DE1470257B - Process for the preparation of disubstituted isoxazole derivatives and their pharmaceutically acceptable salts - Google Patents

Description

The invention relates to a process for the preparation of disubstituted isoxazole derivatives of the general Formulas

CH, - CH, - N

N - CH, - CH ₂

in which R is a phenyl group or the pyridyl radical and R ₁ and R _{2 are} low molecular weight alkyl radicals or, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, and of their pharmaceutically acceptable salts. The process is characterized in that, in a manner known per se, a compound of the general formulas III or IV

CH, - C - N

NC-CH ₂

in which R, R ₁ and R _{2 have} the meaning given above, reduced with lithium aluminum hydride and, if desired, the base obtained is converted into the salt with an acid.

Isoxazole derivatives with a substituted or unsubstituted alkylamino group on the isoxazole ring are not yet known. The inventive method provides such isoxazole derivatives, the various have pharmacological activities.

ι ο The carbamoylalkylisoxazole starting compounds 111 or IV can be obtained by conventional methods. They are generally just difficult to achieve crystallize, and they are obtained in the form of yellow resinous material. The use though such carbamoylalkylisoxazole compounds of the general formula II in such a resinous one Shape has no adverse effect on the reaction process of the process according to the invention.

According to the invention the reaction can be carried out so that, usually, the treated Carbamoylalkylisoxazolverbindung of the general formulas III or IV with lithium aluminum hydride in an inert solvent at room temperature (15 to 30 ⁰ C) to the reflux temperature. Ether, tetrahydrofuran, dioxane and N-alkylmorpholines, for example, can be used as inert solvents.

The isoxazole derivatives of the general formulas III and II are liquid or solid in the free state.

They can expediently be converted into their salts during production with the aid of customary processes will.

The isoxazole derivatives of the general formulas I and II and their non-toxic salts have stronger antipyretic, analgesic, anti-inflammatory and / or antitussive activities as that of oxolamine, a commercially available remedy (see table).

IV

connection

acute toxicity
LD ₅₀ ¹ ) Antipyretic
Effectiveness ² ) Analgesic
effectiveness
ED ₅ ,, ³ ) Inflammatory
inhibiting
Effectiveness ⁴ ) Throat irritation
mitigating effect
ED ₅₀ ⁵ ) mg / kg C. mg / kg 0 ■
! (I. mg / kg 775 -0.46 131 6.8 43.2 353 -1.46 133 30.5 29.6 500 to 600 -3.02 93 35.4 28.9 455 -3.68 43 • 39.8 16.4 > 800 ~ ³ ' ⁵ .106 37.6 68.2 682 -1.18 > 400 23.5 > U0 411 -2.42 77 37.8 71.5 238 -4.54 71 42.8 41 700 to 800 -3.8 68
I. 27.1 > 110 800 to 1000 . -1.12 290 . 3.7 > 65.0 700 to 900 -1.04 109 14.4 > 65.0

3- phenyl-5- (2-diethylaminoethyl) -

1,2,4-oxadiazole (oxolamine)

3- (2-diethylaminoethyl) -5-phenyl-

isoxazole citrate

3- (2-pyrrolidinoethyl) -5-phenylisoxazole hydrochloride .............

3- (2-piperidinoethyl) -5-pheny 1-

isoxazole hydrochloride

3- (2-morpholinoethyl) -5-phenyl-

isoxazole hydrochloride

3-phenyl-5- (2-dimethylaminoethyl) -

isoxazole hydrochloride

3- Pheny l-5- (2-pyrrolidinoäthy I) -

isoxazole hydrochloride

3- Pheny l-5- (2-piperidinoethyl) -

isoxazole hydrochloride

3-PhenyI-5- (2-morpholinoethyl) -

isoxazole hydrochloride

3- (2-pyridyl) -5- (2-dimethylaminoethyl) -

isoxazole citrate

3- (2- pyridyl) -5- (2-diethylaminoethyl) -

isoxazole citrate

continuation

connection acute toxicity
LD ₅₀ ¹ )
mg / kg Antipyretic
Effectiveness ² )
C. Analgesic
effectiveness
-ED ₅₀ ³ )
mg / kg Inflammatory
inhibiting
Effectiveness*)
% Coughing
mitigating effect
sameness ED ₃₁ , ⁹ )
mg / kg 3- (2-pyridyl) -5- (2-piperidinoethyl) -
isoxazole hydrochloride
3- (3-pyridyl) -5- (2-diethylaminoethyl) -
isoxazole citrate 200 to 300
500 to 600 -4.46
-0.38 100
177 26.9
18.7 38.3

Comment: " "

') Acute toxicity: the test compounds were administered subcutaneously to mice.

') Antipyretic activity: the test compounds were administered subcutaneously to mice at a dose of 100 mg kg body weight, and the depression of body temperature was measured.

') Analgesic efficacy: The test compounds were administered subcutaneously to mice, and the efficacy was determined according to Haffner method (Deutsche Med. Wochenschrift. 55 [1929], pp. 731 to 733) determined.

