SU1676452A3 - Method for preparation of furobenzisoxazol derivatives - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1-R4 represent H, halogen atom or lower alkyl; R5 represents hydroxymethyl, COOH or lower alkoxycarbonyl; X represents S or -CH=CH-) and salt thereof. EXAMPLE:7,8-Dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. USE:A remedy for hyperuricemia, edema and hypertension. PREPARATION:A compound expressed by formula II is reacted with a peracid to obtain a compound expressed by formula I wherein the group R5 represents hydroxymethyl. Then a compound wherein the group R5 is COOH can be obtained, as desired, by oxidizing with an oxidizing agent.

Description

The invention relates to a method for producing new derivatives of furo-benz-isoxazole, which have hypotonic, uricosure and diuretic activity, which can be used in medicine.

The purpose of the invention is to obtain new-, derivative derivatives of furobenzisoxazole, possessing valuable biologically active properties with minimal side effect.

Example 1 about To an ice-cooled solution of α-allyl-6-hydroxy-3-phenyl -1,2-benzisoxazole (17.5 g) in methylene chloride (500 ml) is added

m-chloroperbenzoic acid (20.8 g) in small portions with stirring and the mixture is refluxed for 4 hours. After cooling this mixture, water and an aqueous solution of 2N sodium hydroxide (80 ml) are added, and the mixture is extracted with chloride methylene chloride layer is washed with water and dried. By distilling off the solvent, 18 g /, 8-dihydro-3-phenylfuro (2,3-d) -1,2-benzisoxazole-7-methanol are obtained. Topl 10/109 ° C (This compound is characterized by a mass spectrum having a molecular ion peak at m / e 26 /.

about

Xi

J

SL

Yu

with

16 1.2 g /, 8-di

Example 20 Mixture

hydro-3-phenylfuro (2,3-d) -1,2-benziox sazol - / - methanol prepared in Example 1, 35 ml of acetic anhydride and 160 ml of benzene are refluxed for 5 h. “After the solvent is distilled off in vacuo under vacuum, the residue is dissolved in 200 ml of methylene chloride and 4.8 g of bromine is slowly added to this stirred solution. After the mixture is stirred for 10 hours at room temperature, the solvent is distilled off. The residue is purified using capillary chromatography using methylene chloride as an eluant. 1.6 g / -acetoxymethyl-5-bro - /, 8-dihydro-3-phenylfuro (2,3-c1) -1,2-benzisoxazole. A part (1.5 g) of this compound is mixed with 30 ml of ethanol and 10 ml of an aqueous solution of 2N sodium hydroxide, and this mixture is refluxed for 10 minutes. After cooling, this mixture is made acidic by adding 15 ml of 2N HC1. Water is added to the mixture, and the resulting crystals are separated by filtration. The crystals are washed with water, to obtain 0.9 g of 5-bromo- /, 8-dihydro-3-phenylfuro (2,3-c) -1,2-benzieoxazole - / - Methanol, mp 164-165.5 C "This compound has a mass spectrum that has a molecular ion peak at tn / e 345 and 34 /"

i

Example 3. A portion (0.7 g) of 5-bromo - /, 8-dihydro-3-phenylfuro (2, 3-d -1,2-beisoxazo - / - methanol, prepared in Example 2, was dissolved in 50 ml acetone To a stirred solution is constantly added dropwise a mixture of chromium (VI) oxide (1 g), water (3 ml) and concentrated sulfuric acid (1.4 g), and the solution is then stirred at room temperature for 6 h. Insoluble After the distillation of acetone, water is added to the residue, and the mixture is extracted with ether. The ethyl ether layer is washed with water and dried "After distillation, dissolve the residue is recrystallized with acetone - water, and 0.4 g of 5-bromo - /, 8-dihydro-3-phenylfuro (2, 3-d -1,2-benzisoxazole - / - carboxylic acid, TO pls 241, 5-243 ° С (with decomposition) t

