JPH02138218A - Hypoglycemic agent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is phenyl or substituted thiazolyl; R<2> is H or lower alkyl: Q is single direct bond or lower alkylene) or salt thereof. EXAMPLE:2-[(2-Phenylthiazol-4-yl)methyl]-6-[(2,4-dioxothiazolidin-5-yl )methyl]-3- oxo-1,4-benzoxazine. USE:A hypoglycemic agent. PREPARATION:A compound expressed by formula II is diazotated in the presence of a hydrohalogenic acid and then reacted with methyl acrylate in the presence of a copper catalyst, such as copper (I) oxide to provide a compound expressed by formula III (X<1> is halogen), which is subsequently reacted with thiourea in the presence of a base, such as sodium acetate, to afford an imine compound expressed by formula IV. The resultant compound is then hydrolyzed in the presence of an acid (e.g., p-toluenesulfonic acid) in a suitable solvent (e.g., ethylene glycol monomethyl ether) to provide the compound expressed by formula I.

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 urinary disease. 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 relates to the general formula υ (wherein R1 is a phenyl group or a substituted thiazolyl group, R2
represents a hydrogen atom or a lower alkyl group, and Q represents a single bond or a lower alkylene group. ) The present invention relates to a hypoglycemic agent comprising a benzoxazine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The benzoxazine derivative (1) and its salt, which are the active ingredients of the hypoglycemic agent of the present invention, are both new compounds and have an excellent hypoglycemic effect based on insulin sensitivity enhancing effect, and can be used for the treatment of diabetes. It is a useful pharmaceutical compound in the prophylaxis, especially in the treatment of patients with non-insulin dependent diabetes.

This therapeutic 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 has a feature that conventional hypoglycemic agents do not have: it has almost no effect on normal animals. have Furthermore, this compound (1) has low toxicity, for example, 2-[(2-phenylthiazol-4-yl)methyl)-6-[(2,
CMC suspension of 4-dioxothiazolidin-5-yl)methyl]-3oxo-1,4-benzoxazine was orally administered to mice (dose m 1000 mg/kg
) Afterwards, the animals were observed for 72 hours, but no deaths were observed.

As a specific example of the benzoxazine derivative which is an active ingredient of the hypoglycemic agent of the present invention, in the general formula (1), R1 is a substituted thiazolyl group such as a phenyl group or a 2-phenylthiazol-4-yl group, and 1? 2 is a hydrogen atom or
It is an alkyl group having 1 to 4 carbon atoms, and there are compounds in which the mouth is a single bond or an alkylene group having 1 to 3 carbon atoms.

Compounds that exhibit particularly excellent therapeutic effects include −&[(
In 1), compounds in which R1 is a 2-phenylthiazol-4-yl group, R2 is a hydrogen atom or a methyl group, and Ω is a single bond or a methylene group can be mentioned.

These compounds (1) can be used for the purpose of the present invention either in their 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 hypoglycemic agent of the present invention can be administered either orally or parenterally, and is used in the form of an appropriate pharmaceutical preparation such as a tablet, granule, capsule, filC, or injection by a conventional method.

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 0.05 to 100 mg/kg per day.
It is preferable to set it to about 0 mg/kg.

In addition, compound (1) can also be used as an active ingredient of the present invention in the form of an optically active substance.

The active ingredient compound (1) of the present invention is prepared by diazotizing a compound represented by the general formula (however, the symbols have the same meanings as above) in the presence of hydrohalic acid, and then diazotizing the compound with a copper catalyst (for example, copper oxide). I)) is reacted with acrylic acid methyl ester to form a compound represented by the general formula (where x1 represents a halogen atom, and the other symbols have the same meanings as above), and then this is treated with a base. (for example, sodium acetate) to obtain an imine compound represented by the general formula (however, the symbols have the same meanings as above), and further, in a suitable solvent (for example, ethylene glycol monomethyl ether), an acid ( For example p-)
It can be produced by hydrolysis in the presence of luenesulfonic acid).

Table 1 Experimental example (hyperglycemic effect in mice) The test compound was mixed with powdered feed (CE-2, Nippon Talea) (mixing amount: 50.25, 1O and 5mg%), and KK-
A' mouse (Tokyo Experimental Animals, 1.511 months old, 1 group 4)
mice) were given free access for 5 days. Collect blood from the tip of the pressure part,
Blood sugar levels were measured by the glucose oxidase method. The rate of decrease was calculated from the blood sugar level using the following formula.

