JPH10237049A - Benzisoxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject novel compound that has hypoglycemic action and hypolipidemic action and is useful as a hypoglycemic agent and a hypolipidemic agent for treatment of diabetes, hyperlipemia and the like. SOLUTION: This novel compound is a benzisoxazol derivative represented by the formula (A is an aryl or a heterocyclic ring group which may be substituted; B is carboxyl, cyano, a 2-7C alkoxycarbonyl; Y<1> is a (substituted) 1-8C alkylene; Y<2> is a (substituted) 1-8C alkylene; X<1> is a bond, O-atom, S-atom; X<2> is a bond, O-atom, S-atom) or its salt, typically 5-[[3-[2-(2-pyridyl)ethyl]-1,2- benzisoxazol-6-yl]methyl]-2,4-thiazolidine dione. The compound of formula I is prepared by subjecting an appropriate aminobenzisoxazole derivative to the Meerwein reaction, by allowing a thiol of the formula: R<11> SH (R<11> is phenyl) to react with the product of the Meerwein reaction followed by hydrolysis of the resultant derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a benzisoxazole derivative having a hypoglycemic effect and a hypolipidemic effect.
Specifically, the following general formula (I):

Embedded image [In the formula, A represents an aryl group or a heterocyclic group which may have a substituent, and B represents a carboxyl group, a cyano group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a C7 to C11 An acid group such as an aryloxycarbonyl group, a sulfonic acid group or a phosphonic acid group, or a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring constituent atoms Wherein Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; Y ² represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; ¹ is a bond, an oxygen atom, a sulfur atom or NR ¹ (R
¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group. And X ² represents a bond, an oxygen atom, a sulfur atom or NR ² (R ² is a hydrogen atom, a carbon number of 1 to 8)
Represents an alkyl group or an aralkyl group. ). And a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, for the treatment of diabetes, an insulin preparation as an injection, a biguanide such as metformin hydrochloride as an oral preparation, and a sulfonylurea such as tolbutamide have been used. By the way, insulin preparations have the troublesome use of injections,
Biguanides, which are orally administered, cause lactic acid-cis, and sulfonylureas have the side effect of severe hypoglycemia. Recently, troglitazone (troglita) has a new mechanism of action to improve insulin dysfunction (insulin resistance) which does not have these disadvantages.
tazone: European Patent 139,421), pioglitazone hydrochloride
loride: European Patent 193, 256)
Attention has been directed to substituted benzyl-2,4-thiazolidinedione derivatives. Troglitazone has a hypoglycemic effect and a triglyceride-lowering effect, improves impaired insulin receptor function, works on glucose transporters and glucokinase, and is said to improve insulin dysfunction. ing.

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[0003] In addition to the above-mentioned 5-substituted benzyl-2,4-thiazolidinedione derivatives, it has been reported that the following compounds also have an insulin resistance improving action.

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[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a hypoglycemic agent and a hypolipidemic agent having a novel chemical structure.

Under these circumstances, the present inventors have conducted research on 2,4-thiazolidinedione derivatives having a hypoglycemic effect, and as a result, have found that the benzisoxazole represented by the above general formula (I) The present inventors have found that the derivative has excellent hypoglycemic action and hypolipidemic action, and completed the present invention. That is, the present invention provides the following general formula (I):

Embedded image [In the formula, A represents an aryl group or a heterocyclic group which may have a substituent, and B represents a carboxyl group, a cyano group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a C7 to C11 An acid group such as an aryloxycarbonyl group, a sulfonic acid group or a phosphonic acid group, or a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring constituent atoms Wherein Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; Y ² represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; ¹ is a bond, an oxygen atom, a sulfur atom or NR ¹ (R
¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group. And X ² represents a bond, an oxygen atom, a sulfur atom or NR ² (R ² is a hydrogen atom, a carbon number of 1 to 8)
Represents an alkyl group or an aralkyl group. ). A benzisoxazole derivative or a salt thereof.

Further, the present invention provides the following general formula (II):

Embedded image [In the formula, A ¹ represents an aryl group or a heterocyclic group which may have a substituent, and Q represents 2,4-thiazolidinedione-
5-ylmethyl group, 2,4-oxazolidinedione-5
-Ylmethyl group or the following general formula (III),

Embedded image (Wherein G represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aryl group which may have a substituent, and Y ⁴ represents a bond or a carbon atom which may have a substituent. Represents an alkylene chain of Formulas 1 to 8, Z ¹ represents a bond, an oxygen atom, a sulfur atom or NR ³ (R ³ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group), and Z ² represents a bond, an oxygen atom, a sulfur atom or NR ⁴ (R ⁴ represents a hydrogen atom,. an alkyl group or an aralkyl group having 1 to 8 carbon atoms) groups represented by the representative.) the, Y ³ Represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent, and X ³ represents a bond, an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom,
Represents an alkyl group or an aralkyl group having 1 to 8 carbon atoms. )
And X ⁴ represents a bond, an oxygen atom, a sulfur atom or NR ⁶ (R ⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group). A benzisoxazole derivative or a salt thereof.

Further, the present invention relates to a pharmaceutical composition containing a benzisoxazole derivative represented by the above general formula (I) or (II) or a salt thereof as an active ingredient.
Furthermore, the present invention relates to the above general formula (I) or general formula (I
It relates to a hypoglycemic agent containing the benzisoxazole derivative represented by I) or a salt thereof as an active ingredient. Furthermore, the present invention relates to a therapeutic agent for hyperlipidemia containing a benzisoxazole derivative represented by the above general formula (I) or (II) or a salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail. In the general formula (I), A represents a methyl group, an ethyl group,
C1-C6 alkyl groups such as propyl group and isopropyl group; C1-C6 alkoxy groups such as methoxy group and ethoxy group; halogen atoms such as chlorine atom and fluorine atom; 2-chloroethyl group; trifluoromethyl An alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms such as a group, an alkoxy group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms such as a 2-chloroethoxy group, An amino group such as a hydroxy group, a nitro group, an amino (NH ₂ ) group, a methylamino group, an ethylamino group, a dimethylamino group, and a diethylamino group; C1-C6 alkoxy groups such as C1-C6 alkyl groups, methoxy groups and ethoxy groups; and halogen atoms such as chlorine atoms and fluorine atoms Child may have a like hydroxy group.), A thienyl group (a methyl group as a substituent, an ethyl group, a propyl group, 1 to 6 carbon atoms such as isopropyl
Having 1 carbon atom such as an alkyl group, a methoxy group and an ethoxy group
Or a halogen atom such as an alkoxy group, a chlorine atom or a fluorine atom, or a hydroxy group. ),
Furyl group (as a substituent, an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group,
It may have an alkoxy group having 1 to 6 carbon atoms such as a methoxy group and an ethoxy group, a halogen atom such as a chlorine atom and a fluorine atom, and a hydroxy group. ), Thiazolyl group (alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, alkoxy group having 1 to 6 carbon atoms such as methoxy group and ethoxy group, chlorine atom, fluorine A halogen atom such as an atom, a hydroxy group, etc.), a pyridyl group (a C1-C6 alkyl group such as a methyl group, an ethyl group, a propyl group, or an isopropyl group as a substituent, a methoxy group, (It may have an alkoxy group having 1 to 6 carbon atoms such as an ethoxy group, a halogen atom such as a chlorine atom or a fluorine atom, or a hydroxy group.). Phenyl, naphthyl, pyridyl, thiazolyl, oxazolyl, chromanyl, thienyl, furyl, pyrrolyl, benzoxazolyl, morpholinyl , Indolyl group, benzimidazolyl group, benzothiazolyl group, a piperidinyl group, a pyrimidinyl group.

