours.

[0090]

INDUSTRIAL APPLICABILITY Compound (I) or a salt thereof according to the present invention has an excellent blood glucose and blood lipid lowering action, as illustrated in the following experimental examples. Experimental Example Blood glucose and lipid lowering action in mice The test compound was added to powder feed (CE-2, CLEA Japan, Inc.) at 0.0.
The mixture was mixed with 05% and was allowed to freely give KKA ^y mice (9 to 14 weeks old) for 4 days. During this time, water was given freely. Blood was collected from the orbital vein, and plasma was used to enzymatically analyze glucose and triglyceride, respectively, with iatrochem-G.
LU (A) Kit (Yatron) and Iatro-MA70
It was quantified using a 1TG kit (Yatron). The value of each drug administration group is the reduction rate (%) compared to the drug non-administration group
And is shown in Table 1.

[0091]

[Table 1]

As described above, the 2,4-thiazolidinedione derivative (I) according to the present invention has excellent blood glucose and lipid lowering effects, and is useful as a drug such as a therapeutic agent for diabetes, a therapeutic agent for hyperlipidemia and a therapeutic agent for hypertension. Is.

[0093]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1 3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) cinnamaldehyde (2.4 g), 2,4-thiazolidinedione (1.8 g), piperidine (0.192 g) and ethanol ( A mixture of 50 ml) was heated under reflux for 5 hours.
After cooling, the precipitated 5- [3- (5-methyl-2-phenyl-
4-Oxazolylmethoxy) cinnamylidene] -2,4
Crystals of thiazolidinedione (1.3 g, 42%) were filtered off. Recrystallized from ethyl acetate-methanol. Pale yellow prism crystal. Melting point 226-227 [deg.] C. Elemental _{analysis: C 23 H 18 N 2 O} 4 S Calculated: C, 66.01; H, 4.34 ; N, 6.69 Found: C, 65.91; H, 4.26 ; N , 6.64 Examples 2 to 4 In the same manner as in Example 1, the compounds in Table 2 were obtained.

[0094]

[Table 2]

Example 5 In the same manner as in Example 1, (E) -4- [2- (5-methyl-
2-phenyl-4-oxazolyl) vinyl] cinnamaldehyde is condensed with 2,4-thiazolidinedione to give (E)-
5- [4- [2- (5-Methyl-2-phenyl-4-oxazolyl) vinyl] cinnamylidene] -2,4-thiazolidinedione was obtained. Yield 33%. Recrystallized from N, N-dimethylformamide-water. Yellow needles. Melting point 300 ° C
that's all. Example 6 In the same manner as in Example 1, (E) -3- [6- (5-methyl-
2-phenyl-4-oxazolylmethoxy) -2-naphthyl] acrolein and 2,4-thiazolidinedione are condensed to give 5- [3- [6- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) -2-naphthyl] propenylidene] -2,4-thiazolidinedione was obtained. Yield 73%.
Recrystallized from chloroform-methanol. Yellow prism crystal. Melting point 267-268 [deg.] C.

Example 7 5- [3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) cinnamylidene] -2,4-thiazolidinedione (0.90 g), palladium-carbon (5%, 2 A mixture of 0.0 g) and chloroform (200 ml) -methanol (50 ml) was subjected to catalytic reduction at 1 atm and room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5- [3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione. (0.58g,
64%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 123-124 [deg.] C. Elemental _{analysis: C 23 H 22 N 2 O} 4 S Calculated: C, 65.38; H, 5.25 ; N, 6.63 Found: C, 65.49; H, 5.26 ; N , 6.74 Examples 8 to 10 The compounds in Table 3 were obtained in the same manner as in Example 7.

[0097]

[Table 3]

Example 11 (E) -5- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) vinyl] cinnamylidene] -2,4-thiazolidinedione was prepared in the same manner as in Example 7. By catalytic reduction of 5- [3- [4- [2- (5-methyl-2-phenyl-4-
Oxazolyl) ethyl] phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 22%. Recrystallized from ether-hexane. Colorless prism crystals. Melting point 99-100
° C. Example 12 In the same manner as in Example 7, 5- [3- [6- (5-methyl-
2- [Phenyl-4-oxazolylmethoxy) -2-naphthyl] propenylidene] -2,4-thiazolidinedione is catalytically reduced to give 5- [3- [6- (5-methyl-2-phenyl-4-oxa). Zolylmethoxy) -2-naphthyl] propyl] -2,4-thiazolidinedione was obtained. Yield 50%.
Recrystallized from chloroform-ethanol. Pale yellow prism crystal. Melting point 208-209 [deg.] C.

Example 13 2- (5-Methyl-2-phenyl-4-oxazolylmethoxy) cinnamartehide (2.00 g), 2,4-thiazolidinedione (1.10 g), piperidine (0.10 g). A mixture of 267 g) and acetic acid (15 ml) was heated at reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and crystals of 5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamylidene] -2,4-thiazolidinedione were precipitated ( (1.64 g) was collected by filtration and washed with ether. The crystals were dissolved in tetrahydrofuran (150 ml), 5% palladium-carbon (1.64 g) was added, and the mixture was subjected to catalytic reduction under a hydrogen pressure of 3.4 kgf / cm ² at room temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure and the obtained crystals were recrystallized from dichloromethane-methanol to give 5- [3- [2-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione
(0.742 g, 34%) was obtained. White crystals. Melting point 173 ~
174 ° C.

Example 14 (E) -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] in the same manner as in Example 13.
After condensation of 2-butenal and 2,4-thiazolidinedione, catalytic reduction was carried out to give 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyl].
-2,4-thiazolidinedione was obtained. Yield 6%. Recrystallized from isopropyl ether. Pale yellow prism crystal. 64-65 ° C. Example 15 Ethyl 2-chloro-4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] butyrate
(0.20g), thiourea (0.145g), sodium acetate
A mixture of (0.115 g) and ethanol (15 ml) was heated under reflux for 30 hours. 6N Hydrochloric acid (15 ml) was added, and the mixture was further heated under reflux for 15 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography, and was eluted with methanol-chloroform (2:98, v / v) from the portion 5- [2- [4
-[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] ethyl] -2,4-thiazolidinedione (0.11 g, 56%) was obtained. Recrystallized from dichloromethane-ethanol. Colorless prism crystals. Melting point 151-1
52 ° C.