It is considered effective when the blood sugar lowering rate is 20% or more, and the minimum effective amount (mg of the test compound contained in 100 μg of powdered feed) is shown in Table 1 below.

Production example 1 (1) 6-amino-2-benzyl-3-oxo-1,
A solution of 1.3 g of sodium nitrite in 3 ml of water is added dropwise to a mixture of 4.8 g of 4-benzoxazine, 3 ml of concentrated hydrochloric acid, and 60 ml of acetone while cooling with water. After stirring at room temperature for 30 minutes, 10.6 ml of methyl acrylate was added, and the
C. and add 500 mg of copper oxide (1) little by little. After stirring for 30 minutes, the reaction solution was poured into water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. The residual aroma was purified using silica gel column chromatography (solvent: chloroform:methanol = 100:1).
Methyl (2-benzyl-3-oxo1,4-benzoxazin-6-yl)-2-chloropropionate 4.95
get g.

Yield 73% m, p, 124-127°C (n-hexane) Mas
s (m/e) 361, 359 (M”), 323 (2
) Main island 4.9g, Diourea 2.07g.

A mixture of 1.3 g of sodium acetate and 30 ml of ethylene glycol monomethyl ether is heated at 100° C. for 7 hours. After cooling, the reaction solution was poured into water, and the precipitated crystals were filtered, washed with water and ether, and dried to obtain 2-benzyl-6-[(2-imino-4-oxothiazolidin-5-yl)methyl]- 378 g of 3-oxo-1,4-henzoxazine are obtained.

Yield 76% m, p, 251-254°C (decomposition) R Mass (m/e) 367 (M”), 252 (3)
A mixture of 3.78 g of Honjima, 2.86 g of p-toluenesulfonic acid monohydrate, 6 ml of water, and 30 ml of ethylene glycol monomethyl ether was heated under reflux for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was distilled off. The residual fragrance was removed by silica gel column chromatography (vehicle: chloroborm dimethano-
2-benzyl-
6-[(2,4-dioxodeacylidin-5-yl)methyl]-3-oxo-1,4-benzoxazine 3.2
g is obtained as a pale brown foam.

Yield 84% Mass (m/e) 368 (M”), 253.252
Production Examples 2-B The corresponding starting compounds were treated in the same manner as in Production Example 1 to obtain the compounds listed in Table 2 below.

Table 2 [Preparation of raw material compounds] Reference example 1 (1) 12.0 g of 3-phenylpropionic acid was converted into acid chloride with thionyl chloride, and this was brominated with N-bromosuccinimide to produce 2-bromo-3-phenylpropionic acid chloride. This was then subjected to a condensation reaction with 12.3 g of 2-amino-4-ditrophenol in the presence of N,N-dimethylaniline. Furthermore, the ring is closed by heating in the presence of potassium carbonate to obtain 12.25 g of 2-hensyl-6-nitro-3-oxo-1,4-benzoxazine.

m, p, 194.5-197.5°C (2) 6.5 g of Honjima was alkylated with methyl iodide to give 2-benzyl-4-methyl-6-nitro-3-oxo-1.
, 5.86 g of 4-benzoxazine are obtained.

m, p, 166-169''C (3) 6.2 g of Honjima was contacted and reduced in the presence of a palladium-carbon catalyst to give 6-amino-2-benzyl-4-
Methyl-3-oxo-1,4-benzoxazine is obtained.

m, p, 82-85°C (ether-〇-hexane) Reference Examples 2 to 8 The corresponding starting compounds were treated in the same manner as in Reference Example 1 to obtain the compounds listed in Table 3 below. (However, Reference Example 2゜4.5.7 was treated according to Reference Example 1-(1) and (3), and Reference Examples 3 and 6.8 were treated according to Reference Example 1-(1) to (3).) Table 3 (II)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is a phenyl group or a substituted thiazolyl group, R
^2 represents a hydrogen atom or a lower alkyl group, and Q represents a single bond or a lower alkylene group. ) A hypoglycemic agent comprising a benzoxazine derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2.Claim 1, wherein R^1 is a phenyl group or a 2-phenylthiazol-4-yl group, R^2 is a hydrogen atom or a methyl group, and Q is a single bond or a methylene group.
Hypoglycemic agents listed. 3. The hypoglycemic agent according to claim 2, wherein R^1 is a 2-phenylthiazol-4-yl group. 4,2-[(2-phenylthiazol-4-yl)methyl]-6-[(2,4-dioxothiazolidin-5-yl)methyl]-3-oxo-1,4-benzoxazine or its pharmacology A hypoglycemic agent containing a legally acceptable salt as an active ingredient.