[0008] B is a carboxyl group, a cyano group,
An alkoxycarbonyl group having 2 to 7 carbon atoms (eg, a methoxycarbonyl group or an ethoxycarbonyl group),
1, an aryloxycarbonyl group (eg, phenyloxycarbonyl group), an acidic group such as a sulfonic acid group and a phosphonic acid group, or a 2,4-thiazolidinedione-5-yl group;
5-membered member containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms as ring-constituting atoms, such as a 2,4-oxazolidinedione-5-yl group and a tetrazol-5-yl group. And a heterocyclic group.

As Y ¹ , an alkyl group having 1 to 6 carbon atoms such as oxo, hydroxy, methyl, ethyl, propyl and isopropyl groups, and a carbon atom which may have a substituent such as phenyl group. 1-8, preferably 1-carbon
3 alkylene chains. Oxo as Y ² ,
An alkyl group having 1 to 6 carbon atoms such as a hydroxy group, a methyl group, an ethyl group, a propyl group, an isopropyl group, or the following general formula (IV):

Embedded image 1 carbon atom which may have a substituent such as a group represented by
To 8, preferably an alkylene chain having 1 to 3 carbon atoms. In the general formula (IV), G ¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a methyl group, an ethyl group, a propyl group, an isopropyl group, and the like. Has 1 to 1 carbon atoms
An alkyl group having 6 to 6 carbon atoms such as an alkyl group, a methoxy group and an ethoxy group; a halogen atom such as a chlorine atom and a fluorine atom; a phenyl group which may have a substituent such as a hydroxy group; a naphthyl group; Is mentioned. As Y ⁵ , a bond, or an oxo, hydroxy, methyl, ethyl, propyl, isopropyl group having 1 to 6 carbon atoms which may have a substituent such as an alkyl group having 1 to 6 carbon atoms such as an isopropyl group; 8, preferably an alkylene chain having 1 to 3 carbon atoms. As Z ³ , a bond, an oxygen atom, a sulfur atom or NR ⁷ (R ⁷ is a hydrogen atom, a methyl group, an ethyl group,
Examples thereof include an alkyl group having 1 to 8 carbon atoms such as a propyl group and an isopropyl group, and an aralkyl group such as a benzyl group and a phenethyl group. ). As Z ⁴ , a bond, an oxygen atom, a sulfur atom or NR ⁸ (R ⁸ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a benzyl group, a phenethyl group And aralkyl groups.).

X ¹ is a bond, an oxygen atom, a sulfur atom or NR ¹ (R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, or a benzyl group) , An aralkyl group such as a phenethyl group). X ² is a bond, an oxygen atom, a sulfur atom, or NR ² (R ² is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, etc.
And an aralkyl group such as a benzyl group and a phenethyl group. ).

In the benzisoxazole derivative represented by the general formula (I), the benzene ring of the benzisoxazole ring is

Embedded image (Y ² and B are the same as those described above.) In addition to the group represented by the formula (1), an alkyl group having 1 to 8 carbon atoms such as a methyl group and an ethyl group;
A halogen atom such as a chlorine atom or a fluorine atom, a chloroethyl group, a C1-8 alkyl group substituted with a halogen atom such as a trifluoromethyl group, a chloroethoxy group, a trifluoromethoxy group or the like having 1-8 carbon atoms. It may have a substituent such as an alkoxy group.

Next, the symbols of the general formula (II) will be described. A ^{1 in the} general formula (II) is A in the general formula (I), Y ³ in the general formula (II) is Y ¹ in the general formula (I),
X ³ in I) is the same as X ^{1 in} formula (I) and X ¹ in formula (II)
⁴ is the same atom or group as X ² in the general formula (I). Q is a 2,4-thiazolidinedione-5-ylmethyl group, a 2,4-oxazolidinedione-5-ylmethyl group or the following general formula (III):

Embedded image (Wherein G represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aryl group which may have a substituent, and Y ⁴ represents a bond or a carbon atom which may have a substituent. Represents an alkylene chain of Formulas 1 to 8, Z ¹ represents a bond, an oxygen atom, a sulfur atom or NR ³ (R ³ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group), and Z ² includes a bond, an oxygen atom, a sulfur atom or a group represented by NR ⁴ (R ⁴ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group). Here, the substitution position of Q is preferably the 5- or 6-position of the benzisoxazole ring.

In the general formula (III), G represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group or an isopropyl group, or a methyl group, an ethyl group, a propyl group or an isopropyl group. 1 to 6 carbon atoms
Having 1 carbon atom such as an alkyl group, a methoxy group and an ethoxy group
And phenyl group and naphthyl group which may have a substituent selected from alkoxy group, halogen atom such as chlorine atom and fluorine atom, and hydroxy group. Y
⁴ is a bond, or oxo, a hydroxy group, a methyl group, an ethyl group, a propyl group, a carbon number of 1 to 6 which may have a substituent selected from an alkyl group having 1 to 6 carbon atoms such as an isopropyl group. 8, preferably an alkylene chain having 1 to 3 carbon atoms. Z ¹ is a bond, an oxygen atom, a sulfur atom or NR ³ (where R ³ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an propyl group, an isopropyl group or the like, or a benzyl group) And an aralkyl group such as a phenethyl group.). Z ² represents a bond, an oxygen atom, a sulfur atom, or NR ⁴ (where R ⁴ represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an propyl group, an isopropyl group, etc. And an aralkyl group such as a phenethyl group.).

