FI70011B - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC THERAPEUTIC 3-METHYL-4-HALOGEN-5-AMINOXIMETHYL-ISOXAZOLER - Google Patents

Description

1 70011

A process for the preparation of novel therapeutically useful 3-methyl-4-halo-5-aminooxymethylisoxazoles.

The invention relates to a process for the preparation of new therapeutically useful 3-methyl-4-halo-5-aminooxymethylisoxazoles of the general formula (I) and their pharmaceutically acceptable salts,

Vnf Λ 0 CH2-O-NH2 wherein R is chlorine or bromine.

It is known that 3-hydroxy-5-methylisoxazole can be used as a plant protection agent (Merck Index, 9 (1961), p. 123).

Incompletely saturated isoxazole derivatives used as antitumor agents are described in Tetra-20 hedron Letters 2549 (1973) and J. Antib. 28A, 91 (1975).

The compounds according to the invention have e.g. antihypertensive, anti-inflammatory and antipyretic effect. Preferred are compounds of general formula (I) in which halogen is chlorine.

25

Acid addition salts of compounds 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, etc. ).

Compounds of formula (I) are prepared by reacting 3-methyl-4-halo-5- (phthalimidooxymethyl) isoxazoles of general formula (II) with hydrazine hydrate, 35 2 70011

CH3 \ _ / R

I S (11) 5 \ A / Vn

CH, -0-N

and the product thus obtained is, if desired, converted into a pharmaceutically acceptable acid addition salt.

The reaction is carried out in an organic solvent. Chlorinated hydrocarbons (e.g. dichloromethane, dichloroethane or chloroform) are preferably used for this purpose. The reaction temperature can range from about 20 ° C to the boiling point of the reaction mixture. The final product is preferably converted to its hydrochloride with hydrochloric acid.

The compounds of general formula (I) can be converted into acid addition salts in a known manner by reacting them with about one molar equivalent of acid in a suitable solvent. The compounds thus obtained can be isolated by methods known per se. The starting compounds of general formula (II) are prepared by reacting compounds of general formula (III) with N-hydroxyphthalimide.

25 CH-. R

j ^ (HI)

Due to the reactivity of the bromine atom in the allyl position, the compounds of general formula (III) are highly reactive.

The 3-substituted 4-halo-5-bromomethyl derivatives of the general formula (III) can be prepared as follows: 370011

Acetylacetone is reacted with sulfuryl chloride and the 3-chloroacetylacetone thus obtained is converted to 3,5-dimethyl-4-chloroisoxazole by reaction with hydroxylamine. The corresponding bromine derivative 5 is prepared by bromination of 3,5-dimethylisoxazole in the presence of nitric acid. Reaction of 3,5-dimethyl-4-haloisoxazole with N-bromosuccinimide gives almost exclusively the corresponding 3-methyl-4-halogen-5-bromoethyl isoxazole.

One tenth of the iD 2 dose of 3-methyl-4-bromo-5-aminooxymethylisoxazole (288 mg / kg. Determined by intravenous injection into a mouse) produced a strong and short-term antihypertensive effect when injected into the artery of a cat.

The novel compounds of the invention further have an anti-inflammatory and antipyretic effect. The anti-inflammatory effect was determined as follows: rats were given one-tenth of the LD4 dose of 3-methyl-4-bromo-5-aminooxymethylisoxazole 288 mg / kg. and 3-methyl-4-chloro-5-aminooxymethylisoxazole: 185 mg / kg. determined by injection-20 rack into the artery of a mouse) and the inhibition of edema caused by topical injection of 0.05 mg / 3 mg dextran was determined. The following table summarizes the results obtained:

Percent inhibition of compound_edema according to the invention 25 chlorine derivative 38

The compounds 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.)

4,70011

The daily dose of the compounds of general formula (I) depends on a number of 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.

The following examples illustrate the preparation of the compounds of the invention and the compounds of general formula (II) and (III) used as starting materials.

Preparation 1 1 0 Preparation of 3-methyl-4-halo-5-bromomethylisoxazoles (compound of formula (III))

0.1 mol of the corresponding 3,5-dimethyl-4-haloisoxazole was dissolved in 150 ml of anhydrous carbon tetrachloride, then 0.5 g of benzoyl peroxide was added and the solution was heated to reflux. 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-halo-5-bromoethylisoxazole (ca. 90-100%) remained, which was worked up without further purification.

Preparation 2 Preparation of 3-methyl-4-chloro (bromo) -5- (phthalimidooxymethyl) isoxazole (Compound of Formula (II))

0.1 mol of 3-methyl-4-chloro (bromo) -5-bromomethylisoxazole was dissolved in 120 ml of anhydrous N, N-dimethylformamide, then 0.11 mol of N-hydroxyphthalimide 30 and 0.11 mol of triethylamine were added. and the mixture was allowed to stand in a water bath at 100 ° C. It was then cooled, diluted with water, and the precipitated crystals were isolated by filtration, washed with cold water, and recrystallized.

7001 1

The chloro derivative

Yield: 89%

M.p .: 152-153 ° C

Recrystallization: from ethanol 5 Analysis: calculated C 53.54% H 3.10% N 9.57% Cl 12.11% obtained C 53.08% H 2.99% N 9.58% Cl 12.15%

Bromine derivative .j q Yield: 90%

M.p .: 154-156 ° C

Recrystallization: from a mixture of ethanol and 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% 15

Example 1 Preparation of 3-methyl-4-chloro (bromo) -5-aminooxymethylisoxazole hydrochloride 0.14 moles of 3-methyl-4-chloro (bromo) -5- (phthalimidooxymethyl) isoxazole 500 was dissolved. to 1 ml of anhydrous dichloromethane or dichloroethane, then 60 g of 98% hydrazine hydrate was added and the solution was stirred for 16-20 hours at room temperature. The precipitated phthaloyl hydrazide 25 was filtered off, washed with dichloroethane and the combined filtrate and washings were evaporated. The residue was dissolved in 200 ml of anhydrous ether, and the solution was dried over anhydrous magnesium sulfate with anhydrous hydrogen chloride. The precipitated product was isolated by filtration, washed with anhydrous ether and recrystallized.

6 70011

Chlorine and derivatives

Yield: 87%

M.p .: 198-200 ° C

Recrystallization: from anhydrous ethanol 5 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 Bromine derivative

Yield: 83%

M.p .: 180-182 ° C

Recrystallization: from anhydrous ethanol Analysis: calculated C 24.66% H 3.11% N 11.5% Cl 14.56% 15 Br 32.80%

Found: C 25.11% H 3.08% N 11.37% Cl ~ 14.50%

Br 32.72% 20

Claims (1)

7,70011 Claim A method for the development of novel therapeutically useful j. for the preparation of 3-methyl-4-halo-5-aminooxymethylisoxazoles of the general formula (I) and their pharmaceutically acceptable salts, CH 2 - / 10 [mu] l) in which R is chlorine or bromine, characterized in that the 3-methyl-4-halo-5- (phthalimidooxymethyl) isoxazoles of the general formula (II) are reacted with hydrazine hydrate, CH3 R M1 N \ -A / Ar ii xcr xch2- on | Wherein R is as defined above, and the product thus obtained is, if desired, converted into a pharmaceutically acceptable acid addition salt. 30 35