Example 16 In the same manner as in Example 15, ethyl 2-chloro-4- (4-isopropoxyphenyl) butyrate to 5- [2- (4-isopropoxyphenyl) ethyl] -2,4-thiazolidine was obtained. The dione was obtained as an oil. Yield 100%. NMR (δ ppm in CDCl ₃ ): 1.32 (6H, d, J = 6H
z), 2.05-2.9 (4H, m), 4.19 (1H, dd, J =
9.5 & 4Hz), 4.4 to 4.6 (1H, m), 6.83 (2H,
d, J = 8.5Hz), 7.08 (2H, d, J = 8.5Hz), 8.
29 (1H, br s). Example 17 5- [2- (4-hydroxyphenyl) ethyl] -2,4-
A solution of thiazolidinedione (0.30 g) in N, N-dimethylformamide (20 ml) was treated with oily sodium hydride (60 ml).
%, 0.10 g) was added and the mixture was stirred at room temperature for 15 minutes. Then, 4-chloromethyl-5-methyl-2-phenyloxazole (0.29 g) was added, and the mixture was stirred at 90-100 ° C for 2 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-chloroform (1: 9, v / v) from the portion of 5- [2- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] -2,4-thiazolidinedione (0.
30 g, 59%). Recrystallized from dichloromethane-isopropyl ether. Colorless needles. Melting point 146-147
° C. Examples 18 to 22 The compounds in Table 4 were obtained in the same manner as in Example 17.

[0102]

[Table 4]

Example 23 4-Isopropoxycinnamaldehyde (6.00 g),
2,4-thiazolidinedione (5.54 g), piperidine
A mixture of (2.69 g) and acetic acid (30 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure to precipitate 5
Crystals of-(4-isopropoxycinnamylidene) -2,4-thiazolidinedione (4.40 g) were collected by filtration and washed with ethyl acetate. Tetrahydrofuran (100 ml)
Dissolved in water, 5% palladium-carbon (2.20 g) was added, and the mixture was subjected to catalytic reduction at room temperature under a hydrogen pressure of 3.8 kgf / cm ² . After the catalyst was filtered off, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography. 5 parts from the portion eluted with ethyl acetate-chloroform (1: 9, v / v)
-[3- (4-isopropoxyphenyl) propyl] -2,
4-Thiazolidinedione (3.61 g, 39%) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.32 (6H, d, J = 6H
z), 1.6 to 2.3 (4H, m), 2.61 (2H, t, J = 7.5)
Hz), 4.28 (1H, dd, J = 8.5 & 4.5Hz), 4.4
~ 4.65 (1H, m), 6.82 (2H, d, J = 8.5Hz),
7.06 (2H, d, J = 8.5Hz), 8.34 (1H, br s).

Example 24 In the same manner as in Example 23, 2- [3- (4-isopropoxyphenyl) propyl] -1,3-dioxolane and 2,4-
After condensation of thiazolidinedione, catalytic reduction was carried out to give 5- [4-
Crystals of (4-isopropoxyphenyl) butyl] -2,4-thiazolidinedione were obtained. Yield 68%. Recrystallized from ether-hexane. Colorless prism crystals. Melting point 72-73
° C. Example 25 In the same manner as in Example 23, (E, E) -5- (4-isopropoxyphenyl) -2,4-pentadienal and 2,4-
After the thiazolidinedione is condensed, it is catalytically reduced to give 5- [5-
(4-Isopropoxyphenyl) pentyl] -2,4-thiazolidinedione was obtained as an oil. Yield 26%. NMR (δ in CDCl ₃ ): 1.2 to 1.75 (6 H, m),
1.32 (6H, d, J = 6Hz), 1.8 to 2.3 (2H, m),
2.54 (2H, t, J = 7.5Hz), 4.26 (1H, dd, J =
9 & 4.5Hz), 4.4 to 4.6 (1H, m), 6.80 (2H,
d, J = 8.5Hz), 7.05 (2H, d, J = 8.5Hz), 8.
06 (1H, br s).

Example 26 6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydro-2 was prepared in the same manner as in Example 1.
-Naphthoaldehyde and 2,4-thiazolidinedione are condensed to give 5- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydro-2-naphthylmethylidene] -2. There was obtained 4,4-thiazolidinedione. Yield 5
0%. Recrystallized from dichloromethane-methanol. Yellow needles. Melting point 271-272 [deg.] C. Example 27 In the same manner as in Example 1, (E) -3-methoxy-4- (2
-Phenyl-4-oxazolylmethoxy) cinnamaldehyde is condensed with 2,4-thiazolidinedione to give 5- [3
-Methoxy-4- (2-phenyl-4-oxazolylmethoxy) cinnamylidene] -2,4-thiazolidinedione was obtained. Yield 57%. Recrystallized from chloroform-methanol. Yellow needles. Melting point 230-231 [deg.] C.

Example 28 In the same manner as in Example 1, (E) -3-methoxy-4- (2
-Phenyl-4-thiazolylmethoxy) cinnamaldehyde and 2,4-thiazolidinedione are condensed to give 5- [3-
Methoxy-4- (2-phenyl-4-thiazolylmethoxy) cinnamylidene] -2,4-thiazolidinedione was obtained. Yield 49%. Recrystallized from chloroform-methanol. Yellow needles. Melting point 248-249 [deg.] C. Example 29 5- [6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydro-2-naphthylmethylidene] -2,4-as in Example 7. Catalytic reduction of thiazolidinedione to give 5- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1,2,3,4-tetrahydro-2-naphthylmethyl] -2,4-thiazolidine Got Zion. Yield 73%. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 194-195
° C.

Example 30 In the same manner as in Example 7, 5- [3-methoxy-4- (2-
Phenyl-4-oxazolylmethoxy) cinnamylidene]
Catalytic reduction of -2,4-thiazolidinedione to 5- [3-
[3-Methoxy-4- (2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 71%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 131-132 [deg.] C. Example 31 In the same manner as in Example 7, 5- [3-methoxy-4- (2-
Phenyl-4-thiazolylmethoxy) cinnamylidene]-
By catalytic reduction of 2,4-thiazolidinedione, 5- [3-
[3-Methoxy-4- (2-phenyl-4-thiazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 57%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 123-124 [deg.] C.

Example 32 In the same manner as in Example 13, after condensing 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-trifluoromethylcinnamaldehyde and 2,4-thiazolidinedione. After catalytic reduction, 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-trifluoromethylphenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 31%. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 154
~ 155 ° C. Example 33 In the same manner as in Example 13, 3-methoxy-4- [2- (2
-Furyl) -5-methyl-4-oxazolylmethoxy] cinnamaldehyde and 2,4-thiazolidinedione are condensed and then catalytically reduced to give 5- [3- [3-methoxy-4- [2-
(2-Furyl) -5-methyl-4-oxazolylmethoxy] phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 9%. Recrystallized from chloroform-diethyl ether. Colorless prism crystals. Melting point 109-110 [deg.] C.

Example 34 In the same manner as in Example 17, 5- [3- [3-methoxy-4]
-[2-[(E) -2-Phenylethenyl] -4-oxazolylmethoxy] phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 37%. Recrystallized from chloroform-ethanol. Pale yellow prism crystal. Melting point 154-1
55 ° C. Example 35 In the same manner as in Example 17, 5- [3- [3-methoxy-4]
-[2-[(E) -2-Phenylethenyl] -4-thiazolylmethoxy] phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 30%. Recrystallized from chloroform-ethanol. Pale yellow prism crystal. Melting point 161-16
2 ° C.

