JPH02167225A - Hypoglycemic agent - Google Patents

Abstract

PURPOSE:To obtain a hypoglycemic agent containing a specific benzoxazole derivative or salt thereof as an active ingredient without side effects, such as grave hypoglycemia. CONSTITUTION:A hypoglycemic agent containing a compound expressed by formula I (R is phenyl, naphthyl, cycloalkyl or heterocyclic group optionally having a substitutent group; Alk is single direct bond, lower alkenylene, lower alkynylene or lower alkylene optionally having a substitutent group; the dotted line indicates that the bond may be double bond), e.g. 5-[(2,4-dioxothizaolidin-5-yl) methyl]-2-[(2-naphthyl)methyl]benzoxazole, as an active ingredient. The does of the above-mentioned compound is 0.005-100mg/kg, preferably 0.01-10mg/kg a day. The compound expressed by formula I is a novel compound and obtained by, e.g. subjecting an amide compound expressed by formula II to dehydrating reaction.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to hypoglycemic agents.

(Prior Art) Hypoglycemic agents such as biguanide compounds and sulfonylurea compounds have conventionally been used to treat diabetes. However, biguanide compounds have the side effect of lactic acidosis, and sulfonylurea compounds have serious hypoglycemic side effects, and there is a desire to develop new hypoglycemic agents that do not have these drawbacks.

(Structure and effects of the invention) The present invention is based on the general formula (wherein R is a phenyl group, naphthyl group, cycloalkyl group, or heterocyclic group that may have a substituent, and Alk is a single bond, a lower alkenylene group, a lower An alkynylene group or a lower alkylene group that may have a substituent, and a dotted line indicates that the bond at the site may be a double bond.

) Blood t, Ml! containing as an active ingredient a benzoxazole derivative or a pharmacologically acceptable salt thereof. f! Concerning laxatives.

The active ingredients, Penzo; Tosazole conductor (1) and its salts, are all new compounds and have excellent blood thinning action based on insulin sensitivity enhancing action. Therefore, the hypoglycemic agent of the present invention is useful for treating and preventing diabetes, and is particularly suitable for treating patients with non-insulin-dependent diabetes.

This effect of the active ingredient compound (1) of the present invention is thought to be due to increasing the insulin sensitivity of cells, and it is said that it has almost no effect on normal animals.
It has features not found in conventional hypoglycemic agents. Furthermore, this compound (1) has low toxicity, for example, 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2-[(2-
A CMC suspension of (naphthyl)methyl)benzoxazole was orally administered to mice (dose: 3000 mg/'kg) and then observed for 72 hours, but no deaths were observed.

Specific examples of the benzoxazole derivatives that are the active ingredients of the hypoglycemic agent of the present invention include -C formula (1) where R is a phenyl group, a naphthyl group, a cyclohexyl group, 1.3-
Thiazol-4-yl L 1,3-oxazole-4-
yl group, pyridyl group, benzoxacylyl group, thienyl group, quinolyl group or benzofuranyl group, or these groups are (lower alkoxy)carbonyl group, lower alkoxy group, lower alkyl group, trihalogeno lower alkyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, phenyl group, phenoxy group, phenyl group-substituted lower alkoxy group, hydroxyl group, halogen atom, nitro group, amino group, lower alkanoylamino group, di(lower alkyl)amino group, cyclo Examples include compounds substituted with a group selected from an alkyl group, a pyrrolidino group, a piperidino group, a morpholino group, and a pyrrolyl group. Other specific examples of the benzoxazole derivative (1) include Alk being a single bond, a linear or branched lower alkylene group, and lower alkenylene! Alternatively, there are compounds that are a lower alkynylene group, or a lower alkylene group substituted with an autoso group, a phenyl group, or a cycloalkyl group.

Compounds with better therapeutic effects include those with shaku (1
) 1 selected from a lower alkoxy group, a trihalogeno-lower alkyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a phenyl group, a halogen atom, a nitro group, and a di(lower alkyl)amino group
A phenyl group optionally substituted with ~12 groups; (
2) A naphthyl group optionally substituted with a lower alkoxy group, a lower alkyl group, or a nitro group; (3) Substituted with 1 to 2 groups selected from a lower alkyl group, a lower alkylthio group, a cycloalkyl group, and a phenyl group (4) A pyridyl group which may be substituted with a lower alkyl group.

