SU1053750A3 - Process for preparing derivatives of isoxazole - Google Patents

Abstract

Isoxazole derivatives of the general formula (I) and acid addition salts thereof <IMAGE> (wherein R represents a C1-4 alkyl or a phenyl group, R2 denotes a halogen atom or a (C1-4 alkoxy)-carbonyl group, R1 represents a group of the formula -CH(NH2)-COOH, or a guanyl-thio, a bis- C1-4 alkoxycarbonyl-C1-4alkanoyl-amido- methyl, an amino-oxy, a carbamoylamino-oxy, a guanidino- oxy, a phthalimido-oxy group or a group of the general formula -NR3R4, wherein R3 stands for a hydrogen atom or a C1-4 alkyl, C3-6 cycloalkyl, omega -halogen-(C1-4 alkyl), di-(C1-4 alkyl)- amino-(C1-4 alkyl), 2,6- dihalogenbenzyl group or a p-amino- phenyl-sulfonyl group which latter may be N-substituted by a C1-4 alkanoyl group, and R4 stands for a hydrogen atom or a C1-4 alkyl group, or R3 and R4 together represent a 2,6- dihalogen-benzylidene group, or R3 and R4 form, together with the adjacent nitrogen atom a 6 membered heterocyclic ring which may optionally contain an oxygen as a further hetero atom, with the proviso that if R represents methyl and R1 stands for a guanyl-thio group, R2 may represent only chlorine), possess hypotensive, antiinflammatory and antipyretic activity.

