JPS62111990A - Dioxolobenzoisoxazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is phenyl which may be substituted with halogen, lower alkyl-substituted phenyl which may be halogenated, thienyl; R<2> is H, lower alkyl; X1, X2 are H, halogen] and its salt. EXAMPLE:Methyl 3-phenyl-1,3-dioxolo[4,5-g]-1,2-benzoioxazole-7-carboxylate. USE:A diuretic with the action to excrete uric acid. PREPARATION:For example, A benzoisoxazole of formula II is allowed to react with a compound of the formula: (Y)2CHCOOR2 (Y is halogen) such as methyl dichloracetate, preferably in an inert solvent such as ether, in the presence of a base such as sodium hydride to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel dioxobenziisoxazole derivative useful as a diuretic that eliminates uric acid LJIll11.4'.

=1- Follow (! and drum: Fu) Phenoxyacetic acids represented by chenilic acid (US Pat. No. 3,758,508) are known as diuretics that have uric acid excretion effects like the compounds of the present invention.

Antihypertensive diuretics conventionally used are widely used as first-line drugs for hypertension, but they tend to cause hyperuricemia as a side effect. - Hypertension is often accompanied by hyperuricemia, and most of the hyperuricemia is thought to be due to impaired uric acid excretion.

Under these circumstances, there is a strong desire in the medical field to develop a diuretic that has a uric acid excretion effect. Although chenilic acid is known as a diuretic having such an effect, it has not yet been commercialized because it has side effects such as liver damage.

Question 1 Kaoru 1 "Beast 4"jJ"" The present inventors conducted intensive research in view of the above circumstances and found that the dioxobenziisoxazole derivative of the present invention has both uric acid excretion 1III action and diuretic action. The present inventors have discovered that the present invention has been found to have less side effects on the liver.

The present invention relates to diogisorobenzisoxazole derivatives represented by general formula (I).

(In the formula, R14t phenylno, U, halogen position 1? means a phenyl group, a lower alkyl-substituted phenyl group, a halogenated lower alkyl-substituted phenyl group, and a chenyl group,
R2 means a hydrogen atom or lower alkylno, (X
1 and X2 are the same or different and each represents a hydrogen atom or a halogen atom. )--In the compound of the present invention represented by the general formula (I), the halogen atom of the halogen-substituted phenyl group represented by R1 includes, for example, chlorine, fluorine, and fluorine. Specific examples of the lower alkyl-substituted phenyl group include toluylno and circle. Further, the halogenated lower alkyl-substituted phenyl group is, for example, a trifluoromethylphenyl group. Lower alkylno represented by R2 (for example, a carbon number of 1 to 4
is a branched or straight-chain alkyl group. XL
Examples of the halogen atom represented by 2 include chlorine and bromine atoms.

The compound of the present invention can form a salt with a base when R2 is a hydrogen atom. Such salts include those that are pharmaceutically acceptable, such as alkali metal salts, alkaline earth metal salts, amine salts and substituted amine salts, and specifically include, for example, sodium salts, potassium salts, calcium salts, etc. Examples include salts, magnesium salts, ammonium salts, lower alkylamine salts, and ethanolamine salts.

The dioxobenziisoxazole derivative represented by the general formula (I) of the present invention is a new compound, for example, the general formula (II) X.

(wherein R1, XI and It can be produced by reacting the compounds represented by (meaning the same thing). This reaction is preferably carried out in the presence of a salt in an inert solvent. Examples of the inert solvent include ethers, alcohols, hydrocarbons, aromatic hydrocarbons, water, and aprotic outer polar ↑11 solvents such as N,N-dimethylformamide and dimethyl sulfoxide. Examples of the base include alkali metal hydrides and alkoxides.

Hydroxide, carbonate, J: bi(+'machine salt), (etc.,
Specific examples include thorium hydride, sodium methoxide, sodium ethoxide, thorium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and triethylamine. The reaction temperature is approximately 0°C to 150°C.
The temperature is appropriately selected between °C.

From the reaction mixture, -. of the compound of the present invention represented by the general formula (I)! , 1 ill is extracted by a conventional method, for example, I1
This is done by applying it to a means such as a crystal.

In the present invention, the compound represented by general formula (II) is produced by subjecting the corresponding O-alkyl compound to a dealkylation reaction with pyridine hydrochloride, boron tribromide, or the like.

Sakuichi ■ The dioxobenzisoxazole derivative represented by the general formula (I) of the present invention is useful as a diuretic having a uric acid excretion effect, and can be used for the treatment of edema or hypertension.

The diuretic effect and uric acid excretion effect of the compound of the present invention was confirmed by the experiment shown below.

(Test method) 7 week old Wi star-Imami fasted for 24 hours
Chi rats were used. After forcing rats to urinate, they were divided into groups (4 to 5 animals per group) so that the amount of urine was equal.
Test compounds were administered orally. The test compound is suspended in physiological saline containing 3% gum arabic at a dose of 25 ml per 1 kg of body weight, usually 100 mg/kg.
was administered. Control animals received only saline containing 3% gum arabic. Animals were housed in their own metabolic cages under fasted and water-fed conditions for 6 hours and 2 hours after dosing.
Urine was collected for 4 hours. Urine was collected in a graduated cylinder, and after forced urination, the urine volume was read directly from the graduated cylinder to calculate the urine volume per 1 kg of body weight. Also, uric acid υ in the urine
] The amount of excretion was calculated by quantifying uric acid using the uricase-catalase method.

(Test Results) As shown in the following table, the compound of the present invention exhibited unique diuretic effect and uric acid IJI excretion effect. Furthermore, these effects are recognized to be persistent and dependent on 1i1. Note that the compound numbers in the table correspond to the scents in the examples below.

Example 1 6,7-cyhydroquine-3-phenyl-1,2-benzisoxazole2. 8g, dichloroacetic acid methyl ester 3.5gsJ. 5 Yohi N. /II' of 50 ml of N-dimethylformamide. 1.2 g of IJum (hydrogenated at 60%) was added little by little to the mixture under water cooling and stirring.

After stirring at 90-100°C for 5 hours, ice water was added, extracted with ether, washed with water, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography using dichloromethane as a developing solvent. Recrystallization from a mixed solvent of methanol and water gave 3-phenyl-1,3-dioxo[4. 5-g
l −1. 1.3 g of 2-benzisoxazole-7-carboxylic acid methyl ester was obtained. Melting point 78-80℃
. The mass spectrum of the crystal showed a molecular ion peak at m/e297.

Example 2 2.1 g of 6,7-dihydroquine-3-phenyl-1,2-benzisoxazole, 7.7 g of potassium carbonate
2.7 g of dichloroacetic acid methyl ester and N, N-
A mixture of 50 ml of dimethylformamide
Stir at 100'C for 5 hours (100ml of water)
The mixture was stirred at 90 to 100°C for 30 minutes, cooled, acidified with hydrochloric acid, extracted with ether, washed with water, dried, and the solvent was distilled off.

The residue was recrystallized from acetonitrile to give 3-phenyl-1
, 3-dioxo [4. 5-gl-1. 1.5 g of 2-benzisoxazole-7-carboxylic acid was obtained. Melting point: 187-190°C0 The mass spectrum of this product is m/e
A molecular ion peak was shown at 283.

Examples 3-13 It was treated in the same manner as in Example 2 to obtain the compounds shown in the following table.

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. , R2 means a hydrogen atom or a lower alkyl group, and X1 and Sex salt.