In the above general formula (II), A ¹ , Q and -X ^3-
Preferred combinations of Y ³ -X ^4- include the following. A ¹ : phenyl group, naphthyl group, pyridyl group, substituted oxazolyl group (eg: 5-methyl-2-phenyloxazo-
Ru-4-yl group, 5-methyl-4-phenyloxazo-
2-yl group) Q: 2,4-thiazolidinedione-5-ylmethyl group, 2,4-oxazolidinedione 5-ylmethyl _{group, -CH 2 CH (OEt) CO} 2 H, -CH 2 CH (S
_{. Ph) CO 2 H, -CH} 2 CH (OPh) CO 2 H ( wherein, Et represents an ethyl group, Ph represents a phenyl group) Here, the substitution position of Q is Benzuisokisazo - 6-position of Le ring Is preferred. ^{-X 3 -Y 3 -X 4 -:} -CH 2 CH 2 -, - N (CH 3)
CH ₂ CH ₂ —, —NHC (＝ O) CH ₂ —, —SCH ₂ C
_{H 2 --CH 2 O -, -} CH 2 CH 2 O-

The benzisoxazole derivative represented by the above formula (I) or (II) (the compound of the present invention)
May be present as a pharmacologically acceptable salt, and examples of such salts include acidic salts such as hydrochloric acid and acetic acid, and basic salts such as alkali metal (sodium and potassium) salts. Further, when Q in general formula (II) is 2,4-
The 5-position carbon atom of the thiazolidinedione ring and the 2,4-oxazolidinedione ring is an asymmetric carbon atom, and the group represented by the formula (III) may also have an asymmetric carbon atom. Therefore, the compound of the present invention includes optical isomers and racemates, and both are included in the present invention.

The compound represented by the above general formula (II) of the present invention can be obtained, for example, by the following production method. (Synthesis method 1)

Embedded image (In the above reaction formula, R ¹⁰ represents an alkyl group having 1 to 6 carbon atoms such as a methyl group and an ethyl group, T ¹ represents a halogen atom such as a chlorine atom and a bromine atom, and W represents A ¹ -X ^3-. Y ³
—X ⁴ — represents a group. Here, A ¹ , X ³ , Y ³ and X ⁴
Is the same as above. The aminobenzisoxazole derivative represented by the general formula (a) is acidified with hydrobromic acid, hydrochloric acid, etc. under ice-cooling in a solvent which does not participate in the reaction such as water, acetone-water mixture, etc. After diazotizing with sodium nitrite, alkyl acrylate (eg methyl acrylate) in the presence of cuprous oxide
To give a propionic acid derivative represented by the general formula (b). Then, a thiourea is allowed to act on the obtained propionic acid derivative represented by the general formula (b) in the presence of sodium acetate to obtain a 2-iminothiazolidine-4-one derivative represented by the general formula (c). Can be
This is reacted with an acid such as hydrochloric acid in a solvent which does not participate in the reaction such as ethanol to obtain a benzisoxazole derivative represented by the general formula (d). In addition, an aminobenzisoxazole derivative represented by the general formula (a) as a raw material,
For example, 6-amino-3-phenethyl-1,2-benzisoxazole is 6-acetamido-3-methyl-1,
A benzyl halide (eg, benzyl iodide) is allowed to act on 2-benzisoxazole in the presence of LDA (lithium isopropylamide) or the like, and the resulting 6-acetamido-3-phenethyl-1,2-benzisoxazole is obtained. Can be obtained by hydrolysis with hydrochloric acid or the like.

(Synthesis method 2)

Embedded image (In the above reaction formula, W is the same as described above.) The benzisoxazole carbaldehyde derivative represented by the general formula (e) is converted into a solvent not involved in the reaction such as ethanol or benzene in the presence of a base such as piperidine or triethylamine. By conducting a condensation reaction with 2,4-thiazolidinedione below, a benzisoxazole derivative represented by the general formula (f) can be obtained. The benzisoxazole derivative represented by the general formula (f) is replaced with ethanol,
Catalytic reduction using platinum oxide, palladium carbon, or the like, or reduction of sodium borohydride, etc., in a solvent that does not participate in a reaction such as 1,4-dioxane, dimethylformamide or 1,3-dimethylimidazolidin-2-one Reduction using an agent gives a benzisoxazole derivative represented by the general formula (g).

(Synthesis method 3)

Embedded image (In the above reaction formula, T ² is chlorine, bromine, iodine,
Represents a leaving group such as mesyloxy and tosyloxy, and W is the same as defined above.) The alcohol derivative (h) includes thionyl chloride, hydrogen chloride,
Compound (i) is obtained by reacting mesylate chloride or the like, and tert. By reacting 2,4-thiazolidinedione in the presence of alkyl lithium such as -butyllithium and n-butyllithium,
A benzisoxazole derivative represented by the general formula (j) is obtained.

(Synthesis method 4)

Embedded image (In the reaction formula, R ¹¹ is a phenyl group, and T ¹ , R ¹⁰ and W are the same as described above.) Compound (b) in Synthesis Reaction 1 is involved in a reaction with DMF or the like under ice-cooling in the presence of sodium hydride. Not in the solvent,
By acting R ¹¹ SH, a propionate derivative represented by the general formula (k) can be obtained, and by hydrolyzing the derivative, a benzisoxazole derivative represented by the general formula (l) can be obtained. it can.

(Synthesis reaction 5)

Embedded image (In the reaction formula, R ¹² represents an alkyl group having 1 to 6 carbon atoms such as methyl and ethyl, R ¹³ represents methoxy, ethoxy, isobutyloxy group, 2-methoxyethoxy group and the like, and W is the same as the above. )

(Synthesis reaction 6)

Embedded image (In the reaction formula, R ¹⁴ represents an alkyl group having 1 to 6 carbon atoms such as methyl and ethyl; and R ¹⁵ represents an alkyl group having 1 to 6 carbon atoms such as phenyl, methyl and ethyl; Represents an alkoxy group represented by Formulas 1 to 6, T ³ represents a halogen atom, and W is the same as described above.

(Synthesis reaction 7)

Embedded image (In the reaction formula, PH represents a phenyl group, R ¹⁶ represents an alkyl group having 1 to 6 carbon atoms such as phenyl, methyl, and ethyl, TMS represents a trimethylsilyl group, and W is the same as described above.) The benzisoxazole derivatives represented by the general formulas (I) and (II) can also be obtained by a method similar to the above method.