Description

f, 1 The invention relates to a process for the preparation of new isoxazode derivatives possessing pharmacological activity that can be used as medicinal drugs in medicine. The known method of semi-hemi isoxazol-5 Ilglyoxal-2-oxime formula N Vi. O -t H lf-Oli il. where I am hydrogen, lower alkl or fe by the interaction of the corresponding isoxazole-3-car aldehyde with nitrnmethane -in the presence of an excess of the main agent at temperatures from -2o to either by the interaction of the corresponding 5-tilisoxazole with adsilonrite at a temperature of -10 to 50 ° C. These compounds have ripoTtrooBoc papillary and analgesic effects of Cl 3, the purpose of which is to obtain new proliferative isoxaol that expand the arsenal of means of influencing living matter; an organism. Zetz is achieved by the proposed method of obtaining isoxazole derivatives of the general formula Ш1 {о ™ 1 0 СН2 0-1Ш2 where f - C С. alkyl j is halogen which is: in that the compound of the general formula Iv.E2I v-r 0-CH2-0-F JAX where R and. r.L R 2 have the indicated value. Subject to the interaction with hydrazino B environment chlorinated hydrocarbon at room temperature. The outcome of the compound is by in-co-acting with N-oxyphthalimide of the compound of the formula W, where R is r and R HMeioT, the indicated values are 0.2. Target product of the reporter: but it can be separated with hydrochloric acid in the form of hydrochloride. The new compounds of the formula (1) obtained according to the invention have a strong1) III and relatively long-term blood pressure lowering action, and in the case of some, present the first group of this compound, which also combines inflammation. .1 Antipyretic effect, At a dose of 1/20 of LDjQ, the target compounds have a strong but short-term effect. At a dose of 1/10 of. 3-methyl 4g-chloro. 4-amino-himetyxone angry at 38% suppressed swelling caused by locale1 :, administering 0.05 ml of decCTjjaHa. in mice. Biologically active} 1st compounds of general formula (1) or their pharmaceutically acceptable salts for the sale of conventional pharmaceutical bases and secondary substances, vianpHMep talc, carbonate ca. pcci, magnesium stearate, chalk, water, and alkaline / school, starch, can be processed into ready-made forms; Pharmaceutical preparations can be 6biTb in the form of hardness (iianpnvjep, tablets, kalsa) Candidates, pills, give liquid (for example, solutions, suspensions or emulsions) compositions. PRI m and p. a) Pulling out 3-methyl-gapogey 5-brommegig1Hyxazoles, Ojl mode corresponding to 3,5.-dimethyl-4-halogenoxide: 1 solution s in 150 ml of anhydrous uLLerod tetrachloride. After addition of 0.5 g of benzoyl peroxide, the solution is heated to boiling. To the mixture in Is54, the mixture is processed in small portions. The addition of 1 .0.0 MO of N-bromosuk-Shshmid is added, after which the reaction mixture is boiled for 4-5 hours. After cooling the filter, the precipitated succnimide precipitates. The remaining syrupy 3.-me; thi.-4-halogen ™ 5 ™ bromomethylisoxazole without further purification is mossing the use of it to give 7% gum1: to transformations. Yield of 9O-1OO% b) Preparation of 3 methyl 4 -halogen-5 (4) thalimidooxyl) isle; sazolus O, 1 mol of 3-methyl 4-haloH 5 bromo methylisoxazole is dissolved in 120 ml of anhydrous dimethylformacene. After addition, 0.11 mol N oxyphthalmide and 0.11 moss / triethyl / AMA mixture for 2 h of heating): in a water bath (temperature 100 ° C). The reaction mixture is cooled, ejected with cold water, the precipitated crystalline precipitate is filtered off, washed with boiling water and recrystallized, 4-chloro-derivative is obtained by recrystallization from ethanol, 89% yield, T.Sh1, 152-153 C. The elemental analysis is calculated. %: C 53.54 | , 1O; N 9.57; ce 12.11; Naiden,%; C 53.08; H 2.99; N 9.58; ce 12,15 By recrystallization from ethanol with water, 4-bromo-derivative is obtained, yield 90%, m.p. 154-156 ° C. Elemental analysis for C. Nd BrN-O Calculated:%: C, 46.31; H 2.59; N 8.31; In g 23.7. Found,%: C 47.00; H 2.59; N 8.25; Br 23.67. c) Preparation of 3-methyl-4-halogen-5 amioxymegylisoxazoles of hyprochoryp B, 0.14 mol of 3-methyl-4-halogen-5- (ft-limidoxymethyl) isoxazole is dissolved in 50 O ml of anhydrous dichloromethane or dichloroethane. After the addition of 6O g of 98% hydrazine hydrazine, the mixture is not stirred at room temperature for 16–20 h. The leaching of phthaloyl hydrazide is filtered off, washed with 1 x naphthite, fluorohydrate is combined with Pf xyllfluid fluids and Bioriwot dos7 / -ho. The effluent is dissolved in 20 ml of beaBoc. Nsgo zhra, zfirgy growth1: yur suiteat n d; ,P. with magnesium, it is concentrated by about a third and cyxHi-.f gas-purgate. hydrogen chloride, hpl; to V11Gpysm product OAfiltroEvayuT; Industrial grade g of ester PM II recrystalline, 11 electrons, n: -aipe 1 from basalter ethanol but; g / 4g: lorra production, 87% yield, mp, 198-200 C. Elemental analysis of d / w C ,. O, “X NA: 5 / Vgghasleno,%: S ZOD7; H 4.05; N 14.08; , 81; All 17.81. Found,%: C 30.02; H N14.06; All 17.77; CC 17/73 / Recrystallization from non-ethanol according to T. Ch1at 4-b) es} pro; gosoohe, yield 83%, m.p. 180 .. Element anashish for C HH, x hNSE. . . J 1 22 Calculated,%: C 24.66; P ZD1; N11.5-, Sat14.56; Br 32.80. Found,%: C 25D1, H 3.08, N11.37,, 50, Br32.72.

Claims (1)

METHOD FOR PRODUCING GENERAL FORMULA ISOXAZOLE DERIVATIVES where —C _and —C ₄ alkyl, ~ halogen, characterized in that the compound of the general formula where and R have the indicated meanings are reacted with hydrazine in a chlorinated hydrocarbon medium at room temperature, In ₂ ch ₂ -o-nh SU, ... 1053750