Elemental analysis „

,,

/ 6452 10

15

20

25

- - C 53.36; H 2.80;

thirty

40

45

50

Calculated N 3.89 „

C, 6H10VMOF

Found,%: C 53.66; H 2.89; N 3, / 3 „

Example 4. A portion of (10 g) /, 8-dihydro-3-phenylfuro (2,3-d) -1,2-benzisoxazole - / - methanol, prepared in Example 1, was dissolved in 300 ml of methylene chloride chilled sulphuryl chloride (9 g) is added with ice while stirring. The mixture is then stirred at room temperature for 8 hours. The solvent is distilled off and the resulting residue is purified by capillary chromatography using methylene chloride as an eluant. 3.3 g are obtained. 5-chloro-7.8- dihydro-3-phenylfuro (2,3-th) -1,2-benz-isoxazole - / - methanol. This compound (3.3 g) was dissolved in 100 ml of acetone, and to this stirred solution was added dropwise a mixture of chromium oxide (VI) (4 g), water (6 ml) and concentrated sulfuric acid (5.9 g ) The solution is then stirred at room temperature for 2.5 hours. Insoluble particles are filtered off with suction. After the acetone is distilled off, water is added to this residue and the mixture is extracted with ether. The ether layer is washed with water and dried, after which the solvent is distilled off This residue is recrystallized with acetonitrile, and I get 1 g of 5-chloro- /, 8-dihydro-3- -phenylfuro (2,3-d) -1,2-benzisoxazole- / -carboxylic acid, m.p., 221 - 224 C. This compound is characterized by mass spectrum having a molecular ion peak at m / e 315

An example is an ice-cooled solution of (-allyl-5-chloro-3 - (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole (9.5 g) in methylene chloride (200 ml) in small portions m-chlorobenzoic acid (16.4 g) was stirred under stirring and this solution was subsequently refluxed for 3 hours. After the solution was cooled, water and 100 ml of an aqueous solution of 2N sodium hydroxide were added, and the mixture was extracted with methyl chloride, methylene is washed with water and dried. By distilling off the solvent, 6.5 g of 5-chloro - -. 8-dihydro-3- (2-fluorophenyl) furo are obtained.

51

(2,3-d) -1,2-benzisoxazol-7-methanol, Toiui. 136-139 ° C. This compound has a mass spectrum having a molecular ion peak at m / e 319.

Example 6: Part (6.4 g) of 5-chloro-7,8-dihydro-3- (2-fluorophenyl) - -furo (2, 3-d) -1,2-benzisoxazole - / - methanol, obtained in of example 5, dissolved in 150 ml of acetone. To the stirred solution is added dropwise a mixture of chromium oxide (VI) (1, 2 g), water (15 ml) and concentrated sulfuric acid (10.2 g), and this mixture stirred for 8 hours at room temperature. Insoluble substances are filtered off by suction. After distillation of acetone, water is added and the mixture is extracted with ethyl ether. This layer of ethyl ether is washed with water and dried. After the solvent is distilled off, the residue is recrystallized with acetone-water, and 6.0 g of 5-chloro-7.8 are obtained -dihydro-3- (2-fluoro-phenyl) furo (2,3) 1-2 -benzisoxazole-7-carboxylic acid, mp 199-200 ° C. This compound has a mass spectrum having a molecular ion peak at / e 333

Elemental analysis, .. Calculated,%: C 57.59; H 2, / 2; N 4.20,

C, 6H9ClFNO j,

Found,%: C 57.50; H 2.77; N 4.40 „

Example /. In an ice-cooled solution of-allyl-5-chloro-3- (2-chlorophenyl) -6-hydroxy-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml) with stirring 6.6 g of m-chloro-perbenzoic acid are added in small portions and the mixture is subsequently refluxed for