The representative compounds of the present invention thus obtained are shown below. (1) 5-[[3- [2- (2-pyridyl) ethyl]-
1,2-Benzisoxazol-6-yl] methyl]-
2,4-thiazolidinedione (2) 5-[[3- [2- (3,4-dimethoxyphenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidine Dione (3) 5-[[3- [2- (methyl-2-pyridylamino) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidinedione (4) 5- [ [3- [2- (4-chlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidinedione (5) 5-[[3- [2- (4- Trifluoromethylphenyl) ethyl] -1,2-benzisoxazole-
6-yl] methyl] -2,4-thiazolidinedione (6) 5-[[3- [2- (methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazole-6 Yl] methyl] -2,4-thiazolidinedione (7) 5-[[3- [2- (2-pyridyl) ethyl]-
1,2-Benzisoxazol-6-yl] methyl]-
2,4-oxazolidinedione (8) 5-[[3- [2- (3,4-dimethoxyphenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-oxazolidine Dione (9) 5-[[3- [2- (methyl-2-pyridylamino) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-oxazolidinedione (10) 5- [[3- [2- (4-Chlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-oxazolidinedione

(11) 5-[[3- [2- (4-trifluoromethylphenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-oxazolidinedione (12 ) 5-[[3- [2- (Methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-oxazolidinedione (13) 2 -Ethoxy-3- [3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2
-Benzisoxazol-6-yl] propionic acid (14) 2-ethoxy-3- [3- [2- (2-pyridyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid ( 15) 2-ethoxy-3- [3- [2- (3,4-dimethoxyphenyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (16) 2-ethoxy-3- [3 -[2- (4-chlorophenyl) ethyl] -1,2-benzisoxazole-
6-yl] propionic acid (17) 2-ethoxy-3- [3- [2- (4-trifluoromethylphenyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (18) 2 -Ethoxy-3- [3- [2- (methyl-2
-Benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (19) 2- (2-methoxyethoxy) -3- [3-
[2- (2-Phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (20) 2- (2-methoxyethoxy) -3- [3-
[2- (2-pyridyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid

(21) 2- (2-methoxyethoxy)-
3- [3- [2- (3,4-Dimethoxyphenyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (22) 2- (2-methoxyethoxy) -3- [3 −
[2- (4-Chlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (23) 2- (2-methoxyethoxy) -3- [3-
[2- (4-trifluoromethylphenyl) ethyl]-
1,2-benzisoxazol-6-yl] propionic acid (24) 2- (2-methoxyethoxy) -3- [3-
[2- (Methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (25) 2- (3-phenylpropyl) -3- [3-
[2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (26) 2- (3-phenylpropyl) -3- [3 −
[2- (2-pyridyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (27) 2- (3-phenylpropyl) -3- [3-
[2- (3,4-dimethoxyphenyl) ethyl] -1,
2-benzisoxazol-6-yl] propionic acid (28) 2- (3-phenylpropyl) -3- [3-
[2- (4-Chlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (29) 2- (3-phenylpropyl) -3- [3-
[2- (4-trifluoromethylphenyl) ethyl]-
1,2-benzisoxazol-6-yl] propionic acid (30) 2- (3-phenylpropyl) -3- [3-
[2- (Methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl] propionic acid

(31) 5-[[3- [2- (2,4-dichlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidinedione (32) 5 -[[3- [2- (2-fluorophenyl)
Ethyl] -1,2-benzisoxazol-6-yl]
Methyl] -2,4-thiazolidinedione (33) 5-[[3- [2- (3,4-dimethoxyphenyl) ethyl] -1,2-benzisoxazole-5-
Yl] methyl] -2,4-thiazolidinedione (34) 5-[[3- [2- (2,4-dichlorophenyl) ethyl] -1,2-benzisoxazol-5-yl] methyl] -2, 4-thiazolidinedione (35) 5-[[3- [2- (methyl-2-pyridylamino) ethyl] -1,2-benzisoxazole-5-
Yl] methyl] -2,4-thiazolidinedione (36) 5-[[3- [2- (4-chlorophenyl) ethyl] -1,2-benzisoxazol-5-yl] methyl] -2,4- Thiazolidinedione (37) 5-[[3- [2- (4-trifluoromethylphenyl) ethyl] -1,2-benzisoxazole-
5-yl] methyl] -2,4-thiazolidinedione (38) 5-[[3- [2- (methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-5-yl ] Methyl] -2,4-thiazolidinedione (39) 5-[[3- [2- (2-fluorophenyl)
Ethyl] -1,2-benzisoxazol-5-yl]
Methyl] -2,4-thiazolidinedione (40) 5-[[3- [2- (2-pyridyl) ethyl]
-1,2-Benzisoxazol-5-yl] methyl]
-2,4-thiazolidinedione

(41) 5-[[3- [2- (4-methyl-5-phenyl-2-oxazolyl) ethyl] -1,2
-Benzisoxazole-6-yl] methyl] -2,4
-Oxazolidinedione (42) 5-[[3- [2- (3,4-dimethoxyphenyl) ethyl] -1,2-benzisoxazole-6-
Yl] methyl] -2,4-oxazolidinedione (43) 5-[[3- [2- (methyl-2-pyridylamino) ethyl] -1,2-benzisoxazole-6-
Yl] methyl] -2,4-oxazolidinedione (44) 5-[[3- [2- (4-chlorophenyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4- Oxazolidinedione (45) 5-[[3- [2- (4-trifluoromethylphenyl) ethyl] -1,2-benzisoxazole-
6-yl] methyl] -2,4-oxazolidinedione (46) 5-[[3- [2- (methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl ] Methyl] -2,4-oxazolidinedione (47) 5- [3- [3- [2- (Methyl-2-benzoxazolylamino) ethyl] -1,2-benzisoxazol-6-yl] Methyl] -2,4-oxazolidinedione (48) 2-ethoxy-3- [3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2
-Benzisoxazole-6-yl] propionic acid

Next, the results of pharmacological experiments on the blood glucose lowering action and neutral lipid lowering action of the compound of the present invention will be shown. (Pharmacological test) The compounds of the present invention were examined for their blood glucose lowering effect and triglyceride lowering effect using KKA ^y mice, which are model animals of insulin-independent diabetes. KK
^Ay mice (9 to 11 weeks old) were divided into homogeneous groups according to plasma glucose concentration, and then each compound of the present invention suspended in a 1% methylcellulose solution was orally administered once a day for 3 days. did. A 1% methylcellulose solution was orally administered to the non-drug-administered group (control). Blood was collected 18 hours after the last administration, and the glucose concentration and triglyceride concentration in plasma were measured. The measurement was performed using commercially available measurement kits (Glucose CII-Test Wako- and Triglyceride G-, respectively).
Test Wako, Wako Pure Chemical Industries, Ltd.). The ratio of plasma glucose concentration and triglyceride concentration in the group to which the compound of the present invention was administered to the non-drug-administered group was calculated (percent), and the results are shown in Table 1.

(Result)

[Table 1]

Compound 1: 5-[[3-phenethyl-1,
2-benzisoxazole-6-yl] methyl] -2,
4-thiazolidine-dione compound 2: 5-[[3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6yl] methyl] -2, 4-thiazolidinedione compound 3: 2- (phenylthio) -3- [3- [2-
(2-Phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid Compound 4: 2-ethoxy-3- [3- [2- (2-phenyl- 5-methyl-4-oxazolyl) ethyl] -1,
2-benzisoxazol-6-yl] propionic acid From Table 1, the compound of the present invention significantly reduced glucose concentration and triglyceride concentration as compared with the non-drug-administered group.
It was revealed that it has an excellent hypoglycemic effect and blood lipid lowering effect.