Example 36 In the same manner as in Example 17, 5- [3- [3-methoxy-4]
-(5-Methyl-2-phenyl-4-thiazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione was obtained. Yield 40%. Recrystallized from ethyl acetate-hexane. Pale yellow needles. Melting point 149-150 [deg.] C. Example 37 In the same manner as in Example 17, 5- [3- [3,5-dimethoxy-4- [2-[(E) -2-phenylethenyl] -4-oxazolylmethoxy] phenyl] propyl was obtained. ] -2,4-thiazolidinedione was obtained. Yield 37%. Recrystallized from ethyl acetate-hexane. Pale yellow prism crystal. Melting point 163-
164 ° C.

Example 38 5- [3- [3-Methoxy-4- [2-[(E) -2-phenylethenyl] -4-oxazolylmethoxy] phenyl] propyl] -2,4-thiazolidine A mixture of dione (0.37 g), palladium on carbon (5%, 0.74 g) and tetrahydrofuran (20 ml) was subjected to catalytic reduction at 1 atm at room temperature. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 5- [3- [3
-Methoxy-4- (2-phenethyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione (0.20 g, 54%) was obtained. Colorless prism crystals. 126-127 ° C. Example 39 In a manner similar to Example 38, 5- [3- [3-methoxy-4
-[2-[(E) -2-Phenylethenyl] -4-thiazolylmethoxy] phenyl] propyl] -2,4-thiazolidinedione is catalytically reduced to give 5- [3- [3-methoxy-4]. −
(2-Phenethyl-4-thiazolylmethoxy) phenyl]
Propyl] -2,4-thiazolidinedione was obtained. Yield 5
9%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 104-105 [deg.] C.

Example 40 In the same manner as in Example 1, 4-isopropoxy-3-methoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5- (4-isopropoxy-3-methoxycinnamylidene). -2,4-thiazolidinedione was obtained. Yield 61%. Recrystallized from ethyl acetate-hexane. Yellow prism crystal. Melting point 230-231 [deg.] C. Example 41 In the same manner as in Example 1, 4-benzyloxy-3,5-
Dimethoxycinnamaldehyde and 2,4-thiazolidinedione were condensed to give 5- (4-benzyloxy-3,5-dimethoxycinnamylidene) -2,4-thiazolidinedione. Yield 57%. Recrystallized from chloroform-ethanol. Yellow prism crystal. Melting point 217-218 [deg.] C.

Example 42 In the same manner as in Example 7, 5- (4-isopropoxy-3
-Methoxycinnamylidene) -2,4-thiazolidinedione was catalytically reduced to give 5- [3- (4-isopropoxy-3-
Methoxyphenyl) propyl] -2,4-thiazolidinedione was obtained as an oil. Yield 75%. NMR (δ ppm in CDCl ₃ ): 1.35 (6H, d, J = 6)
Hz), 1.65 to 2.2 (4H, m), 2.62 (2H, t, J =
7Hz), 3.85 (3H, s), 4.28 (1H, dd, J = 8 &
4Hz), 4.47 (1H, m), 6.67 (1H, dd, J = 8 &
2Hz), 6.69 (1H, s), 6.83 (1H, d, J = 8H
z), 8.45 (1H, br s). Example 43 In the same manner as in Example 7, 5- (4-benzyloxy-3,
Catalytic reduction of 5-dimethoxycinnamylidene-2,4-thiazolidinedione to give 5- [3- (4-benzyloxy-
3,5-dimethoxyphenyl) propyl] -2,4-thiazolidinedione was obtained. Yield 76%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 101-10
2 ° C.

Formulation Example 1 (Example of tablet production) (1) 5- [3- [4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propyl] -2,4- Thiazolidinedione 30 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, dried in a vacuum and granulated, and 14 g of (4) is added to the granulated powder.
1000 g of tablets containing 10 mg of (1) per tablet are produced by mixing 1 g of (5) and 1 g of (5) and tableting with a tableting machine.

Formulation Example 2 (Production Example of Tablet) (1) 5- [3- [3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2, 4-thiazolidinedione 10 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), the total amount of (3) and 30 g of ( 4) is kneaded with water, vacuum dried and granulated. 14g of this granulated powder (4)
By mixing 1 g of (5) and 1 to form tablets in a tableting machine, 1000 tablets containing 30 mg of (1) per tablet are produced.

Reference Example 1 Sodium hydride (oil, 60%, 2.40 g) was added to triethyl phosphonoacetate (12.3 g) in tetrahydrofuran (20%).
0 ml) solution was added little by little at 0 ° C. and stirred for 10 minutes. Then, 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (14.7 g) was added, and the mixture was stirred at 0 ° C for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (Mg
After SO ₄ ) the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography. Crystals of ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate (14.8 g, 81%) were obtained from the eluate of ethyl acetate-hexane (1: 3, v / v). It was Recrystallized from ethanol. Colorless prism crystals. Melting point 94-95 [deg.] C. Elemental analysis: Calculated as _{C 22 H 21 NO 4: C} , 72.71; H, 5.82; N, 3.58 Found: C, 72.61; H, 5.57 ; N, 3. 85

Reference Examples 2 to 6 In the same manner as in Reference Example 1, the compounds shown in Table 5 were obtained.

[0118]

[Table 5]

Reference Example 7 In the same manner as in Reference Example 1, by reacting 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone with trimethylphosphonoacetate, (E) -3- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Obtained methyl phenyl] -2-butenoate. Yield 54%.
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 125-126 [deg.] C. Reference Example 8 In the same manner as in Reference Example 1, 4-isopropoxybenzaldehyde was reacted with triethylphosphonoacetate to obtain ethyl 4-isopropoxycinnamate as an oil. Yield 93%. NMR (δ ppm in CDCl ₃ ): 1.33 (3H, t, J = 7H
z), 1.35 (6H, d, J = 6Hz), 4.25 (2H, q, J =
7Hz), 4.5-4.7 (1H, m), 6.30 (1H, d, J =
16Hz), 6.87 (2H, d, J = 9Hz), 7.46 (2H,
d, J = 9Hz), 7.63 (1H, d, J = 16Hz).

Reference Example 9 In the same manner as in Reference Example 1, ethyl (E, E) -5- (4-isopropoxyphenyl) pentadienoate was obtained by reacting 4-isopropoxybenzaldehyde with triethyl 4-phosphonocrotonate. Obtained as crystals. Yield 58%. Recrystallized from ether-hexane. Colorless prism crystals. 64-65 ° C. Reference Example 10 Toluene solution of diisobutylaluminum hydride (1.5
M (51 ml) was added dropwise to a solution of ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate (14.0 g) in dichloromethane (200 ml) at 0 ° C. After stirring for 30 minutes, 2N hydrochloric acid (150 ml) was added at 0 ° C, and the mixture was stirred for another hour. The dichloromethane layer was separated, washed with saturated brine, dried (MgSO _4), and the solvent was distilled off under reduced pressure (E) -3- [3- (5- methyl-2-phenyl-4-
Crystals of oxazolylmethoxy) phenyl] -2-propenol (11.5 g, 92%) were obtained. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 118-119 [deg.] C. Elemental analysis: Calculated as _{C 20 H 19 NO 3: C} , 74.75; H5.96; N, 4.36 Found: C, 74.78; H5.76; N , 4.39

Reference Examples 11 to 16 In the same manner as in Reference Example 10, the compounds shown in Table 6 were obtained.