- (2,6-difluorophenyl) -6-hydroxy-1,2-ben-isoxazole (3.1 g) in methylene chloride (80 ml) while stirring in small portions, add 6 g

35 m-chloroperboenic acid, and this mixture is refluxed for 5 hours. After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide are added and the mixture is extracted with methylene chloride, a layer of methylene chloride is washed with water and dried. The solvent is distilled off to obtain 2 , 8 g of 5-chloro-3- (2f6-difluorophenyl) - /, 8-dihydrofuro (2, 3-d) -1.24 h. After cooling the mixture, 45-benzisoxazole-7-methanol, m.p. water and 50 ml of an aqueous solution of 2H-166-169 ° C. This compound is a characteristic sodium oxide, and this mixture is extracted by a mass spectrum that has a molecular ion peak at m / e 337. Example 10 V stirred

are dying with methylene chloride Layer

methylene chloride is washed with water and

dried By distilling off the solvent, a solution of 2.8 g of 5-chloro-3- (2,6-difluoro-

4.6 g of 5-chloro-3- (2-chlorophenyl) -phenyl) -7,8-dihydrofuro (2,3-d) -1,2-benzisoxazole-7-methanol, obtained in example 9, are obtained in acetone (50 ml)

oxide mixture is added dropwise

-7,8-dehydrofuro (2, 3-d) -1,2-benzisoxazazol-7-methanol, m.p., 162-163 ° C "This compound has a mass spectrum that has a molecular ionic 55 chromium ( VI) (3 „0 g), water (7 ml) and peak at m / e 335. concentrated sulfuric acid

Example 80 Part (4.5 g) of 5-chloro-3- (2-chlorophenyl) -7,8-dihydro-furo (2,3) -1,2-benzisoxazole-7-meta (4.2 g) . Stirring is continued at room temperature for 9 hours. Insoluble matter

of the obtained in example / is dissolved in 200 ml of acetone. In the stirring solution is added dropwise a mixture

chromium oxide (VI) (4.9 g), water (10 ml) and concentrated sulfuric acid (.6.9 g), and the resulting mixture is stirred at room temperature for 8 h. Insoluble substances are filtered off by suction. After distilling off the acetone, the residue is added. water, and the solution is extracted with ethyl ether. The ethyl ether layer is washed with water and dried. “After distillation

5 solvent residue is recrystallized from a mixture of acetone - water and obtain 2.6 g of 5-chloro-3- (2-chlorophenyl) -7,8-dihydrofur (2, 3-d) -1,2-benzieoxazole-7- carboxylic acid, t3pl, 220

221.5 C. This compound is characterized5

It is a mass spectrum having a molecular ion peak at m / e 349,

Elemental analysis „

Calculated,%: C 54.88; H 2.59; N 4.00

Cf6H9ClzN04

Found,%: C 54.86; H 2.66; N 4.01 „

Example 9. In chilled

0 with ice a solution of 7-allyl-5-chloro-3- (2,6-difluorophenyl) -6-hydroxy-1,2-ben-isoxazole (3.1 g) in methylene chloride (80 ml) with stirring in small portions add 6 g

After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide are added and the mixture is extracted with methylene chloride, a layer of methylene chloride, washed with water and dried. The solvent is distilled off to obtain 2 , 8 g of 5-chloro-3- (2f6-difluorophenyl) - /, 8-dihydrofuro (2, 3-d) -1.25-benzisoxazole-7-methanol, m.p. 166-169 ° C. This compound is characterized by a mass spectrum having a molecular ion peak at m / e 337. Example 10 V stirred

oxide mixture is added dropwise

chromium (VI) (3 „0 g), water (7 ml) and concentrated sulfuric acid

(4.2 g). Stirring is continued at room temperature for 9 hours. Insoluble substances are filtered off by suction. Acetone is distilled off. Water is added to the residue and the solution is extracted with ethyl ether. The ethyl ether layer is washed with water and dried. After the solvent is distilled off, the residue is recrystallized from acetone - water and 1.0 is obtained 5-chloro-3- (2,6-difluorophenyl) - /, 8-dihydrofur (2,3-с1) - 1,2-benzisoxazole - / - carboxylic acid, tspl “239.5- 241 C. This compound has a mass spectrum having a molecular ion peak at m / e 351