The compound of the present invention can be administered orally or parenterally. Oral dosage forms include tablets, capsules, powders, granules and syrups, and parenteral administration methods include mucosal administration such as eye drops, inhalants, sprays, suppositories, and ointments. And intravascular administration such as injections. The production of the above oral preparations is carried out using ordinary excipients, disintegrants, binders, lubricants, pigments, diluents and the like. As excipients, glucose, lactose, etc., as disintegrants, starch, carboxymethylcellulose calcium, etc., as lubricants, magnesium stearate, talc, etc., as binders, hydroxypropylcellulose, gelatin, For example, polyvinylpyrrolidone is used. In the case of parenteral administration preparations for injections, they are prepared using distilled water for injection, physiological saline, and Ringer's solution.

The dose of the compound of the present invention is usually about 0.1 mg to 200 mg per day for injection and about 1 mg to 2000 mg per day for oral administration in adults.
It can be increased or decreased depending on the symptoms. As described above, the compound of the present invention has excellent plasma glucose concentration-lowering effect and triglyceride concentration-lowering effect, and thus is useful as a therapeutic agent for diabetes and hyperlipidemia.

[0033]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 5-[[3-phenethyl-1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidine-dione (1) 6-acetamido-3-phenethyl-1,2- Benzisoxazole 6-acetamido-3-methyl-1,2-benzisoxazole (500 mg, 2.62 mmol) was dried in TH.
F25ml, and then 2M LDA (lithium diisopropylamide) at -78 ° C under nitrogen atmosphere
(2.6 ml, 5.2 mmol) was added dropwise over 10 minutes, and the mixture was further stirred for 10 minutes under the same conditions. Subsequently, a THF solution of benzyl iodide (573 mg, 2.62 mmol / 4
ml) was added dropwise over 1 minute, followed by stirring for 30 minutes under the same conditions. After confirming the completion of the reaction, the temperature was returned to room temperature, and a saturated aqueous solution of ammonium chloride and ethyl acetate were added. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, filtered, and then ethyl acetate was distilled off. The resulting residue is purified by silica gel chromatography (chloroform-chloroform / methano-
To give the title compound as white crystals. (Yield 48%)

[0034] _{^{1 H-NMR (CDCl 3)}} δ; 2.20 (3H, s) 3.1-3.3 (4H, m) 7.1-7.3 (6H, m) 7.35 (1H , D, J = 9 Hz) 8.05 (1H, br-s)

(2) 6-amino-3-phenethyl-1,
2-benzisoxazole 6-acetamido-3-phenethyl-1,2-benzisoxazole obtained in the above (1) (290 mg, 1.
03 mmol) was suspended in 1N hydrochloric acid (15 ml), and the reaction temperature was raised to 100 ° C., and the mixture was heated under reflux for 6 hours. After confirming the completion of the reaction, the temperature was returned to room temperature, a saturated aqueous solution of sodium carbonate was added to neutralize the mixture, and ethyl acetate was further added to separate an ethyl acetate layer. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to give the title compound (200 mg) as white crystals in the residue. (Yield 81
%)

[0036] _{^{1 H-NMR (CDCl 3)}} δ; 3.1-3.3 (4H, m) 4.02 (2H, br-s) 6.58 (1H, dd, J = 2,8Hz) 6 0.71 (1H, d, J = 2 Hz) 7.2-7.4 (6H, m)

(3) Methyl 2-bromo-3- [3-phenethyl-1,2-benzisoxazol-6-yl] propionate 6-amino-3-phenethyl-propionate obtained in the above (2)
1,2-benzisoxazole (480 mg, 2.01
mmol) in a mixed solvent of acetone (5 ml) and water (2 ml), and 47% HBr (1.43 g) under ice-cooling.
Was added. After 10 minutes, the aqueous solution of sodium nitrite (157 mg, 2.27 mmol, 0.2 m
l) was added dropwise over 1 minute. After stirring at the same temperature for 10 minutes, methyl acrylate (1.11 ml, 12.
3 mmol) was added dropwise over 1 minute, and 10 minutes later, cuprous oxide (19 mg) was gradually added. The external temperature was raised to 45 ° C., and the mixture was vigorously stirred for 15 minutes under the same conditions. After confirming the completion of the reaction, an aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. After washing the organic layer with water,
Dry over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, ethyl acetate was distilled off to obtain the title compound in a crude form. The obtained crude product was carried on to the next step without purification.

3.2-3.3 (4H, m) 3.40 (1H, dd, J = 7, 14 Hz) 3.63 (1H, dd, J = 7) ¹ H-NMR (CDCl ₃ ) δ; , 14 Hz) 3.75 (2H, br-s) 4.45 (1H, t, J = 7 Hz) 7.12 (1H, d, J = 7 Hz) 7.3-7.8 (7H, m)

(4) 5-[[3-phenethyl-1,2-
Benzisoxazol-6-yl] methyl] -2-iminothiazolidine-4-one 2-bromo-3- [3-phenethyl-1,2-benzisoxazol-6-yl] obtained in (3) above Crude methyl propionate (690 mg) and thiourea (135)
mg, 1.78 mmol), sodium acetate (145 m
g, 1.78 mmol) was dissolved in ethanol (10 ml), and the mixture was heated and stirred for 5 hours. After confirming the completion of the reaction, the reaction mixture was allowed to cool, ethanol was distilled off, and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was distilled off. The obtained crystals were washed with a mixed solvent of hexane and ethyl acetate to give 140 mg of the title compound as pale brown crystals.

¹ H NMR (DMSO-d ₆ ) δ; 3.0-3.2 (3H, m) 3.2-3.3 (2H, t, J = 7 Hz) 3.53 (1H, dd, J = 4, 14 Hz) 4.69 (1H, dd, J = 4, 14 Hz) 7.1-7.3 (6H, m) 7.54 (1H, s) 7.77 (1H, d, J = 8 Hz) 8.68 (1H, brs) 8.90 (1H, brs)

(5) 5-[[3-phenethyl-1,2-
Benzisoxazol-6-yl] methyl] -2,4-
Thiazolidine-dione 5-[[3-phenethyl-1,2 obtained in the above (4).
-Benzisoxazol-6-yl] methyl] -2-iminothiazolidine-4-one (140 mg, 0.40 m
mol) with 1N hydrochloric acid (4 ml) and ethanol (4 ml)
And then heated and stirred at 80 ° C. for 20 hours. After confirming the completion of the reaction, the mixture was allowed to cool, and neutralized with saturated aqueous sodium hydrogen carbonate. Ethyl acetate was added thereto, and the mixture was stirred under the same conditions for 10 minutes. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography (hexane / ethyl acetate = 1/2).
The title compound was obtained as white crystals. (Yield 50
%)

