DE1470257C - Process for the preparation of disubstituted1 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

R ₁ .

N-CH ₂ - CH,

II

20th

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

III

R ₁ ,

s Il · ■

N - C - CH,

30th

35

IV 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 process according to the invention provides such isoxazole derivatives which have different pharmacological activities. The carbamoylalkylisoxazole starting compounds III or IV can be obtained with the aid of customary processes. They are generally difficult to crystallize and are obtained in the form of yellow resinous material. However, the use of such carbamoylalkylisoxazole compounds of the general formula II in such a resinous form 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 by treating the carbamoylalkylisoxazoi compound of the general formulas III or IV with lithium aluminum hydride in an inert solvent, usually at room temperature (15 ° to 30 ° C.) to reflux temperature. Ether, tetrahydrofuran, dioxane and N-alkylmorpholines, for example, can be used as inert solvents.

The isoxazole derivatives of the general formulas I 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).

connection

Acute toxicity LD ₅₀ ¹ )

mg / kg

Antipyretic Effectiveness ² ) Analgesic

effectiveness

ED ₅₀ ³ )

mg / kg

Anti-inflammatory
Effectiveness*)

Cough-reducing effectiveness ED ₅₀ ⁵ )

mg / kg

3-phenyl-5- (2-diethylaminoethyl) - 1,2,4-oxadiazole (oxolamine) ........

3- (2-diethylamihoäthyl) -5-phenyl-

isoxazole citrate

3- (2-pyrrolidinoethyl) -5-phenyl-

isoxazole hydrochloride

3- (2-piperidinoethyl) -5-phenyl-

isoxazole hydrochloride

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

isoxazole hydrochloride

3- Phenyl-5- (2-dimethylaminoethy I) - isoxazole hydrochloride

3- Phen, yl-5- (2-pyrrolidinoethyl) - isoxazole hydrochloride -,

3-Phenyi-5- (2-piperidinoethyl) - isoxazole hyarochloride

3- phenyl-5- {2-niorpholinoethyl) - isoxazole hydrochloride

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

3- (2-pyridyl) -5- (2-diethylammoethyl) isoxazole citrate

775

353 500 to 600

455> 800

682

411

238

700 to 800 80OWsIOOO 700 to 900 -0.46

-1.46

-3.02

-3 ", 68

-3.5

-1.18

-2.42

-4.54

-3.8

-1.12

-1.04

131

133

93

43

106

> 400

77

71

68

290

109

6.8
30.5
35.4
39.8
37.6
23.5
37.8
42.8
27.1

3.7
14.4

43.2
29.6
28.9
16.4
68.2

> 110

71.5
41

> 110
> 65.0
> 65.0

continuation

connection acute toxicity
LD ₅₀ ¹ )
mg / kg Antipyretic
Effectiveness ² )
° C Analgesic
effectiveness
ED ₅₀ ³ )
mg / kg Inflammatory
inhibiting
Effectiveness ⁴ )
% Coughing
mitigating effect
ED ₅₀ ¹ )
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.

² ) Antipyretic activity: the test compounds were subcutaneously administered to mice at a dose of 100 mg / kg body weight, and the depression of body temperature was measured.

³ ) Analgesic activity: the test compounds were administered subcutaneously to mice, and the activity was determined according to the Haffner method (Deutsche Med. Wochenschrift, 55 [1929], pp. 731 to 733).

^Λ ) Anti-inflammatory activity: the test compounds were administered subcutaneously to rats at a dose of 100 mg / animal,

the rats mentioned were previously with. Treated 0.05 ml of 3.7% formalin solution. The percent inhibition of the edema produced

was measured.
⁵ ) Antitussive activity: The test compounds were subcutaneously administered to guinea pigs, and then the animals became

sprayed with 12.5% ammonia. The percentage of non-coughing guinea pigs became the effective dose of 50

calculated.

The method according to the invention is described below explained by the following example.

_, B e i s ρ i e 1

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 ° C after recrystallization from 50% ethanol.

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

The picrate forms yellow needles, mp = 183 to 185 ° C, after Umkristallisätion from 50% strength ethanol ^em.

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 .l90 ° C),.

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

3 - (2 - pyrrolidinoethyl) - 5 - phenylisoxazole (hydrochloride, m.p. 188.5 to 190 ° C),
3 - (2 - piperidinoethyl) - 5 - phenylisoxazole (b.p. ₂ = 173 ⁰ C; Hydrochloric M. = 216 to 217 ° C),

3- (2-Morpholinoethyl) -5-phenylisoxazole (F. = 95.5 to 96.5 ⁰ C; Hydrochloric F. = 223 to 224 ° C), 3-Phenyl-5- (2-dimethylaminoethyl) -isoxazole ( Kp. ₄

= 151 ° C; Hydrochloric F. = 187 to 188 ° C),
3 - Phenyl - 5 - (2 - diethylaminoethyl) - isoxazole (b.p. ₅ = 161 ° C; Hydrochloric M. = 162 to 163 ° C; Citrate, M. = 162 to 163 ° C; Picrate, M. = 175 to

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

up to 44 ° C; Hydrochloric F. = 205 to 206 ⁰ C),
3-Phenyl-5- (2-piperidinoethyl) -isoxazole (m.p. = 55

to 56 ⁰ C; Hydrochloric F. = 223 to 225 ° C), 3-phenyl-5- (2-morpholinoethyl) -isoxazole (M. = 70

up to 71 ° C; Hydrochloric F. = 253 to 255 ° C),
3 - (2 - pyridyl) - 5 - (2 - dimethylaminoethyl) - isoxazole

Bp ₂ = 127 ° C; Citrate, F. = 110 to IH ⁰ C),
3 - (2 - pyridyl) - 5 - (2 - diethylaminoethyl) - isoxazole

(Bp! = 127 ° C; citrate, m.p. = 150 to 151 ° C),
3- (2-Pyridyl) -5- (2-piperidinoethyl) -isoxazole (bp ₁₁

= 153 ° C; Hydrochloric F. = 218 to 219 ⁰ 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 CH ₂ - CH, -N ^l \ N-CH ₅ 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 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 R ₁ - NC-CH ₂ CH ₂ -CN III N / R ₃ . 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.