Elemental analysis ",

Calculated,%: C 54.64; H 2.29; N 3.98. C, 6HSC1FN04

Found,%: C 54.77; H 2.29; N 3,980

Example 11 A portion (1.51 g) of 5-chloro-7,8-dihydro-3-phenylfuro (2,3-d -1,2-benzisoxazole - / - methanol is dissolved in 80 ml of 2-dichloroethanas. To the solution is added 1 , 11 g of potassium permanganate and 185 mg of 18-Crown-6, and the mixture is stirred for 16 hours at a temperature ranging from room temperature to 50 ° C. After that, 126 mg of sodium sulfite and 30 ml of water are added, and the mixture is stirred at room temperature. After adding dilute HCl and ethyl acetate, the insoluble residue is filtered off and the ester layer is washed with a saturated aqueous solution of sodium hydrogencarbonate. An aqueous solution of 4N I1C1 was added to the aqueous alkaline solution and ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of NaCi, dried and distilled. Ethyl acetate After recrystallization from a mixed solvent consisting of tetrahydrofuran and acetone, 5-chloro, 8-dihydro 3-phenylfuro (2,3-сО-1,2-benzisoxazole - / - carboxylic acid in the amount of 500 mg (32% yield), tlsho 253-255 ° С

Example 12. 5-chloro- /, 8-di-hydro-3-phenylfuro (2,3-c) -1,2-benziso-xazol-1-methanol (1.8 g) is dissolved in 80 ml of 1,2- dichloroethane. 2.8 g of potassium permanganate and 1.9 ml of TDA-1 (CH 3 OCH 2 CH 3 H 3 CH 3) 3 k 3 are added to the solution and the mixture is boiled under heating for 1.25 hours. After cooling the mixture, 1. 9 g of sodium sulfite and 80 ml of water are added and the mixture is stirred for 30 minutes at room temperature.

0 with Q 5

five

While stirring, 20 ml of 4N HCl aqueous solution and ether are added to the mixture and the insoluble precipitate is filtered off. The ether layer is washed with 0.5 N sodium hydroxide and 4N HCl aqueous solution is added to the resulting alkaline aqueous solution and the ether IfeCl , dried and distilled off the ether. After recrystallization from a mixed solvent consisting of tetrahydrofuran and acetone, 5-chloro-7,8-dihydro-3-phenylfuro (2,3- (1) -1,2- benzisoxazole-7-carboxylic acid in the amount of 800 mg (yield 43%), t0pl0 253-255 ° С „

Example 13 Water (20 ml) is added to 3.58 g of potassium permanganate,. To this solution, cooled in an ice-water bath, is added a solution of Aliquet 336, a trademark of the company Henkel A C for (CH3) 7- CH3 3C1 in 4 ml of toluene. Then a suspension in toluene (6 ml) of 1.0 g of 5-chloro-, 8-dihydro-3-phenyl-furo (2,3-d) -1,2-benzisoxazole is added. 7-methanol, and then another 20 ml of toluene. After stirring for 23 hours at room temperature to 50 ° C, 4.8 g of sodium sulfite heptacrystalline hydrate and a small amount of water are added, and the mixture is stirred for 30 minutes at room temperature. After adding dilute HC1 and ether, the insoluble precipitate is filtered off and the organic layer is washed with an aqueous solution of 1N sodium hydroxide. To the resulting aqueous alkaline solution is added an aqueous solution of 4H HC1 and ether. The ether extract is washed with an aqueous solution of NaCi, dried and the ether is distilled off, resulting in receive 5-chloro-7,8-dihydro-3-phenylfuro (2, 3-d) -1,2-benzisoxazole-7-carboxylic acid in an amount of 300 mg (yield 28%), Topl 252-255 ° C „