Other compounds with particularly good therapeutic effects are those in which Alk is a single bond or a branched or straight-chain lower alkylene group and/or 2,4-dioxothiazolidin-5-yl (
or ylidene) methyl group is bonded to the 5th or 6th position of the benzoxazole ring.

Furthermore, in the benzoxazole derivative (1) which is an active ingredient of the present invention, the number of carbon atoms in the lower alkoxy group, lower alkyl group, lower alkanoyl group, lower alkylene group, lower alkenylene group, and lower alkynylene group is 6 or less. Although some are included, those having 4 or less carbon atoms are particularly preferred, and those in which the cycloalkyl group has 3 to 9 carbon atoms, especially 4 to 7 carbon atoms are preferred.

These benzoxazole derivatives (1) can be used for the purpose of the present invention either in free form or in the form of their pharmacologically acceptable salts. Examples of salts that can be used include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and acid addition salts such as hydrochlorides and sulfates.

The blood-tock-lowering agent of the present invention can be administered either orally or parenterally, and is used in the form of appropriate pharmaceutical preparations such as tablets, granules, capsules, powders, and injections in a conventional manner. .

The dosage of the active ingredient compound of the present invention varies depending on the administration method, age, weight and condition of the patient, but is usually about 0.005 to 100 mg/kg per day, especially 0.005 to 100 mg/kg per day.
It is preferable to set it as about 01-10 mg/kg.

Both the 911 form and the optically active form of the benzoxazole derivative (1) can be used as the active ingredient of the present invention.

The benzoxazole derivative (1), which is an active ingredient of the present invention, has the following formula: , R and Alk have the same meanings as above) and the dioxothiazolidine compound shown by the general formula (however, the symbols have the same meanings as above) using a condensing agent (for example, polyphosphoric acid trimester). (2) The amide compound represented by the general formula (however, the symbols have the same meanings as above) is treated with a dehydrating agent (for example, polyrin The azomethine compound of the form (3) (wherein the symbols have the same meanings as above) is subjected to a dehydrogenation reaction in the presence or absence of a dehydrogenating agent (e.g. It can be produced by subjecting it to a dehydrogenation reaction in the presence of lead (lead).

In addition, compounds represented by the - format (however, the symbols have the same meanings as above), which are the active ingredients of the present invention, are the compounds represented by the general formula (however, the symbols have the same meanings as above). It can also be produced by hydrolyzing the igon compound shown in (1).

In addition, in the benzoxazole derivative (1) which is an active ingredient of the present invention, the compound (1) in which R is a lower alkylthiophenyl group is oxidized to form a compound in which R is a lower alkylsulfinylphenyl group or a lower alkylsulfonylphenyl group. Furthermore, the compound (1) in which R is a benzyloxyphenyl group can be debenzylated to give a compound in which R is a hydroxyphenyl group.

Experimental example (hyperglycemic effect in mice) The test compound was mixed with the powder side (GE-2, Nippon Talea), and KK
-Av mice (Tokyo Experimental Animals, 1.5-11 months old, 3-4 mice per group) were given ad libitum for 5 days. Blood was collected from the tip of the main part, and the blood sugar level was measured by the glucose oxidase method.

The rate of decrease was calculated from the blood sugar level using the following formula.

The results are shown in the table below.

Table Note 1) In the experiments, the products obtained in each of the production examples described below were used as test compounds.

Note 2) I) Repellency (mg%) of the test compound mixed with non-feed
].

Production example 1 (1) 5-amino-2-phenylbenzoxazole 4
．． 5 d of an aqueous solution of 1.76 g of sodium nitrite was added dropwise to a mixture of 87 g of sodium nitrite, 6 d of concentrated hydrochloric acid, and 50 d of acetone while cooling with water. Stir for 10 minutes at the same temperature, then add 12.1 g of methyl acrylate, and gradually add 150 mg of cuprous oxide while heating to 40°C. After the evolution of nitrogen gas has finished, the mixture is heated to 35°C for 20 minutes, the reaction mixture is diluted with water, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off and the residual aroma was removed by silica gel column chromatography (
3-
(2-phenylbenzoxazol-5-yl)-2-
5.13 g of chloropropionic acid methyl ester are obtained as a pale brown oil.