[0122]

[Table 6]

Reference Example 17 (E) -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] in the same manner as in Reference Example 10.
Methyl-2-butenoate was reduced with diisobutylaluminum hydride to give (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-butenol. Yield 63%. Recrystallized from ethyl acetate-ether. Colorless crystals. 126-127 ° C. Reference Example 18 In the same manner as in Reference Example 10, ethyl 4-isopropoxycinnamate was reduced with diisobutylaluminum hydride,
(E) -3- (4-isopropoxyphenyl) -2-propenol was obtained as an oil and purified by silica gel column chromatography [ethyl acetate-hexane (1: 4, v /
v) Elution]. Yield 83%. NMR (δ ppm in CDCl ₃ ): 1.33 (6H, d, J = 6
Hz), 1.38 (1H, t, J = 6Hz), 4.30 (2H, td,
J = 6 & 1.5Hz), 4.45 to 4.65 (1H, m), 6.2
3 (1H, dt, J = 16 & 6Hz), 6.56 (1H, d, J = 1
6Hz), 6.84 (2H, d, J = 8.5Hz), 7.31 (2
H, d, J = 8.5 Hz).

Reference Example 19 In the same manner as in Reference Example 10, ethyl (E, E) -5- (4-isopropoxyphenyl) -2,4-pentadienoate was reduced with diisobutylaluminum to give (E, E)- Crystals of 5- (4-isopropoxyphenyl) -2,4-pentadienol were obtained. Yield 76%. Recrystallized from isopropyl ether. Colorless needles. Melting point 91-92 [deg.] C. Reference Example 20 Activated manganese dioxide (25.0 g) was added to (E) -3- [3- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Phenyl] -2-propenol (11.0 g) was added to a dichloromethane (200 ml) solution, and the mixture was stirred at room temperature for 2 hours.
The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamaldehyde (10.5 g, 96%). Recrystallized from ethyl acetate-hexane. Colorless columnar crystals. Melting point 103-
104 ° C.

Reference Examples 21 to 26 In the same manner as in Reference Example 20, the compounds shown in Table 7 were obtained.

[0126]

[Table 7]

Reference Example 27 (E) -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] in the same manner as in Reference Example 20.
-2-Butenol is oxidized with activated manganese dioxide,
(E) -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] crotonaldehyde was obtained. Yield 87%. Recrystallized from ethyl acetate-ether. Colorless crystals. Melting point 94-95 [deg.] C. Reference Example 28 In the same manner as in Reference Example 20, (E) -3- (4-isopropoxyphenyl) -2-propenol was oxidized with activated manganese dioxide to obtain 4-isopropoxycinnamaldehyde as an oil. Yield 89%. NMR (δ ppm in CDCl ₃ ): 1.37 (6H, d, J = 6)
Hz), 4.5 to 4.7 (1H, m), 6.61 (1H, dd, J = 1)
6 & 8Hz), 6.92 (2H, d, J = 9Hz), 7.42 (1
H, d, J = 16Hz), 7.51 (2H, d, J = 9Hz), 9.
65 (1H, d, J = 89Hz).

Reference Example 29 In the same manner as in Reference Example 20, (E, E) -5- (4-isopropoxyphenyl) -2,4-pentadienol was oxidized with activated manganese dioxide to give (E, E). ) -5- (4-Isopropoxyphenyl) -2,4-pentadienol was obtained as an oil. Yield 99%. NMR (δ ppm in CDCl ₃ ): 1.36 (6H, d, J = 6)
Hz), 4.5-4.7 (1H, m), 6.22 (1H, dd, J = 1)
5 & 8Hz), 6.8 to 7.05 (4H, m), 7.26 (1H, d
d, J = 15 & 10Hz), 7.44 (2H, d, J = 9Hz),
9.59 (1H, d, J = 8Hz) -Reference Example 30 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (3.0g) and pyruvic acid (3.44g) Was added dropwise to a solution of sodium carbonate (4.14 g) in water (80 ml). Mix 7
After stirring at 0 to 80 ° C for 24 hours, the mixture was poured into water and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration. The crystals were mixed with hydrogen chloride in ethanol (5%, 1
5 ml) and the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, the residue was washed with water dissolved in chloroform, dried (MgSO _4), and concentrated. The residue was purified by silica gel column chromatography. From the part eluted with ethyl acetate-chloroform (1: 9, v / v), (E) -4
Ethyl-[2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidenepyruvate (1.0 g,
25%). Recrystallized from dichloromethane-ethanol. Pale yellow needles. Melting point 99-100 [deg.] C.

Reference Example 31 Ethyl (E) -4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidenepyruvate (0.
A mixture of 85 g), palladium-carbon (10%, 0.1 g) and dioxane (80 ml) was subjected to catalytic reduction at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), sodium borohydride (0.08 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was purified by silica gel column chromatography. Chloroform-ethyl acetate (1: 9,
v / v) elutes 2-hydroxy-4- [4-
[2- (5-methyl-2-phenyl-4-oxazolyl)
Ethoxy] phenyl] ethyl butyrate (0.55 g, 64%) was obtained. Recrystallized from ethyl ether-hexane. Colorless needles. Melting point 67-68 [deg.] C. Reference Example 32 In the same manner as in Reference Example 30, after condensation of 4-isopropoxybenzaldehyde and sodium pyruvate, esterification was performed to obtain ethyl (E) -4-isopropoxybenzylidenepyruvate as an oil. Yield 36%. NMR (δ ppm in CDCl ₃ ): 1.37 (6H, d, J = 6)
Hz), 1.41 (3H, t, J = 7Hz), 4.39 (2H, q, J
= 7 Hz), 4.55 to 4.75 (1 H, m), 6.91 (2 H,
d, J = 9Hz), 7.23 (1H, d, J = 16Hz), 7.58
(2H, d, J = 9Hz), 7.83 (1H, d, J = 16Hz).