[0042] _{^{1 H NMR (DMSO-d 6}} ) δ; 3.12 (2H, t, J = 7Hz) 3.18 (1H, dd, J = 9,14Hz) 3.2-3.3 (2H, m) 3.54 (1H, dd, J = 4, 14 Hz) 4.66 (1H, dd, J = 4, 9 Hz) 7.1-7.3 (6H, m) 7.54 (1H, s) 7.77 (1H, d, J = 8Hz)

[0043]

Example 2 5-[[3- [2- (2-phenyl-5-methyl-4-)
Oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] methyl] -2,4-thiazolidinedione (1) 6-acetamido-3- [2- (2-phenyl-
5-Methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole 6-acetamido-3-methyl-1,2-benzisoxazole (1.5 g, 7.89 mmol) in dry THF
After dissolving in 25 ml, 2M LDA (9.0 ml, 18.0 mmol) was added to 10 ml at −78 ° C. under a nitrogen atmosphere.
The mixture was added dropwise over a period of minutes, and further stirred for 10 minutes under the same conditions.
Subsequently, a THF solution of 4-iodomethyl-5-methyl-2-phenyloxazole (1.9 g, 7.89 mmol) was used.
/ 4 ml) over 1 minute, followed by stirring for 30 minutes under the same conditions. After confirming the completion of the reaction, the temperature was returned to room temperature, and a saturated aqueous solution of ammonium chloride and ethyl acetate were added. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and filtered, and then ethyl acetate was distilled off. The obtained residue was purified by silica gel chromatography (chloroform-chloroform / methanol = 100/1) to obtain the above-mentioned title compound as white crystals. (Yield 32%)

¹ H-NMR (CDCl ₃ ) δ; 2.14 (3H, s) 2.19 (3H, s) 3.02 (2H, t, J = 8 Hz) 3.32 (2H, t, J) = 8 Hz) 7.13 (1H, dd, J = 2.9 Hz) 7.35-7.45 (4H, m) 7.83 (1H, br-s) 7.9-8.0 (2H, m ) 8.08 (1H, d, J = 2Hz)

(2) 6-amino-3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,
2-benzisoxazole 6-acetamido-3- [2- obtained in the above (1)
(2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole (700 mg,
1.9 mmol) was suspended in 1N hydrochloric acid (9 ml), the reaction temperature was raised to 100 ° C., and the mixture was heated under reflux for 6 hours.
After confirming the completion of the reaction, the temperature was returned to room temperature, a saturated aqueous solution of sodium carbonate was added, and the mixture was neutralized. Ethyl acetate was added, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, filtered and the ethyl acetate was distilled off to obtain 530 mg of the title compound as a colorless oil in the residue. (Yield 81
%)

[0046] _{^{1 H-NMR (CDCl 3)}} δ; 2.15 (3H, s) 3.00 (2H, t, J = 7Hz) 3.27 (2H, t, J = 7Hz) 4.01 (2H , Br-s) 6.54 (1H, dd, J = 2.9 Hz) 6.70 (1H, d, J = 2 Hz) 7.2-7.5 (4H, m) 8.0-8.2. (2H, m)

(3) 2-bromo-3- [3- [2- (2
-Phenyl-5-methyl-4-oxazolyl) ethyl]
Methyl -1,2-benzisoxazol-6yl] propionate 6-amino-3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl]-obtained in the above (2).
1,2-benzisoxazole (500 mg, 1.64
mmol) in acetone (5 ml) and methanol (2 m
1) and dissolved in ice-cooled 47% HBr
(1.16 g) was added. After 10 minutes, an aqueous solution of sodium nitrite (128 mg, 1.86 m
mol / 0.2 ml) was added dropwise over 5 minutes. After stirring at the same temperature for 10 minutes, methyl acrylate (0.91 ml, 10.1 mmol) was added dropwise over 1 minute, and 10 minutes later, cuprous oxide (15 mg) was gradually added. The external temperature was raised to 45 ° C., and the mixture was vigorously stirred for 15 minutes under the same conditions. After confirming the completion of the reaction, an aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer is washed with water, dried over anhydrous sodium sulfate,
The mixture was filtered and the ethyl acetate was distilled off to give the title compound as a crude product. The obtained crude product was carried on to the next step without purification.

[0048] _{^{1 H-NMR (CDCl 3)}} δ; 2.15 (3H, s) 3.00 (2H, t, J = 7Hz) 3.36 (2H, t, J = 7Hz) 3.3-3 .4 (1H, m) 3.62 (1H, dd, J = 7, 14 Hz) 3.73 (1H, s) 4.43 (1H, t, J = 7 Hz) 7.09 (1H, d, J) = 8 Hz) 7.4-7.6 (4H, m) 7.95-8.05 (2H, m)

(4) 5-[[3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-
Benzisoxazolyl-6-yl] methyl] -2-iminothiazolidine-4-one 2-bromo-3- [3- [2-] obtained in the above (3)
(2-Phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6yl] methyl propionate (675 mg) and thiourea (109
mg, 1.44 mmol), sodium acetate (117 m
g, 1.44 mmol) was dissolved in ethanol (10 ml) and stirred with heating for 8 hours. After confirming the completion of the reaction,
The precipitated crystals were separated and washed with ether and water. The obtained crystals were dried overnight to give 350 mg of the title compound as white crystals.

[0050] _{^{1 H NMR (DMSO-d 6}} ) δ; 2.15 (3H, s) 2.99 (2H, t, J = 7Hz) 3.12 (1H, dd, J = 9,14Hz) 3. 3-3.4 (2H, m) 3.52 (1H, dd, J = 4, 14 Hz) 4.67 (1H, dd, J = 4, 9 Hz) 7.24 (1H, d, J = 8 Hz) 7.5-7.6 (3H, m) 7.54 (1H, s) 7.76 (1H, d, J = 8 Hz) 7.90-7.95 (2H, m) 8.68 (1H, m) brs) 8.90 (1H, brs)

(5) 5-[[3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-
Benzisoxazol-6-yl] methyl] -2,4-
Thiazolidinedione 5-[[3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2 obtained in the above (4).
-Benzisoxazol-6-yl] methyl] -2-iminothiazolidine-4-one (190 mg, 0.40 m
mol) with 2N hydrochloric acid (3 ml) and ethanol (3 ml)
And mixed with heating at 80 ° C. for 20 hours. After confirming the completion of the reaction, the mixture was allowed to cool. Further, saturated aqueous sodium hydrogen carbonate was added to neutralize the reaction solution, and then ethyl acetate was added, followed by stirring for 10 minutes under the same conditions. The organic layer was separated, dried over anhydrous sodium sulfate and collected by filtration, and then ethyl acetate was distilled off. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 1/3) to obtain the above-mentioned title compound as white crystals. (Yield 31%)