^J ) Anti-inflammatory activity: the test compounds were administered subcutaneously to rats at a dose of 100 mg / animal; the rats mentioned were previously treated with 0.05 ml of 3.7 "strength formalin solution. The percentage inhibition of the edema produced was measured.

^s ) Antitussive activity: The test compounds were administered subcutaneously to guinea pigs, and then the animals were sprayed with 12.5% ammonia. The effective dose 50 was calculated from the percentage number of non-coughing guinea pigs.

The method according to the invention is illustrated in the following by the following example.

example

A solution of 3.1 g of 3-dimethylcarbamoylmethyl-5-phenylisoxazole in 15 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 1.1 g of lithium aluminum hydride in 70 ml of anhydrous tetrahydrofuran at 30 to 35 ° C and the resulting solution for 4 hours at 40 ° C stirred. The reaction mixture is then mixed with 3 ml of water at a temperature lower than 20 ° C. and filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in benzene and shaken with dilute hydrochloric acid. The aqueous phase is then made alkaline with 20% sodium hydroxide solution and shaken with ether. The ether extract is washed with water, dried over anhydrous potassium carbonate and the solvent is evaporated. The oil obtained is distilled under reduced pressure, and 1.4 g of 3- (2-dimethylaminoethyl) -5-phenylisoxazole are obtained in the form of a pale yellowish oil with a b.p. ₄ = 132 to 133 ° C.

The oxalate consists of colorless needles with a melting point of 204 to 205 ⁰ C after recrystallization from 50% ethanol.

The citrate forms colorless prisms, F. = 139 to 140 ⁰ C, after recrystallization from ethanol.

The Picrat forms yellow needles, F. = 183 to 185 ° C, after recrystallization from 50% ethanol.

The following isoxazole derivatives are obtained in a corresponding manner:

3 - (2 - diethylaminoethyl) - 5 - phenylisoxazole (b.p. ₂ = 144 to 146 ° C; Hydrochloric M. = 156 to 157 ° C; citrate, M. = 145 to 146 ° C; picrate, M. = 189 to 190 ⁰ C),

3- (2-dibutylaminoethyl) -5-phenylisoxazole (b.p. _o , = 180 ⁰ C; oxalate, m.p. = 148 to 149 ° C),

3 - (2 - pyrrolidinoethyl) - 5 - phenylisoxazole (hydrochloride, F. = 188.5 to 19O ⁰ C),
3 - (2 - piperidinoethyl) - 5 - phenylisoxazole (b.p. ₂ = 173 ° C; Hydrochloric M. = 216 to 217 ° C),

3- (2-Morpholinoethyl) -5-phenylisoxazole (m.p. = 95.5 to 96.5 ° C; hydrochloride, m.p. = 223 to 224 ⁰ Q ^ 3- phenyl-5- (2-dimethylaminoethyl) -isoxazole ( Kp. ₄

= 151 ° C; Hydrochloride, F. = 187 to 188 ^J C),
3-Phenyl-5- (2-diethylaminoethyl) -isoxazole (bp ₅ = 16Γ C; hydrochloride, m.p. = 162 to 163 ° C; citrate, m.p. = 162 to 163 ° C; picrate, m.p. = 175 to

176 ⁰ C),
3 - Phenyl - 5 - (2 - pyrrolidinoethyl) - isoxazole (F. = 43

up to 44 ° C; Hydrochloride, m.p. = 205 to 206 ° C),
3 - Phenyl - 5 - (2 - piperidinoethyl) - isoxazole (F. = 55

up to 56 ° C; Hydrochloride, m.p. = 223 to 225 C),
3-Phenyl-5- (2-morpholinoethyl) -isoxazole (F. = 70

up to 71 ° C; Hydrochloride, m.p. = 253 to 255'C),
3 - (2 - pyridyl) - 5 - (2 - dimethylaminoethyl) - isoxazole

Bp ₂ = 127 ° C; Citrate, F. = 110 to 11 PC),
3 - (2 - pyridyl) - 5 - (2 - diethylaminoethyl) - isoxazole

(Bp, = 127 ° C; citrate, m.p. = 150 to 15PC),
3- (2-pyridyl) -5- (2-piperidinoethyl) -isoxazole (bp.,

= 153 ° C; Hydrochloride, m.p. = 218 to 219 ° C),
3 - (3 - pyridyl) - 5 - (2 - diethylaminoethyl) - isoxazole (b.p. ₃ = 159 ° C; citrate, m.p. = 151 to 152 ° C).

Claims (1)

Claim: Process for the preparation of disubstituted isoxazole derivatives of the general formulas I and II R, - N-CH ₂ - CH, in which R is a phenyl group or the pyridyl radical and R and R _{2 are} low molecular weight alkyl radicals or together with the nitrogen atom to which they are bonded form a pyrrolidine, piperidine or morpholine ring, and of their pharmaceutically acceptable salts, characterized in that one in on 5 a compound of the general formulas III or IV is known Ϊ. / ^Rl ■ R, v? N - C - CH ₂ I M NIi / l N "O' IV in which R, R, and R ₂ reduce the abovementioned range and, if desired, have the meaning of the base obtained, converted into the salt with an acid using lithium aluminum hydride.