The proposed compounds have hypotonic, uricosoric and diuretic activity and are therefore useful for the treatment of hyperuricemia, edema and hypertension,

Compounds which have uricosure and diuretic activities are known, as are the proposed compounds, and are phenoxyacetic acids, a typical representative of which is thienyl acid,

Normal diuretic hypotonic agents are widely used as first-aid drugs in the treatment of hypertension, but they may very likely cause hyperuricemia as a side effect. Moreover, hypertension is often complicated by hyperuricemia and it is believed that many cases of hyperuricemia are caused by disturbances in uric acid excretion. It is known that thienic acid should be a potential diuretic with uricosuric activity, but the sale or development of this compound most countries have been suspended due to the high likelihood of side effects, such as liver failure.

The proposed compounds have both uricose and diuretic activity and have minimal side effects on the liver.

;

The diuretic and uricose activity of the proposed compounds is determined using the following experiment.

Experimental technique

Seven week old Wistar-Luamichi rats that were fasted for 24 hours were divided into two groups of four or five individuals so that the animals of each group should produce almost the same amount of urine. After compelling urinating rats was orally administered the test compounds, which were suspended in physiological sodium chloride solution containing 3% gum arabic, in a metered volume of 25 ml per 1 kg of live weight. 0 The proposed compounds are usually administered in an amount of 10 mg / kg. rats are given only a physiological solution of sodium chloride containing 3% gum arabic. Animals are housed in individual metal cages, and urine collected from each animal is collected for 6-24 hours after administration. claimed compounds or physiological solution of sodium chloride, after complete starvation. The volume of urine is directly read by the measuring cylinder after urination is forced into it, and the amount of urine per kg of animal weight is calculated. The amount of uric acid excreted in urine is determined using the urnase catalysis method. The results of the experiment are presented in tab. 1 and 2 (the numbers of the compounds listed in the tables relate to the numbers of the examples)

As follows from the table. 1 and 2 of the proposed compounds exhibit significant levels of diuretic and uricose activity, which are prolonged and dose dependent.

A comparison of the activity of the excretion of uric acid with the proposed compounds with the excretion of thienic acid by the method similar to the one shown above showed the first to show the relevant activity at a reduced dose level compared to the last

The proposed compounds have been found to have low toxicity. For example, the LD (mouse, oral use) of the compound of Example 4 has a toxicity of 1.1 g / kg o This confirms that all other proposed compounds have the same low toxicity as this compound.

Claims (2)

Invention Formula 1o Method for the preparation of furobenzisoxazole derivatives of general formula one s R, soon R and R are hydrogen or halogen; R.J - halogen, characterized in that the compound of the general formula ° CH2OH. where R - R have the indicated values are oxidized by the action of an oxidizing agent in an inert organic solvent medium J 2. A process according to pe1, characterized in that the oxidizing agent is selected from the group consisting of metal oxides, such as chromium oxide or potassium permanganate. Table 1 Compounded compound Amount of urine 3 rpvirna 10 0-6 hl / kgI  5,, 9 24,, 9 20,, 8 22,, 1 16,, 1 20.5 + 3.0 100 152.6 100 113.8 100 125.3 34,, 8 39 ,, / 36,9.1,1 39,2i1,1 32,3 + 1,0 39,, 9 T a 6 l in 2 2.23 + 0.15 3.85 + 0.20 3.23 + 0.09 4.52 + 0.12 3.61 + 0.16 4.14 + 0.43 IOO11.6E ± 0.83 119,013,76 + 0, 76 10010.95 + 0.36 139,813.30 + 0.71 10011.11 + 0.60 114,815.20 + 1.01 100 118.3 100 121.4 100 136.8