[0052] _{^{1 H NMR (DMSO-d 6}} ) δ; 2.16 (3H, s) 3.05 (2H, t, J = 7Hz) 3.32 (1H, dd, J = 9,14Hz) 3. 36 (2H, t, J = 7 Hz) 3.64 (1H, dd, J = 4, 14 Hz) 4.58 (1H, dd, J = 4, 9 Hz) 7.10 (1H, dd, J = 2) 7-7.5 (4H, m) 7.53 (1H, d, J = 8 Hz) 7.95-8.00 (2H, m) 8.0-8.1 (1H, brs) IR (KBr): cm ^-1 3300, 3050, 2900, 2750, 1760,
1710, 1690, 1650, 1640, 162
0, 1550, 1480, 1450, 1420, 1
390, 1330, 1250, 1220, 1150, 1
130, 1030, 870, 820, 780, 72
0,700,630

[0053]

Example 3 2-phenylthio-3- [3- [2- (2-phenyl-
5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid (1) 2-chloro-3- [3- [2- (2-phenyl-
Methyl 5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionate The title compound was obtained in the same manner as in Example 2, (1) → (3). _{^{1 H-NMR (CDCl 3)}} δ; 2.16 (3H, s) 3.04 (2H, t, J = 7Hz) 3.36 (2H, t, J = 7Hz) 3.31 (1H, dd, J = 7, 14 Hz) 3.51 (1H, dd, J = 7, 14 Hz) 3.75 (3H, s) 4.49 (1H, t, J = 7 Hz) 7.11 (1H, d, J = 9-Hz) 7.4-7.5 (4H, m) 7.51 (1H, m) 7.98 (2H, dd, J = 2.9 Hz)

(2) 2-phenylthio-3- [3- [2
-(2-Phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionate Sodium hydride (28 mg, 0.70 mmol) under ice-cooling
l) was slowly added in DMF (4 ml) followed by thiophenol (0.07 ml, 0.70 mmol) over 1 minute. After 30 minutes, the temperature is returned to room temperature and 2-chloro-3-
[3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole-6
-Yl] methyl propionate (270 mg, 0.64 m
mol) in DMF (2 ml) was added slowly. 3
After 0 minute, the reaction temperature was raised to 80 ° C., and the mixture was heated and stirred for 2 hours. After confirming the completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 210 mg of the title compound as a colorless oil. (Yield 68%)

[0055] _{^{1 H NMR (CDCl 3) δ}} ; 2.14 (3H, s) 3.03 (2H, t, J = 7Hz) 3.18 (1H, dd, J = 9,14Hz) 3.25- 3.4 (3H, m) 3.91 (1H, dd, J = 7, 10 Hz) 7.07 (1H, d, J = 8 Hz) 7.3-7.5 (10H, m) 7.9- 8.0 (2H, m)

(3) 2-phenylthio-3- [3- [2
-(2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl]
-Propionic acid 2-phenylthio-3- [3- obtained in the above (2)
Methyl [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionate (200 mg, 0.41 mmol)
l) was dissolved in 4 ml of ethanol and 1N at room temperature.
-NaOH (1 ml) was added, and the mixture was further stirred for 1 hour. After confirming the completion of the reaction, 1N-HCl was added to neutralize the reaction solution, and the mixture was further stirred overnight. After filtering the precipitated crystals,
Wash with water and dry under reduced pressure to give the title compound 1 as a white powder
75 mg were obtained. (88% yield)

Mp 145-147 ° C. ¹ H NMR (DMSO-d ₆ ) δ; 2.16 (3H, s) 2.98 (2H, t, J = 7 Hz) 3.14 (1H, dd, J = 7) , 14Hz) 3.2-3.4 (3H, m) 4.14 (1H, t, J = 7Hz) 7.3-7.7 (10H, m) 7.75 (1H, d, J = 7Hz) 7.90 (2H, dd, J = 2.7 Hz) 12.7 (1H, brs) IR (KBr): cm ^-1 3050, 2900, 1720, 1700, 1650,
1620, 1540, 1480, 1440, 143
0, 1420, 1410, 1340, 1220, 1
180, 1170, 1130, 1220, 1180, 1
170, 1130, 1020, 840, 820, 7
80, 740, 710, 680

[0058]

Example 4 2-ethoxy-3- [3- [2- (2-phenyl-5-
Methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionate (1) 6-bromo-3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl ] -1,2-Benzisoxazole 6-amino-3- [2- (2-phenyl-5-methyl-
4-oxazolyl) ethyl] -1,2-benzisoxazole (400 mg, 1.25 mmol) was dissolved in a mixed solvent of methanol-acetone (2/5, 5 ml), and then cooled under ice (internal temperature 1 ° C.). ) At 47% hydrobromic acid (0.9
4g) was added over 1 minute. After 10 minutes, an aqueous solution of sodium nitrite (110 mg, 1.58 mmol / 0.2 m
l) was added dropwise over 1 minute, and the mixture was stirred for 10 minutes under the same conditions. Subsequently, a copper (I) bromide / 47% hydrobromic acid solution (11
(0 mg / 520 mg) was similarly added dropwise over 1 minute, and the reaction temperature (internal temperature) was raised to 40 ° C., followed by stirring for 30 minutes.
After confirming the completion of the reaction, the mixture was cooled on ice and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 640 mg of the title compound as white crystals. (Yield 8
9%) ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s) 3.04 (2H, t, J = 7 Hz) 3.36 (2H, t, J = 7 Hz) 7.35 (1H) , Dd, J = 2.9 Hz) 7.4-7.5 (4H, m) 7.73 (1H, d, J = 2 Hz) 7.95-8.0 (2H, m)

(2) 3- [2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole-6-carbaldehyde 6-bromo-3- [2- ( 2-phenyl-5-methyl-
4-oxazolyl) ethyl] -1,2-benzisoxazole (380 mg, 1.00 mmol) was dissolved in dry tetrahydrofuran (10 ml), and then n-butyllithium (2.5 M ) (1.
5 ml, 3.80 mmol) was slowly added dropwise over 5 minutes. After 30 minutes, this time, a solution of dry DMF in tetrahydrofuran (366 mg, 5.0 mmol / 1 ml) was added to 3 portions.
After dropwise addition over a period of minutes, the mixture was stirred for 30 minutes under the same conditions. After confirming the disappearance of the raw materials, the temperature was returned to room temperature, a saturated aqueous solution of ammonium chloride and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 125 mg of the title compound as a colorless oil.
I got (Yield 38%) ¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H, s) 3.07 (2H, t, J = 7 Hz) 3.43 (2H, t, J = 7 Hz) 4-7.5 (3H, m) 7.71 (1H, d, J = 8 Hz) 7.78 (1H, dd, J = 8 Hz) 7.9-8.0 (2H, m) 8.03 ( 1H, s) 10.14 (1H, s)