IRI/ saw (C11-'): 1740 (2) 5.13 g of main island, 2.30 g of thiourea, 1.50 H of sodium acetate and 35 ml of ethylene glycol monomethyl ether! Heat the mixture to 100°C for 8 hours. After the first night of the reaction, the solvent was distilled off, water and n-hexane were added to the residual aroma, and the precipitated crystals were collected by filtration, washed, and dried.
-[(2-imino-4-oxothiazolidin-5-yl)methyl]-2-phenylbenzoxazole 4.35
g as a colorless powder.

M, p, 281-283°C (decomposition) (3) t
-Item 3. Dissolve 18 g in 50 in of ethylene glycol monomethyl ether, add 2.05 g of toluene sulfonic acid l hydrate and 6 d of water, and reflux for 1 hour and 45 minutes. The solvent is distilled off from the reaction solution, water is added to the residual aroma, extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. By purifying the residual aroma by silica gel column chromatography [solvent: chloroform-methanol (20:1)], 1.83 g of 5[(2,4-dioxothiazolidin-5-yl)methyl)-2-phenylbenzoxazole was obtained. get.

M, p, 192-194 "C Mass (i/e): 324 (M"") Production example 2
~4 By treating the corresponding raw material compounds in the same manner as in Production Example 1, the following compounds listed in Table 1 are obtained.

Table 1 Production Example 5 (1) 3.10 g of 5-(3-aminohydroxybenzyl)-2,4-dioxothiazolidine, N,
2-phenyl-4-thiazoleacetic acid chloride 2 to a mixture of 3.63 g N-dimethylaniline, 25 ml tetrahydrofuran and 5 rn I dimethylformamide.
．． A solution of 38 g in 10 ml of tetrahydrofuran is added dropwise at 0°C and stirred for 20 minutes at room temperature. After the reaction, pour into water,
After extraction with ethyl acetate, washing and drying, the solvent was distilled off. By crystallizing the residual aroma from ethyl acetate, N-(5-(2
,4-dioxothiazolidin-5-yl)methyl-2-
Hydroxyphenyl go 2-phenylthiazole-4-
3.35 g of acetamide are obtained.

M, p, 227-229°C (decomposition) (2) Main island 1
．． 5g, 3.2g of phosphorus pentoxide, 6.6ml of hexamethyldisiloxane and 1. 2-dichloroethane 12.5m
A mixture of polyphosphoric acid trimethylsilyl ester solutions prepared from 1 was heated at 100°C for 30 minutes. After the reaction,
Pour into ice water, extract with ethyl acetate, dry, and evaporate the solvent. By recrystallizing the residual aroma from methanol, 5-[
(2,4-dioxothiazolidin-5-yl)methyl)
880 mg of -2-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzoxazole is obtained.

Yield 61% M, p, 86-89°C IRv wax (cm-'): 1750.1690
Mass (m/e): 421 (M''), 305 Production example 6 (1) 2-phenyl-4-oxazole acetic acid 2゜03g
, 5-(3-amino-4-hydroxybenzyl)-2,
4-dioxothiazolidine 2.38g, dicyclohexylcarbodiimide 2.06g, dimethylformamide 2
ml and 20 ml of tetrahydrofuran are stirred at room temperature for 18 hours. After the reaction, insoluble matter was removed, poured into ice water, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off.

The residual aroma was purified using silica gel column chromatography (solvent: chloroform:methanol-10:1) and crystallized from ethyl acetate to obtain N-(5-(24-dioxothiazolidin-5-yl)methyl-2- Hydroxyphenyl]-2-phenyloxazole-4-acetamide 2.8
Obtain 3g.

M, p, 19'F, 5-199.5"c (2) Heat 635 mg of the main island at 230 °C for 40 minutes. After cooling, purify with silica gel column chromatography (solvent: chloroform: methanol = lO: 1). , 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2-[(2-phenyl-
3113 mg of 1,3-oxazol-4-yl)methyl]benzoxazole are obtained.

Yield 63% M, p, 174-17? , 5°CIRv @ax
(cm-') :1730.1710+Mass(
m/e):405(M'')+289 Production examples 7-3
0 The corresponding raw material compounds were treated in the same manner as in Production Example 5 or 6 to obtain the compounds listed in Table 2 below.