Reference Example 33 Ethyl (E) -4-isopropoxybenzylidene pyruvate (19.0 g), a mixture of 5% -palladium on carbon (3.00 g) and 20% (v / v) acetic acid-ethanol (500 ml). 1
It was subjected to catalytic reduction at atmospheric pressure and room temperature. The catalyst was filtered off, 5% -palladium carbon (3.00 g) was newly added to the filtrate, and catalytic reduction was continued under the same conditions. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 2-hydroxy-4- (4-isopropoxyphenyl) ethyl acetate (11.2 g, 58) was extracted from the portion eluted with ethyl acetate-hexane (1: 4, v / v). %) As an oil. NMR (δ ppm in CDCl ₃ ): 1.29 (3H, t, J = 7)
Hz), 1.32 (6H, d, J = 6Hz), 1.8 to 2.2 (2
H, m), 2.65 to 2.75 (2H, m), 2.80 (1H, d, J
= 5.5 Hz), 4.1 to 4.25 (1 H, m), 4.21 (2 H,
q, J = 7 Hz), 4.4 to 4.6 (1 H, m), 6.81 (2 H,
d, J = 8.5Hz), 7.10 (2H, d, J = 8.5Hz).

Reference Example 34 A mixture of ethyl 2-hydroxy-4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] butyrate (320 mg) and thionyl chloride (3 ml) was refluxed. Heated for 2 hours below. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 4, v / v) to give 2-
Chloro-4- [4- [2- (5-methyl-2-phenyl-
4-Oxazolyl) ethoxy] phenyl] ethyl butyrate (21
0 mg, 63%) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.29 (3H, t, J = 7)
Hz), 205 to 2.45 (2H, m), 2.38 (3H, s),
2.6 ~ 2.85 (2H, m), 2.97 (2H, t, J = 6.5H
z), 4.15 to 4.3 (5H, m), 6.84 (2H, d, J = 8.
5Hz), 7.09 (2H, d, J = 8.5Hz).

Reference Example 35 In the same manner as in Reference Example 34, 2-hydroxy-4- (4-
Ethyl isopropoxyphenyl) butyrate was chlorinated with thionyl chloride to give ethyl 2-chloro-4- (4-isopropoxyphenyl) butyrate as an oil. Yield 27%. NMR (δ ppm in CDCl ₃ ): 1.29 (3H, t, J = 7)
Hz), 1.32 (6H, d, J = 6Hz), 2.1 to 2.35 (2
H, m), 2.6 to 2.9 (2H, m), 4.15 to 4.3 (3H,
m), 4.4 to 4.6 (1H, m), 6.82 (2H, d, J = 8.5)
Hz), 7.09 (2H, d, J = 8.5Hz). Reference Example 36 Sodium hydride (oil, 60%, 4.60 g) was added to 2- (1,
A solution of 3-dioxolan-2-yl) ethyltriphenylphosphonium bromide (51.0 g) in N, N-dimethylformamide (200 ml) was added slowly at 0 ° C. After stirring for 15 minutes, 4-isopropoxybenzaldehyde
(18.0 g) was added, and the mixture was stirred at 80 to 85 ° C for 5 hr.
Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and extracted with ether. After ether layer was washed with water, dried (MgSO _4),
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Ethyl acetate-hexane (1:
4, v / v), the intermediate oily substance obtained from the elution portion was dissolved in ethanol (250 ml), 5% -palladium on carbon (5.00 g) was added, and the mixture was catalytically reduced at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 5, v / v) was used to elute 2- [3- (4
-Isopropoxyphenyl) propyl] -1,3-dioxolane (6.70 g, 24%) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.32 (6H, d, J = 6)
Hz), 1.6 to 1.8 (4H, m), 2.5 to 2.65 (2H,
m), 3.8 to 4.0 (4H, m), 4.4 to 4.6 (1H, m),
4.8 to 4.9 (1H, m), 6.80 (2H, d, J = 8.5H
z), 7.07 (2H, d, J = 8.5Hz).

Reference Example 37 5- [2- (4-isopropoxyphenyl) ethyl] -2,
4-thiazolidinedione (1.35 g) in dichloromethane
Titanium tetrachloride (3.67 g) was added dropwise to the (70 ml) solution at 0 ° C. After stirring for 2 hours, the mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 3,
v / v) to elute 5- [2- (4-hydroxyphenyl) ethyl] -2,4-thiazolidinedione (0.72)
g, 63%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 175-176
° C. Elemental analysis: Calculated as C ₁₁ H ₁₁ NO ₃ S: C, 55.68; H, 4.67; N, 5.90 Found: C, 55.63; H, 4.57; N, 5 .83

Reference Examples 38 to 40 In the same manner as in Reference Example 37, the compounds shown in Table 8 were obtained.

[0135]

[Table 8]

Reference Example 41 4-chloromethyl-5-methyl-2-phenyloxazole (0.623 g), triphenylphosphine (0.787)
A mixture of g) and acetonitrile (10 ml) was heated under reflux for 24 hours. After cooling, it was precipitated (5-methyl-2-
Crystals of phenyl-4-oxazolylmethyl) triphenylphosphonium chloride (1.25 g, 89%) were obtained. Melting point 277-278 [deg.] C. Elemental analysis: Calculated as C ₂₉ H ₂₅ ClNOP: C, 74.12; H5.36; N, 2.98 Found: C, 73.79; H5.32; N, 2.97

Reference Example 42 (5-Methyl-2-phenyl-4-oxazolylmethyl)
Triphenylphosphonium chloride (25.4g) in ethanol with sodium ethoxide [sodium (1.4g)
And adjusted with ethanol (300 ml)] under cooling.
After stirring the mixture at room temperature for 5 minutes, 4-bromobenzaldehyde (10.0 g) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography. From the portion eluted with ether-hexane (1:20, v / v), (E) -4- [2- (4-bromophenyl)
Vinyl] -5-methyl-2-phenyloxazole (1
3.1 g, 71%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 138-139 [deg.] C.

Reference Example 43 (E) -4- [2- (4-Bromophenyl) vinyl] -5-methyl-2-phenyloxazole (13.0 g) in a solution of tetrahydrofuran (140 ml) at -70 ° C. A solution of butyllithium in hexane (1.6 M, 28.7 ml) was added dropwise. After stirring this mixture at -70 ° C for 15 minutes,
A solution of N, N-dimethylformamide (4.2 g) in tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at −70 ° C. for 30 minutes and then warmed to room temperature, 1
Normal hydrochloric acid (150 ml) was added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 2, v / v), (E) -4- [2- (5-methyl-2-phenyl-
4-oxazolyl) vinyl] benzaldehyde (5.9 g,
54%). Recrystallized from ethyl acetate-hexane. Light brown prismatic crystals. Melting point 158-159 [deg.] C.

Reference Example 44 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 g), p-hydroxyacetophenone (7.9 g)
A mixture of g), potassium carbonate (6.73 g) and N, N-dimethylformamide (100 ml) was stirred at 70 to 80 ° C for 2.5 hours, poured into water and extracted with ethyl acetate. After ethyl acetate layer was washed with water, dried (MgSO _4), concentrated under reduced pressure to give 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone (11.6 g, 85%). Recrystallized from ethyl acetate-ether. Colorless prism crystals. 126-127 ° C.