(3) 6- (2-methoxyvinyl) -3-
[2- (2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole (methoxymethyl) phosphonium chloride (598m
g, 1.74 mmol) in dry tetrahydrofuran (6
ml), and then lithium diisopropylamide (2.0M) (0.87m) at -15 ° C under a nitrogen atmosphere.
1,1.74 mmol) was added over 1 minute. After stirring for 40 minutes under the same conditions, 3- [2- (2-phenyl-5)
-Methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole-6-carbaldehyde solution in tetrahydrofuran (290 mg, 0.87 mmol / 2 ml)
Was added over 1 minute. After returning to room temperature and stirring for 30 minutes, a saturated aqueous solution of ammonium chloride and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (68 mg) as a colorless oily substance as a mixture of E-form and Z-form. (Yield 22%)

(4) 6- (2,2-diethoxyethyl)
-3- [2- (2-Phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazole 6- (2-methoxyvinyl) -3- [2- (2-phenyl-5 -Methyl-4-oxazolyl) ethyl] -1,2
-Benzisoxazole (65 mg, 0.18 mmol
l) and p-toluenesulfonic acid hydrate (4 mg) were dissolved in ethanol (4 ml).
C. and heated to reflux overnight. After confirming the completion of the reaction, ethanol was distilled off, and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to separate the organic layer. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 70 mg of the title compound as a colorless oil in the residue. (Yield 92%) ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7 Hz) 2.15 (3H, s) 3.0-3.1 (4H, m) 35 (2H, t, J = 7 Hz) 3.4-3.5 (2H, m) 3.6-3.75 (2H, m) 4.65 (1H, t, J = 6 Hz) 7.14 ( 1H, dd, J = 2.9 Hz) 7.4-7.5 (5H, m) 7.9-8.1 (2H, m)

(5) 2-ethoxy-3- [3- [2-
(2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionitrile 6- (2,2-diethoxyethyl) -3- [2- ( 2-
Phenyl-5-methyl-4-oxazolyl) ethyl]-
1,2-benzisoxazole (67 mg, 0.16 m
mol) was dissolved in dry dichloromethane (2 ml), and trimethylsilyl cyanide (0.08 ml) was added dropwise over 1 minute. Subsequently, a boron trifluoride etherate (5 μl, 0.05 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After 1 hour and 2 hours, boron trifluoride etherate (5 μl) was added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, chloroform and a saturated aqueous solution of sodium hydrogen carbonate were added. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Subsequently, after the solvent was distilled off, the residue was subjected to column chromatography (hexane / hexane).
Purification by ethyl acetate (4/1) yielded 34 mg of the title compound as a colorless oil. (Yield 53%) ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7 Hz) 2.17 (3H, s) 3.05 (2H, t, J = 7 Hz) 2-3.3 (2H, m) 3.37 (2H, t, J = 7 Hz) 3.4-3.6 (1H, m) 3.8-3.9 (1H, m) 4.32 ( 1H, t, J = 7 Hz) 7.16 (1H, d, J = 8 Hz) 7.4-7.5 (4H, m) 7.53 (1H, d, J = 8 Hz) 7.9-8. 0 (2H, m)

(6) 2-ethoxy-3- [3- [2-
(2-phenyl-5-methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionic acid 2-ethoxy-3- [3- [2- (2-phenyl-5-
Methyl-4-oxazolyl) ethyl] -1,2-benzisoxazol-6-yl] propionitrile (34 m
g, 0.085 mmol) in ethanol (1.5 ml)
And dissolved in a 6N aqueous sodium hydroxide solution (0.5%).
0 ml) was added slowly. Raise the reaction temperature to 90 ° C 9
The mixture was heated under reflux for 0 minutes. After confirming the disappearance of the raw materials, the reaction solution was cooled on ice, concentrated hydrochloric acid was slowly added to adjust the pH of the reaction solution to 4 to 5, and the solution was left overnight. The precipitated crystals were collected by filtration, washed with 30 ml of water, and dried under reduced pressure at 50 ° C. for 3 hours to obtain 19 mg of the title compound as white crystals. (56% yield) ¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (3H, t, J = 7 Hz) 2.16 (3H, s) 2.99 (2H, t, J = 7 Hz) 3.0-3.2 (2H, m) 3.3-3.5 (3H, m) 3.37 (2H, m) 3.5-3.6 (1H, m) 4.07 (1H, m) dd, J = 4, 8 Hz) 7.24 (1 H, d, J = 8 Hz) 7.4-7.6 (4 H, m) 7.73 (1 H, d, J = 8 Hz) 7.9-8. 0 (2H, m) 12.7 (1H, brs)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 417/04 261 C07D 417/04 261 417/14 213 417/14 213

Claims (6)

[Claims] (1) a compound represented by the general formula (I): [In the formula, A represents an aryl group or a heterocyclic group which may have a substituent, and B represents a carboxyl group, a cyano group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a C7 to C11 An acid group such as an aryloxycarbonyl group, a sulfonic acid group or a phosphonic acid group, or a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring constituent atoms Wherein Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; Y ² represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent; ¹ is a bond, an oxygen atom, a sulfur atom or NR ¹ (R
¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group. And X ² represents a bond, an oxygen atom, a sulfur atom or NR ² (R ² is a hydrogen atom, a carbon number of 1 to 8)
Represents an alkyl group or an aralkyl group. ). ] Or a salt thereof. 2. A compound of the general formula (II): [In the formula, A ¹ represents an aryl group or a heterocyclic group which may have a substituent, and Q represents 2,4-thiazolidinedione-
5-ylmethyl group, 2,4-oxazolidinedione-5
-Ylmethyl group or the following general formula (III): (Wherein G represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aryl group which may have a substituent, and Y ⁴ represents a bond or a carbon atom which may have a substituent. Represents an alkylene chain of Formulas 1 to 8, Z ¹ represents a bond, an oxygen atom, a sulfur atom or NR ³ (R ³ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group), and Z ² represents a bond, an oxygen atom, a sulfur atom or NR ⁴ (R ⁴ represents a hydrogen atom,. an alkyl group or an aralkyl group having 1 to 8 carbon atoms) groups represented by the representative.) the, Y ³ Represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent, and X ³ represents a bond, an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom,
Represents an alkyl group or an aralkyl group having 1 to 8 carbon atoms. )
And X ⁴ represents a bond, an oxygen atom, a sulfur atom or NR ⁶ (R ⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an aralkyl group). ] Or a salt thereof. 3. The benzisoxazole derivative or a salt thereof according to claim 2, wherein Q is substituted at the 5- or 6-position of the benzisoxazole ring. 4. A benzisoxazo- according to claim 1, wherein
A pharmaceutical composition comprising a derivative or a salt thereof as an active ingredient. 5. A benzisoxazo- according to claim 1, wherein
A hypoglycemic agent comprising a thiol derivative or a salt thereof as an active ingredient. 6. A benzisoxazo- according to claim 1, wherein
A therapeutic agent for hyperlipidemia, which comprises a thiol derivative or a salt thereof as an active ingredient.