(However, in the formula, ``S'' is an oxygen atom, `` is a hydroxyl group, and the group represented by ``H'' forms a methylene group.) Production Example 31 Phosphorus pentoxide 4.0 g and hexamethyldisiloxane lom 1,1. A mixture of 20 ml of 2-dichlorobenzene was heated under reflux for 5 minutes to obtain polyphosphoric acid trimethylsilyl ester phenyl-5-methyl-4-oxazole acetic acid 152B.
and 5-(3-amino-4-hydroxybenzyl)-2
．． 4-Dioxothiazolidine 2.

Add 17g and heat at 150'C for 2 hours.

After 6 hours, the mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off. The residual aroma was purified using silica gel column chromatography (solvent: chloroform:methanol = 100:l), and recrystallized from a mixture of ethyl acetate and n-hexane overnight to obtain 5-[(2,4-dioxothiazolidine-5- yl)methyl]-2-[(2-phenyl-5-methyl-1
, 3-oxazol-4-yl)methyl]benzoxazole is obtained.

Yield 68% M, p, 175-17 B'C (that l.

is an oxygen atom, R1 is a hydroxyl group, Formula /\ Mass (m/e): 419 (M ''), 348,
303! l! Production Examples 32 to 72 The corresponding raw material compounds were treated in the same manner as Production Example 31 to produce the following third
The compounds listed in the table are obtained.

Table 3 Note: *): Sodium salt (No. 2, Y is an oxygen atom, R1 is a hydroxyl group, the group represented by k) forms a methine group) 4 g is obtained as a pale yellow powder.

M, p, 207-209°C (2) 5.64g of the product from (1) above was heated to 220°C for 5 minutes.
After heating for 0 minutes and cooling, silica gel column chromatography [? Vehicle: Chloroform-methanol (50:1)
) and recrystallized from ether to give 5-
[(2,4-dioxodeacylidin-5-yl)methyl)-2-(4-chlorobenzyl)benzoxazole 4
．． Obtain Og.

M, p, 169.5-170.5°C Mass (+1/e): 374,372 (M”
″) Production Example 73 (1) N-(5-amino-2-hydroxyphenyl)-
N-(5-(2,
4-dioxothiazolidin-5-yl)methyl-2-hydroxyphenyl)2-(4-chlorophenyl)acetamide 5.6 Production example 74 N-(5-amino-2-hydroxyphenyl)-4-hydroxy-3,5 -Di(tert-butyl)benzamide was treated in the same manner as in Production Example 73 to obtain 5-[(
2,4-dioxothiazolidin-5-yl)methyl)-
2-(4-hydroxy 3,5-di(tert-7'thyl)phenyl)benzoxazole is obtained.

M, p, 213-216°C Mass (m/e): 452 (M”) Production example 75 N-(4-amino-2-hydroxyphenyl)-2-(
By treating 4-chlorophenyl)acetamide in the same manner as in Production Example 73, 6-[(24-dioxothiazolidin-5-yl)methyl)-2-(4-chlorobenzyl]benzoxazole is obtained.

M, p, 219.5-220.5°C Mass (m/e): 374.372 (M”) Production example 76 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2 -(4-nitrobenzyl)benzoxazole (3.48 g) was dissolved in a mixture of 70 d of tetrahydrofuran and methanol (10 ml), and 10% palladium-carbon 2
．． 5 g was heated and subjected to a reduction reaction in hydrogen at normal pressure. Insoluble matter was filtered off from the reaction solution, and the filter solution was concentrated, purified by silica gel column chromatography (0:1)), and recrystallized from ethyl acetate to obtain 5-[(2.4-dioxothiazolidine- 1.86 g of 5-yl)methyl)-2-(4-acnobenzyl)benzoxazole are obtained.

M, p, 180-183°C Mass (m/e): 353 (M”) Production example 77 5-[(2.4-dioxothiazolidin-5-yl)methyl)-2-(4-aminobenzyl ) A mixture of 0.99 g of benzoxazole, 2 d of acetic anhydride, and 10 I of pyridine was stirred at room temperature overnight, then 10% hydrochloric acid was added, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off. By crystallizing, 5-[(2.4-
Dioxothiazolidin-5-yl)methyl)-2- (
4-acetamidobenzyl)benzoxazole 0.56
get g.

