FI72512C - PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC 3-METHYL-4-CHLORO-5- (BROMETYL-AMINOMETHYL) ISOXAZOLE - Google Patents

Description

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Process for the preparation of therapeutically useful 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole 5 Separated from patent application 810838

The invention relates to a process for the preparation of a therapeutically useful 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole of formula (I) and its pharmaceutically acceptable salts CH 3 X / Cl

Il I | W

15

It is known that 3-hydroxy-5-methylisoxazole can be used as a plant protection agent (Merck index 9 (1961) 123). Incompletely saturated isoxazole derivatives used as antitumor agents are described in Tetra-20 Hedron Letters 2549 (1973) and J. Antib 28A (1975) 91. In addition, compounds having a structure similar to the compound of formula (I) and their properties are described in e.g. U.S. Patent Nos. 3,290,301, 3,808,221 and 3,950,333.

The compound of the invention has e.g. antihypertensive, anti-inflammatory and antihypertensive effects.

Acid addition salts of a compound of general formula (I) may be prepared with pharmaceutically acceptable inorganic or organic acids (e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, tartaric, fumaric, maleic and citric acid.

The compound of formula (I) is prepared by reacting 3-methyl-4-chloro-5-bromime-35-style isoxazole of formula (II) 2,72512_ / C1

Tl I Γπ (ID

-CH 2 Br 5 is reacted with ethyleneimine, and the product thus obtained is, if desired, converted into a pharmaceutically acceptable salt in a manner known per se.

The reaction is preferably carried out in an organic solvent (e.g. acetone). It is preferred to add ethylene-10 imine to the starting material of general formula (II) at a temperature of -5 ° to 10 ° C and then to heat the reaction mixture to boiling point. The final product is preferably converted to its hydrochloride by precipitation with hydrogen chloride.

Due to the reactivity of the bromine atom in the allyl position, the compound of general formula (II) is highly reactive and can be used for the preparation of various isoxazole derivatives.

The 3-substituted 4-chloro-5-bromomethyl derivative of the general formula (II) can be prepared as follows: Acetylacetone is reacted with sulfyryl chloride and the 3-chloroacetylacetone thus obtained is converted into 3,5-dimethyl-4-chloroisoxazole by giving it react with hydroxylamine. Reaction of 3,5-dimethyl-4-haloisoxazole with N-bromosuccin-25-imide gives almost exclusively the corresponding 3-methyl-4-halo-5-bromomethylisoxazole.

Therapeutic Properties of the Compound of the Invention: In cats, one twentieth of the LD-_30-30 dose of 3-methyl-4-chloro-5- (bromoethylaminomethyl) -isoxazole hydrochloride, determined by intravenous injection into mice, caused a 44% decrease in blood pressure.

When one-tenth of the LD50 dose of the same compound, as determined by intravenous injection into a mouse, was injected intravenously into anesthetized rabbits, blood-35 blood pressure fell sharply and permanently. Thirty minutes after dosing, blood pressure was 18% and 90 minutes after dosing was 48% lower than previous pressure.

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The compound did not significantly affect heart rate. When administered intravenously, one-tenth of the LDj.q dose of L-α-methyl lidopa (determined by intravenous injection) reduced blood pressure in rabbits by 14% 30 minutes after dosing 5 and by 37% 90 minutes after dosing. This means that the potency of 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole hydrochloride is of the same order of magnitude as that of L-α-methyldopa. An advantage of the novel compound of the invention is that it is effective when administered orally or intravenously, whereas L-β-methyldopa is effective only when administered intravenously.

The anti-inflammatory effect of the novel compound of the invention was also determined. Rats were given one-tenth of the LD4 g dose (determined by intravenous injection into mouse 15) and the inhibition of edema induced by topical injection of 0.05 ml / 3 mg dextran was determined. the percentage inhibition of edema by 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole according to the invention was 34%.

The compound of the invention may be formulated into pharmaceutical compositions containing as active ingredient a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof and a suitable unreacted, non-toxic, solid or liquid pharmaceutical carrier.

As the carrier, conventional carriers can be used in pharmacy, e.g. calcium carbonate, magnesium stearate, water, polyalkylene glycol, starch, etc. The above-mentioned pharmaceutical composition can be formulated in a known manner into solid (e.g. tablets, capsules, granules, suppositories, emulsions, etc.)

The daily dose of a compound of general formula (I) depends on several factors (e.g. the activity of the compound in question, the condition of the patient, etc.) and must always be calculated according to the doctor's instructions.

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The following embodiments illustrate the invention. Example 1 describes the preparation of a compound of general formula (II) used as a starting material.

Example 1 (starting material) Preparation of 3-methyl-4-chloro-5-bromomethylisoxazole

0.1 mol of 3,5-dimethyl-4-chloroisoxazole was dissolved in 150 ml of anhydrous carbon tetrachloride, then 0.5 g of benzoyl peroxide was added and the solution was heated to boiling. 0.12 moles of N-bromosuccinimide was then added in small portions over 1.5 hours and the mixture was boiled for 4-5 hours. After cooling the solution, the precipitated succinimide was removed by filtration and the filtrate was evaporated. A syrupy 3-methyl-4-chloro-5-bromoethylisoxazole (ca. 90-100%) remained which could be used without further purification.

Example 2 Preparation of 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole hydrochloride

0.35 moles of 3-methyl-4-chloro-5-20 bromomethylisoxazole was dissolved in 390 ml of anhydrous acetone, the solution was cooled to -5 to 10 ° C and a solution of 19.6 ml was added with stirring. ethyleneimine in 80 ml of anhydrous acetone. The reaction mixture was then stirred for two hours, cooled and poured into one liter of ice water.

The isolated sticky mass was extracted first with 200 ml and then twice with a total of 100 ml of ether. The ether phase was isolated from the precipitate (8.2 g, m.p. 138 ° -141 ° C), washed twice with 400 ml of water, dried over magnesium sulfate, concentrated to one third of its original volume and saturated with anhydrous hydrochloric acid. The precipitated product was isolated by filtration and recrystallized from anhydrous ethanol.

Yield: 25%. M.p .: 164 ° -166 ° C

Analysis: calculated C 33.03% H 4.35% N 9.66% Cl 12.22% 35 Cl_12.22% Br 27.55% obtained C 37.87% H 4.31% N 10.05%

Cl 12.28% Cl "12.34% Br 27.44%

Claims (2)

A process for the preparation of a therapeutically useful 3-methyl-4-chloro-5- (bromoethylaminomethyl) -5-isoxazole of formula I and pharmaceutically acceptable salts thereof, ch3 Cl li | u> 10. J-CHO-NH- (CHO) O-Br2 22 characterized in that CH3 ^ Cl P i of the 3-methyl-4-chloro-5-bromomethylisoxazole of the formula II. (II) N J-CH.Br 2 O is reacted with ethyleneimine, and the product thus obtained is, if desired, converted into a pharmaceutically acceptable salt in a manner known per se.