DK151012B - ANALOGY PROCEDURE FOR PREPARING 3-METHYL-4-HALOGEN-5-AMINOOXYMETHYL-ISOXAZOLES OR ANY ACID ADDITION SALT - Google Patents

Description

151012 o

It is known that 3-hydroxy-5-methylisoxazole can be used as a plant protection agent (Merck index, 9.

(1961), page 123). Partially saturated isoxazole derivatives used as tumor suppressors are described in 5 Tetrahedron Letters 2549 (1973) and in J. Antib. 28A, 91 (1975).

The present invention relates to an analogous process for the preparation of novel 3-methyl-. -4-halo-5-aminooxymethyl-isoxazoles of the general formula (I)

CH, R

"W

N II

Wherein R 2 represents a halogen atom, or a pharmaceutically acceptable acid addition salt thereof.

These compounds of formula (I) are useful for use as pharmaceuticals, as they have hypotensive, antiphlogistic and antipyretic activity. Unlike known compounds, they can also be administered both orally and intravenously.

Preferred representatives of the novel compounds of general formula (I) are those in which R 2 is chlorine.

The acid addition salts of the compounds of the general formula (I) can be formed with pharmaceutically acceptable inorganic or organic acids (e.g. hydrochloric acid, hydrogen bromic acid, sulfuric acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid or citric acid).

The analogous process of this invention is characterized by reacting a compound of the general formula (Id) 35

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2 151012 CH3 R2 XX

II

wherein R 2 is as defined above with hydrazine hydrate and, if desired, converts a compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt thereof.

In the process of the present invention, a compound of the general formula (Id) 15 is reacted with hydrazine hydrate. The reaction is carried out in an organic solvent. Chlorinated hydrocarbons (e.g., dichloromethane, dichloroethane or chloroform) are preferably used for this purpose. The temperature of the reaction can be varied from approx. 20 ° C to the boiling point of the reaction mixture. The final product can preferably be converted to its hydrochloride with hydrochloric acid.

The novel compounds prepared by the method of the present invention exhibit a strong hypotensive effect, and some of the compounds also exert antiphlogistic and antipyretic effects.

When a tenth of the LD 50 dose of 3-methyl-4-bromo-5-aminooxymethyl-isoxazole determined intravenously on mice is administered intravenously to anesthetized cats, a large hypotensive effect is observed for a short duration. The advantage of the novel compounds of the invention 30 is that they are effective, whether orally or intravenously, while L-α-methyl-dopa is only active when administered intravenously.

The anti-inflammatory effect of the novel compounds prepared according to the present invention is also determined. One-tenth of the LD 50 dose (intravenously, in mice) is administered to rats and the inhibition of the edema, induced by topical administration of (0.05 ml / 3 mg dextran) is determined.

Hereby, with the chlorine derivative described in the example, an inhibitor is obtained

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ring edema of 38%.

The compounds prepared are used in pharmaceutical compositions containing as active agent a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof and a suitable inert non-toxic, solid or liquid pharmaceutical carrier.

The carriers may be those commonly used in the pharmaceutical industry (e.g., calcium carbonate, magnesium stearate, water, polyalkylene glycol or starch). The above 10 pharmaceutical compositions can be formulated by known solid methods (e.g. tablets, capsules, dragees or suppositories) or liquid form (e.g. solutions, suspensions or emulsions).

The daily dose of the compounds of the general formula (I) depends on various factors (e.g., the activity of the given compound, the patient's condition, etc.) and is always determined by the physician's regulations.

The present invention is illustrated by the following example.

20

Example

Preparation of 3-methyl-4-chloro (bromo) -5-aminooxymethyl-isoxazole hydrochloride 0.14 mol of 3-methyl-4-chloro (bromo) -5- (phthalimido-oxymethyl) -isoxazole is dissolved in 500 ml of anhydrous dichloromethane or dichloroethane, then 60 g of 98% hydrazine hydrate is added and the solution is stirred at room temperature for 16-20 hours. The separated phthaloyl hydrazide is dissolved, washed with dichloroethane and the filtrate, which is combined with the washing liquid, is evaporated. The residue is dissolved in 200 ml of anhydrous ether, the solution is dried over magnesium sulfate, concentrated to 1/3 of the previous weight and saturated with anhydrous hydrogen chloride. The separated product is filtered off, washed with anhydrous ether and recrystallized.

151012 4

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chloroderivative:

Yield: 87%

Mp 198-200 ° C

Recrystallization: from anhydrous ethanol.

Analysis:

Calculated: C = 30.17%, H = 4.05%, N = 14.08%, Cl = 17.81%

Cl = 17.81%.

Found: C = 30.02%, H = 3.99%, N = 14.06%, Cl = 17.77%;

Cl = 17.78.

10

bromoderivative:

Yield: 8 3%

Mp: 180-182 ° C

Recrystallization: from anhydrous ethanol.

Analysis:

Calculated: C = 24.66%, H = 3.11%, N = 11.5%, Cl Cl = 14.56%,

Br = 32.80%.

Found: C = 25.11%, H = 3.08%, N = 11.37%, Cl "= 14.50% Br 20 Br = 32.72%.

Preparation of the starting material 3-methyl-4-chloro (bromo) - 5- (phthalimido-oxymethyl) -isoxazole 0.1 mole of 3-methyl-4-chloro (bromo) -5-bromomethyl-isoxazole is dissolved in 120 ml of anhydrous N, N-dimethylformamide, then 0.11 mole of N-hydroxy-phthalimide is added and 0.11 mole of triethylamine jog mixture is maintained on a water bath heated to 100 ° C. Then it is cooled, diluted with water and the separated crystals are filtered off, washed with cold water and recrystallized.

chloroderivative:

Yield: 89%

Mp: 152-153 ° C

Recrystallization: from ethanol

Analysis:

Calculated: C = 53.54%, H = 3.10%, N = 9.57%, Cl = 12.11%. Found: C = 53.08%, H = 2.99%, N = 9.58%, Cl = 12.15%.

5 151012

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bromoderivative:

Yield: 90%

Snip: 154-156 ° C.

Recrystallization: from ethanol / water.

Analysis:

Calculated: C = 46.31%, H = 2.59%, N = 8.31%, Br = 23.7%. Found: C = 47.0%. H = 2.59%, N = 8.25%, Br = 23.67%.

Claims (1)

O 151012 Patent claim. Analogous Process for the Preparation of 3-Methyl-4-Halo-5-Aminooxymethyl-Isoxazoles of the General Formula (X) 5 CH R9 _ / 2 ii in N 1 CH2ONH2 wherein R2 represents a halogen atom or a pharmaceutically acceptable acid addition salt thereof , characterized in that a compound of the general formula (Id) is reacted with hydrazine hydrate and, if desired, converts a compound of the formula (Id) 15 CH3 R XoX ch2-o - / ^ Y ^ <Id> 20 II o obtained compound of general formula (I) to a pharmaceutically acceptable acid addition salt thereof.