M. p. 233-236°C Mass (m/e): 395 (M”) Production example 7
8 5-[(2.4-dioxothiazolidin-5-yl)methyl 3-2-(4-methylthiobenzyl)benzoxazole 1.0 g, 80% m-chloroperbenzoic acid 0.58
A mixture of g and 25!1 methylene chloride is stirred at room temperature for 10 minutes. Distill the solvent, add ethyl acetate, wash,
After drying, the solvent was distilled off and purified using silica gel column chromatography (solvent: chloroform:methanol = 20:l) to obtain 5-[(2.4-dioxothiazolidin-5-yl).
0.67 g of methyl]-2-(4-methylsulfinylbenzyl)benzoxazole are obtained as a colorless foam.

Yield 64% Mass (m/e): 400 (M') Production example 79 5-[(2.4-dioxothiazolidin-5-yl)methyl)-2-(4-methylthiobenzyl)benzoxazole 1. 2g, 80% m-chloroperbenzoic acid 2.1g
and 30 ml of methylene chloride are stirred at room temperature for 20 minutes. After the same treatment as in Example 7B, recrystallization from a tetrahydrofuran-n-hexane mixture gave 5-[(
2.4-dioxothiazolidin-5-yl)methyl]-
1.2 g of 2-(4-methylsulfonylbenzyl)benzoxazole are obtained as a colorless powder.

Yield 69% M. p. 168-169"C Production example 80 5-[(2.4-dioxothiazolidin-5-yl)methyl)-2-(4-benzyloxybenzyl)benzoxazole 0.95 g, 25% hydrogen bromide acetic acid solution 10 J
d and vinegar MI Oml! Stir the mixture at room temperature overnight. Ethyl acetate and water are added to the reaction solution, and the ethyl acetate layer is washed with water, dried, and then the solvent is distilled off. The residue was crystallized from n-hexane and further recrystallized from a mixture of edyl acetate and n-hexane to give 5-[(2,4-dioxothiazolidine-5
0.42 g of -yl)methyl)-2-(4-hydroxybenzyl)benzoxazole are obtained as colorless needles.

Yield 55% M, p, 201-204°C [Preparation of raw material compound] Reference example 1 (1) 6°16 g of 2-amino-4-nitrophenol and 4.77 g of benzaldehyde were condensed under heating to form 2-
After converting it into benzylideneamino-4-nitrophenol,
5-nitro-2 is obtained by heating and ring-closing the main island in the presence of lead tetranosate.
-5.08 g of phenylbenzoxazole are obtained.

M, p, 169-171.5"C (2) 8.85 g of the above product was catalytically reduced in the presence of a palladium-carbon catalyst to give 5-amino-2-phenylbenzoxazole7.
Obtain 02g.

M, p, 150.5-153'C Reference example 2 (1) 147 g of 2-amino-4-nitrophenol and (
1-Methylcyclohexyl)carbonyl chloride 16.
0g and condensed in the presence of N,N-dimethylaniline.
and then ring-closed by heating in the presence of thionyl chloride.
21.7 g of -(l-methylcyclohexyl)-5-nitrobenzoxazole are obtained.

M, p, 57-59°C (2) The above product is treated in the same manner as in Reference Example 1-(2) to obtain 5-amino-2-(1-methylcyclohexyl)benzoxazole as a colorless oil.

Mass (m/e): 230 (M') Reference Examples 3 and 4 The corresponding starting compounds were treated in the same manner as in Reference Example 1 or 2 to obtain the following compounds.

Reference example 5 (1) 4-chlorophenylacetic acid f3.55B was chlorinated, and then 2-amino-4-di10phenol 7.70
g and condensed in the presence of N,N-dimethylaniline.
N-(5-nitro-2-hydroxyphenyl)-2-
14.2 g of (4-chlorophenyl)acetamide is obtained.

M, 9. 250-252°C (decomposition) (2) Main island 1
3.93. was reduced with stannous chloride to obtain 9.86 g of N-(5-amino-2-hydroxyphenyl)-2-(4-chlorophenyl)acetamide.

M, p, 164-161"C Reference Example 6 4-Hydroxy-3,5-di(ter L-butyl)benzoic acid and 2-amino-4-nitrophenol in Reference Example 5-(1) and Reference Example 1 - Process in the same way as (2) and N
-(5-amino-2-hydroxyphenyl)-4-hydroxy-3,5-di(tert-butyl)benzamide is obtained.

M, p, 222-225°C (decomposition) Reference example 7 (1) 4-hydroxy-3-nitrobenzaldehyde 1
8.0 g and 2.4-dioxothiazolidine 12. '74
g is heated and condensed in the presence of piperidine to form 5-(4
14.82 g of -hydroxy-3-nitrobenzylidene)-2,4-dioxothiapridine are obtained.