Reference Example 45 2-Bromo-3- [3-fluoro-4- (5-methyl-2)
Methyl -phenyl-4-oxazolylmethoxy) phenyl] propionate (14.2 g), 1,8-diazabicyclo
A mixture of [5.4.0] -7-undecene (DBU) (4.83 g) and toluene (150 ml) was stirred at 80 to 90 ° C. for 2 hours, poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ after, and concentrated under reduced pressure to give 3-fluoro-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate methyl (10.
0 g, 86%). Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 167-168 [deg.] C. Reference Example 46 In the same manner as in Reference Example 45, 2-bromo-3- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
Dehydrobromination of methyl 3-trifluoromethylphenyl] propionate to give 4- (5-methyl-2-phenyl-
Methyl 4-oxazolylmethoxy) -3-trifluoromethylcinnamate was obtained. Yield 80%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 148-1
49 ° C.

Reference Example 47 In the same manner as in Reference Example 1, 3-methoxy-4- [2- (2-
Furyl) -5-methyl-4-oxazolylmethoxy] benzaldehyde and 3-methoxy-4- [2- (2-furyl) -5-methyl-
Methyl 4-oxazolylmethoxy] cinnamate was obtained. Yield 90%. Recrystallized from dichloromethane-diethyl ether. Colorless prism crystals. Melting point 129-130 [deg.] C. Reference Example 48 In the same manner as in Reference Example 1, by reacting 3-methoxy-4- (2-phenyl-4-oxazolylmethoxy) benzaldehyde with triethylphosphonoacetate, 3-methoxy-
Obtained ethyl 4- (2-phenyl-4-oxazolylmethoxy) cinnamate. Yield 96%. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 128-129 [deg.] C.

Reference Example 49 In the same manner as in Reference Example 1, 3-methoxy-4 (2-phenyl-4-thiazolylmethoxy) benzaldehyde was reacted with triethylphosphonoacetate to give 3-methoxy-4.
Obtained ethyl-(2-phenyl-4-thiazolylmethoxy) cinnamate. Yield 93%. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 92-93 [deg.] C. Reference Example 50 In the same manner as in Reference Example 1, 4-isopropoxy-3-methoxybenzaldehyde was reacted with triethylphosphonoacetate to obtain ethyl 4-isopropoxy-3-methoxycinnamate. Yield 91%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 103-104 [deg.] C.

Reference Example 51 In the same manner as in Reference Example 1, 4-benzyloxy-3,5-
Reaction of dimethoxybenzaldehyde with triethylphosphonoacetate gave ethyl 4-benzyloxy-3,5-dimethoxycinnamate. Yield 96%. Recrystallized from diethyl ether-hexane. Colorless plate crystals. Melting point 68-
69 ° C. Reference Example 52 In the same manner as in Reference Example 10, methyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-trifluoromethylcinnamate was reduced to give (E) -3- [. 4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
3-Trifluoromethylphenyl] -2-propenol was obtained. Yield 87%. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 152-
153 ° C. Reference Example 53 In the same manner as in Reference Example 10, 3-methoxy-4- [2- (2
Methyl (furyl) -5-methyl-4-oxazolylmethoxy] cinnamate to reduce (E) -3- [3-methoxy-4
-[2- (2-Furyl) -5-methyl-4-oxazolylmethoxy] phenyl] -2-propenol was obtained. Yield 8
4%. Recrystallized from dichloromethane-diethyl ether. Colorless needles. Melting point 128-129 [deg.] C.

Reference Example 54 In the same manner as in Reference Example 10, (E) -3- [3-methoxy was prepared by reducing ethyl 3-methoxy-4- (2-phenyl-4-oxazolylmethoxy) cinnamate. -4- (2-Phenyl-4-oxazolylmethoxy) phenyl] -2-propenol was obtained. Yield 98%. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 113-114 [deg.] C. Reference Example 55 In the same manner as in Reference Example 10, ethyl 3-methoxy-4- (2-phenyl-4-thiazolylmethoxy) cinnamate was reduced to give (E) -3- [3-methoxy-4-. (2-phenyl-
4-thiazolylmethoxy) phenyl] -2-propenol was obtained. Yield 86%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 71-72 [deg.] C.

Reference Example 56 A solution of aluminum chloride (AlCl ₃ ) (6.1 g) in diethyl ether (70 ml) was added to lithium aluminum hydride (LiAl).
H ₄ ) (6.4 g) in diethyl ether (270 ml) suspension 0
The mixture was added dropwise at 0 ° C and stirred at room temperature for 10 minutes. Then ethyl 4-isopropoxy-3-methoxycinnamate (35.4 g)
Diethyl ether-tetrahydrofuran (3: 1, 22
0 ml) solution was added dropwise at room temperature. After stirring at room temperature for 2 hours, water (170 ml) and 6N sulfuric acid (270 ml) were added dropwise under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with water, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 2, v / v) to (E) -3- (4-isopropoxy-3-methoxyphenyl) -2-. Propenol (27.0g, 91%)
Was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.37 (6H, d, J = 6)
Hz), 1.52 (1H, s), 3.87 (3H, s), 4.30 (2)
H, dd, J = 6 & 1Hz), 4.52 (1H, m), 6.24 (1
H, dd, J = 16 & 6Hz), 6.55 (1H, d, J = 16H)
z), 6.83 (1H, d, J = 8Hz), 6.90 (1H, dd, J
= 8 & 2Hz), 6.94 (1H, d, J = 2Hz).

Reference Example 57 In the same manner as in Reference Example 56, 4-benzyloxy-3,5
-Ethyl dimethoxycinnamate is reduced to (E) -3- (4
-Benzyloxy-3,5-dimethoxyphenyl) -2-
I got propenol. Yield 91%. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 72-73 [deg.] C. Reference Example 58 In the same manner as in Reference Example 20, (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-trifluoromethylphenyl] -2-propenol was oxidized. To give 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-trifluoromethylcinnamaldehyde. Yield 89%. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 13
8 to 139 ° C.

Reference Example 59 In the same manner as in Reference Example 20, (E) -3- [3-methoxy-
3- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] -2-propenol was oxidized to 3
-Methoxy-4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] cinnamaldehyde was obtained.
Yield 94%. Recrystallized from dichloromethane-diethyl ether. Colorless prism crystals. Melting point 125-126 [deg.] C. Reference Example 60 In the same manner as in Reference Example 20, (E) -3- [3-methoxy-
4- (2-Phenyl-4-oxazolylmethoxy) phenyl] -2-propenol was oxidized to 3-methoxy-4-
(2-Phenyl-4-oxazolylmethoxy) cinnamaldehyde was obtained. Yield 88%. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 144-145 [deg.] C.