Yield 52% M, p, 256.5-258°C (2) Motoichi 12
．． 85 g were reduced with sodium hypophosphite in the presence of a palladium-carbon catalyst to give 5-(3-amino-4-hydroxybenzylidene)-2,4-dioxothiazolidine 10.
Obtain 86g.

Yield 95% M, p, 260.5-261.5°C (decomposition) Reference Example 8 (1) 13.3 g of L-4-hydroxy-3-nitrophenylalanine was dissolved in 3N sulfuric acid in the presence of potassium bromide. was treated with sodium nitrite to give 2-bromo-3-(4
-hydroxy-3-nitrophenyl)propionic acid 15
．． 2 g are obtained as a brown solid.

(2) 15.1 g of Motoichi and 6.14 g of thiourea were heated and condensed in the presence of sodium acetate to produce 12.2 g of 5-(4-hydroxy-3-nitrobenzyl)-2-imino-4-oxothiazolidine. Obtained as a yellow powder.

M, p, 221-223°C (decomposition) (3) Hydrolyze 12.1 g of Motoichi in the presence of hydrochloric acid to give 5
- (4-hydroxy-3-nitrobenzyl)-2,4
-10.4 g of dioxothiazolidine are obtained as a yellow powder.

M, p, 141-143.5°C (4) 10.3 g of Motoichi was catalytically reduced in the presence of a palladium-carbon catalyst to give 5-(3-amino-4-hydroxybenzyl)-2,4-dioxo 8.77 g of thiazolidine are obtained as a pale yellow powder.

M, p, 215-217.5°C

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R is a phenyl group, a naphthyl group, a cycloalkyl group, or a heterocyclic group, which may have a substituent, Alk is a single bond, a lower alkenylene group, a lower alkynylene group, or a lower alkylene group that may have a substituent, and the dotted line indicates that the bond at the site may be a double bond. A hypoglycemic agent containing a derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2, R is a phenyl-substituted lower alkoxy group, lower alkoxy group, lower alkyl group, trihalogeno lower alkyl group, lower alkylthio group, lower alkylsulfinyl group,
Substituted with 1 to 2 groups selected from a lower alkylsulfonyl group, a cycloalkyl group, a phenyl group, a phenoxy group, a halogen atom, a nitro group, a piperidino group, a morpholino group, a pyrrolyl group, and a di(lower alkyl)amino group. Claim 1 which is a phenyl group, a naphthyl group, a 1,3-thiazol-4-yl group, a 1,3-oxazol-4-yl group, a pyridyl group, a benzoxazolyl group, a benzofuranyl group or a quinolyl group. Hypoglycemic agents listed. 3, R is selected from (1) a lower alkoxy group, a trihalogeno lower alkyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a phenyl group, a halogen atom, a nitro group, and a di(lower alkyl)amino group; A phenyl group which may be substituted with ~2 groups; (2) a naphthyl group which may be substituted with a lower alkoxy group, a lower alkyl group or a nitro group; (3) a lower alkyl group, a lower alkylthio group, a cyclo 1,3-thiazol-4-yl group or 1,3-thiazol-4-yl group optionally substituted with 1 to 2 groups selected from alkyl group and phenyl group
The hypoglycemic agent according to claim 1, which is a 3-oxazol-4-yl group; (4) a pyridyl group optionally substituted with a lower alkyl group. 4, R is lower alkoxy group or di(lower alkyl)
The hypoglycemic agent according to claim 1, which is a phenyl group or a naphthyl group which may be substituted with an amino group. 5. The hypoglycemic agent according to claim 1, 2, 3 or 4, wherein Alk is a single bond or a branched or straight chain lower alkylene group. 5. The hypoglycemic agent according to claim 1, 2, 3, or 4, wherein the 6,2,4-dioxothiazolidin-5-yl (or ylidene) methyl group is bonded to the 5th or 6th position of the benzoxazole ring. 7,5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-[4-(dimethylamino)benzyl]
A hypoglycemic agent containing benzoxazole or a pharmacologically acceptable salt thereof as an active ingredient. Hypoglycemic agent containing 8,5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-[(2-naphthyl)methyl]benzoxazole or a pharmacologically acceptable salt thereof as an active ingredient .