Reference Example 61 In the same manner as in Reference Example 20, (E) -3- [3-methoxy-
4- (2-Phenyl-4-thiazolylmethoxy) phenyl] -2-propenol is oxidized to 3-methoxy-4-
(2-Phenyl-4-thiazolylmethoxy) cinnamaldehyde was obtained. Yield 80%. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 115-116 [deg.] C. Reference Example 62 In the same manner as in Reference Example 20, (E) -3- (4-isopropoxy-3-methoxyphenyl) -2-propenol was oxidized to obtain 4-isopropoxy-3-methoxycinnamaldehyde. Yield 90%. Recrystallized from ethyl acetate-hexane. Colorless plate crystals. Melting point 93-94 [deg.] C.

Reference Example 63 In the same manner as in Reference Example 20, (E) -3- (4-benzyloxy-3,5-dimethoxyphenyl) -2-propenol was oxidized to give 4-benzyloxy-3,5-. Dimethoxycinnamaldehyde was obtained. Yield 93%. Recrystallized from ethyl acetate-hexane. Colorless plate crystals. Melting point 114-11
5 ° C. Reference Example 64 In the same manner as in Reference Example 37, 5- [3- (4-isopropoxy-3-methoxyphenyl) propyl] -2,4-thiazolidinedione was treated with titanium tetrachloride to give 5- [3- ( 4-
Hydroxy-3-methoxyphenyl) propyl] -2,4
-Thiazolidinedione was obtained as an oil. Yield 87
%. NMR (δ ppm in CDCl ₃ ): 1.65 to 2.2 (4H,
m), 2.61 (2H, t, J = 7Hz), 3.89 (3H, s),
4.28 (1H, dd, J = 9 & 4Hz), 5.51 (1H, s),
6.66 (1H, dd, J = 9 & 2Hz), 6.66 (1H, d, J
= 2 Hz), 6.84 (1 H, d, J = 9 Hz), 8.37 (1 H,
br s).

Reference Example 65 In the same manner as in Reference Example 37, 5- [3- (4-benzyloxy-3,5-dimethoxyphenyl) propyl] -2,4-thiazolidinedione was treated with titanium tetrachloride to give 5- [3- (4
-Hydroxy-3,5-dimethoxyphenyl) propyl]
-2,4-thiazolidinedione was obtained as an oil. 82% yield. NMR (δ ppm in CDCl ₃ ): 1.75 to 2.15 (4H,
m), 2.61 (2H, t, J = 7Hz), 3.88 (6H, s),
4.29 (1H, dd, J = 8 & 4Hz), 5.42 (1H, s),
6.39 (2H, s). Reference Example 66 4-chloromethyl-5-methyl-2-phenyloxazole (19.2 g), 6-hydroxytetralone (15.0 g)
A mixture of g), potassium carbonate (15.4 g) and DMF (100 ml) was stirred at 80-90 ° C for 2 hours. The reaction mixture was poured into water to precipitate 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) tetralone crystals (2
(9.5 g, 96%) was collected by filtration. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 143-1
44 ° C.

Reference Example 67 Sodium methoxide (28%, 43.4 g) was concentrated to dryness to give 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) tetralone (15.0 g) and dimethyl carbonate. (8
A solution of 1.0 g) in THF (40 ml) was added dropwise with stirring at room temperature. After heating under reflux for 1 hour, concentrated hydrochloric acid was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ).
Afterwards, it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-chloroform (2:98, v
/ V) to give an oil (17.6 g). This oil was dissolved in THF (40 ml) -methanol (120 ml), and sodium borohydride (850 mg) was gradually added at 0 ° C. After stirring for 2 hours, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. Wash the organic layer with water and dry (Mg
After SO ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-chloroform (2: 9
8, v / v) to elute 1-hydroxy-6- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Obtained methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate (5.77 g, 33%). Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 1
46-147 ° C.

Reference Example 68 1-Hydroxy-6- (5-methyl-2-phenyl-4)
To a solution of methyl (oxazolylmethoxy) -1,2,3,4-tetrahydronaphthalene-2-carboxylate (5.46 g) in dichloromethane (200 ml) was added boron trifluoride diethyl ether complex (4.14 g). Dropwise at ° C. After stirring 1 hour at room temperature, the reaction mixture was washed with water, dried (MgSO ₄₎
Afterwards, it was concentrated. The residue was subjected to silica gel column chromatography, and was eluted with chloroform to give 6-
There was obtained methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydronaphthalene-2-carboxylate (4.30 g, 83%). Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 130-131 [deg.] C. Reference Example 69 In the same manner as in Reference Example 10, methyl 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydronaphthalene-2-carboxylate was reduced to give 6- (5 −
Methyl-2-phenyl-4-oxazolylmethoxy)-
3,4-dihydro-2-naphthylmethanol was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 141-142 [deg.] C.

Reference Example 70 In the same manner as in Reference Example 20, 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3,4-dihydro-
2-naphthylmethanol was oxidized to give 6- (5-methyl-
2-Phenyl-4-oxazolylmethoxy) -3,4-dihydro-2-naphthaldehyde was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 114-115 [deg.] C. Reference Example 71 Methylhydrazine (3.49 g) was added dropwise to a solution of methyl benzimidate hydrochloride in methanol (80 ml) at 0 ° C. After stirring for 3 hours, the reaction mixture was concentrated to 2-methyl-3.
-Phenylamidrazone hydrochloride (12.5 g, 89%) was obtained. Recrystallized from methanol-diethyl ether. Colorless prism crystals. 197-198 ° C.

Reference Example 72 2-Methyl-3-phenylamidrazone hydrochloride (3.15)
g), chloroacetyl chloride (1.92 g) and benzene
The mixture (40 ml) was heated to reflux for 2 hours while stirring. Ethyl acetate was added to the reaction mixture, washed with water and dried (MgS
O ₄ ), then concentrated to 3-chloromethyl-1-methyl-5-
Phenyl-1H-triazole (1.00 g, 28%) was obtained. Recrystallized from diethyl ether-hexane. Colorless prism crystals. Melting point 112-113 [deg.] C.

Claims (30)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R represents an optionally substituted hydrocarbon residue or heterocyclic residue that may be bonded via a carbon chain, n is 0 or 1, X is CH or N, and Y is Each is a divalent hydrocarbon residue. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and either R ¹ or R ² and a part of Y And may combine with each other to form a ring. Embedded image L and M each represent a hydrogen atom, or L and M
And may be bonded to each other to form one bond. ] The 2,4-thiazolidinedione derivative represented by these or its salt. 2. General formula (I-A1): The 2,4-thiazolidinedione derivative or salt thereof according to claim 1, represented by 3. The 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, wherein n is 1 and R is a heterocyclic residue bonded through a carbon chain. 4. The carbon chain has —CH═CH— or —CH ₂
The 2,4-thiazolidinedione derivative or salt thereof according to claim 3, which is CH ₂ —. 5. The 2,4-thiazolidinedione derivative according to claim 3, wherein the heterocyclic residue is a 5- or 6-membered ring having 1 to 3 oxygen atoms, sulfur atoms and nitrogen atoms as ring-constituting atoms. Its salt. 6. A heterocyclic residue has the formula: [Wherein B ¹ is a group represented by S, O or NR ⁴ (wherein R ⁴ represents a hydrogen atom, a lower alkyl group or an aralkyl group), B ² is a nitrogen atom or C—R ⁵ (R ⁵ is a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue), and R ³ is a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue. When R ³ and R ⁵ are respectively substituted on adjacent carbon atoms, R ³ and R ⁵ may combine with each other to form a condensed ring. ] The 2,4-thiazolidinedione derivative or a salt thereof according to claim 3, which is an aromatic 5-membered ring residue represented by the following formula. 7. The heterocyclic residue has the formula: [In the formula, R ⁵ and R ⁶ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon residue or a heterocyclic residue, and B represents an oxygen atom or a sulfur atom. ] The 2,4-thiazolidinedione derivative or a salt thereof according to claim 6, which is a group represented by: 8. A heterocyclic residue is of the formula: [In the formula, B represents an oxygen atom or a sulfur atom, and R ⁷ , R ⁸
Are the same or different and represent hydrogen or an optionally substituted hydrocarbon residue or a heterocyclic residue, or R ⁷
And R ⁸ may combine to form a condensed ring. ] The 2,4-thiazolidinedione derivative or a salt thereof according to claim 6, which is a group represented by: 9. The 2,4-thiazolidine according to claim 6, wherein B ¹ is NR ⁴ (in the formula, R ⁴ represents a hydrogen atom, a lower alkyl group or an aralkyl group), and B ² is a nitrogen atom. A dione derivative or a salt thereof. 10. The 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, wherein Y is a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms. 11. The 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, wherein Y is —CH ₂ CH ₂ —. 12. The 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, wherein L and M are each a hydrogen atom. 13. The 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, wherein each of R ¹ and R ² is a hydrogen atom. 14. A heterocyclic residue in which n is 1, R is bonded via a carbon chain having 1 or 2 carbon atoms, and Y is 1 to 4 carbon atoms.
The divalent saturated aliphatic hydrocarbon residue, L and M are each a hydrogen atom, and R ¹ and R ² are each a hydrogen atom. salt. 15. The method according to claim 14, wherein Y is —CH ₂ CH ₂ —.
2. The described 2,4-thiazolidinedione derivative or a salt thereof. 16. A heterocyclic residue in which n is 1, R is bonded via a carbon chain having 1 or 2 carbons, and Y is 1 to 4 carbons.
3. The 2,4-thiazolidinedione according to claim 2, wherein L and M each represent a hydrogen atom, R ¹ represents a halogen atom, and R ² represents a hydrogen atom. Derivative or salt thereof. 17. A heterocyclic residue in which n is 1, R is bonded via a carbon chain having 1 or 2 carbons, and Y is 1 to 4 carbons.
3. A divalent saturated aliphatic hydrocarbon residue of each of L and M are hydrogen atoms, R ¹ is an optionally substituted hydroxyl group, and R ² is a hydrogen atom. A 2,4-thiazolidinedione derivative or a salt thereof. 18. N is O, R is a heterocyclic residue bonded via ethylene or vinylene, Y is a divalent saturated aliphatic hydrocarbon residue having 1 to 4 carbon atoms, and L and M
Each is a hydrogen atom, and R ¹ and R ² are each a hydrogen atom, and the 2,4-thiazolidinedione derivative or a salt thereof according to claim 2. 19. 5- [3- [3-methoxy-4- (5-
2. A 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, which is methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione. 20. 5- [3- [3-fluoro-4- (5-
2. A 2,4-thiazolidinedione derivative or a salt thereof according to claim 1, which is methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione. 21. 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyl]
2. The compound according to claim 1, which is 2,4-thiazolidinedione.
4-thiazolidinedione derivative or a salt thereof. 22. The 2,4 according to claim 1, which is 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione. -Thiazolidinedione derivatives or salts thereof. 23. The 2,4 according to claim 1, which is 5- [3- [4- (5-methyl-2-naphthyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-thiazolidinedione. -Thiazolidinedione derivatives or salts thereof. 24. General formula (I): [In the formula, R represents an optionally substituted hydrocarbon residue or heterocyclic residue that may be bonded via a carbon chain, n is 0 or 1, X is CH or N, and Y is Each is a divalent hydrocarbon residue. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and either R ¹ or R ² and a part of Y And may combine with each other to form a ring. Embedded image L and M each represent a hydrogen atom, or L and M
And may be bonded to each other to form one bond. ] The pharmaceutical composition containing the 2,4-thiazolidinedione derivative represented by these or its pharmacologically acceptable salt. 25. The pharmaceutical composition according to claim 24, which is an insulin sensitivity enhancer. 26. The pharmaceutical composition according to claim 24, which is a therapeutic agent for diabetes. 27. The pharmaceutical composition according to claim 24, which is a therapeutic agent for hyperlipidemia. 28. A compound represented by the general formula (III): [In the formula, R represents an optionally substituted hydrocarbon residue or heterocyclic residue that may be bonded via a carbon chain, n is 0 or 1, X is CH or N, and Y is Each is a divalent hydrocarbon residue. R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and R 1
^One of R ¹ and R ² and a part of Y may be bonded to each other to form a ring. [Chemical 10] ] The general formula (I-B2) characterized by hydrolyzing the iminothiazolidinone compound represented by: [In the formula, each symbol has the same meaning as described above. ] 2,
Process for producing 4-thiazolidinedione derivative. 29. A compound represented by the general formula (I-B1): [In the formula, R represents an optionally substituted hydrocarbon residue or heterocyclic residue that may be bonded via a carbon chain, n is 0 or 1, X is CH or N, and Y is Each is a divalent hydrocarbon residue. R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and R 1
^One of R ¹ and R ² and a part of Y may be bonded to each other to form a ring. [Chemical 13] ] The compound represented by the general formula (I-B2a) characterized by reducing the compound: [In the formula, R ′ represents an optionally substituted hydrocarbon residue or a heterocyclic residue which may be bonded via a saturated carbon chain, and Y ¹ represents a divalent saturated hydrocarbon residue. , R ¹ or R ² and a part of Y ¹ may be bonded to each other to form a ring. [Chemical 15] Other symbols have the same meanings as above. ] 2,4
-A method for producing a thiazolidinedione derivative. 30. General formula (V): [In the formula, Y represents a divalent hydrocarbon residue, respectively. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon residue, and either R ¹ or R ² and a part of Y And may combine with each other to form a ring. L and M each represent a hydrogen atom, or L and M may combine with each other to form one bond. [Chemical 17] With the compound represented by Formula by] (VI): R "-CH 2 -Q (VI) [ wherein, R" is a heterocyclic residue, Q is a leaving group. ] The compound represented by the general formula (I-D1) characterized by reacting with a compound represented by: [In the formula, each symbol has the same meaning as described above. ] 2,
Process for producing 4-thiazolidinedione derivative.